xvEPA
University of
North Carolina
Biological Sciences
Research Center
Chapel Hill NC27514
United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 27711
EPA-600/9-77-043
December 1978
Multidisciplinary Perspectives
in Event-Related Brain
Potential Research
JV^^^-^NV V
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EPA-600/9-77-043
December 1978
Multidisciplinary Perspectives
in Event-Related Brain
Potential Research
Proceedings of the Fourth International Congress
on Event-Related Slow Potentials of the Brain
(EPIC IV)
Hendersonville, North Carolina, April 4-10, 1976
Edited by
David A. Otto
Health Effects Research Laboratory
Office of Research and Development
Research Triangle Park, North Carolina 27711
and
Biological Sciences Research Center
University of North Carolina
Chapel Hill, North Carolina 27514
Grant No. R803494-02
Program Element No. IAA8I7
EPA Project Officer: M. Thomas Wagner, Jr.
Prepared for
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Washington, D.C. 20460.
-------
Editor-in-Chief
David A. Otto
Neurotoxicology Division
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina, U.S.A.
Associate Editors
Robert M. Chapman
Center for Visual Science
University of Rochester
Rochester, New York, U.S.A.
Emanuel Donchin
Cognitive Psychophysiology Laboratory
Departments of Psychology and Physiology
University of Illinois
Champaign, Illinois, U.S.A.
Rathe Karrer
Illinois Institute for Developmental Disabilities
Chicago, Illinois, U.S.A.
John R. Knott
Tufts University School of Medicine
Boston, Massachusetts, U.S.A.
W. Cheyne McCallum
Burden Neurological Institute
Bristol, England
Demetrios Papakostopoulos
Burden Neurological Institute
Bristol, England
Charles S. Rebert
Life Sciences Division
SRI International
Menlo Park, California, U.S.A.
Lawrence W. Reiter
Neurotoxicology Division
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina, U.S.A.
Joseph J. Tecce
Laboratory of Neuropsychoiogy
Department of Psychiatry
Tufts University School of Medicine
Boston, Massachusetts, U.S.A.
Patricia Tueting
Maryland Psychiatric Research Center
University of Maryland Medical School
Baltimore, Maryland, U.S.A.
Hal Weinberg
Brain Behavior Laboratory
Department of Psychology
Simon Fraser University
Burnaby, British Columbia, Canada
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DEDICATION TO WILLIAM GREY WALTER, M.A., Sc.D.
February 19, 1910-May6, 1977
The Proceedings of the Fourth International Con-
gress on livent-Related Slow Potentials of the Brain
(FPIC IV) arc dedicated to the memory of William
Grey Walter, who died May 6, 1977. lie left a world
wiser in consequence of his many active and imagi-
native years as an investigator into the physiology of
the mind.
Grey Walter was one of the very early pioneers in
the electrical activity of the human brain. Originally
a student of Adrian, he joined Professor Golla at the
Maudsley Hospital in 1935 to pursue the area of FUG
research opened up by Berger and Adrian. His first
and very major contribution to FUG was the dis-
covery of delta activity and its locali/ing value in
brain tumor suspects.
Grey Walter was a pioneer who kept moving
ahead of the frontiers he himself established. In 1940,
he turned his efforts to automatic frequency analysis,
"on line," and sought psychological correlates of the
changing voltage-frequency profiles. Since single-
channel display was frustratingly limiting, he under-
took to develop one of the first truly electro-ana-
tomical displays of the brain with his "toposcope"
(1952-53). Frequency, voltage, and phase could be
derived from 22 electrode points on the scalp. The
elfects ot sensory modulation of the brain were also
defined in terms of frequency, voltage, phase, and
area.
In 1962, Grey noticed a negative shift that oc-
curred between paired stimuli. His initial interest
apparently was in possible modification of sensory
evoked potentials during Pavlovian conditioning.
With this observation, he opened another frontier,
that of the event-related slow potential which he
named the Contingent Negative Variation. The work
was presented in England and the United States in
1964, and published in Nature. While the initial
instrumentation that uncovered this phenomenon
was crude, further pioneering in computer analysis
and display, up to and beyond his retirement in 1975,
kept Grey abreast (if not ahead) of the times, and
stimulated an increasingly large group of experi-
mentalists to explore the neurophysiology of be-
havior. Here at last was a key that might fit some
of the locks many had been struggling with for years.
These are some of the things Grey Walter has left
us; other things are even more important: memories
of a probing mind that stimulated others to think,
memories of a devoted scientist who would not re-
quire that others work harder than himself, and mem-
ories of a warm and embracing fellowship upon
which all other attributes revolved.
The continued growth of event-related potential
research is a tribute to Grey Walter's scientific en-
deavors, his imagination, and his forceful leadership.
The ongoing series of International FRP Congresses
is hut a small part of his scientific legacy. Grey
Walter bequeathed to future generations his in-
spiration and intellect in the form of extensive and
eloquent writings. He was a giant in the field of
neurophysiology - a remarkable scientist, author, and
personality whose memory will always be cherished
by those privileged to know him.
J. R. Knott
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PREFACE
This volume is the Proceedings of the Fourth
International Congress on Event-Related Slow Poten-
tials of the Brain (EPIC IV) held in Hendersonville,
North Carolina on April 4-10, 1976. The volume con-
tains ten sections devoted to the following areas of
ERP research: (1) electrogenesis and neurochemistry,
(2) motor control, (3) information processing and
cognition, (4) language, (5) development and aging,
(6) psychopathology, (7) environmental neurotoxi-
cology, (8) scalp distribution, (9) alternatives to sig-
nal averaging, and (10) theoretical models. Sections
are based on plenary sessions at the Congress and in-
clude, in varying form, correspondence summaries,
data and review papers, and condensations of
discussion.
In memorium.
This series of meetings began with Grey Walter's
discovery of the CNV. In failing health, Grey did not
attend EPIC IV. As these proceedings were being
assembled, we learned with great sadness of his pass-
ing. In tribute to the man whose vision and leader-
ship nurtured event-related potential research, this
volume is humbly dedicated to William Grey Walter.
Collective planning.
A collective approach to conference planning,
pioneered at Bristol in 1973, was used extensively
in preparation for EPIC IV. Correspondence panels
in the areas listed above were established a year
before the meeting to (1) define critical issues, (2)
review and synthesize available evidence, and (3)
formulate experiments or strategies to resolve issues.
Correspondence summaries were precirculated to
conference participants and plenary sessions were
organized around correspondence panels. Corres-
pondence chairmen served as discussion leaders
at EPIC IV and as section editors of the proceed-
ings. This volume is the final product of this lengthy
but fruitful experiment in collective planning and
communication.
Environmental theme.
Two plenary sessions were devoted to "neurobe-
havioral indices of environmental insult." The objec-
tives of these sessions were to evaluate the utility of
ERP techniques in environmental toxicology and to
encourage neurobehavioral research in problems of
environmental concern. Neurobehavioral evidence
has played a relatively insignificant role in deter-
mining current U.S. environmental standards. Reports
in this volume from investigators in Austria,
Finland, Germany, Italy, and the USSR, on the other
hand, indicate that behavioral and evoked potential
data play an important role in setting threshold limit
values (TLVs) in Eastern and Western Europe. Data
presented in the toxicology section and elsewhere
in this volume document the sensitivity of ERPs and
other neurobehavioral measures to the effects of
psychoactive drugs, pesticides, industrial solvents,
and other physical insults such as noise and elec-
tromagnetic radiations. The evidence argues strongly
for increased application of neurobehavioral methods
in studying the adverse health effects of environ-
mental toxicants.
Interdisciplinary bridge-building.
Progress in the ERP field depends on the inte-
gration of evidence from many disciplines within
the neurosciences. ERP investigators include psycho-
logists, psychiatrists, neurologists, and neurosurgeons,
although the disciplines of neurophysiology, neuro-
anatomy, and neurochemistry have not been repre-
sented until recently. A major objective of EPIC IV
was to recruit investigators from the latter disciplines
to begin to bridge fundamental gaps in ERP know-
ledge. The infusion of new blood and new perspec-
tives produced an exciting concatenation of ideas
reflected in the series of tutorial papers and theo-
retical models which appear in this volume.
Review procedures.
The editing of this volume took far longer than
anticipated. Two factors deserve mention. In order
to achieve some degree of quality control, all data
papers and many review papers were submitted to
peer review. Although few papers were rejected,
many authors were required to make extensive and
repeated revisions. In order to achieve greater clarity
and consistency, the editorial staff further revised
most manuscripts. The benefits of these efforts,
however, must be weighed against the resulting
publication lag. I am grateful to the section editors
and individual contributors for their cooperation
and patience in this frustrating and time-consuming
enterprise.
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Vlll
Supplements.
Dr. Jon Peters prepared an extensive "Biblio-
graphy of CNV and Other Slow Potentials of the
Brain: Part III" which covers the period between
the Bristol Congress (August 1973) and EPIC IV. To
facilitate distribution and avoid redundancy with
other reference sections in this volume, Dr. Peters'
excellent bibliography was published separately in
June 1978 as an EPA Research Report (EPA-600/
1-78-042). This document is available from the
National Technical Information Service, Springfield,
Virginia 22161.
A set of manuscripts submitted by several investi-
gators from the USSR who were unable to attend
EPIC IV will also be published as a separate EPA
Research Report and should be available from NTIS
in mid-1979. Further information on these docu-
ments may be obtained from D. Otto.
Acknowledgments.
EPIC IV was sponsored jointly by the Biological
Sciences Research Center, School of Medicine,
University of North Carolina at Chapel Hill and by
the Health Effects Research Laboratory, U.S. Envi-
ronmental Protection Agency, Research Triangle
Park, North Carolina. We are deeply indebted to both
organizations and their respective directors, Dr.
Morris Lipton and Dr. John Knelson, for enthu-
siastic support and administrative assistance. Fund-
ing was provided by EPA Grant R803494-02 to the
University of North Carolina. Dr. Lipton was Princi-
pal Investigator and Dr. Thomas Wagner was EPA
Project Officer.
Many others generously contributed time and
talent in organizing EPIC FV and editing this vol-
ume. I would especially like to acknowledge the
administrative assistance of Bill Heriford and Bobby
Wagoner (UNC Extension Division), Jeanne Hernan-
dez (Institute of Environmental Studies), and
Elizabeth Clark (BSRC); the technical editorial
and graphics support of Bob Kolbinsky, Earnie
Caldwell, Webb White, Miriam Harper, Cathy Jo
Poole, Pam Barnwell, Mary Woodard, Paul Holder,
and Charlie Keadle (EPA General Services Division);
clerical support from Barbara Queen and the HERL
Word Processing Center, Jo Nichols and the Clinical
Studies Division (EPA), Marty Byrd (BSRC), and
Pat Reefe; and general assistance from Alex Adams,
Gayla and Vernon Benignus, Dick Calvert, Marchell
Franklin, Mary Hicks, Debbie Markley, Kim Nguyen,
Jim Prah, and Kathy Seiple.
Finally, I would like to express my deep apprecia-
tion to W. Cheyne McCallum, Congress President,
and John R. Knott, Past President, for their invalu-
able advice, encouragement, and assistance in all
aspects of the organization of the Congress and
editing of the Proceedings. The Program Committee
also deserves special thanks for strenuous and inspired
efforts in organizing correspondence, leading discus-
sion at the Congress, and editing the resultant sec-
tions of this volume.
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CONTENTS
Page
Dedication to W. Grey Walter v
Preface vi
Contents ix
Participants xvi
Abbreviations xviii
Keynote address: The significance of neurobehavioral data in setting air quality standards.
R. R. Beard xix
Section
I. ELECTROGENESIS AND NEUROCHEMISTRY 1
Electrogenesis of slow potential changes in the central nervous system: A summary of issues.
CS. Rebert 3
Slow postsynaptic responses of sympathetic ganglion cells as models for slow potential changes
in the brain. B. Libet 12
Contribution of neuroglia to extracellular sustained potential shifts. G. G. Somjen 19
Neurochemical mechanisms in the genesis of slow potentials: A review and some clinical
implications. T. J. Marczynski 25
Reward contingent positive variation (RCPV) and patterns of neuronal activity in the visual
cortex of the cat. T. J. Marczynski and G. Karmos 36
Acquisition of sustained potentials dissociated from massed action potentials in temporal
conditioning. V. Rowland 39
Events contingent upon cortical potentials can lead to rapid learning. /. S. Stamm,
O. A. Gillespie, andB. B. Sandrew 43
Sustained activation of cortical neurons in stimulus-recognition tasks. /. M. Faster 48
Preliminary study of pharmacology of contingent negative variation in man. /. W. Thompson,
P. Newton, P. V. Pocock, R. Cooper, H. Crow, W. C. McCallum, and D. Papakostopoulos ... 51
Effects of amphetamine and pentobarbital on event-related slow potentials in rats.
/. H. Pirch 56
Cholinergic mechanism of sleep onset positive variation and slow potentials associated with
K - complexes in cats. T. J. Marczynski 61
Electrogenesis references 64
II. MOTOR CONTROL 75
The present state of brain macropotentials in motor control research: A summary of issues. 77
D. Papakostopoulos
Spinal cord stimulation and event-related potentials. P. Abraham, T. Doherty, S. Spencer,
A. L. Cook, A. Oygar, L. Illis, andM. Sedgewick 82
Functional significance of cerebral potentials preceding voluntary movement. L. Deecke 87
Experimental manipulation of motor positivity: A pilot study. J. Delaunoy, A. Gerono,
andJ. C. Rousseau 92
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Section Page
Telereceptive, proprioceptive, and cutaneous information in motor control. B. Dubrovsky ... 93
Methodological criteria for the validation of movement-related potents. L. Gerbrandt 97
Effects of movement on sensory input. P. Hazemann 105
Influence of force, speed and duration of isometric contraction upon slow cortical potentials
in man. P. Hazemann, S. Metral, and F. Lille 107
Neuroanatomical organization of the primate motor system: Afferent and efferent connections
of the ventral thalamic nuclei. K. Kalil 112
Relationships between Bereitschaftspotential and contingent negative variation.
W. C. McCallum 124
Slow positive shifts during sustained motor activity in humans. D. Otto and V. Benignus 131
Electrical activity of the brain associated with skilled performance. D. Papakostopoulos 134
The electromyogram, H-reflex, autonomic function and cortical potential changes during
the Jendrassik maneuver. D. Papakostopoulos and R. Cooper 138
Oculomotor components of event-related electrocortical potentials in monkeys. S. Rosen,
J. Robinson, and D. Loiselle 143
Motor control references 149
HI. INFORMATION PROCESSING AND COGNITION 157
Event-related potentials, cognitive events, and information processing: A summary of
issues and discussion. P. Tueting 159
How many late positive waves are there? W. T. Roth 170
Latency of event-related potentials and reaction time. W. Ritter 173
Equivocation and P300 amplitude. D. S. Ruchkin andS. Sutton 175
The late positive component and orienting behavior. D. Friedman 178
Does P300 reflect template match/mismatch? /. M. Ford 181
Evoked potentials and feedback. 5, Sutton, P. Tueting, andM. Hammer 184
Potentials associated with the detection of infrequent events in a visual display. R. Cooper,
P. V. Pocock, W. C. McCallum, andD. Papakostopoulos 189
Analysis of nonsignal evoked cortical potentials in two kinds of vigilance tasks. D. Friedman,
W. Ritter, andR. Slmson 194
Variations In the latency of P300 as a function of variations in semantic categorizations.
M, Kutas and E. Donchln 198
Topographical study of the emitted potential obtained after the omission of an expected
visual stimulus, B. Renault and N. Lesevre 202
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XI
Section Page
Auditory evoked potentials, skin conductance response, eye movement, and reaction time
in an orienting response paradigm. W. T. Roth, J. M. Ford, P. L. Krainz, and B. S. Kopell . . 209
Sequential dependencies of the waveform of the event-related potential: A preliminary
report. K. C. Squires, C. D. Wickens, N. K. Squires, and E. Donchin 215
Functional equivalence of signal-present, signal-absent, and threshold-detect P3s. N. K.
Squires, K. C. Squires, and S. A. Hillyard 218
A CNV rebound function: Preliminary report. /. /. Tecce 222
Average evoked potentials and time perception. P. Tueting 226
Attention at the cocktail party: Brainstem evoked responses reveal no peripheral gating.
D. L. Woods and S. A. Hillyard 230
Information processing references 234
IV. LANGUAGE 243
Language and evoked potentials: A summary of issues. R. M. Chapman 245
Issues in Neurolinguistics: Evoked-potential analysis of cognition and language.
R. W. Thatcher 250
Distinguishing linguistic and stimulus effects. D. L. Molfese 255
Lateral asymmetry of evoked potentials and linguistic processing. D. Friedman 258
Individual differences and similarities in language effects on evoked potentials.
W. S. Brown 261
Contributions of linguistics and other data bases. T. J. Teyler 263
Methods of evoked-potential analysis in linguistic research. R. M. Chapman 265
Event-related potentials associated with linguistic stimuli: Semantic vs low-order effects.
A. L. Megela and T. J. Teyler 267
Visual evoked potentials to language stimuli in children with reading disabilities.
5. A. Shelburne, Jr. 271
Choice of active electrode site and recording montage as variables affecting CNV amplitude
preceding speech. 5. H. Curry, J. F. Peters, and H. Weinberg 275
Language references 280
V. DEVELOPMENT AND AGING 289
Development and developmental disorders: A summary of issues. R. Karrer . . . .' 291
Maturation of pattern evoked potentials and visual preference in 6- to 45-day old infants:
Effects of check size. M. R. Harter, F. K. Deaton, and J. V. Odom 297
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xn
Section
Contingent negative variation, evoked potential, and psychophysical measures of selective
attention in children with learning disabilities. M. F. Musso andM. R. Harter 300
Hemispheric effects of stimulus sequence and side of stimulation on slow potentials in
children with reading problems, fl. Fenelon 303
Task-related cortical potentials in children in two kinds of vigilance tasks. D. Friedman,
H. Vaughan, Jr., and L. Erlenmeyer-Kimling 309
Evoked and slow potentials during sensory conditioning in autistic, mentally retarded
and normal children. F. Laffont, N. Bruneau, Ph. Jusseaume, and G. Lelord 314
CNV and EEC patterns in children with cerebral palsy and known brain lesions.
M. Papini, R. Zappoli, A. Pasquinelli, M. G. Mar tine tti, and S. Guerri 319
Slow potentials of the brain preceding cued and noncued movements: Effects of
development and mental retardation. R. Karrer, C. Warren, and R. Ruth 322
Age-dependence of the Bereitschaftspotential. L. Deecke, H. -G. Englitz, and G. Schmitt .... 330
Aging effects on the human evoked potential. G. Marsh 333
Discussion summary 337
Development and aging references 339
VI. PSYCHOPATHOLOGY ................................................ 345
Event-related potentials and psychopathology : A summary of issues and discussion.
J. R. Knoll and]. J. Tecce ............................................ 347
Experimental production of postimperative negative variation in normal subjects.
J. Delaunoy, A. Gerono, andJ. C. Rousseau ................................. 355
Effects of visual distraction on contingent negative variation and type A and B CNV
shapes. /. J. Tecce, J. Savignano-Bowman, and J. R. Kahle ....................... 358
Personality traits and electrophysiological factors during sensory conditioning in normal
and psychiatric populations. N. Bruneau, P. Dubost, Ph. Jusseaume, F. Laffont, and
G. Lelord [[[ 364
Contingent negative variation in patients affected by specific phobias. H. Barbas, L. Solyom,
and B. Dubrovsky ..................................................
Reliability of contingent negative variation in psychopathology. M. Timsit-Berthier,
JDeZnoy, B. Xhenseval, and M. Timsit .................................. 373
after osvchosurgery affecting thaiamocortical pathways to prefrontal
*<><< F Denoth> A' A*"l*ldlr' L *OSS/' * G~ MaraaM'
and S. Guerri [[[
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Xlll
Section Page
Some methodological and theoretical issues of ERP in psychiatric populations.
B. Dubrovsky and M. Dongier 387
Morphological analyses of the CNV in psychiatry: Comparison of resolution mode and
cumulative curve methods. M. Timsit-Berthier, J. Delaunoy, and A. Gerono 389
Somatosensory evoked potential as a measure of tolerance to ethanol. D. M. Scales,
P. Naitoh, L. C. Johnson, and M. A. Schuckit 392
Stimulant and depressant effects of cigarette smoking, nicotine, and other drugs on the
CNV in man. H. Ashton, J. E. Miilman, M. D. Rawlins, R. Telford, and
J. W. Thompson 397
Psychopathology references 401
VII. ENVIRONMENTAL NEUROTOXICOLOGY 407
Neurobehavioral assessment of environmental insult: A summary of issues.
D. Otto and L. Reiter 409
Carbon monoxide and superior colliculus evoked potentials. R. S. Dyer and Z. Annau 417
Effects of ozone on human central nervous system function. N. W. Grandstaff and
R. R. Beard 420
Neurobehavioral assessment of effects of environmental insults early in development.
/-. D. Grant 421
Neuro- and psychophysiological effects of moderate carbon monoxide exposure.
E. Groll-Knapp, M. Haider, H. Hoeller, H. Jenkner, and H. G. Stidl 424
Application of ERP techniques in noise research. N, E. Loveless 431
Low-frequency noise, selective attention, and event-related potentials. D. A. Otto and
V. A. Benignus 437
Paradoxical effects of carbon monoxide on vigilance performance and event-related
potentials. D. A. Otto, V. Benignus, J. Prah, and B. Converse 440
The use of evoked potential and behavioral measures in the assessment of environmental
insult. M. I, Rudnev, A. I. Bokina, N. D. Eksler, andM. A. Navakatikyan 444
Diagnostic utility of neuroelectric measures in environmental and occupational medicine.
A. M. Seppalainen 448
Effect of carbon monoxide hypoxia and hypoxic hypoxia on cerebral circulation.
R. J, Traystman . 453
Contingent negative variation as an index of environmental distraction. H. Weinberg,
S. H. Curry, and J. F. Peters 458
Carbon monoxide, trichloroethylene, and alcohol: Reliability and validity of neuro-
behavioral effects. G. Winneke, G. G. Fodor, and W. Schlipkoter 453
Dissociation between time course of acetylcholinesterase inhibition and neurophysio-
logical effects of parathion in rat and monkey. D. E. Woolley and L. R. Reiter 470
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XIV
Section
CNV and SEP in shoe industry workers with neuropathy resulting from toxic effect of
adhesive solvents. R. Zappoli, G, Giuliano, L. Rossi, M. Papini, O. Ronchi,
A. Ragazzoni, and A. Amantini 476
Electroencephalographic analysis of subacute effects of methylparathion in the mouse.
G. A. Zapponi, C. J. Undsey, and A. Loizzo 481
Environmental toxicology references 485
VIII. SCALP DISTRIBUTION 499
Use of scalp distribution as a dependent variable in event-related potential studies:
Excerpts of preconference correspondence. E. Donchin 501
Problems in using volume conduction theory to localize evoked potential generators.
R. Cooper 511
Calculated and empirical evoked potential distributions in human recordings.
T. Allison 513
Methodology and meaning of human evoked potential scalp distribution studies.
T. W. Picton,D. L. Woods, D. T. Stuss, and K. B. Campbell 515
Intracranial sources of event-related potentials. W. Ritter 523
Scalp topography in the localization of intracranial evoked potential sources. W. R. Goff,
T. Allison, P. D. Williamson, andJ. C, VanGilder 526
Spatial frequency analysis of an EEC event in the olfactory bulb. W. J. Freeman 533
Scalp distribution references 543
IX. ALTERNATIVES TO SIGNAL AVERAGING 547
Excerpts of preconference correspondence 549
Multivariate analysis of event-related potential data: A tutorial review. E. Donchin and
E. Heffley 555
Before averaging: Preprocessing slow potential data with a Wiener filter. P. Naitoh and
S. Sunderman 573
Simple digital filters for examining CNV and P300 on a single-trial basis. D. Ruchkin and
E. Glaser 579
Implicit spatial averaging of surface macropotentials. L. Gerbrandt 582
Neurometrics: Quantitative electrophysiological analysis for diagnosis of learning
disabilities and other brain dysfunctions. E. R. John, L. Prichep, H. Ahn, D. Brown,
P. Easlon, B. Karmel, R. Thatcher, and A. Toro 585
Comments on methods of signal analysis and signal detection. H. Weinberg 593
Alternatives references 601
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XV
Section Page
X. THEORETICAL APPROACHES AND MODELS 607
A theoretical framework for evoked potential and slow potential research. W. C. McCallum , . . 609
The behavioral approach. N. E. Loveless 612
A neurophysiological model for regulation of sensory input to cerebral cortex.
/. E. Skinner 616
A parsimonious model of mammalian brain and event-related slow potentials.
T. J. Marczynski 626
Integrative models: Macropotentials as a source for brain models. D. Papakostopoulos 635
The role of the Bereitschaftspotential and potentials accompanying the execution of
movement. L. Deecke 640
The place of consciousness in brair^ research. W. Ritter 642
Significance of slow potential shifts in anticipation of and during task performance.
R. Nadtdnen 646
Some general considerations in formulating electrophysiological brain models.
R. Cooper 650
Bimodal slow potential theory of cerebral processing. R. Cooper, W. C. McCallum, and
D. Papakostopoulos 651
General discussion of theoretical issues related to evoked and slow potential changes 657
Concluding remarks. W. C. McCallum 660
Theoretical models references 662
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PARTICIPANTS
Peter Abraham
Truett Allison
Rodney Beard
Warren Brown
L. Burns
Enoch Callaway
Robert Chapman
Jerome Cohen
Raymond Cooper
S. Hutch Curry
Luder Deecke
Jacques Delaunoy
Emanuel Donchin
Maurice Dongier
Bernardo Dubrovsky
Robert Dyer
Bernard Fenelon
Judith Ford
Walter Freeman
David Friedman
Joachim Fuster
Lauren Gerbrandt
William Goff
Netta Grandstaff
Lester Grant
Elisabeth Groll-Knapp
M. Russell Harter
Paule Hazemann
Steven Hillyard
Timo Jarvilehto
E. Roy John
{Catherine Kalil
Rathe Karrer
John Knott
Gilbert Lelord
Nicole Lesevre
Benjamin Libet
Morris Lipton
Alberto Loizzo
Norman Loveless
W. Cheyne McCallum
Thaddeus Marczynski
Gail Marsh
Dennis Molfese
Risto Naatanen
Paul Naitoh
Helen Neville
David Otto
Demetrios Papakostopoulus
Southampton, England
West Haven, Connecticut, U.S.A.
Stanford, California, U.S.A.
Los Angeles, California, U.S.A.
Chicago, Illinois, U.S.A.
San Francisco, California, U.S.A.
Rochester, New York, U.S.A.
Chicago, Illinois, U.S.A.
Bristol, England
Bristol, England
Ulm, German Federal Republic
Liege, Belgium
Champaign, Illinois, U.S.A.
Montreal, Quebec, Canada
Montreal, Quebec, Canada
Research Triangle Park, North Carolina, U.S.A.
Short land, New South Wales, Australia
Palo Alto, California, U.S.A.
Berkeley, California, U.S.A.
New York, New York, U.S.A.
Los Angeles, California, U.S.A.
Northridge, California, U.S.A.
West Haven, Connecticut, U.S.A.
Stanford, California, U.S.A.
Chapel Hill, North Carolina, U.S.A.
Vienna, Austria
Greensboro, North Carolina, U.S.A.
Dakar, Senegal
La Jolla, California, U.S.A.
Helsinki, Finland
New York, New York, U.S.A.
Madison, Wisconsin, U.S.A.
Chicago, Illinois, U.S.A.
Boston, Massachusetts, U.S.A.
Tours, France
Paris, France
San Francisco, California, U.S.A.
Chapel Hill, North Carolina, U.S.A.
Rome, Italy
Dundee, Scotland
Briston, England
Chicago, Illinois, U.S.A.
Durham, North Carolina, U.S.A.
Carbondale, Illinois, U.S.A.
Helsinki, Finland
San Diego, California, U.S.A.
La Jolla, California, U.S.A.
Chapel Hill, North Carolina, U.S.A.
Bristol, England
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XV11
Jon Peters
Terence Picton
James Pirch
Leslie Prichep
Charles Rebert
Lawrence Reiter
Walter Ritter
John Rohrbaugh
Steven Rosen
Walton Roth
Vernon Rowland
Daniel Ruchkin
Mikhail Rudnev
Russell Ruth
June Savignano-Bowman
David Scales
Anna Maria Seppalainen
Samuel Shelburne
James Skinner
George Somjen
Kenneth Squires
Nancy Squires
John Stamm
Samuel Sutton
Karl Syndulko
Joseph Tecce
Timothy Teyler
Robert Thatcher
John Thompson
Martine Timsit-Berthier
Meyer Timsit
Richard Traystman
Patricia Tueting
Charles Warren
Linda Warren
Hal Weinburg
Gerhard Winneke
Dorothy Woolley
Roberto Zappoli
Omaha, Nebraska, U.S.A.
Ottawa, Ontario, Canada
Lubbock, Texas, U.S.A.
New York, New York, U.S.A.
Menlo Park, California, U.S.A.
Research Triangle Park, North Carolina, U.S.A,
Riverdale, New York, U.S.A.
Los Angeles, California, U.S.A.
New York, New York, U.S.A.
Stanford, California, U.S.A.
Cleveland, Ohio, U.S.A.
Baltimore, Maryland, U.S.A.
Kiev, U.S.S.R.
Chicago, Illinois, U.S.A.
Boston, Massachusetts, U.S.A.
San Diego, California, U.S.A.
Helsinki, Finland
Washington, D.C., U.S.A.
Houston, Texas, U.S.A.
Durham, North Carolina, U.S.A.
Orange, California, U.S.A.
Orange, California, U.S. A.
Stony Brook, New York, U.S.A.
New York, New York, U.S.A.
Los Angeles, California, U.S.A.
Boston, Massachusetts, U.S.A.
Rootstown, Ohio, U.S.A.
New York, New York, U.S.A.
Newcastle Upon Tyne, England
Liege, Belgium
Liege, Belgium
Baltimore, Maryland, U.S.A.
Baltimore, Maryland, U.S.A.
Chicago, Illinois, U.S.A.
Birmingham, Alabama, U.S.A.
Burnaby, British Columbia, Canada
Dusseldorf, German Federal Republic
Davis, California, U.S.A.
Florence, Italy
-------
ABBREVIATIONS
The following standard abbreviations are used in this volume. Other abbreviations are defined in the text when
first used. Note that numbers in EP component, stimulus, and international 10-20 electrode designations have
not been subscripted in this volume.
AEP auditory evoked potential msec
ARAS ascending reticular activating system MRF
BP Bereitschaftspotential (synonymous with Nl.N2.etc
RP) PI n, etc.
BPM beats per minute (heart rate) P300
COHb carboxyhemoglobin
CNS central nervous system
CNV contingent negative variation PINV
CS conditional stimulus PMP
d.c. direct current or, when used in relation PNS
to amplifiers, 'directly coupled' po
ECoG electrocorticogram PSP
EDR electrodermal (skin potential) response RCPV
EKG electrocardiogram (also ECG)
EMG electromyogram rms
EOG electro-oculogram RP
EP evoked potential
EPSP excitatory postsynaptic potential RT
ERP event-related potential SI ,S2, etc.
FFT fast Fourier transform sc
GSR galvanic skin response SCV
HR heart rate SEP
Hz Hertz or cycles per second SP
IPSP inhibitory postsynaptic potential SPL
ip intraperitoneal administration TC
ISI interstimulus interval TLV
ITI intertrial interval US
MCV motor nerve conduction velocity VEP
MP motor potential
millisecond
midbrain reticular formation
.first negative peak, second, etc.
first positive peak, second, etc.
positive wave with peak latency ap-
proximately 300 msec after stimulus
onset (also P3)
post imperative negative variation
premotion positivity
peripheral nervous system
perioral (by mouth) administration
postsynaptic potential
reinforcement contingent positive varia-
tion
root mean square
readiness potential (synonymous with
BP)
reaction time
stimulus one, stimulus two, etc.
subcutaneous administration
sensory nerve conduction velocity
somatosensory evoked potential
slow potential
sound pressure level
time constant
threshold limit value
unconditioned stimulus
visual evoked potential
-------
KEYNOTE ADDRESS
THE SIGNIFICANCE OF NEUROBEHAVIORAL DATA
IN SETTING AIR QUALITY STANDARDS
R. BEARD
Department of Family, Community, and Preventive Medicine, Stanford University,
Medical Center, Stanford, CA, U.S.A.
It is an honor to be invited to take part in this
distinguished Congress, and a special honor to be per-
mitted to make some remarks at the opening of the
sessions. It was suggested that you might be inter-
ested in a very practical topic: the significance of
neurobehavioral data in setting air quality standards.
Having been involved in some way with such activities
for about fifteen years, I shall offer you some
observations.
First it must be recognized, that in the United
States, neurobehavioral data were significantly used
in setting only two community air quality stand-
ards—those for carbon monoxide and for lead, and
the latter only in the state of California. The carbon
monoxide standard was set in California by the Air
Resources Board (1970) because the legislature had
ordered that air quality standards must be established
by a specific date. The only evidence then available
on the effects of carbon monoxide in concentrations
close to those observed in urban centers were the
studies of McFarland's laboratory on the effects on
vision (McFarland et al. 1944; Halperin et al. 1947,
1950), Schulte's work (1963) on performance of
psychological tests, and work from our laboratory
(Beard and Wertheim 1967) on the discrimination of
short intervals of time. These all showed effects when
5% or less of the body's hemoglobin had been oc-
cupied by carbon monoxide. All the other data then
available referred to industrial exposures at much
higher levels, with no systematic study of behavioral
responses.
It was widely accepted that if the product of the
exposure time in hours multiplied by the ambient
carbon monoxide concentration in parts per million
did not exceed the number 800 there was little prob-
ability of any perceptible effect. Applying this form-
ula as a standard would lead to an ambient level of
forty-four parts per million, assuming that a stable
equilibrium could be reached in eighteen hours. The
California standard was established with 15 parts per
million averaged over 12 hours, and subsequently
changed to 10 parts per million averaged over 8
hours. Later a Federal Primary Air Quality Standard
for carbon monoxide (Environmental Protection
Agency 1971) was set at 10 mg/m3 or 9 parts per
million, based on very much the same information.
The California lead standard was set about three
years ago, based on evidence about the interference
of lead with hemoglobin synthesis. Recently, that
standard was reconsidered. Reports of impairment in
intellectural and behavioral performance of children
were at this time taken into account. The stringent
standard of 1 1/2 jug/m3 was reaffirmed (California
Air Resources Board 1975,1976).
In order to understand the outlook for the use of
behavioral data in air quality standard setting, it will
be profitable to turn to the standards which have
been established in industry for the protection of
workers' health. Such standards have been in effect
for many decades. There are profound differences
between the United States and some other nations in
this regard. "In [our country] no serious threat to
health is considered to exist as long as the level of
exposure does not induce a. . .demonstrable disturb-
ance of a kind and degree that is accepted as an in-
dication of potential sickness; [in the USSR] a
potential for ill-health is said to exist as soon as the
organism undergoes the first detectable change of any
kind from its normal state" (Hatch 1972). Eastern
European nations generally follow the Russian
pattern, while other nations generally follow the pat-
tern used in the United States, with a great many
differences in the interpretation of data. Conse-
quently, international agreements on occupational air
quality standards are very few in number and the
-------
XX
limits recognized among the nations may differ by a
factor of ten. The leading agency for setting such
standards for the United States does not recognize
that effects demonstrated by evoked potentials are
sufficient evidence on which to base standards. On
the other hand, Eastern European countries have used
such information for many years.
U.S. industrial management, government, and for
the most part, labor are comfortable with the kind of
standard-setting for occupational health which has
become familiar. Efforts to bring new methods which
might lead to more stringent controls will be resisted,
especially if costly changes in materials, processes, or
equipment do not promise immediate tangible bene-
fits for workers. It is not likely to be seen as sound
policy to invest heavily in protection from a hypoth-
etical injury which might, if prolonged or oft-
repeated, produce only subtle changes in the mental
processes of a minority of workers.
Air quality standards for industry are generally
based on two major assumptions: (1) that the dura-
tion and frequency of exposure can be controlled and
(2) that individuals who are unusually susceptible can
be detected and transferred to other work. The guide-
lines for community air quality standards are not so
clear arid not so generally accepted. Obviously, they
must be designed for continuous exposure over many
generations. But whom must they protect? It is easy
to proclaim that no citizen should be made to suffer
the ill-effects of man-made pollution. But does that
mean protection for every aged pulmonary cripple,
gasping away a life misspent in the consumption of
several tons of cigarettes, or the protection of the
prematurely born infant not yet ready for inde-
pendent life?
Some years ago in California, the decision was
made to protect the most susceptible group of people
which could be identified. This has led to considera-
tion of the effects of air pollution on infants, the
aged, those with chronic pulmonary disease, and
those with cardiovascular disease. It is recognized that
it is necessary for people with extreme susceptibility
to be protected by the provision of filtered, purified
air on an individual basis.
In the face of so much uncertainty about the cri-
teria for air quality standards, what will be the place
of neurobehavioral observations? To some degree this
will depend on the extent to which they can be cor-
related with the threat of disease, or with the impair-
ment of practical functions which are recognized as
being important. If the alteration of the contingent
negative variation can be shown to be a reliable sign
of a process which leads to increased risk of auto-
mobile accidents, it will carry a great deal of weight.
If it is an isolated instance, it is apt to be neglected.
The most interesting case is likely to be the one in
Beard
which the presumed toxicant at a small dose causes
enhanced performance on some neurobehavioral task.
This phenomenon is well-known to pharmacologists
and psychophysiologists, and has been observed in
our laboratory with a small dose of ozone in a test of
visual perception (Grandstaff and Beard, this
volume).
The Environmental Protection Agency as it now
stands is not likely to give much attention to neuro-
behavioral data. In setting a new standard, essential
steps are first, publication of the document which
reports the criteria on which the new standards will
be based-that is, all the relevant data. The drafting of
such documents has in the past been done by various
groups under contract to the agency. The selection of
contractor will influence the content of the draft. At
present, only one of the leading figures in the EPA
hierarchy has much feeling for neurobehavioral
science. The draft, when prepared, will be open to
public criticism, but its final form will be decided by
a sixteen member advisory committee, which as pres-
ently constituted has only one member who has
shown an interest in, and an understanding of this
kind of work. Finally, the Administrator will act on
the advice of his staff and still another advisory com-
mittee to promulgate a regulation.
As I read some of the reports prepared for this
meeting, several areas for comment emerged. One was
the frequency of seemingly discrepant observations
and the analysis of those discrepancies. In most in-
stances these could not be resolved because the con-
ditions of experimentation were not the same. There
is a need for better controls. That, of course, is what
this meeting is all about, and this free and easy ex-
change of ideas will help to improve the com-
parability of different studies.
Another thing which emerged is the need for real
interdisciplinary cooperation. The first rate psycholo-
gist cannot really get useful help from a tyro toxi-
cologist, nor even from a first rate lexicologist, if he
keeps him in a purely ancillary role. I am concerned
that there is developing an in-group which initiates its
new members by making them learn a special lan-
guage. It is, of course, inevitable that these new ideas
require new modes of expression, and that there will
be conventional phrases which will be understood by
the initiate as symbols for large constellations of
ideas. But we must beware of mistaking new com-
plexities of expression for new ideas. Ultimately, our
ideas will have value to our fellow men only to the
extent that they are understood. The research which
is being discussed here this week should be made
known much more widely. It should be publicly re-
ported in journals which are seen by a wide range of
scientists. It should be reported in a language which
can be understood by specialists from other fields.
-------
Keynote Address
xxi
In the long run, the real contribution of neuro-
behavioral studies will be deepened understanding of
the processes of the nervous system and of the ways
they can be affected by external agents. We should
not be impatient for practical and applicable results
from this very new field of science. It is progressing
rapidly as shown by the reports prepared for this
meeting. The insights and cumulative data base that
derive from meetings such as EPIC IV provide the
foundation essential for future applications of neuro-
behavioral methods to environmental problems in-
cluding the setting of air quality standards.
References
BEARD, R.R. and WERTHEIM, G. Behavioral im-
pairment associated with small doses of carbon
monoxide. Amer. J. Pub. Health, 1967,
57:2012-2022.
CALIFORNIA AIR RESOURCES BOARD. Ambient
Air Quality Standards, 1970, Sacramento, Cali-
fornia.
CALIFORNIA AIR RESOURCES BOARD. Two-day
hearing conducted on health effects of lead in
air. CARS Bulletin, 1975, 6(10): 4-5.
CALIFORNIA AIR RESOURCES BOARD. Standard
for lead in air is unchanged. CARB Bulletin,
1976,7(2):3-4.
ENVIRONMENTAL PROTECTION AGENCY. Na-
tional Primary and Secondary Ambient Air
Quality Standards. Fed. Reg., 30 Apr 1971,
36(84):8186-8261.
HALPERIN, M.N., NIVEN, J.I., McFARLAND, R.A.,
and ROUGHTON, F.J.W. Variation in visual
thresholds during carbon monoxide and hy-
poxic anoxia. Fed. Proc., 1947,6:120-121.
HALPERIN, M.H., McFARLAND, R.A., NIVEN, J.I.
and ROUGHTON, F.J.W. The time course of
the effects of carbon monoxide on visual
thresholds. J. Physiol., 1959. 146:583-593.
HATCH, Theodore F. The role of permissible limits
for hazardous airborne substances in the work-
ing environment in the prevention of occupa-
tional disease. Bull. World Health Org., 1972,
47:151-159.
McFARLAND, R.A., ROUGHTON, F.J.W., HAL-
PERIN, M.H. and NIVEN, J.I. The effects of
carbon monoxide and altitude on visual thresh-
olds. J. Aviat.Med., 1944,15:381-394.
SCHULTE, H. Effects of mild carbon monoxide in-
toxication. Arch. Environ. Hlth, 1963,
7:524-530.
U.S. PUBLIC HEALTH SERVICE. Air Quality Cri-
teria for Carbon Monoxide. January 1969,
Washington, D.C.
-------
I. ELECTROGENESIS AND NEUROCHEMISTRY
Section Editor:
Charles S. Rebert
Life Sciences Division
SRI International
Menlo Park, California, U.S.A.
-------
ELECTROGENESIS OF SLOW POTENTIAL CHANGES IN
THE CENTRAL NERVOUS SYSTEM: A SUMMARY OF
ISSUES
C. S. REBERT
Life Sciences Division, SRI International, Menlo Park,CA, U. S. A.
Introduction
This summary is based on preconference corre-
spondence concerning the electrogenesis and pharma-
cological substrate of slow potential changes in the
central nervous system. The following individuals
contributed to this correspondence:
1. E. Evarts, National Institutes of Mental Health,
Bethesda, Maryland.
2. J. Fuster, University of California, Los Angeles,
California.
3. B. Libet, University of California, San Francis-
co, California.
4. T. Marczynski, University of Illinois, Chicago,
Illinois.
5. V. Rowland, Western Reserve University, Cleve-
land, Ohio.
6. J. Skinner, Baylor College of Medicine, Hous-
ton, Texas.
7. G. Somjen, Duke University, Durham, North
Carolina.
8. J. Stamm, State University of New York .Stony
Brook, New York.
Discovery of the contingent negative variation
(CNV) by Grey Walter and his colleagues (1964) and
Bereitschaftspotential (BP) by Kornhuber and Deeke
(1965) gave significant impetus to the recent study of
SP changes in relation to overt behavior. These
findings were paralleled by discovery of a slow posi-
tive potential (the P300 wave) and related compo-
nents that reflect cognitive events (Sutton et al.
1965). The basic approach to this work may be char-
acterized as "electrophrenerrianology" (EPology)-
that is, the study of the localization of psychological
processes in the brain through analysis of electrical
"bumps" on the human skull, with the Skinnerian
assumption that the determination of the variables
that influence those "overt" events is sufficient to
their explanation. The assumptions inherent in this
approach may lead to fallacious conclusions in rela-
tion to human perception and subjective sensory
experiences unless there is rigorous validation of
subjective experience and knowledge of the phys-
iological bases of the potentials. Whereas the psy-
chological aspects of such work are usually well
controlled and operationally defined, the neglect
of intracerebral neurophysiology is evidenced by the
lack of a single investigation of cortical neuronal
firing patterns associated with the CNV, and only one
relating the BP to single neuron activity ( Gantchev
1974). Furthermore, very little discussion at three
previous ERP Congresses was devoted to recordings
in animals, and among those papers (Borda 1970,
Donchin et al. 1971, Hablitz 1973, McSherry 1971,
Robert 1972), only McSherry directed attention to
causal mechanisms.
Yet knowledge of the causal mechanisms of the
CNV and other event-related phenomena is critical to
their full understanding and to their proper inter-
pretation in relation to behavior and covert psycho-
logical processes. It is possible, for example, to record
an identical scalp potential under a variety of intra-
cerebral conditions—that is, when the specific neu-
ronal/glia elements involved differ (e.g., generation
of a surface-negative potential by dendritic depolari-
zation in contrast to somatic hyperpolarization).
Whereas the surface potential in the two conditions
could be the same, the physiological consequence
would be opposite. Such details must be known to
adequately relate scalp potentials to molar events.
There has, of course, been a long history of
interest in SP phenomena of the brain aside from the
CNV, BP, and P300-indeed, from the very inception
-------
Rebert
of cerebral electrophysiology (Caton 1875). Because
Caton used slow recording galvanometers that inte-
grated oscillatory potentials, he could not clearly
distinguish real SPs from rhythmic after potentials.
Modern entry into this field was initiated by Gerard
and Libet (1940) who were able to clearly distinguish
SPs from oscillatory activity. Their work laid the
early foundation for delineating mechanisms of SP
genesis and it continues to this day (Libet, this vol-
ume). From that somewhat independent stream of
research, a body of evidence has accumulated that is
relevant to studies of the CNV. The specific neuro-
physiological and neurochemical mechanisms elabo-
rated by Libet and his colleagues in the sympathetic
ganglion provide useful models for the study of CNV
genesis centrally. Another general stream of research
that can shed light on the mechanisms of event-
related SPs are studies of intracerebral neurophysi-
ology undertaken in behavioral contexts similar to
those used in the study of SPs (Fuster 1973). Given
comparable situations, interexperimental similarities
between SPs and neuronal responses can be evaluated.
There are also several investigations involving direct
comparisons of SP and unit responses (Fromm and
Bond 1964, 1967; Rowland 1974; Rebert 1969,
1973b), but few involving the behaving organism.
Because it is increasingly obvious that EPology is
not an adequate approach to the full understanding
of event-related SP phenomena, consideration of
electrogenesis has been included as part of this fourth
congress on event-related SPs. The primary objective
of this review is to delineate important issues with
regard to mechanisms of SP genesis in order to facili-
tate their early resolution. Investigators from neuro-
physiology (Evarts, Fuster, Skinner), neuropharma-
cology (Libet, Marczynski, Somjen), and physiologi-
cal psychology (Rebert, Rowland, Stamm) engaged
in a correspondence to develop a multidlciplinary
view of the problem of SP genesis with the following
objectives:
1. Delineate critical issues concerning SP genesis,
the unknowns at this point in time.
2. Describe the state of the data to determine
what needs to be done experimentally, theo-
retically, and technically to resolve critical
issues.
3. Determine in a broad sense where SP electro-
genesis research is headed: What trends are
occurring, and whether the research is leading
to any general principles of brain function.
Three general categories of critical issues were
raised:
1. Typology of Sft-Several types of SPs can be
identified and defined from different frames
of reference. From a pheno'menological view,
SPs have been defined as "motor readiness"
events, "expectancy waves," and "postrein-
forcement potentials." In contrast, SPs have
also been defined in terms of their temporal
characteristics, for example, "phasic" (CNV-
like) versus "tonic" long-lasting (postrein-
forcement) SPs.
2. Experimental /ssHes-These issues include spe-
cific questions such as the relationship of SPs
to neuronal activity, the neurochemical medi-
ators of SPs, and the role of potassium and
glia in SP genesis.
3. Technical Issues—These issues relate to techni-
cal limitations that preclude or impede ad-
vances and interpretations in specific research
strategies.
These issues are reviewed below.
Review of issues
Typology of SPs
Several ways of categorizing or defining SPs are
discussed here. This list is probably not exhaustive,
and the categories are not mutually exclusive. SPs can
probably be best differentiated on the basis of multi-
ple categories.
Temporal classification: There are relatively con-
stant potentials between almost any two regions of
the brain or between the brain and extracerebral sites.
The potential of the mammalian cortical surface is
approximately 15 mV positive with respect to corti-
cal layers V-VI (Aladjalova 1964), and the surface is
1 to 3 mV negative with respect to frontal bone
(Fromm and Bond 1964). These potentials, while
relatively constant, may fluctuate with very long
periods (Aladjalova 1964) or with the sleep-wakeful-
ness cycle (Caspers 1963; Wurtz 1965a,b). The
"resting" potential exists in contrast to "reactive"
SPs that are of relatively short duration (1 to 20 sec)
and that are usually evoked by transient sensory or
psychological events (e.g., CNV). SPs may, then, be
either oscillatory or nonoscillatory, and the latter can
be further subdivided on the basis of their duration
into two general classes-(l) tonic (resting) potentials
with durations of minutes or hours and (2) phasic
(reactive) potentials with durations of seconds. This
latter dichotomy might also parallel SP types that do
and do not correlate with massed unit activity
(Sheafor and Rowland 1974) and phasic CNV-like
SPs observed in many parts of the monkey's brain, in
contrast to cumulative postreinforcement potentials
observed only in the cortex (Steinmetz and Rebert
1973).
-------
Summary of Electrogenesis Issues
Functional classification: The functional signifi-
cance of SPs may be considered at two different
levels, i,e., with respect to neuronal activity or molar
behavioral/psychological events. Negative and positive
postsynaptic potentials (PSPs) measured at the outer
neuronal membrane surface with microelectrodes are
associated with excitation and inhibition of the neu-
rons, respectively, but the relationship of slow field
potentials (measured with macroelectrodes) to neu-
ronal firing is not clear. Given clarification of that
relationship, SPs might be defined in terms of their
excitatory or inhibitory consequences.
A variety of factors related to sensory input,
behavior, and covert psychological processes may
elicit SPs, which can be differentiated into (1) those
elicited unconditionally by external events such as
sensory stimulation and reinforcement; and (2) those
elicited conditionally during situations like the cued
RT task. Other classes of SPs include those related
(1) to "spontaneous" alterations of arousal, atten-
tion, and sleep-wakefulness; and (2) endogenous or
induced tissue abnormality such as the SPs preceding
seizures or accompanying cortical spreading depres-
sion or surgical injury (Irwin et al. 1975).
Other functional classifications have been sug-
gested based on phenomenological interpretations of
the most salient psychological process presumed to be
represented by the SP. For example, the CNV has
been related to cognition, expectancy, motivation,
waiting, and attention. Until the functional signi-
ficance of SPs is unequivocally established, such
presumptive labels should be avoided.
Mechanistic classification: Three general classes
of SPs are delineated here based on (1) neuroanatomi-
cal arrangements, (2) membrane and neurochemical
mechanisms in neurons, and (3) extraneuronal mecha-
nisms.
SPs may be classified with respect to both par-
ticular and general neuronal arrangements. The orga-
nization of neurons varies from locale to locale in the
brain. Some regions like the cerebral cortex, hippo-
campus, and cerebellar cortex are characterized by
systematically oriented neurons that develop electric
dipoles directly related to the physical organization.
In contrast, regions like the reticular formation and
caudate nucleus do not have such well-defined neural
arrangements, yet they also exhibit SP responses
(Rebert 1972). The SPs generated in these two types
of tissue might be referred to as "dipole" and "reticu-
lar" types. A difficult question is to determine the
mechanisms of SP genesis in the latter type of tissue.
Since the neurons are not systematically oriented, the
net field produced by neuronal membranes might be
zero, the separate fields cancelling one another. But,
as Ubet asked, if a field-recorded SPis generated by a
type of glial cell, would there not have to be a suf-
ficient gradient in SP somewhere along the cell axis to
develop the external field? What is the evidence for
such axial gradients in glial cells? In addition, would
it not be necessary for glial processes to have some
systematic arrangement to preclude cancelling of
their fields? What alternatives can be suggested?
Somjen (this volume) provides a model of how glia
might be involved in SP genesis.
The general intracerebral system involved in the
production of surface potentials may also differen-
tiate apparently equivalent surface potentials. This
is reflected by data of Skinner and Yingling (1976)
showing that frontocortical SPs evoked by either a
novel stimulus or a neutral reinforced stimulus appear
to be the same in that the identical physical stimulus
evokes them and their anatomical distributions are
the same. However, the subcortical correlates of those
two seemingly identical SP events are different. The
response in n. reticularis thalami to a novel stimulus
does not require the integrity of the inferior thalamic
peduncle (a bidirectional pathway interconnecting
the medial thalamus and frontal cortex), whereas the
conditioned response recorded in this structure does
require intact connections with the frontal cortex.
Thus, knowledge of the subcortical correlates of the
frontal potentials separates them into distinct SP
events, even though the actual local response para-
meters are the same and are presumably mediated by
the same local generators. The latter presumption
requires further examination because different local
neural aggregates could be generating morphologically
similar waveforms.
Many neurons are "mosiac" in the sense of being
sensitive to a variety of transmitter substances. In
addition, the effect of synaptic events depends upon
the influence of nontransmitter chemicals that are
both endogenous and exogenous to neurons. Chemi-
cal "modulators" are endogenous substances that
function in a homeostatic way to regulate the rate of
' depolarization or hyperpolarization initiated by a
synaptic transmitter. Similarly, blood-borne sub-
stances exogenous to neurons can facilitate (medi-
ator) or attenuate (moderator) the rate of synaptic
transmission or axonal conduction, or act to alter
transmitter release or change the action of a modula-
tor (Myers 1974). As indicated by Libet (this vol-
ume), slow SPs are associated with such actions and
can be classified on the basis of their neurochemical
substrate.
A variety of extraneuronal factors are also
known to produce SPs. They include potentials
generated by glial membranes, vascular flow, differen-
tial pH, C02, blood-brain barrier, and perhaps others.
-------
Rebert
Tonic and phasic SPs constitute two major
classes that can be differentiated on a number of
definitional factors. Tonic SPs are contrasted with
phasic ones, by definition, in terms of temporal
characteristics. In addition, phasic SPs appear to be
closely related to transmitter release, neuronal organi-
zation (dipoles), and waking psychological/behavioral
events, while tonic SPs appear to vary with metabolic
factors, injury, and the blood-brain barrier. Tonic SPs
may not differ from one intracerebral locale to
another, may not relate to neuronal organization, and
are, perhaps, associated with modulator and modera-
tor/mediator actions on neurons.
We are left with the general question as to the
best way(s) of classifying SPs. Somjen emphasized
the need to avoid the kind of confusion that has
arisen around the term alpha rhythm, customarily
distinguished from EEC spindles, except by Andersen
and Andersson (1968) who regard the two as identi-
cal because of a suspected common generating mech-
anism. He suggests that SP categorization should be
based either on phenomenology or electrogenesis, but
not on both, although, as suggested above, a multi-
dimensional scheme may be most appropriate.
Experimental issues
Specific experimental issues related to electro-
genesis may be summarized in terms of seven major
considerations:
1. Spatial distribution of SPs in the central
nervous system (CNS).
2. Neurochemical factors related to SP genesis.
3. Relations between neural activity /excitability
and SPs.
4. The role of potassium and glia and other
"nonresponsive" cells in SP genesis.
5. Intracerebral relationships inferred from SP
responses.
6. The interaction of SP types.
7. The general question of how knowledge of
SP electrogenesis might improve under-
standing of the behavioral/psychological rele-
vance of SPs.
Spatial distribution: Given the variety of factors
that contribute to SP genesis, it is likely that SPs
can be recorded from any region of the CNS under
one condition or another. The distinction between
resting and reactive SPs is important in this context,
as resting SPs—like those associated with the sleep-i
wakefulness cycle—may appear with similar polarity
and time course throughout the brain (Wurtz 1966),
whereas reactive SPs, e.g., those elicited in the cued
RT task, exhibit different polarities, waveforms and
amplitudes in different regions of the brain (Rebert
1972, McCallum et al. 1973). The question of distri-
bution in the brain is, therefore, most pertinent to
the latter type of SP. Event-related phasic SPs have
been observed in several nuclei of the thalamus, hypo-
thalamus, basal ganglia, nonspecific reticular nuclei,
and limbic structures (amygdala, spetum, cingulate
gyms) as well as over a large extent of the cortical
surface (Haider et al. 1968, Irwin and Rebert 1970,
Rebert and Irwin 1969,McCallum et al. 1973, Rebert
1972, Hayward et al. 1966, Vastola 1955, Rowland
1968; Donchin et al. 1971, Borda 1970, Hablitz
1973). The significance of the scalp distribution of
SPs in humans is the subject of a separate section in
this volume.
Neurochemistry: Two related questions can J>e
asked with respect to the actions of chemicals in the
genesis of SPs. First, which chemicals acting on neu-
rons or glia cells produce or modify slow membrane
potential changes? Second, can SP responses in par-
ticular regions of the brain be related to internuclear
pathways defined by their neurochemical properties?
Some evidence is available with respect to the fust
question (see Marczynski and Libet, this volume). On
logical grounds, the second can probably be answered
in the affirmative, although direct evidence is lacking.
It is probably true, for example, that positive SPs in
the caudate nucleus depend to some extent on the
dopamine pathway that originates in the substantia
nigra.
There is some question concerning the role
of transmitter substances in SP genesis since, as
Marczynski (this volume) points out, the term implies
a brisk and quickly reversible effect on neurons. The
release of acetylcholine (ACh) in the cortex in associ-
ation with surface SPs accompanying wakefulness
suggests a possible transmitter role in SP production.
On the other hand, ACh has muscarinic and nicotinic
actions, the former perhaps not representing a typical
(brisk) transmitter phenomenon, but a modulator ac-
tion (Libet, this volume). An additional confounding
observation is that ACh may also affect glial mem-
branes, producing slow, long-lasting depolarization.
Whether this is a direct effect on glia or a secondary
consequence of potassium released from muscarini-
cally activated neurons is not certain."This consider-
ation is important since the sensitivity of glial cells to'
ACh could, theoretically, result in large SPs without
any obvious correlation with neuronal activity as ob-
served by Sheafor and Rowland (1974). Marczynski
marshals evidence from a variety of sources suggesting
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Summary of Electrogenesis Issues
that cortical surface negative SPs ate mediated by
cholinergic mechanisms. Since the cholinergic
component of the ascending reticular activating
system (ARAS) exerts a strong facilitating effect
on thalamic relay neurons, there is reason to conjec-
ture that thalamic SPs observed by McCallum et al.
(1973) and Robert (1972) may also be choliner-
gically mediated.
Paradoxically, antimuscarinic drugs such as atro-
pine and scopolamine, known to block negative SPs
and the desynchronization induced by ARAS stimu-
lation, in the same dose range also block the occur-
rence of alpha-type synchronization in men and cats
(post-reinforcement synchronization of 7 to 9 c/sec)
associated with epicortical positive SPs (reward con-
tingent positive variation or RCPV). Does this mean
there are pharmacologically identical but functionally
different, and even opposed, cholinergic mechanisms?
After systemic administration of scopolamine, the dc
potential of the cat's cortex (posterior marginal
gyri) remains stable, i.e., the SPs show little fluctu-
ation despite maintenance of bar pressing perform-
ance. Furthermore, subsequent administration of
physostigmine to increase the tone of the cholinergic
systems restores both the negative SPs during unre-
warded bar presses and the RCPV during consump-
tion (Marczynski 1971 and this volume).
Dopaminergic and cholinergic influences in the
production of slow excitatory and inhibitory post-
synaptic slow potentials (s-EPSPs and s-IPSPs) are
reviewed by Libet (this volume). Sympathetic gang-
lion cells are capable of responding to orthodromic
(preganglionic) volleys with a slow IPSP and a slow
EPSP, the s-IPSP in response to the transmitter
dopamine and the s-EPSP in response to acetyl-
choline, acting muscarinically (Libet 1970). Both
slow PSPs have synaptic delays in the tens and
hundreds of msecs and durations of many seconds.
Both are generated without any detectable change in
membrane resistance by electrogenic mechanisms that
may depend on active ion transport. Generation of
these prolonged responses without the necessity of
ionic leakage, in contrast to that of the "classical" or
"fast" PSPs, allows their achievement without the
excessive energy requirements for restoration of ionic
concentrations. If such monosynaptic s-PSPs provide
possible models for some neuronally generated SPs, it
would be profitable to study their incidence in the
CNS in relation to SP responses.
An additional function of dopamine consists of
a true modulating action on neuronal reactivity to
ACh (Libet and Tosaka 1969, 1970; Libet et al.
1975). Brief exposure to dopamine enhances slow
muscarinic response to ACh (s-EPSP responses) up to
several hours or longer. This modulatory function has
important implications for behavioral, motivational,
and memory processes. It could provide a basis for
long-lasting alterations in SP responses, especially
when such alterations are concomitants of behavioral
modifications.
The neurochemistry of the CNV is an issue of
specific concern. Thompson et al. (this volume) pro-
vide preliminary evidence and a brief review of phar-
macological effects on the CNV in man.
Relation of SPs to neural excitability: Slow
potentials at the cortical surface may reflect a variety
of events occurring in cortical neurons, including
somatic and dendritic depolarization or hyperpolar-
ization in any combination. Thus, surface SPs could
occur in the absence of neuronal firing, reflecting
only a change in the dynamic equilibrium of den-
dritic depolarization and somatic hyperpolarization,
perhaps resulting in a more reactive state (McSherry
and Borda 1973). In contrast, extracellular slow field
potential changes may accompany changes in the
average firing rate of neurons. Study of these two
questions requires substantially different experimen-
tal approaches. The first necessity is to determine the
relationship between SP responses and neuronal
firing, and in the absence of changes in firing, to
determine if SP responses reflect changes in neuron
thresholds.
There are two types of evidence available for
assessing the relationships of SP and neuronal activ-
ity: (1) indirect, inferential data based on inter-
experimental comparisons and (2) direct correlation
of units and SPs. Indirect evidence regarding cortical
SPs comes from SP and unit behavior observed by
different experimenters using similar experimental
paradigms. Fuster (1973), Fuster and Alexander
(1971), Stamm (1964), and Stamm and Rosen (1972)
have studied units and SPs in monkeys performing
delayed response tasks. The results suggest that
surface-negative SPs are associated, in some portions
of the delay period, with increased neuronal dis-
charge. Another comparison can be made between
studies of promotion behavior of cortical units
(Evarts 1966, 1973) and studies of slow readiness
potentials (Kornhuber and Deeke 1965). The occur-
rence of increased cellular firing in the cortex in asso-
ciation with surface-negative SPs implies that SPs
are due, at least in part, to dendritic depolarization,
since a preponderance of somatic depolarization
would be reflected by a surface positive SP.
Data from direct comparisons of SPs and single
units in immobile preparations are inconsistent (Li and
Salmoiraghi 1963) and has rarely been obtained in
behavioral contexts. However, Gantchev (1974) con-
currently recorded single unit activity and readiness
potentials in monkeys and found a preponderance of
units increasing firing during surface-negativity, with
-------
8
Rebert
a mixture of no responding and decreased cortical
cell firing in association with surface-positive SPs.
Marczynski (this volume) found surface-negative
components of postreinforcement synchronization
in phase with cortical cell firing. A small sample
study of ten neurons suggested that marked reduc-
tion of firing accompanied postreinforcement posi-
tive SPs. Yingling and Skinner (1975) and Skinner
and Yingling (1976) observed that single units in
n. reticularis thalami increased firing in association
with negative SPs and decreased firing with positive
shifts.
Measurements of massed unit (MU) activity in
the cortex and subcortical regions give similar results.
Rebert (1969, 1973b) showed that negative and posi-
tive SPs evoked by light flash in the lateral geniculate
accompanied increased and decreased MU activity,
respectively. Sheaffor and Rowland (1974) found
that reactive cortical surface-negative SPs accom-
panied increased cellular discharge. This result was
complicated by additional findings that long-duration
"expectancy" SPs were not associated with system-
atic changes in MU activity. The technical consider-
ation of the sensitivity of MU measures to small unit
discharge was raised. It appears that, despite differ-
ences in neuronal morphology and specific generating
mechanisms, the polarity of surface SPs and those in
subcortical regions reflect the state of neuron activity
in a similar way, i.e., negativity is associated with
increased firing. However, either relationship is pos-
sible and at this time the determination of SP/unit
relations requires substantiation in each case. Ulti-
mately, repeated demonstration of the same relation-
ship in a variety of experimental settings and nuclei
might allow a firm generalization about SP polarity
and unit firing to be made.
Role of "nonresponsive" cells and potassium in
SP genesis: Neural membrane shifts may occur via
regulation of the extracellular ionic concentration of
K+, a mechanism that Ranson and Goldring (1973a,
b,c) have linked with glial cell transactions. The elec-
trogenesis of extracellular SPs could derive, in part,
from glial membrane shifts, or SP generators could
be associated with other biophysical processes of neu-
rons and glia that have not as yet been explored.
Rosen thai and Somjen (1973), for example, showed
a correlation between cellular metabolic activities and
local SP shifts. Metabolic end products could, in turn,
affect cerebrovascular flow, a phenomenon that has
also been associated with SP shifts (Woody et al.
1970). Somjen emphasizes the importance of recog-
nizing the source of potassium when it accumulates
in extracellular fluid. Sources include terminal axon
arborizations; cell bodies, dendrites, and axons of
spiking neurons; cell bodies and dentrites exhibiting
nonspike synaptic currents; and small (short axon)
cells. Determination of the precise source is difficult
due to the complicated architecture of tissue.
The role of neuroglia as a generator source of
sustained potential shifts is extensively reviewed by
Somjen (this volume). He suggests that the theory of
glial generation is compatible with the theory ofcho-
linergjc mediation of event-related SPs (Marczynski,
this volume). It is conceivable that, in normal cortex
under physiologic conditions, the most abundant
sources of potassium are activated by cholinergic
input. The idea of direct ACh action on the glial cell
membrane is less attractive because it implies the
extrasynaptic diffusion of ACh.
Whereas glia have received considerable attention
as possible SP sources, Rowland points out that not
all "silent" cells of the cortex are glia. He suggests
that attention be directed to a possible role of such
cells in the production of SPs. Skinner suggests too
that calcium has not been adequately studied in terms
of its role in the production of SPs.
Intracerebral relations: In the cued RT task, SP
polarity appears to differentiate mesencephalic and
thalamic nonspecific arousal mechanisms from basal
ganglia/limbic structures. The former exhibit negative
and the latter exhibit positive SPs (Rebert 1972). It
has been suggested (Rebert 1977) that these SP para-
meters reflect a reciprocal interactive state between
the two arousal systems described by Routtenberg
(1968).
Observing SP changes in one region of the brain
in response to manipulations of other regions appears
to be a useful method of studying intracerebral rela-
tionships (O'Leary and Goldring 1964, Arduini 1958,
Skinner and Yingling 1976). However, caution needs
to be exercised in generalizing from experimentally
derived relationships under one set of conditions to
relationships in other circumstances. For example,
evidence suggests that activity in mesencephalic reti-
cular regions has a primary role in the production of
surface-negative SPs (Arduini 1958), but trial-by-trial
analyses of SPs in nonspecific nuclei and on the cor-
tical surface in the cued RT task indicate that the two
regions were not coupled in terms of SP covariation
(Rebert 1977). In contrast, the latter analyses sug-
gested that the caudate nucleus and amygdala were
coupled during the foreperiod of RT. Therefore, one
cannot conclude from the demonstration of anatomi-
cal connections and functional interaction between
nuclei in one situation that the nuclei are functionally
coupled in other situations.
The foregoing indicates the necessity for deter-
mining intracerebral dynamics related to particular
behavioral/psychological states. Analysis of SP
-------
Summary of Electrogenesis Issues
fluctuations appears to be one way to achieve this ob-
jective. Skinner's work (this volume) combining SP
measures and selective intracerebral blocking has also
been fruitful in defining functional paths related to
specific behaviors. He suggests an important role of
tnalamocortical projections, especially the inferior
thalamic peduncle, in frontal SP genesis. In contrast,
Zappoli et al. (this volume) argue that CNVs in
humans occur despite extensive prefrontal isolation
and disruption of thalamocortical projections. It has
been alternatively suggested that the ventral motor
thalamus is involved in CNV genesis (Haider et at.
1968). Also since the caudate nucleus exerts an inhib-
itory influence on the cortex, reflected in surface
positive SPs (Buchwald et al. 1967), and positive SPs
occur in the caudate in association with cortical
CNVs (Rebert 1972, McCallum et al. 1973), it is con-
ceivable that the CNV could be due, in part, to re-
lease from caudate inhibition. In addition, Fuster
(this volume) has proposed that prefrontal unit activ-
ity, and correlatively SPs, are modulated in part by a
visual transcortical pathway involving inferotemporal-
prefrontal connections. These findings represent the
humble beginning of an understanding of how dif-
ferent brain regions interact to generate SP responses.
These results also indicate the usefulness of em-
ploying SP responses to assess intracerebral relation-
ships.
Interaction of SP types: The determination of
how different SP types interact is an essentially un-
tapped area of inquiry. Some specific questions and
possible ways of studying interactions include the
following. How might slow glial membrane depolar-
izations affect neural membranes? Could glial cells
regulate the neural equilibrium potential of K+ and,
therefore, the membrane resting potential? Can glia
be selectively blocked (e.g., by application of mor-
phine to the cortical surface-Roitbak 1969) to deter-
mine their contribution to SPs?
Tonic and phasic SPs and their interaction can
be observed concurrently in some behavioral con-
texts. Rebert et al. (1976) observed dc level changes
on the human scalp preceding CNV trials in associ-
ation with forearm muscle tension induced by having
subjects lift weights with a hand grip. There was a
direct relationship between the amount of weight
pulled and the tonic dc level up to a point (30 Ib),
after which additional tension produced no further
SP shift. However, CNV amplitude showed no incre-
ment between0 and 15 Ib, but increased S/uV between
15 and 30 Ib. It remained at the larger value at 45 Ib.
While the pretrial tonic dc shift reached asymptote
at 30 Ib, an enhanced CNV was superimposed on it,
suggesting that the two potentials were independently
generated. Similarly, in monkeys there was no appar-
ent interaction between CNVs and a tonic postinges-
tion frontal negativity observed by Steinmetz and
Rebert (1973). However, when the cortical dc level
shifted several mV negative for an unknown reason
in one instance, CNVs were absent. These findings are
relevant to the hypothesis that CNV reduction under
stress in highly anxious subjects is due to the presence
of a physiological ceiling for SP genesis (Knott and
Irwin 1968, 1973). Although a ceiling appeared to be
produced by muscle tension (which is perhaps analo-
gous to excessive arousal produced by anxiety), CNVs
were still apparent. Thus the data did not support the
type of interaction between tonic and phasic SPs
predicted by the ceiling hypothesis. The monkey data
were partially supportive, but only in the context of
extremely large background shifts, which should be
readily detected on the human scalp. Pirch (this sec-
tion) presents further evidence concerning the rela-
tionship of tonic and phasic negative shifts in rats,
suggesting that the ceiling hypothesis is valid.
Relevance of SP genesis to behavioral interpre-
tations: All the issues discussed above are pertinent
to the attempt to relate SP phenomena to behavioral/
psychological processes. The location of SP phenom-
ena in the brain provides information about particular
nuclei and general systems involved in specific behav-
iors, while SP changes produced by anatomical and
neurochemical manipulations can reveal functional
pathways that couple nuclei. SP and unit recordings
may reveal excitatory and inhibitory patterns in
general intracerebral systems that mediate particular
behaviors. The delineation of ionic mechanisms in SP
genesis would provide additional detailed information
about brain-behavior relationships. With respect to
SPs, however, efforts to define systems are at a primi-
tive level. With few exceptions (Skinner, this volume),
SP measures are not currently being used as a tool to
delineate general cerebral systems related to the cued
RT task or conditioning paradigms or to specify
dynamic intracerebral interactions. In other contexts,
however, this kind of systems approach is making
significant strides (John et al. 1973).
It is worth reiterating that a given behavioral/
psychological state is a dynamic affair in terms of
configurations of brain states, and that the behavioral
significance of a given electrophysiological event such
as the CNV, no doubt, depends upon the simulta-
neous state of SPs (and other events) in many brain
regions. The dynamic and multivariate nature of brain
activity is, perhaps, related to the difficulty in pre-
dicting even simple behaviors from physiological
events like the CNV. Reaction time, for example,
correlates weakly with a wide variety of biological
indicators (heart rate deceleration, CNV amplitude,
alpha abundance, alpha phase, alpha asymmetry,
muscle tension). It would seem useful to apply multi-
variate techniques (cf. Donchin, this volume) to
determine what combination of biological indicators
-------
10
Rebert
taken together best accounts for RT variability. In
this case, SP responses recorded from an array of
intracerebral electrodes would contribute substan-
tially to our understanding of the general psycho-
physiological system that underlies reaction time
behavior.
Technical issues
Rowland raised the question whether MU re-
cordings are sensitive enough to reflect small unit
changes associated with SPs. This is important for
interpreting apparent dissociations between SP and
unit activity. He also raised the issue of SPs being
confounded with impedance shifts. Study of the rela-
tionship of this parameter to other electrical events
is badly needed.
Another question of interest is the adequacy of
sytemic administration of pharmacological agents in
the study of SPs. For example, if a shift is produced
or altered following a systemic dose of atropine to
block cholinergic synapses, what can be concluded?
The nucleus in which recordings are being made
might be reacting to a local change in adrenergjc
synapses consequent to cholinergic alteration of a
nucleus which sends efferents to the recorded area.
For example, cholinoceptive cells in pars compacta
of the substantia nigra project dopaminergic fibers
to the caudate nucleus. Systemic administration of
an anticholinergic agent could block the nigra and
indirectly cause a change in the caudate, a change
that would, in all likelihood, be erroneously attri-
buted to direct cholinergic mediation in the caudate.
Thus, the use of intracerebral perfusion of neuro-
chemicals (Myers 1974) in conjunction with electro-
physiological recordings is another valuable combina-
tion too little used in SP research.
The growth of glia around electrode tips seems
to impair the quality of dc recordings (Skinner,
personal communication), and electrode impedance
changes also appear to do odd things to Emde on-line
calibrators. In the absence of changes in event-related
potentials, on-line calibration signals have been ob-
served to either slowly appear or disappear over
several weeks of recording from a particular electrode
"in a particular monkey, while not changing in other
monkeys (Rebert, unpublished observations).
Ldbet expressed the need for improved intra-
cellular recording techniques that would permit rapid
impaling of cells combined with the capability to
hold the cell for long periods without significant leak-
age across the membrane. Without better techniques,
the critical questions of neuronal PSPs and excita-
bility in relation to various SPs and behavioral func-
tions will probably remain unresolved. A recent
development of a "sharpened" glass micropipette by
Brown and Flaming (1975) offers some hope along
this line. Chronic implantation of subdural and sub-
cortical nonpolarizing dc recording electrodes, which
are not toxic to neural and glial tissues, is also neces-
sary for the longitudinal study of behavior in relation
to SPs. Rowland (1961) and Rebert and Irwin (1973)
have described the construction of nonpolarizing elec-
trodes suitable for this purpose.
Libet expressed the need for geometric models of
different types of neural and glial configurations from
which slow potential parameters can be predicted.
Volume conduction models have been proposed for
auditory (Vaughan and Ritter 1970), visual (Vaughan
1974), and somatosensory EP components (Goff et
al., this volume). Models relating field potentials to
neural architecture have been worked out in greater
detail for the olfactory bulb (Rail and Shepherd
1968; Freeman 1975,1976).
Conclusions
This summary has only partially addressed the
goals set forth in the introduction. The ultimate
objectives of this area of research have not been
clearly defined nor have the practical applications
been adequately examined, although there are cer-
tainly pursuits in the applied direction, e.g., studies
related to epileptogenic mechanisms (Prince et al.
1973). A pertinent question here is the extent to
which obtaining "molecular" information about SPs—
especially the CNV, which may have diagnostic uses-
increases the power of their medical application.
Would the CNV be more useful if its exact electro-
genesis and pharmacological genesis were known? Per-
haps, then, abnormalities in various CNV parameters
would indicate specific intracerebral abnormalities. In
this same vein, changes in the dynamic intracerebral
patterns of SP responses might be sensitive indicators
of brain alteration by low levels of environmental
toxicants; and, if so, knowing the mechanisms of SP
genesis might help to pinpoint the mechanisms of
action of toxic agents. An exciting possibility for
future application is presented by Stamm et al. (this
volume), who suggest that biofeedback procedures
that alter frontal SP levels influence the rate at which
learning occurs. Some critical issues have been delin-
eated in this summary and several points of direct
experimental attack have been suggested. A summary
of the general state of knowledge concerning SP
genesis has been provided, and an indication of trends
in research has been included implicitly.
It is apparent that the electrophrenerrian ap-
proach to the study of SP and behavioral relation-
ships is inadequate. Elaboration of SP electrogenesis
is necessary and demands interdisciplinary coopera-
tion as much as any other specialized area in neuro-
science. Because SPs are sensitive indicators of
-------
Summary of Electrogenesis Issues
11
endogenous and exogenous influences on the brain,
the experimental psychologist in league with the
electrophysiologist possesses a powerful tool for
studying brain-behavior relationships. Such studies
have ranged from the evaluation of memory in ro-
dents (Rebert et al. 1974) to assessment of cognitive
divisions of the human mind (McAdam and Whitaker
1971). At the molecular level, an understanding of
SP electrogenesis requires evaluation by the physio-
logist, neurochemist, and neuroanatomist of neural
spiking patterns, synaptic transmitters, modulators,
mediators and moderators, glial functions, ionic
mechanisms, blood flow, energy metabolism, and
macro- and microanatomy. Because of the variety,
ubiquity and involvement of slow potentials in so
many cerebral processes, the interdisciplinary study
of SPs should greatly enhance the understanding of
brain function in general. An outstanding question is
whether SPs are mere signs of neurophyriological
activity or whether they have a direct role in neural
function per se. Some evidence suggests that the
latter is true (Schmitt et al. 1976). If so, the study of
SPs may contribute to our understanding of synthetic
and integrative properties of the brain not easily
accounted for in terms of digital information trans-
mission systems. It is known that graded potentials at
the neuronal level act to integrate converging inputs
and provide a decision point in information flow.
Might similar functions be attributed to SP events
occurring at widespread points in the brain? The
detailed explication of SP genesis will hopefully
provide an answer to this intriguing question.
Has SP research contributed to the development
of any general principles of brain function? The final
section of this volume provides an impressive af-
firmative in the theories proposed by Cooper et al,
Marczynski, Papakostopoulos, and Skinner. These
general models are complemented by molecular
models at the level of cellular membranes and ionic
mechanisms proposed by Somjen and Libet (this sec-
tion). These heuristic contributions are not surprising
in view of the integrative nature of SP research. Slow
potential phenomena thus appear to provide an in-
creasingly important bridge between the mind and
matter of the human brain.
-------
SLOW POSTSYNAPTIC RESPONSES OF SYMPATHETIC
GANGLION CELLS AS MODELS FOR SLOW POTENTIAL
CHANGES IN THE BRAIN
B. LIBET
University of California School of Medicine, San Francisco, CA, U.S.A.
When Gerard and I initially explored the existence
and significance of slow potentials (SPs) in the brain,
we utilized the relatively simpler system available
in the isolated cerebrum of the frog (Gerard and
Libet 1940, Ubet and Gerard 1941). The absence of
vascular circulation eliminated any possible blood-
brain SPs, and the thin-walled outer pallium of the
cerebrum made it feasible to record and apply SPs
across a layer of similarly oriented cerebral neurons.
These studies led us to suggest that SPs were gen-
erated as gradients along the dendroaxonal axes
of neurons and that substantial extracellular fields
of current could be developed when this occurred in
masses of similarly oriented neurons. In spite of
many developments since that time, questions about
the precise cellular origins and electrogenic processes
for SPs are obviously still open ones.
In the late 1950's, my interest was aroused in the
potentialities of an even simpler system as a model
for SP mechanisms. Findings of slow potential
responses to orthodromic inputs were being reported
for isolated sympathetic ganglia (see Libet 1970).
These structures have no complicating interneuronal
networks (although the existence of one type of
intemeuron has now been established); they are
quiescent except when activated by neuronal or
chemical inputs; composition of external medium
is easily manipulated; and the postsynaptic responses
of the principal neurons or "ganglion cells" them-
selves can be readily studied. We have been able to
establish that the ganglion cells can exhibit, in addi-
tion to the well-known excitatory postsynaptic
potential (EPSP), a slow inhibitory postsynaptic
potential (ffSP) and an even slower EPSP (Libet
1970). The unique features of these slow post-
synaptic potentials (PSPs) and of an additional
enduring modulatory action (Libet and Tosaka 1970)
will now be listed, with a brief reference in each case
to potential significance for SPs and for other slow
functions of the brain,
Neuronal origin
Slow ganglionic potentials can be recorded with
surface electrodes in response to brief trains of
orthodromic, preganglionic volleys. These can be
shown to be independent of the true afterpotentials
that follow cell-firing by their appearance in the
partially curarized ganglion (Fig. 1). In the latter
the (fast) EPSPs are depressed to below firing level;
superimposed upon and following each train of
EPSPs is a surface-positive (hyperpolarizing) and a
later surface-negative (depolarizing) slow potential.
These slow potentials are also demonstrable by
direct intracellular recordings in almost all cells
proven to be principal neurons (i.e., ganglion cells,
Fig. 2). The slow hyperpolarizing and depolarizing
postsynaptic potentials (Fig. 2 II) are properly to be
regarded as a s-IPSP and s-EPSP, respectively: they
are obviously neuronal, not glial, in origin; they can
be elicited independently, in the absence of any
EPSPs (Fig. 2 II, tracings E.F); they are selectively
blocked not by curare but by atropine (Fig. 2 II,
tracings B-D) and, in the case of the s-IPSP, by an
oadrenerglc antagonist; and they appropriately alter
neuronal excitability (Libet 1964i Dunant and
Dolivo 1967, Brimble and Wallis 1974). It is clear
that true postsynaptic potentials with the slow timing
features described below can be generated by a syn-
aptic action at the single-cell level; the corollary is
that an extracellularly recorded SP of neurons! origin
need not be an envelope of a series of faster indiv-
idual cell responses.
Repetitive input
Although a single orthodromic volley can elicit a
relatively small s-IPSP and s-EPSP, the amplitudes
and durations of these responses can be built up
greatly by a repetition of 5 or 10 volleys (Fig. 1 and
2 IQ. Optimal repetitive frequency is about 10 to 20
per sec for the s-EPSP and about 40 per sec for the
-------
Slow PSPs as Basis for Recorded SPs
13
Fig. L Surface recordings of responses of isolated superior cervical ganglion (rabbit) to stimulation ofpregang-
lionic (cervical sympathetic) nerve. Upper section, I, taken before, and lower section, II at higher gain, after
partial curarization. Responses are to a single volley (A,E), or to a train at the pulse frequency Indicated and
recorded at the slower sweep speed of I sec per dlv, (For the upper horizontal row in each section, stimulus inten-
sity is below threshold for preganglionic C fibers; for lower rows, stimuli are supramaxtmal for both B and C fiber
inputs.) Note the following points: (1) The compound action potential, and its surface-positive afterpotential,
are absent in the curarized state; single responses in the latter consist of the (fast) EPSP (section II, A and E),
and repetition at 40/sec produces a sustained EPSP with almost no spike components (J). (2) In spite of the ab-
sence of cell firing and of any true afterpotentials, the train responses of the curarized ganglion exhibit a slow
surface-positive (hyperpolarizing) and an even slower surface-negative (depolarizing) component, superimposed
on and outlasting the summated EPSPs produced during the stimulus train. These are the s-IPSP and s-EPSP,
respectively, (3) Evidence of the slow depolarizing component is visible as a negative hump in the form of the
posttetantc afterpotential of the firing, uncurarized ganglion. This hump can be selectively eliminated by atro-
pine (see Libel 1964), with the positive after-potential then showing a long, exponential decay. (From Eccles
and Libet 1961.)
s-IPSP, but increases are substantial even with 2-per.
sec trains. This large effect of repetition appears
to be a postsynaptic function, not a presynaptic one
as in classical posttetanic potention (FTP): (1) It
occurs without a parallel effect on the EPSP response.
(2) The effective repetition interval is much longer
than for presynaptic FTP. (3) Effective train dura-
tions are much shorter than for presynaptic FTP. The
slow PSPs thus can exhibit considerable temporal
facilitation with physiologically reasonable inputs,
both as to frequency and duration of the arriving
group of impulses.
Durations
The slow PSPs have durations from a few seconds
after a single preganglionic volley to 10 to 30 sec
following a brief train of S to 20 preganglionic volleys
(at 2 to 40/sec). It should be reemphasized that these
prolonged PSPs cannot be assigned to any sustained
presynaptic delivery of acetylcholine (ACh); the
fast EPSP, which is also cholinergic, shows a relative-
ly sharp termination after the end of each brief pre-
ganglionic train. The long period of heightened
excitability that accompanies the s-EPSP provides
a form of postsynaptic PTP, which can summate
with a heterosynaptic input (Libet 1964). This
feature is far more significant for brain function than
that of classical presynaptic PTP, which is only
effective homosynaptically (i.e., when test volleys
are delivered via the same fiber inputs that carried
the train of conditioning volleys). There has been a
tendency to regard as "modulatory" all synaptic
changes that are slower than the classic PSPs. It
would be better, however, to expand the view of
possible types of excitatory and inhibitory synaptic
actions so as not to exclude responses like the s-IPSP
and s-EPSP simply on the basis of slower temporal
properties or different electrogenic mechanisms. The
term "modulatory" should be reserved for cases
in which a transmitter alters the reactivity in a syn-
aptic pathway by actions that go beyond the changes
in cell excitability associated with its own PSP
(see discussion under "Dopamine modulation..."
below), and for the additional cases in which a
-------
Libet
II. A
50 msec
0.2 sec
Fig. 2. Intracellular recordings from a principal neuron (ganglion cell) in rabbit SCO. Upper section, I: Res-
ponses of normal, uncurarized cell; successive fast EPSPs appear as the stimulus strength applied to the pre-
ganglionic nerve is raised, until the EPSPs reach firing level for both the earlier arriving B fiber input (D) and the
later arriving C fibers (E). Lower section, II: Responses ofcurarized cells. In bottom row, note the single EPSP
in G, with its small s-IPSP component building up with repetition in H and (at slower sweep in another cell) in
I. Upper two rows at slow sweep (see 1-sec bar). Top row responses (A,B,E) are to 10/sec, 1-sec trains and
second row (C,D,F) to 40/sec, 1-sec trains. In A and C, note the small fast EPSPs (mostly blocked by curare and
having a spike-like appearance at this slow sweep), with the s-IPSP and s-EPSP superimposed and following
these. In B and D, both slow PSPs have been eliminated by addition ofatropine (0.3 Hg/ml), leaving behind the
fast EPSPs alone. In E and F, another cell, curarization is strong enough to block the fast EPSPs completely,
but the cell still exhibits s-IPSP and s-EPSP responses. In both portions of figure note that the slow potentials
are recorded in typical neurons that also exhibit fast EPSPs and firing, but that the slow PSPs are also producible
independently of fast EPSPs and of firing. (From Libet and Tosaka 1969.)
"neurohormone" is delivered to the affected neuron
via the blood stream rather than by presynaptic
terminals in its vicinity.
Long synaptic delays
The slow PSPs have extraordinarily long synaptic
delays, in marked contrast to all the known delays
for all fast PSPs, which are on the order of 1 msec
or less (Eccles 1964). In mammalian ganglia, the
delay for the s-IPSP is about 25 msec (80 to 100 msec
in amphibian ganglia), and for the s-EPSP, it is in the
range of 200 to 300 msec (Libet 1967, 1970); an
example of the latter is seen in Fig. 3.
It should be emphasized that these are delays
between the arrival of the impulse in the preganglion-
ic fiber terminals and the onset of the PSPs them-
selves; they are not delays in cell discharge. Further-
more, the delays are for PSPs mediated by only one
(s-EPSP) or at most two (s-IPSP) synaptic steps in the
ganglion; they are not due to the addition of many
short delays in an interneuronal chain. Such delays
and durations of response could easily accommodate
the possibility that slow event-related potentials
(ERPs) in the brain, like the P300 wave or the contin-
gent negative variation (CNV), are developed by a
single class of neurons activated monosynaptically.
It should also be obvious that the traditional method
for estimating the number of successive interneurons
in a pathway-dividing the net central delay by
about 0.5 to 1 msec for the assumed delay at each
junction - could be invalid by a factor of two orders
of magnitude!
-------
Slow PSPs as basis for recorded SPs
I
A
15
II atropine
20msec
4-f-
100msec
4H-
i
200 msec
+H-
1.0 sec
Fig. 3. Synaptic delays for (fast) EPSP vs. s-EPSP. Surface-recorded responses of curarized celiac ganglion of
cat, column I before and column II after adding atropine (0,1 Hg/™l), A-D show ganglionic responses to single
preganglionic volleys at progressively slower sweep speeds. (E, at 50 msec per div, shows a brief train of res-
ponses, with only a small population action potential appearing on some.) Note that the onset of the s-EPSP
is delayed until about 300 msec after the onset of the (fast) EPSP, as indicated by the arrows.The initial 5- to 6-
msec latency before onset of the (fast) EPSP (see A) already includes conduction time into the presynaptic
terminals of the preganglionic fibers here. Therefore, the extra 300-msec latency for the s-EPSP represents
additional actual synoptic delay. (The relatively small amplitude of s-EPSP is due to use of a single volley rather
than a train; but its reality is indicated by its selective elimination with atropine.) (From Libel 1967.)
Electrogenesis with no increases in membrane
conductances
The slow PSPs do not depend on increases in mem-
brane conductance for their electrogenesis, unlike
all of the well-known (fast) IPSPs and EPSPs (Kobay-
ashi and Libet 1968, 1974). In addition, changes
produced by polarizing the resting membrane poten-
tial are not those expected on any ionic permeability
hypothesis. Both the s-IPSP and s-EPSP responses
are enlarged by increasing the resting membrane
potential in the range of from -50 mV to about
-65 or -70 mV and are rapidly decreased (but not
reversed) by further hyperpolarization (Fig. 4);
both are reduced rapidly by depolarizing to levels
less than -50 mV, but this may be partly an indirect
effect of a reduced membrane resistance associated
with "delayed rectification." The actual electro-
genie mechanisms for the slow PSPs are yet to be
determined. They could involve activation of various
ion pumps that may be electrogenic, although the
specific case of the ouabain-sensitive Na+-K+pump
appears to be excluded (Kobayashi and Libet 1968,
1970; Libet 1970; Libet et al. 1977). It has been pro-
posed that the s-EPSP may result from a decrease or
"inactivation" in the resting membrane conductance
for K+, GK+ (Weight and Votava 1970 for sympa-
thetic ganglia, Krnjevic et al. 1971 for cerebral cor-
tex, also see Krnjevic 1974), as opposed to the increa-
ses in ionic conductances for the fast PSPs. However,
a careful evaluation of all the evidence disproves the
validity of this proposal, at least for s-EPSPs in sym-
pathetic ganglia (Kobayashi and Libet 1974, Libet
and Kobayashi 1974).
The hypothesis that inactivation of GK+ provides
the electrogenic mechanism for the s-EPSP was
initially based on findings of (1) an increase in mem-
brane resistance (rm) accompanying the s-EPSP in
frog ganglion cells, and (2) a kind of reversal of the
polarity of the s-EPSP when these same cells were
hyperpolarized by passing steady currents across
the membrane (Kobayashi and Ubet 1968, 1970).
But these characteristics are relatively restricted
to the case of frog ganglion cells to which nicotine
-------
16
Libet
20 mV DP
0.5 sec
Fig. 4. Effects of polarizing currents on slow PSPs.
Intracellular recordings of ganglion cell In rabbit
superior cervical, partially curartzed; each tracing is
response to 0.25-sec train of supramaxlmal pregang-
llonic volleys at 40/sec. Top tracing, response during
continuous outward current, with resting membrane
potential depolarized by 20 mV; second tracing,
with no polarizing current (resting potential of this
impaled cell = -4SmV); third tracing, during passage
of inward current that hyperpolarized by 15 mV
(i.e., present membrane potential kept at -60 m V);
bottom tracing, during hyperpolarlzatlon of 30 mV
(membrane potential at -75 mV). Note: (1) The
summated EPSPs produced during each train In-
crease progressively as the transmembrane poten-
tial is increased, as expected. (2) The s-IPSP and
s-EPSP responses both Increased with moderate
increases in membrane potential, but both decreased
with hyperpolarizing levels greater than the pre-
sumed normal or physiological resting potential
of -60 to -70 mV. (From Kobayashi and Libet
1968.)
has been applied (for the purpose of blocking the
fast EPSP responses). In curarized frog cells, there is
either a small or no change in rm during the s-EPSP
(Kobayashi and Libet 1970); hyperpolarizing these
cells produces no reversal of s-EPSP at all, but rather
an enhancement of its late phase (Kobayashi and
Libet 1974). Curarized mammalian ganglion cells
show no detectable changes in rm with the s-EPSP,
and moderate hyperpolarization produces an in-
crease, rather than the predicted decrease, in the
amplitude of the s-EPSP (Kobayashi and Libet 1968;
see Fig. 4). Even in the nicotinized frog cells, an
increase in rm with s-EPSP is found only when
the cell membrane is depolarized. At normal or
hyperpolarized levels, no change in rm accompanied
the s-EPSP response (Nishi et al. 1969). Additionally,
the apparent "reversal" of polarity of the s-EPSP
when nicotinized frog cells are hyperpolarized is not
a true reversal; only a brief initial portion of the re-
sponse reverses polarity, and the latency of this
. portion is distinctly shorter than that of the normal
s-EPSP (Kobayashi and Libet 1970, 1974). Finally,
the s-EPSP of nicotinized frog cells does not behave
appropriately in relation to EK+ (equilibrium poten-
tial for K+); the apparent "reversal" of initial phase
of s-EPSP has been found to occur at membrane
potentials different from EK+ (Kobayashi and Libet
1974), and the s-EPSP is relatively insensitive to
the removal of K+ from the external medium (Kobay-
ashi and Libet 1968, Nishi et al. 1969).
A related proposal for generation of the s-IPSP
involves an inactivation of resting conductance
for Na+, GNa+ (Weight and Padjen 1973a). But
the evidence for this hypothesis is all based on
studies of nicotinized ganglion cells of frog, in which
ACh is able to elicit a hyperpolarizing response by
a direct postsynaptic action on ganglion cells
(Weight and Padjen 1973b, Libet and Kobayashi
1974); this form of "s-IPSP" appears to be an ab-
normal component of the response, made possible by
an interesting pharmacological interaction between
side-effects of nicotine and ACh (Libet and Kobaya-
shi 1974). In frog or rabbit cells treated with a
"cleaner," a competitive nicotinic blocker like
curare, the direct transmitter for the s-IPSP is a
catecholamine (Libet and Kobayashi 1974); the
latter must be released by an indirect action of ACh
on an interneuron (Libet 1970, Libet and Kobaya-
shi 1974). The physiological s-IPSP mediated by
a catecholamine is obviously a different type of
response from the ACh-hyperpolarization elicited
in nicotinized frog ganglia. The characteristics
of this response (Kobayashi and Libet 1968, 1970)
and of non-nicotinized cells do not fit with the
requirements of the GNB+ inactivation hypothesis
(Libet and Kobayashi 1974).
Whether an inactivation (decrease) of resting
ionic conductances underlies those slow postsynaptic
responses found in the central nervous system re-
mains to be seen. Pyramidal cells in neocortex exhi-
bit a slow muscarinic depolarizing response to ACh
applied iontophoretically (Krnjevic and Schwartz
1967, Krnjevic 1974). This response strongly resem-
bles the s-EPSP of mammalian sympathetic ganglion
cells (see Marczynski, this section), except for a
reported increase in rm (Krnjevic et al. 1971). Slow
hyperpolarizing responses to norepinephrine have
been described for spinal motoneurons (Engberg
and Marshall 1973) and for cerebellar Purkinje cells
(Siggins et al. 1971). These hyperpolarizing responses
resemble in important ways the s-IPSP of sympa-
thetic ganglion cells, except for reported increases
-------
Slow PSPs as basis for recorded SPs
17
in rm. It is not clear at present whether electro-
genie mechanisms for slow PSPs in the central ner-
vous system are actually different from those in
sympathetic ganglia, or whether the experimental
conditions in central nervous system studies have
introduced additional characteristics that may have
a more pharmacological than physiological signifi-
cance. For example, it is generally recognized that
in tests with iontophoretic application of chemical
agents the local concentrations are unknown and
may be higher than those available in physiological
inputs. Also, the exogenously applied agent can
reach and act on sites other than those involved
in normal local synaptic transmission; such sites may
be nonsynaptic receptor sites on the same cell, with
different response properties from the postsynaptic
receptors, or sites on other types of adjacent cells
which indirectly affect the function of the cell
under study. One example of the latter is the pro-
duction of presynaptic blockade by exogenously
applied catecholamines; this could depress ongoing
background excitatory inputs into a cell and thus
indirectly result in a hyperpolarizing shift and a
rise in r back to nonexcited levels (e.g., Jordan
1973).
In any case, it is generally agreed that there are
at least no increases in ionic conductances (i.e.,
no decreases in rm) in all the slow responses studied,
and even this presents some unique implications
for slow functions in the brain. It means that long-
lasting active PSPs could be generated without the
increased ionic leakages and possible alterations
in cell concentration gradients that characterize the
"fast" PSPs:
1. The cellular energy costs for slow potentials are
thus greatly reduced.
2. Possible effects of otherwise altered extra-and
intracellular changes in ionic concentrations
are eliminated; for example, the rise in extracel-
lular K+ concentration that is an expected
feature of sustained fast EPSPs would not be
produced during slow PSPs.
3. The "anomalous" ways in which slow PSPs
are altered by the passage of polarizing cur-
rents could result in effects of the latter on
slow potentials of brain that are different from
the effects predicted with electrogenic mech-
anlsms based on changes in ionic permeability.
4. Additionally, the i-EPSP mechanism it selec-
tively and relatively rapidly depressed by de-
preisanti of oxidative metabolism, such as
dinltrophenol, sodium azide, cyanide, or simple
anoxia (Kobayashi and Ubet 1968).
This sensitivity of the s-EPSP to loss of oxidative
energy supply, and its synaptic delay of 200 msec
or more, point to the probable involvement of a
sequence of chemical reactions in its electrogenesis.
There is already evidence that the synthesis of cyclic
GMP (guanosine 3 ' 5 -monophosphate) is an early
step in this mechanism (McAfee and Greengard 1972,
Kebabian et al. 1975), but the succeeding reactions
are yet to be unravelled (Ubet et al. 1975). The
special sensitivity of the s-EPSP to anoxia is remi-
niscent of a similar one for many cerebral processes,
and is in contrast to the relative insensitivity of the
fast PSPs in both ganglia and brain.
Transmitters mediating the slow PSPs
The intraganglionic pathways and transmitters for
fast and slow PSPs are schematized in Fig. 5.
CURARE BLOCK
Fig. 5. Schema for synaptic mediation of fast EPSP,
s-IPSP, and s-EPSP, Note; (1) The two types of
postsynaptic receptors for ACh, ntcotintc and mus-
cartnic, on the same ganglion cell. (2) The small
monoamtnergtc tnterneuron (SIF or granule-contain-
ing cell), which "converts" ACh input into a dopa-
mine (DA) transmitter here. (3) The two actions of
DA on the ganglion cell; these are represented in two
types of receptors here, a concept supported by more
rectnt evidence. (From Ltbet 1976.)
Muscartnic transmitter action for s-EPSP
The s-EPSP is elicited by a direct (monosynaptic)
action of preganglionically released ACh on postsyn-
aptic muscarinic receptor sites (Eccles and Libet
1961, Libet 1970). Deeper lying neocortical pyrami-
dal cells have been found to exhibit a slow muscarinic
depolarizing response to ACh, which has important
similarities to the s-EPSP in ganglia. Indeed, most of
-------
18
Libet
the receptor sites involved in responses of cerebral
neurons to ACh are also of the muscarinic type, and
atropinic agents are potent modifiers of various brain
functions. Evidence for participation of such respon-
ses in certain SPs and brain functions is summarized
elsewhere in this symposium (Marczynski).
Adrenergic transmitter action for s-IPSP
The s-IPSP is elicited in ganglion cells by a direct
action of dopamine, although exogenous norepine-
phrine can produce a similar response (Libet 1970,
Libet and Tosaka 1970, Libet and Owman 1974).
Dopamine is released by a special class of inter-
neurons, now recognized as the small, intensely
fluorescent (SIF) cells or, in electronmicroscope
studies, as the small granule-containing cells. The
SIF cells are activated by a muscarinic action of
preganglionically released ACh (Eccles and Libet
1961, Libet 1970, Libet and Owman 1974). In
the brain, it has been found that the norepinephrine
transmitter delivered by fibers arising in the locus
coeruleus can elicit a slow hyperpolarizing response
in cerebellar Purkinje cells (Hoffer et al. 1972) and
in hippocampal pyramidal cells; this response has
important similarities to the s-IPSP of sympathetic
ganglia. The cellular nature of the responses to
various monamines elsewhere in the brain are yet
to be worked out.
Dopamine modulation of the s-EPSP response
to ACh
In addition to its role as an inhibitory transmitter
in ganglia, dopamine was found to induce another
neuronal change, which could persist for hours.
This change is manifested in an enhancement of the
response to ACh, but it is selective for the slow
muscarinic or s-EPSP type of response (Libet and
Tosaka 1970). This novel type of synaptic action,
in which one transmitter alters the postsynapiic
response to another, has now been shown to pos-
sess features of a memory process at the neuronal
level (Libet et al. 1975). At least one cerebral exam-
ple of such a modulatory action has already been re-
ported (Yamamoto 1973). Also, a morphological
substrate for monoaminergic actions, in the form of
widespread cerebral distributions of various mono-
aminergic fibers that arise in certain brain stem
nuclei, has more recently been provided. These
nuclei have already been implicated in the control
of sleep and waking states (Jouvet 1973), and the
self-stimulation or "reward" mechanism of Olds
(German and Bowden 1974). The notion has been
gaining ground that these systems may in part func-
tion to change, in various ways, the reactive levels
of cerebral neurons to other synaptic inputs (e.g.,
Jasper 1975, Reader et al. 1976). In the case of
those ERP components or SPs in the brain that
may be similar to the cholinergic, muscarinically
mediated s-EPSP of ganglion cells, the possibility
arises that monoamine inputs might produce long-
lasting alterations in the amplitudes and durations
of such ERPs produced at selective sites. Such modu-
latory changes by monoamine inputs could con-
ceivably account for certain ERP changes which
accompany psychological processes discussed else-
where in this volume.
Acknowledgment
I dedicated this paper to Ralph Waldo Gerard, whose
scientific imagination helped to pioneer the field of
slow potentials in the central nervous system. The re-
search was supported by Public Health Service Re-
search Grant NB-00884 from the National Institute of
Neurological and Communicative Disorders and Stroke.
-------
CONTRIBUTION OF NEUROGLIA TO EXTRACELLULAR
SUSTAINED POTENTIAL SHIFTS1
G. G. SOMJEN
Department of Physiology, Duke University Medical Center, Durham, NC, U.S.A.
Evidence for neuroglia acting as a generator of
extracellular current
That sustained shifts of extracellular potential
associated with protracted neural activity are, under
certain definable experimental conditions generated,
in part or entirely, by glial elements is indicated by
two sets of observations. First, the time course of
membrane potential changes- of glia cells observed
during neural activity is comparable to sustained
shifts of extracellular potential. Second, extracellular
potential shifts are altered by experimental manipula-
tion in ways more similar to concomitant alterations
of glial responses than to those of neurons.
In mammalian brains, membrane potential re-
sponses related to neural activity, but recorded from
cells originally designated as "idle" or "unresponsive"
and subsequently identified as glia, were first re-
ported from the laboratory of Goldring (Sugaya et al.
1964; Karahashi and Goldring 1966; Castellucci and
Goldring 1970; Ransom and Goldring 1973a, b, c).
Kuffler and collaborators also described the prop-
erties and responses of neuroglia in leech and mud-
puppy nervous systems (Kuffler and Potter 1964,
Kuffler et al. 1966, Orkand et al. 1966).
The classical work of Kuffler's group has pro-
vided a theoretical outline of the possible mechanism
of glial current generation. These investigators found
that the membrane potential of glia cells conforms to
the Nernst equation for potassium much more closely
than that of neurons. In other words, the degree to
which glial membranes favor permeation by potas-
sium over other ions is significantly greater than the
similar but lesser preference of neuronal membranes.
Potential responses were observed in glia cells of the
amphibian optic nerve, and it was suggested that they
are related to presumed increments of extracellular
potassium consequent to neural impulse activity. An
electrotonic coupling between glia cells was, further-
more, demonstrated. The presence of low-resistance
intercellular junctions was seen to provide the condi-
tion of glial contribution to electrical activity of
tissue, for glia cells depolarized by external potassium
could, through such junctions, draw current from
distant, non-depolarized glia cells. The electric circuit
would then be completed by return current flow
through the extracellular medium. The latter would
generate a voltage drop which could be registered by
external electrodes.
A highly simplified model describing the behav-
ior of such a quasi-syncytial electrotonic network has
been developed (Joyner and Somjen 1974; Sornjen
1973, 1974). The model is reproduced in Fig. 1 and
2. The elements of the model are: (1) a set of bat-
teries representing the EMF of depolarized glia cells;
(2) three sets of resistors simulating the conductances
of glial cell membranes, the intercellular electrotonic
junctions, and the extracellular medium; and (3) the
bulk resistance of the body interposed between nerv-
ous system and reference (or ground). Capacitive
components are ignored because the time course of
the potential changes to be mddeled is very long com-
pared to the (probable) time constant of the circuit.
The model demonstrates that the spatial profile of
extracellular potential shifts would accurately map
the spatial distribution of membrane responses (and,
hence, of potassium accumulation) provided that the
"space constant" of the network was small, i.e., mem-
brane resistances were low compared to other resis-
tive components. The profile of extracellular poten-
tial changes might extend beyond the spatial limit of
1 Since the adjective "slow" in electrophysiology can mean any event that lasts longer than 1 or 2 msec, it seems
desirable to distinguish potential shifts that ire maintained for seconds and/or rise and fall with half-times of 0.3
sec or more by another name. "Sustained potential" seems an accurate descriptive term. Processes that have an
hourly or daily rhythm should be given still other names, for they probably represent yet different classes of
events.
In cases where an electrical event has a known generator, that cellular element may justifiably be named,
Thus, evoked sustained potentials of the spinal gray matter appear to be the sum of two components, a smaller
abruptly rising neural potential (probably related to synaptic currents) and a larger, more slowly rising glial
potential.
-------
20
PASSIVE CELLS
•ACTIVE CELLS
Somjen
PASSIVE CELLS-)
VR?>,
RX|1 , VT
-'-S i VMSr-i"
B.
INTRACELLULAR
PLANE
ROUND
EXTRACELLULAR
PLANE
Fig, 1, Two models simulating electrotonic syncytia, A: Simulating a linear array of cells; B: A two-dimen-
sional layer of cells. The cytoplasm of cells is assumed to be isoelectric, represented by the potentials at the
points marked as Vj. Cells are assumed to be coupled by resistances, RX, and connected to their environment by
the membrane resistances RM- The potential immediately outside the cells is given by VE, and the environment
of one cell connected to that of another by the extracellular resistances Rg. The extracellular fluid of the nervous
system is grounded through the tissue resistances Rj\ Some cells are assumed to be depolarized; these are desig-
nated "active," and the EMF of the potential change is represented by batteries ^Ey. The resting potential of
cells is not represented, since it does not contribute to current flow. Also neglected is membrane capacitance
(see text). (After Joyner and Somjen, reproduced, by permission of the publisher, from Somjen 1973).
-------
Neuroglial Basis of SPs
A. VARYING MEMBRANE RESISTANCE
B. VARYING COUPLING RESISTANCE
21
INTRACEUULAR
,.—x a=Ru=io
,' \ *
EXTRACELLULAR
C. VARYING EXTRACELLULAR RESISTANCE
D. VARYING TISSUE TO GROUND RESISTANCE
a RT=0
Fig. 2. Computer solutions of the model network of Fig. 1A. Twenty-one "cells "are represented, the central
five of which are assumed to undergo depolarization. The voltage of the depolarizing effect is taken to be iden-
tical for all cases. The computer-generated profiles show intracellular and extracellular voltages referred to
"ground," as they would be measured in conventional microelectrode recordings. The change of transmembrane
potential would be given by the difference between intracellular and extracellular potentials shown. The absolute
membrane potential would be the resting transmembrane potential (neglected in the model), less the change of
transmembrane potential; i.e., the horizontal "zero" lines of the diagrams represent the "collapsed" resting
membrane potential. In real cells the intracellular potential profiles would lie in the negative domain, below the
zero line and below the extracellular potential profiles. Resistances that are not Indicated in inset legends were
assumed to be uniform within one set of computations. (After Joyner and Somjen, by permission of the pub-
lisher, from Somjen 1973,)
depolarizing EMF (the distribution of the "batteries"
in the model) if the space constant were taken to be
large (Fig. 2A). With the aid of the model, it also
becomes apparent that a relatively small positive
extracellular potential shift may or may not be de-
tectable at the (inactive) extracellular "source" of
current. It furthermore appears that the depolariza-
tion registered by an intracellular probe may fall
short of the value predicted by the Nernst equation,
even if the only charged particles admitted through
the membrane were potassium ions. An erroneously
low reading would always be expected if, as is some-
times done, intracellular potential responses were
referred to a distant reference (or to ground) so that
extracellular potential shifts were neglected (cf.
Somjen 1975, Lothman and Somjen 1975). True
attenuation of the transmembrane potential would
occur if a significant fraction of current flow would
spread well outside the activated region (note the
cases of high membrane resistance and low coupling
resistance in Fig. 2A and B).
The analysis of glisl function by Kuffler and
collaborators (Kuffler and Nicholls 1966) concerned
the nervous system of cold-blooded organisms. For
the mammalian central nervous system, experimental
evidence now available supports the glial theory as
follows:
1. The development of potassium-selective
microelectrodes enabled the measurement of activity
of this ion in central nervous tissue in situ. With these
devices, it was shown that potassium activity can
readily be induced to rise above resting levels signifi-
cantly and reproducibly. Such responses can be
evoked by electrical stimulation of tissue or afferent
-------
22
Somjen
paths leading to it (Vyskocil et al. 1972; Vyklicky
et al. 1975; Krnjevic and Morris 1972, 1974; Kriz
et al. 1974; Lux and Neher 1973; Somjen and
Lothman 1974; Lothman et al. 1975; Lothman and
Somjen 1975) and under more physiological condi-
tions, e.g., in the visual cortex by "adequate" optical
stimulation (Singer and Lux 1975). This response also
occurs spontaneously during "spindle" activity in
barbiturate anesthesia (Somjen et al. 1976).
2. A close correlation between depolarization of
glia cells and sustained shifts of potential in the extra-
cellular environment evoked by repetitive stimulation
of afferent nerves was demonstrated in the spinal
cord by Somjen (1970), Strittmatter and Somjen
(1973), and Lothman and Somjen (1975). No such
correlation exists for extracellular potential shifts
and neuronal membrane potential responses (Somjen
1969,1970).
3. Dependence of the membrane potential of
mammalian glia cells on extracellular potassium
activity was indicated by Pape and Katzman (1972)
and Ransom and Goldring (1973a), and conformity
of this relationship to the Nernst function by
Lothman and Somjen (1975) for the spinal cord
and by Pedley et al. (1976) in cortex.
4. The close correlation between transient ele-
vation of potassium activity and sustained shifts of
extracellular potential, evoked either by direct elec-
trical stimulation of cortex (Lothman et al. 1975), by
afferent nerve stimulation in gray (but not white)
matter of spinal cord (Somjen and Lothman 1974,
Lothman and Somjen 1975), or occurring spontane-
ously during seizure activity (Lothman and Somjen
1976) is also well documented.
The required electrical continuity of intracellular
conduction within glial tissue of mammalian gray
matter has not been demonstrated so far. Electro-
tonic junctions between glial cells have been shown
only in invertebrate and cold-blooded vertebrate nerv-
ous systems (Kuffler and Potter 1964, Kuffler et al.
1966b, Cohen 1970).Yet, even if mammalian glia cells
prove to be electrically insulated from each other,
they could contribute to extracellular current flow,
provided that the processes extend over sufficient
distances in sufficient profusion to provide for cyto-
plasmic continuity between excited and quiescent
regions. Miiller cells of the retina and Bergman fibers
of the cerebellar cortex fulfill this requirement. Only
three-dimensional reconstructions from serial electron
micrographs could determine the issue for other
regions (Katchalsky et al. 1974, Somjen 1975).
In the mammalian nervous system, glial responses
have been studied most intensively in the cerebral
neocortex and in the spinal cord. Although quali-
tatively similar, the two regions appear to differ in
the relative magnitude of response. In the spinal cord,
the amplitude of glial depolarization is approximately
twice the amplitude of the corresponding extracellu-
lar sustained potential shift. In the cortex, this ratio
is consistently greater. Furthermore, in the spinal
cord, smaller potassium transients appear to be asso-
ciated with relatively larger electrical events than in
cortex (reviewed in Somjen 1975). The close corres-
pondence of the spatial profile of potassium re-
sponses and of sustained potential shifts in spinal
cord (Lothman and Somjen 1975) indicates that the
"space constant" of the glial network (see Fig. 2) is
small (i.e., membrane resistance is low). The rela-
tively large extracellular potential shifts observed in
spinal gray matter suggest a higher tissue resistivity
(in relation to membrane resistance and cytoplasmic
coupling resistance) than that of cortical tissue.
Oxidative metabolic activity is another function
normally tied closely to pertubations in the distribu-
tion of ions. Oxidative metabolism can be monitored
by measuring the fluorescence of NADH in neocortex
(Rosenthal and Jobsis 1971, Rosenthal and Somjen
1973, Lothman et al. 1975) or in hippocampus
(Lewis and Semite 1975). The close coupling be-
tween | potassium| responses,! 8UStained |potential
shifts, and oxidative activity is broken during con-
vulsions, as though seizures placed a load on energy
metabolism in excess of the demand made on active
transport by extracellular potassium (Lothman et
al. 1975, Somjen et al. 1976). The relationship of
cellular oxidation and ion transport is illustrated
schematically in Fig. 3.
Significance of potassium and of extracellular
electric current flow for neural function
Even if neurons are less sensitive than glia cells
to small elevations of extracellular potassium, potas-
sium discharged by active cells should, theoretically,
influence the membrane potential of inactive neigh-
bors and synapses between them. Actual intracellular
recordings made from neurons in spinal cord suggest
an indifference to prevailing extracellular potential
(Somjen 1970) and potassium activity (Lothman and
Somjen 1975). Nerve cells appear to be controlled
by specific synaptic transmitters. Any superimposed
influence by changes of potassium activity appears
to be negligible or undetectable in electrical re-
cordings. Transient responses of extracellular potas-
sium and extracellular electric current flow appear
also to be of little significance in the generation of
primary afferent depolarization and the attendant
dorsal root potentials evoked by afferent nerve stimu-
lation (Somjen 1970, 1973, 1974; Somjen and Loth-
man 1974, Lothman and Somjen 1975).
-------
Neuroglial Basis of SPs
Fig. 3. Schematic representation of the relationship
of perturbations of Ion distribution and metabolic
activity in central nervous tissue. Neurons lose
potassium (and gain sodium) when firing action
potentials and also during certain types of synoptic
activity. All lost potassium must eventually be
retrieved by neurons. Part of it may be recaptured
immediately by active transport ("pump") through
the neuronal cell membrane, but part may be tem-
porarily dissipated by diffusion through extracellular
space from high to low activity, and by uptake into
glta. Active transport is fueled by Na+-K+ dependent
membrane-bound ATPase. The A DP generated in the
process enters mitochondria and activates the oxida-
tion of NADH to NAD. NADH*, being fluorescent,
is accessible to optical monitoring. Events in the
intramitochondrial enzyme chain lead to rephospho-
rylation of ADP to ATP, at the expense of oxygen
and substrate utilization. Neuroglial membranes are
also known to contain ATPase. Glia cells, like
neurons, are exposed to the excess potassium accumu-
lated In extracellular space but, unlike neurons, do
not gain sodium in the course of activity. Whether or
not glial ATPase is significantly stimulated by extra-
cellular K+ is not known at this time. Potassium dis-
persed either by way of the glial syncytium or by
diffusion through extracellular space must eventually
return by a reversal of the process. Note that extra-
cellular space in central gray matter (unlike in dia-
gram) occupies only about 15% of the tissue volume.
(Reproduced by permission from Somjen et al.
1976.)
During seizure activity, the distribution of potas-
sium responses within the spinal cord shifts dramat-
23
ically. Cells and fibers in ventral grey matter are
exposed to potassium levels greatly in excess of that
seen under normal conditions. These paroxysmal ele-
vations of potassium may well be the agent respon-
sible for paroxysmal dorsal root potentials which
behave differently from dorsal root potentials evoked
by afferent stimulation in normal spinal cords
(Lothman and Somjen 1976).
The possibility that extracellular current gen-
erated by neurons may influence other neurons in the
vicinity was much discussed a few decades ago (Libet
and Gerard 1941; Terzuolo and Bullock 1956) and
has not been resolved. The interactions of glia, neu-
rons and IK+Io in physiological and pathological
conditions are the subject of two forthcoming publi-
cations (Varon and Somjen, in press; Somjen,in press).
Validity of the glial model for the contingent
negative variation and other event-related
potentials
Potassium-induced depolarization of neuroglia is
a candidate for supplying currents for potential de-
flections which can be measured only in seconds
rather than milliseconds (half rise times and half de-
cay times of 0.3 sec or more). Even for these it is not
a unique source, for we have recorded small negative
potential shifts in white matter and in dorsal roots of
the spinal cord that were not associated with elevated
potassium activity and were, nevertheless, sustained
for seconds. Such non-potassium related potentials
were small with sudden onset and decay compared to
those related to potassium and glial depolarization.
Although not the only possible source of sus-
tained extracellular current, neuroglia deserves special
attention for two reasons: (1) glial theory has with-
stood rigorous experimental testing, albeit under
limited and physiological conditions; (2) its role
could be tested again, under more life-like circum-
stances.
In principle, the experimental testing of glial
theory is simple. To validate glial theory, it is neces-
sary to show that elevation of potassium activity and
shift of potential are closely and reproducibly corre-
lated. Construction of a potassium-sensitive electrode
that can be used under conditions in which CNV can
be induced will be difficult, but certainly possible.
It will probably prove easier to record potassium
activity in a CNV-eliciting situation than to record
the intracellular potential of glia cells.
Source of extracellular potassium
The source of excess potassium to which the
membrane potential of neuroglia responds is neu-
ronal. The question is, what kind of neural activity
-------
24
is most likely to add potassium ions to extracellular
fluid (ECF) at a rate that exceeds their clearance.
If the glial theory of SP generation proves generally
valid and if we can exactly define the conditions
of potassium accumulation in ECF, we then shall
understand the significance of SP shifts. While the
relative contribution of possible sources has not yet
been assayed, clues can be derived from the following
three observations (Lothman and Somjen 1975):
(1) No rise of potassium activity could be detected in
dorsal white matter of the spinal cord near the entry
zone of an excited dorsal root unless stimulation was
intense enough to activate C-fibers; (2) potassium
activity did not detectably increase in the ventral
horn of the spinal cord when the ventral root was
antidromically stimulated; (3) by contrast, sizable
potassium responses (and sustained potential shifts)
were readily evoked in substantia gelatinosa of the
spinal cord, a region where spike potentials are rarely
recorded. Neurons, though abundant, are rarely
entered (by intracellular microelectrodes), while
"unresponsive" (presumed glia) cells are quite fre-
quently entered.
From these observations, one suspects that
impulses carried in myelinated axons and the action
potentials of the somata of large neurons contribute
relatively little potassium to extracellular fluid.
Hence, one must seek the source either in synaptic
currents generated by dendritic trees, in the activity
Somjen
of unmyelinated fibers and axonal arborizations, or
else in small neurons, the impulses of which are hard
to detect and difficult to penetrate with micro-
electrodes (see also discussion in Varon and Somjen,
in press). Furthermore, the possible contribution of
non-spiking neurons cannot be discounted (Rowland,
this section). Electrical activity of non-spiking neu-
rons would, theoretically, be distinguishable from
that of glia cells, for synaptic potentials and synaptic
noise bear readily recognizable features (Somjen
1973, 1975).
The theory of glial generation is compatible with
the theory of cholinergic mediation of event-related
sustained potentials (Marczinsky, this section). In
normal cortex under physiologic conditions, it is con-
ceivable that the most abundant sources of potassium
are activated by cholinergic input. The idea of direct
action of ACh on the glial cell membrane is less at-
tractive because it implies extrasynaptic diffusion of
ACh in tissue rich in cholinesterase. Besides, depolari-
zation by ACh is associated with a rise in membrane
resistance (Krnjevic et al. 1971), and no such change
was observed during the depolarizing response of glia
cells associated with neural activation (Somjen 1970,
Ransom and Goldring 1973b). Finally, the conform-
ity of glial depolarization to the prediction of the
Nernst equation leaves no requirement of an in-
fluence other than that exerted by potassium
(Lothman and Somjen 1975).
-------
NEUROCHEMICAL MECHANISMS IN THE GENESIS OF
SLOW POTENTIALS: A REVIEW AND SOME CLINICAL
IMPLICATIONS
T, J, MARCZYNSKI
Department of Pharmacology, College of Medicine, University of Illinois, Chicago, 1L, U.S.A.
Since there U evidence that SPs are related to
neuronal activity (Robert 1973b, Rowland 1974),
there is reason to consider whether particular neuro-
hormonal substances are involved in their genesis.
Several crucial questions arise in this connection. Is
the concept of a neurotransmltter, which implies a
brisk and quickly reversible effect on ionic traniport
across a neuronal membrane, compatible with a role
in the genesis of SPs, or should our attention be di-
rected to substances capable of acting as modulators
rather than transmitters, I.e., to substances with slow
onset of action and a sustained effect on neuronal
and glia cell membranes? Can the influence of the as-
cending reticular activating system (ARAS) on epi-
cortical (Gaspers 1961) and subcortical SPs (Hayward
et al. 1966) be related to a particular transmitter or
modulator? What is the role in SPs of the cholinergic
component of the ARAS, defined histologically by
Shuts and Lewis (1967,1969) and pharmacologically
by Bradley and his colleagues (Bradley 1958) and by
Rinaldi and Himwich (1955)? Finally, is it possible
to relate the neurohormonal mechanisms which un-
derlie-SPs to a general concept of information flow
in the mammalian brain? (The latter question it dis-
cussed in the final section of this volume.)
Cholinergic mechanisms in epicortical nega-
tive SPs
The cholinergic component of the ARAS ori-
ginating in the legmen tal nuclei projects to the
neocortex (Shute and Lewis 1967), and the release of
acetylcholine (ACh) from the cortex is related to the
tone of the ARAS (Mitchell 1963, Kanai and Szerb
1965, Celesia and Jasper 1966, Pepeu and Mante-
gazzini 1964). The role of ACh In EEC desyn-
chronization has been postulated (Rinaldi and Him-
wich 19SS, Phiilis 1976) and, because surface negative
SPs accompany ARAS stimulation (Arduini 1958), a
role in SP genesis Is also possible.
If ACh is involved in SP genesis, an important
question concerns the type of cholinergic receptors
(muscarinic or nicotinic) that mediate its effect.
There Is strong evidence that the apical dendrites
of some neurons in the neocortex are endowed
with depolarizing muscarinic receptors that can be
selectively blocked by atropine (Sigg et al. 196S).
One can assume with reasonable certainty that
these dendrites belong to large pyramidal cells located
between layers IV and V which are not sensitive to
nicotine, but are very responsive (in terms of spike
generation) to iontophoretlc application of ACh.
These neurons are endowed with "pure" muscarinic
receptori that can be blocked by atropine or sco-
polamine applied topically or systemicaUy (Krnjevic
and Phiilis 1963, Krnjevic 1974). Some cortical
neurons are not excited by ACh, and others are even
inhibited by micro-iontophoretlc application of ACh
(Phiilis 1976). Hence, the question arises as to
whether the cholinoceptive "minority" of large
pyramidal cells is capable of determining the surface
negative SP upon release of ACh from terminals of
ARAS projections.
Several observations support an affirmative answer
to this question. First, tracing the polysynaptic
cholinergic ARAS projections to the neocortex in the
rat and monkey, Shute and Lewis (1967, 1969)
showed that these projections relay in the septal
region. In addition, Pirch and Norton (I967b) demon-
strated that rats with septal lesions show significantly
smaller negative SPs in response to conditional stimuli
than do normal animals. Secondly, laminar recording
of SPs in cortex treated with various concentrations
of ACh showed that the initial surface negativity
rapidly spread to deeper layers and reached its
maximum at the level of large pyramidal cells, or
layers IV and V (Ferguson and Jasper 1971). Finally,
the pharmacological study of surface negative long-
latency components of sensory-evoked potentials and
concomitant measurements of ACh release clearly
point to causal relationships between ACh output and
the amplitude and duration of the negative waves.
Topical application of low concentrations of cho-
linesterase inhibitors prolonged the duration and
increased the amplitude, while hemicholinium-3,
which is known to interfere with choline uptake
-------
26
Marczynski
and ACh synthesis, blocked the negative waves. A
similar blocking effect can be produced by appli-
cation of antimuscarinic drugs (Szerb 1965). These
data strongly indicate that ACh is released pre-
synaptically in the cortex from cholinergic com-
ponents of the ARAS originating in tegmental nuclei,
and that ACh plays a significant role in the genesis
of surface-negative SPs. A state of hyperarousal
associated with sustained depolarization of apical
dendrites, however, may reduce event-related negative
SPs (vide infra).
Functional differences between muscarinic
and nicotinic receptors
Cholinoceptive neurons excited by ACh in the
cortex, caudate nucleus, thalamus, and hypo-
thalamus show responses to ACh markedly different
from those of Renshaw cells in the spinal cord, which
are endowed predominantly with nicotinic receptors.
ACh applied to the the latter neurons acts as a typical
transmitter: excitation of Renshaw cells is almost
instantaneous and lasts only as long as administration
of ACh (the late and prolonged response caused by
activation of muscarinic receptors is usually negli-
gible). On the other hand, the response of neurons
with predominantly muscarinic receptors is slow in
onset and outlasts the application of ACh for many
seconds and even minutes (Krnjevic 1974). More-
over, ionic mechanisms of ACh action on mem-
branes with muscarinic receptors are substantially
different from those with nicotinic receptors. In
the former instance, ACh reduces the potassium
current during the late phase of the action potential.
This reduction results in delayed repolarization after
each action potential and in increased membrane
resistance (Krnjevic 1974). Thus, cortical neurons
"primed" with ACh in subthreshold concentrations
show a long-lasting lower threshold to incoming
volleys or to application of excitatory amino acids,
and a tendency to repetitive firing that can be
blocked by antimuscarinic drugs. Therefore, the
effect of ACh on neurons with muscarinic receptors
can be better described as a modulator rather than
transmitter action.
In view of the physiological role of cholinergic
mechanisms at the cortical level and their contri-
bution to the genesis of negative SPs, it should be
mentioned that ARAS-induced facilitation of
neuronal responses to visual stimuli can be mimicked
with micro-iontophoretic application of ACh. More-
over, both facilitatory influences can be blocked
by antimuscarinic drugs (Spenlmann 1971). This
observation and the negative SPs induced by
increased tonus of the ARAS associated with the
release of ACh suggest that the diminishing gradient
of negativity toward the depth of the cortex should
be associated with an overall reduced threshold to
sensory volleys and enhanced firing of most cortical
neurons. This conclusion is not in agreement with
Fromm and Bond (1964), but agrees well with
Rowland's data 0974) and with our own obser-
vations that surface positivity as well as deep
positivity, accompanied by alpha-like oscillations,
are always correlated with conspicuous inhibition
of neuronal firing in freely moving animals during
operantly conditioned behavior (Marczynski and
Karmos, this volume).
Most likely, there are no substantial differences
in the neurohormonal mechanisms of SPs that are
topographically restricted to specific sensory pro-
jections, e.g., those described by Gumnit and Gross-
man 0^61) and Picton (this volume) over the auditory
cortex, compared with negative SPs distributed
diffusely over larger cortical regions. An enhanced
release of ACh, topographically restricted to the
visual cortex, is observed in response to visual stimuli
while the remaining cortical regions show only
moderate enhancement of ACh release (Collier and
Mitchell 1966, Neal et at. 1968). Our studies in cats
show that both types of SPs are almost equally sen-
sitive to systemic administration of antimuscarinic
drugs (Marczynski, unpublished).
Results of pharmacological studies of CNV in
man are in harmony with cholinergic mechanisms
discussed above. Atropine (0.4 to 0.5 mg, i.m.)
markedly reduced the mean amplitude of CNV,
while small doses of nicotine, taken in cigarette
smoke, increased these SPs in subjects classified on
the basis of psychological tests as extroverted
(Thompson et al., this volume; Ashton et al. 1974).
Since cortical Cholinoceptive neurons in man, like
those in experimental animals, are most likely
endowed with "pure" muscarinic receptors and,
therefore, are not sensitive to nicotine, the locus
of nicotinic action is probably restricted to the
midbrain part of the ARAS or to the pons as shown
in cats and dogs (Kawamura and Domino, 1969;
Knapp and Domino,1962).
Catecholaminergic systems and SPs
Norepinephrine (NE) pathways originate in
tegmental nuclei and project to midbrain and fore-
brain structures, including n. ventralis anterior (VA)
and n. reticularis (R) of the thalamus (Fuxe 1965).
VA and R regulate thalamocortical EEC synchroni-
zation by generating rhythmic sequences of IPSPs
in neurons of specific thalamic relay nuclei (Sasaki
et al. 1976; Frigyesi 1972; Skinner, this volume).
Since NE projections to most areas, including the
thalamus and cortex, may be regarded as inhi-
bitory (Hoffer and Bloom 1976), NE-mediated
modulation of inhibitory neurons in R and VA may
be of crucial significance in normal functioning of
-------
Neurochemical Mechanisms in SP Genesis
27
the sensory gating system and selective attention.
NE terminals, present in all areas of neocortex,
arise from cell bodies located in the tegmental nu-
clei. NE axons run through the medial forebrain
bundle, bypass the septal region, and project
diffusely to the cortex (Fuxe et al. 1968).
Dopaminergic (DA) neurons with cell bodies
in the midbrain also contribute to innervation of
large cortical areas, including the frontal region
(Fuxe et al. 1974, lindvall et al. 1974, Berger
et al. 1974). These DA projections may be as
important in the regulation of integrative pro-
cesses as the DA projections to the limbic and
mesolimbic areas described by Ungerstedt
(1971).
At the cortical level, the function of NE and
DA terminals may be different. NE terminals
establish contacts preferentially with apical
dendrites of pyramidal cells and, therefore, have
a distribution characteristic of nonspecific afferents
(Fuxe et al. 1968). On the other hand, DA ter-
minals in frontal cortex, entorhinal cortex, and
pyriform cortex show highest density in deeper
layers, particularly V and VI. Only in the cingu-
late gyrus do DA terminals show a distribution
comparable to that of NE terminals-i.e., highest
density in layers 1, II, and III (Lindvall et al.
1974, Berger etal. 1974).
Experimental evidence indicates that, at the thal-
amocortical level, catecholaminergic projections may
influence the genesis of SPs by inhibitory action on
inhibitory interneurons that are responsible for
the phasing of EEC activity and positive SPs. Al-
ternatively, these projections may modulate the
sensitivity of excitatory cholinergic receptors of
the muscarinic type, present at the membrane of
cortical pyramidal cells and their apical dendrites.
Both mechanisms, which are of great clinical import-
ance, are dicussed below.
Catecholaminergic modulation of GABA-
mediated hyperpolarizing inhibition
Surface positive SPs are believed to reflect the
hyperpolarization of large pyramidal cells and their
dendrites (Creutzfeldt et al. 1969; Marczynski and
Karmos, this volume).
The following observations support the conten-
tion that recurrent inhibition of cortical pyramidal
cells (as well as thalamic relay neurons) is mediated
by GABA-ergic neurons, which, in turn, are modu-
lated by inhibitory catecholaminergic projections.
These relationships are illustrated in a diagram of
information flow in the mammalian brain
(Marczynski, this volume). (1) Micro-iontophoretic
application of GABA to pyramidal cells lowers
membrane resistance and causes inhibitory post-
synaptic potentials (IPSPs) whose patterns and
time course are virtually identical with spontaneous
IPSPs or those elicited by antidromic stimulation
of the pyramidal tract that activates the inhibitory
interneurons via axon collaterals (Kinjevic 1974,
Johnston 1976). (2) The highest concentration of
GABA-forming neurons (i.e., those that contain
glutamine decarboxylase) is found in layers III and
IV (Albersand Brady 1959), where inhibitory basket
cells are located (Marin-Padilla 1975). (3) GABA is
released from the cortex only during EEG synchron-
ization (Jasper and Koyama 1969) when inhibitory
interneurons show bursts of action potentials that
coincide with inhibition of pyramidal cells
(Steriade and Deschenes 1973). By contrast, GABA
release from the cortex is totally suppressed during
strong arousal or electrical stimulation of the ARAS
associated with EEG desynchronization. During
that time, inhibitory interneurons are suppressed
(Steriade and Deschenes 1973). (4) lontophoretic
application of NE to cortical, as well as cerebellar,
neurons and electrical stimulation of tegmental
nuclei from which NE projections originate (e.g.,
n. coeruleus) elicit IPSPs with different character-
istics from those induced by GABA (Hoffer and
Bloom 1976). (5) GABA releasing inhibitory neurons
(e.g., Purkinje cells of the cerebellum) are under power-
ful inhibitory control of NE projections from n.
coeruleus from which a substantial contingent of
both neocortical and thalamic NE projections also
arise (Hoffer and Bloom 1976).
In conclusion, despite the lack of direct evi-
dence, there are strong indications that the function
of catecholaminergic terminals in deeper cortical
layers is restricted to the process of disinhibition
by suppressant action on the inhibitory interneurons
in the recurrent circuits responsible for the phasing
of EEG patterns. Since rhythmic phasing of neuronal
activity in the cortex and thalamus is associated
with hyperpolarization of large neuron populations
(Andersen and Andersson 1968), and with surface
positive SPs (Marczynski and Karmos, this volume),
catecholaminergic modulation of the GABA releasing
system may play an important role in the genesis
and topographical distribution of SPs.
Catecholaminergic modulation of thalamo-
cortical recruiting responses
Recurrent hyperpolarizing inhibition in specific
thalamic relay nuclei, as well as the powerful in-
hibition generated by R and VA, is most likely
GABA-mediated (Curtis and Johnston 1974). Thala-
mocortical recruiting responses and EEG synchroni-
zation depend on the integrity of these pools 6f
inhibitory neurons (Skinner, this volume) and there
-------
28
Is evidence that a ciitcclioliimliicrglc component of
the ARAS modulates their function. First, IPSPs
In ihaltitnlc relay nuclei arc abolished during
increased (onus of the ARAS (Purpura et al. 1966).
At the same time, rhythmic firing of inhibitory
intcrneurons Is suppressed (Steriade and Deschenes
1973). Secondly, spontaneous arousal and elec-
trical stimulation of the ARAS are associated with
a large positive SP in R, which reflects tonic hyper-
polarizing inhibition (if this nucleus (Skinner,
this volume). Thirdly, the catecholaminergic com-
ponent of the ARAS projects diffusely to R and
VA (Fuxe 1965). Finally, physostigmine-induced
activation of the ARAS and the resulting blockade
of thalamocortical recruiting responses can be pre-
vented by depletion of catecholamines (VanMeter
and Karc/.mar 1971).
Excitatory influences from frontal association
cortex impinging on inhibitory pools of neurons in
R, which, in turn, project to specific thalamic relay
nuclei, determine the gating of sensory input-a
mechanism which may be the basis for selective
attention (Skinner, this volume). Sensory gating re-
quires very selective, well-limed excitation of neurons
in R which can only be effective if there is a mod-
erate inhibitory background in this nucleus. The
inhibitory surround is most likely provided by
catccholamincrgic projections.
Catechi>laniinerf>ir activation of subcortical
cholinergic system
In the cat preparation with the brainstem tran-
sected at the midpontinc pretrigeminal level, d-arn-
phi'iamme administered syslemically increases ACh
output fioni the cortex (Nistri et al. 1972). This
effect could be prevented by septal lesion or pre-
Ireatmenl of the animal with alpha-methyl-p-tyrosine,
a drug thai blocks synthesis of NE and DA. Appar-
ently, such activation of the ACh system does not
depend on the integrity of brainstem ARAS nuclei
since (1) pentoharbital does not block the effect
of amphetamine on ACh output even in doses that
block F.Hi activation and ACh output in response
to electrical stimulation of the ARAS and (2)
amphetamine activates EEC patterns and increases
ACh output in cats transected at the pretentorial
level, a preparation which excludes nuclei from which
the cholinergic component of the ARAS originates
(Nistri et al. 1972). Amphetamine, however, also
activates KEG patterns in cats with septal lesions in
which no cortical enhancement of ACh output is
obseived. This pu//Jing observation can be explained
by the previously discussed possibility that amphet-
amine, by activating the catecholaminergic system,
may suppress the GABA-ergic inhibitory pools of
neurons in the thalamus and cortex, thus preventing
the emeigeiue of synchroni/.cd EEG patterns.
MatT/ynskl
Cholinergic medinnlMiis of ruibcorticnl SPs
Nenronal mechanisms
Large negative SPs have been observed In the
thalamus and other suhcortical areas during the
reaction time forcperiod (McC'allum et al. 1973;
Rebert 1972,1973b) and in icsponsc to electrical
stimulation of the ARAS (Hayward et al. 1966).
These SPs seem to reflect ARAS modulation of
transmission in sensory thalainic nuclei. Evidence
from the microelectrophoretic studies of the lateral
geniculate (Steiner 1968), the ventrobasal nuclei
(McCance et al. 1968), and the medial geniculate
(Tebecis 1970) show that the effect of electrical
stimulation of the ARAS can be mimicked by ACh
application, and that both effects can be blocked
by antimuscarinic drugs given systemically or applied
topically. These studies suggest that the cholinergic
ARAS component exerts a strong facilitatory effect
on sensory transmission. Since negative SPs in specific
thalamic nuclei closely mirror frequency of neuronal
firing (Rebert 1973b), it appears probable that these
SPs reflect increased excitability of relay neurons in
response to afferent input, an effect that is likely to
be mediated by activation of cholinergic ARAS
pathways.
Participation ofglia cells
Preliminary observations (Krnjevic 1974) show
that iontophoretic application of ACh to cells iden-
tified as glia causes a slow onset and prolonged
depolarization that outlasts the application of ACh
by many minutes. At the same time, there is an
increase in membrane resistance i.e., an effect
strikingly similar to that seen in neurons with mus-
carinic receptors. If this is a general property of
glia cell behavior, it could help explain the genesis
of SPs in both cortical and subcortical areas and
could account for certain discrepancies between
neuronal firing patterns and SPs, e.g., those ob-
served by Rebert (1973b) in the lateral geniculate.
Are glia cells depolarized by ACh, or is glia cell
depolarization secondary to an increase in extra-
cellular potassium caused by neuronal firing? The
increase of membrane resistance in both glia cells
and neurons upon application of ACh (Krnjevic
1974) suggests an independent sensitivity to ACh.
Rowland (1974) has also suggested that the depo-
larization of glia cells in response to ACh release
may account for negative SPs without obvious
correlation with grossly integrated multi-unit acti-
vity in some regions of the brain. Somjen (this
section) discusses in detail the possible contri-
bution ofglia cells to SPs.
-------
Neurochemical Mechanisms in SP Genesis
29
Genesis and pharmacology of positive epi-
cortical SPs
Common features of surface positive SPs
Most positive SPs in man, such as the P300,
P450, skilled performance positivity (SPP)
described by Papakostopoulos et al. (this volume),
and detection positivity (DP) of Cooper et al.
(this volume) increase in amplitude with greater
a priori uncertainty of outcome of performance
and/or greater difficulty, in correct event recog-
nition. The unusually large SPP and DP apparently
reflect the demanding task involved in the eliciting
paradigm. If the a priori uncertainty is held con-
stant, positive SPs in most instances increase in
proportion to the a posteriori reduction of uncer-
tainty, i.e., when there is less doubt that the per-
formance was successful (Ruchkin and Sutton, this
volume). In the cat, the level of a priori uncertainty
also plays a major role in the emergence of reward
contingent positive variation (RCPV) recorded over
the pane to-occipital cortex (Marczynski et al. 1969,
197la). Presentation of milk triggers an augmented
RCPV when the reinforcement schedule for bar
pressing is variable (i.e., unpredictable) in comparison
to a schedule in which all bar presses are rewarded
(Marczynski and Burns 1976). RCPV is, however,
more sensitive to a posteriori reduction of uncertain-
ty. For instance, as shown in Fig. 1, when an animal
finds that there is a perfect match between the ex-
pected and actual result of a lever press, RCPVs are
of greater amplitude. If, however, the animal expects
pure milk, but receives water or adulterated milk in-
hoo/tv
2 sec
Fig. 1. The effect of change in quality of reward on the amplitude and duration of the reward contingent positive
variation (RCPV) in the cat trained to press a lever for water (W) and milk (M) rewards. A continuous record.
Epidural electodes were used, and the positivity of '3' and '1' with respect to the reference '2'is downwards In
thJsDe^r°fe "SfMSWi the mirrorjeversal Patterns of RCPV are explained by a decreasing potential gradient
ItSSZS^^SSj^ RCPV ^ aSS°Ciated ^ ™ ClSeC high ^P^^chronization.
-------
30
Marczynski
stead, the electrocoiticogram (K'oC.) synchruni/a-
tion (Sternum and Wyrwicka 1967) and associated
R( TV are suppressed or blocked (Marc/ynski et al.
There is suhstanlial evidence tliat all longer-
duration surface positive SPs result from hyper-
polan/ing inhibition of pyramidal cells and the
electrcilonic spread uf IPSPs to apical dendrites
(Creut/k'ldt e! al. 196')). Ilyperpolari/.ation
lesults tiom recuiieiit and, perhaps, leed-lorward
inhibitory phasing o| nemonal activity, as indi-
cated by the relationships between inhibitory neur-
unal discharge, the time course of IPSPs (Steriade
and Deschenes 11'73), and firing patterns of neurons
dining emergence of the RCPV (Marc/ynski and
KarniDs, tins volume). The close correlation between
cortical release of (JAHA and level of cortical hl-.G
syiii hmni/ation (Jasper and Koyama 1%9) supports
this interpretation. Since inhibitory neurons in the
coilex and thalamus are themselves subject U> in-
hibitory modulation by the ARAS (vide supra), the
general ouulusioii can tie drawn that all aloremcn-
I loiied positive Si's occur during a transient hut pow-
e i fnl suppression of the ARAS by influences orig-
inating in the torebrain (Marc/ynski, this volume).
HecUophysiotogical evidence for ARAS suppression
during emergence of the R(TV is convincing (Mar-
c/ynski and H;n.keft l''6°, llackett and Marczynski
ll'71 , Marc/ynski et al. ll>71a).
C'hulincrKic mechanisms in surface positive
I he physiological (onus of the cholinergic ARAS
component plotting to the th.ilamus and cortex is
necessary foi the emergence ot RCPV. Doses of
scopolanune or atiojiine, whicli do not interfere
with operant behavior, block the RCPV, which can
be restored promptly by administration of physo-
sUi'imne (Tig. 2 top). I he most important aspect ot
this antimtiscarimc blocking action is that the alpha-
like bursts associated with RCPV become irregular
and 'Yhoppy," suggesting that SP production is
directly related to the rhythmic hyperpolari/.int!
phasing ot neuioiial activity. Moreover, the duration
ut choppy alpha-like activity is not significantly
dittaent t'lom control response (Fig. -'). Hence, it
ian he concliuled that aiitimuscaiimcs do not block
the "pmiuuy" effect of toward (or goal achieve-
ment). but meiely interfeie with the "execution
<>t ihal.niHKoitical synclmmi/ation and emergence
nl RCPV (.Vluiv/ynski I 97 I).
The phasing, theory ot neuronal activity ex-
pl.iiinuj' alpha inechanisuis, which is based on re-
cnnent inhibition (Andersen and Andersson 1968),
implies that a certain level of synaptic drive is neces-
sary to mutate the functioning, of the recurrent
inhibitory circuits. Taking into account the facil-
itatory cholinergic influences on sensory trans-
missions at thalaniic and cortical levels, one can pro-
pose that antunuscarinics, by reducing the cholin-
ergic ARAS influences, lower synaptic drive to a
level that is incompatible with normal operation of
recurrent inhibitory circuits (Marczynski and Burns
1976). Blockade of alpha activity by antimuscari-
nics in man (Longo 1966) and blockade of alpha-
like activity associated with K-complexes normally
triggered by sensory stimuli during sleep onset
(Marczynski, this volume) are in agreement with our
interpretation of cholinergic mechanisms. Further
supporting evidence has been presented elsewhere
(Marc/ynski and Burns 1976; Rick and Marczynski
1976; Marczynski and Karmos, this volume).
Assuming that the proposed interpretation of
cholinergic mechanisms is correct, one can make a
second assumption regarding the role of synaptic
drive in the topographical distribution of positive
SPs. Upon completion of task performance, slack-
ening or suppression of the catecholaminergic ARAS
component allows inhibitory interneurons to
function. Only those thalamocortical projections
and corticocortical pathways that received the
strongest synaptic drive can be expected to
activate recurrent inhibitory circuits promptly.
It is, therefore, not surprising that the RCPV in the
cat depends on visual input and occurs over primary
and secondary visual projections (Marczynski et
al. 1971a,b). Similarly, the SPP of Papakostopoulos
et al. occurs over the motor and somatosensory cor-
tex, while the DP of Cooper et al. (this volume),
which requires intensive visual searching but only a
minimal motor response, occurs over the vertex and
midline occipital cortex. On the basis of anatomical
and electrophysiological evidence (Frigyesi 1972), it
is probable that the emergence of SPP depends on ac-
tivation of motor cortex, as well as strong synaptic
drive from the cerebellum, which reaches the cortex
via the bracchium conjunctivum and n. ventralis lat-
eralis. Pyramidal neurons of the cortex, in turn, send
axons back to n. ventralis lateralis as well as axon
collaterals to intracortical inhibitory circuits and to
R. The latter, in turn, project inhibitory axons to
n. ventralis lateralis (Fig. 4). Immediately after post-
performance slackening of the inhibitory ARAS
component (catecholaminergic?), both thalamic and
intracortical recurrent inhibitory circuits may be
activated, resulting in a positive SP and alpha-like
I-.F.Ci oscillations.
Cholinergic activation of the catecholamin-
ergic system
Antimuscarinic drugs block RCPV and alpha
activity in humans. Physostigmine restores RCPV
and associated alpha-like bursts, but also blocks
-------
Neurochemical Mechanisms in SP Genesis
CONTROL SCOPOL.
31
PHYSOST.
,I.M.. 35min.
W
,,, /I' ttLU
HMMNQifr
• i ir ' if
*•
M-SCOPOL.
60 /ng/kg, I.M., 30 min
SCOPOL.
50 A/g/kg. I.M., 30 min.
PHYSOST. 60 jug/kg. I.M.. 30 min
2 sec
Fig. 2. Top: The effect of scopolamine HBr and physostigmine salicylate on reward-induced EEC synchron-
ization and associated RCPV, recorded over the primary visual cortex (posterior marginal gyrus or PM) with
reference to the subjacent white matter. The dc record was filtered out to half-amplitude response at 3 c/sec.
This channel is integrated in the first trace (INT) in which two full-scale upward deflections are equal to one unit
of RCPV. As marked by dotted lines in the upper right record, only those INT deflections were counted that
occurred in the time interval between the reinforced (REINF) and the subsequent rewarded or nonrewarded
(NOR) lever press.
Bottom: 48 hours later, the same cat was pretreated with methylscopolamine HBr; physostigmine suppressed
the RCPV, which subsequently could be partially restored with scopolamine (From: Marczynski 1971J. For
further explanation, see the text.
these responses if given to animals whose peripheral
muscarinic receptors have been "protected" with
methylscopolamine, which does not penetrate through
the blood brain barrier (Marczynski 1971). In some in-
stances, as shown in Fig.2 (bottom right), RCPV and
alpha-like responses can be restored with scopolamine.
Better results have been obtained with chlorpromazine,
a drug known to block dopaminergic and adrenergic
receptors. Hence, it appears that physostigmine and
perhaps other acetylcholinesterase inhibitors, by in-
creasing ACh levels, can activate catecholaminergic
systems. Since similar blockade of EEC responses has
been observed after systemic administration of nico-
tine, an effect reversible with chlorproma/ine
(Marcznski, unpublished), one can postulate that
cholinergic activation of catecholaminergic systems
results from action on nicotinic receptors. The latter
are primarily located in ARAS nuclei at the brainstem
level (Kawamura and Domino 1969, Knapp and
Domino 1962). The mechanism by which activation
-------
32
Marczynski
of the catecholaminergic system may modulate and
block thalamocortical inhibitory and synchronizing
circuits has already been discussed.
Ginical implications
chemical mechanisms
of impaired neuro-
Catecholaminergic
brain dysfunction
hypothesis of minimal
Selective attentional deficits are characteristic
of children with Minimal Brain Dysfunction (MBD).
The role of n. reticularis thalami (R) in gating sensory
input and the putative role of catecholaminergic
projections in regulating the inhibitory background
of this nucleus have been reviewed above. It may
be hypothesized that the inhibitory background in R
of MBD children is deficient, a condition which is
likely to impair the selective gating of sensory input.
Moskowitz and Wurtman (1975), for instance, obser-
ved that the catecholaminergic system in MBD child-
ren seems to be impaired which may lead to uncon-
trolled functioning of the thalamic gating system.
Moreover, MBD children have an unusually low thres-
hold to photic driving which sometimes leads to myo-
clonus. These children also tend to be hypersensitive
CONTROL
M«to^^
ATROPINESULFATE
0.8 mg/kg, I.M., 25 min.
(l(jM4%i^HA^
PHYSOSTIGMINE SALICYLATE
0.1 mg/kg, I.M., 25 min.
llT^t^UiM^^
1444,
5 sec
Fig. 3. Comparison of control reward-induced EEC synchronization (top) with that recorded 25 min after
administration of atropine sulfatefO.8 mg/kg, i.mjin the cat trained to press a bar for 1 ccofmilk. LICK signals
caused by lapping and licking; NOR nonrewarded bar press; REINF rewarded bar press; PM posterior marginal
gyrus /with reference to the anterior ectosylvian gyms). The heavy horizontal bar below each EEG response
marks its duration from the first to the last EEG wave that, if measured peak-to-peak, exceeded 100 pK. The
numbers after each EEG response tell how many oscillations occurred that exceeded lOOuV, Note that the dur-
ation of the "choppy" EEC responses is not significantly different from the control. Note also that physos-
tigmine promptly restored the responses (bottom). For further explanation, see the text.
-------
NiMiroehemicnl Mechanisms in SP Genesis
to amphotnmine and mothylphenldate, as tested by
the blocking action of these drugs on EEC photic
driving and myoclonus (Shetty 1971). Hypersensl-
tivity to amphetamine Implies that catecholamlnergic
pathways and terminals are damaged. Furthermore,
amphetamine and methylphenldate usually amelio-
rate MBI) symptoms.
Fig. 4. Pathways most likely responsible for the
emergence of the skilled performance positivity (SPP)
of Papakostopoulos et al. The arrows and the small
bars denote the excitatory and inhibitory (hyper-
polarizing) synapses respectively. nR nucleus reticu-
laris tlralami: VL n. ventralis lateralis; BC brachium
conjunctivum, conveying input to the VL from the
cerebellum: MCx motor cortex. Filled circles denote
inhibitory neurons. Note that the rhythmic phasing
of ncuronal activity and the emergence of the SPP
are possible only when the inhibitory neurons are re-
leased from tonic inhibition exerted by the ARAS
(ascending reticular activating system; probably its
catecholaminergic component}. For further explana-
tions, see the text, (Modified from Frigyesi 1972).
Stamm and his colleagues (personal communica-
tion) studied the Nl component of auditory evoked
potentials in normal and MBD children. The mean Nl
amplitude uifference between attend and non-attend
conditions was 44 percent for the normal group, but
only 14 percent for the MBD group. Karrer and his
colleagues (this volume) found that children with.
cognitive difficulties show an increased surface posi-
tive SP over frontal and central cortex prior to and
during motor response, both observations support the
hypothesis that "sculpturing" of specific excitatory
spatio-temporal patterns in R and other pools of thai-
amlc inhibitory neurons Is Impaired, leading to a low
signal-to-noise ratio of input to the cortex (Skinner,
this volume).
Cholinergic interpretation of dopaminergic
hypothesis of schizophrenia: a new working
hypothesis
Relationships among catecholaminergic systems
and thalamocortical inhibitory pathways in MBD
children may be opposite to those in adults with
acute anxiety, schizophrenia, or amphetamine-
induced schizophreniform psychosis. That is, in-
creased tonus of catecholaminergic systems is likely
to produce tonic inhibition of R and impaired thala-
mocortical EEC synchronization. This condition is
incompatible with effective gating of sensory input
and leads thus to a state of confusion. Thalamocor-
tical relationships are discussed further in the "Par-
simonious Model of Mammalian Brain"(Marc/ynski,
this volume).
During the last seven years, considerableil.ua have
accumulated indicating that a hyper function of the
DA system and/or increased sensitivity of DA post-
synaptic receptors may be responsible for many
symptoms of schizophrenia (Meltzer and Stahl ll>76).
Moreover, Libet and his colleagues (this section) have
discovered that DA has a unique and powerful poten-
tiating effect on slow muscarinic KPSPs in sympa-
thetic ganglia. As already mentioned, pyramidal cells
of cortical layers IV and V are endowed with "pure"
muscarinic receptors. Stimulation of these receptors
with ACh triggers EPSPs characterized by slow onset
and long duration (Krnjevic 1974). The specificity
of this action is indicated by the fact that these
EPSPs are associated with an increase in membrane
resistance, in contrast to the brisk and short-last ing
EPSPs mediated by nicotinic receptors and associated
with a sudden drop of membrane resistance.
Following ACh application, neurons in the stria-
turn, a nucleus known to be profusely innervated by
DA projections, show typical muscarinic responses
comparable to those seen in the cortex. Therefore,
they may provide a clue regarding the possible inter-
action between DA and ACh systems. Indirect evi-
dence for such a heterosynaptic interaction at post-
synaptic sites comes from intracellular recording of
striatal neurons. Electrical stimulation of the sub-
stantia nigra activates DA projections to the stria-
turn and causes release of ACh in this structure (Por-
tig and Vogt 1969). This dual effect is probabK
caused by the proximity of the ARAS cholinergic
component described by Shute and Lewis (l^e>7).
Electron microscopic study of DA terminals in the
-------
34
Marczynski
striatum shows that DA is likely to be released
through narrow pits directly into relatively large
extracellular spaces, allowing for diffusion of the
transmitter away from the terminal (Tennyson et
al. 1974). These morphological characteristics imply
that a heterosynaptic interaction at postsynaptic sites
is possible, an assumption supported by an intracellu-
lar study of striatal neurons by Hull et al. (1970).
These investigators found that a single volley of
electrical stimuli applied to subs tan tia nigra, or its
close vicinity, produced in most neurons a short-last-
ing hyperpolarization (DA effect ?), followed by an
exaggerated depolarization lasting 30 to 40 seconds.
This phenomenon, which resembles the paroxysmal
depolarization shift of neurons in epileptic foci, was
not observed in other structures.
Although the information concerning the intri-
cate relationship between DA and ACh terminals in
the cortex is not yet available, the possibility of inter-
action between these two neurotransmitters at
muscarinic receptor sites in schizophrenics should
be seriously considered as a working hypothesis
because all the necessary elements are present in the
cortex, including the DA receptor, i.e., DA-sensitive
adenylate cyclase (Bockaert et al. 1977). Consider-
able evidence supporting this hypothesis is already
available. First, there is little doubt that increased
(onus of the DA system plays a crucial role in the
emergence of most schizophrenic symptoms (Meltzer
and Stahl 1976). Secondly, several electrophysio-
logical observations indicate that exaggerated depol-
arization of cortical neurons and their apical dend-
rites may be associated with schizophrenic symptoms.
For instance, schizophrenics show considerable
impairment of amplitude recovery of auditory,
somesthetic, and visual evoked potentials if the
stimuli are presented at short intervals (Shagass 1976).
Thirdly, acute or chronic schizophrenics with florid
symptoms show significantly lower CNV amplitude
than normal adults (Dongier 1973).
Later components of cortical evoked potentials
are produced by postsynaptic potentials and their
electrotonic spread to apical dendrites (Creutzfeldt
et al. 1969). Tonic depolarization of apical dendrites
by cathodal current (Purpura 1967) or by appli-
cation of ACh (Sgg et al. 1965) reduces the slow
negative component of evoked potentials. It is
likely that CNV amplitude is similarly diminished
relative to background depolarization of apical
dendrites during hyperarousal. Hence, modifications
of the CNV paradigm, making it more demanding-
e$., by introducing distracting stimuli-lead to
reduction of CNV amplitude (Tecce and Cole 1976).
Administration of amphetamine to experimental
animals reduces negative Sft over frontal cortex
elicited by conditional auditory stimuli, an effect
that can be reversed by haloperidol or barbiturates
(Pitch, this section). Likewise, the administration
of fluphenazine to schizophrenics with florid symp-
toms considerably enhances CNV amplitude and
improves the clinical picture (Tecce and Cole 1976).
On the other hand, when no drug-induced or disease-
related hyperarousal is present, one would expect a
reduction of CNV amplitude to parallel the slacken-
ing of ARAS tonus or blockade of postsynaptic
receptors. Indeed, Thompson et al. (this section)
found that atropine or a DA antagonist, metoclo-
pramide, decreased CNV amplitude in normal volun-
teers. In conclusion, the above physiological and
pharmacological considerations support the theory
that CNV amplitude is monotonically related to
selective attention, but nonlinearly related (inverted
U) to increasing ARAS tonus and arousal level (Tecce
and Cole 1976).
Finally, the prolongation of the spiral aftereffect
(SAE) described by Herrington and Qaridge (1965)
appears to represent one of the most characteristic
phenomena associated with schizophrenic symptoms
(Abraham and McCallum 1973). A recent study of
SAE in schizophrenics and controls revealed that its
duration faithfully reflects the actual clinical state as
judged by Schneider's first-rank symptoms. This
correlation was present even when amplitude reduc-
tion or prolongation of the CNV was marginal or
absent (Abraham and McCallum, personal communi-
cation).
Little is known about the neurophysiological
basis of SAE This phenomenon may, however, be
related to transient entrainment of neuronal circuits
involved in motion detection. A classical example of
such entrainment is the "waterfall effect." If one
stares at a waterfall and then looks away, a part of
the background corresponding to the size of the
waterfall appears to move upward, while the rest
of the landscape remains stable. This illusion is not
caused by eye movement, but by entrainment of
neuronal circuits most likely involving edge and/or
motion detector cells in the striate cortex.
It is quite probable that SAE duration is regu-
lated by a cholinergjc mechanism of the muscarinic
type. Neurons which normally discharge briefly
(0.5 to 1.0 sec) in response to a sensory volley,
respond to the same input after iontophoretic appli-
cation of ACh with a continuous burst of action po-
tentials lasting 10 to 20 sec (Krnjevic 1974). Thus,
a primary role of the cholinergic ARAS component
projecting to the cortex is to amplify in time the
transient sensory input, a process believed to be
necessary for the emergence of conscious experience
(Tibet 1965, Kmjevic 1974). Hence, prolonged SAE
in schizophrenics is likely to reflect a pathological
potentiation of the normal function of the cholin-
ergic ARAS component, an action that may be
tentatively ascribed to DA modulation of post-
synaptic muscarinic receptors.
-------
Neurochemical Mechanisms in SP Genesis
Summary
The enormous complexity of dynamic inter-
actions among neuronal ensembles and chemical
transmitters or modulators necessitates a multi-
disciplinary approach to the study of brain function.
This review attempts to integrate many anatomical,
electrophysiologjcal, and pharmacological aspects
of the genesis and functional significance of EEC
patterns, evoked potentials, and slow potentials.
Evidence is presented that BEG desynchronization
and slow negative potentials are mediated by a
concerted action of the cholinergic and catecho-
laminergic ARAS components. The cholinergic
component depolarizes neuronal dendrites, reduces
the tiring threshold of large populations of neurons
in specific thalamic nuclei and cortex, and prolongs
their discharge to incoming volleys. Simultaneously,
the catecholaminergic ARAS component appears
to block the function of GABA-ergic recurrent
and/or feedforward inhibitory circuits responsible
for hyperpolarization of large populations of neu-
rons. Conversely, bursts of alpha-like EEC patterns,
surface positive SPs and most positive SPs in the
specific thalamic nuclei seem to result from
slackening in the tonus of catecholaminergic pro-
jections, thus allowing the function of GABA-ergic
hyperpolarizing circuits, the emergence of alpha-like
EEC patterns, and positive SPs.
Antimuscarinic drugs (atropine or scopolamine)
block at the thalamocortical level not only the norm-
al cholinergic facilitation (amplification in time) of
sensory input, the negative SPs and EEC desynchron-
ization, but also abolish opposite phenomena, such as
the bursts of EEC alpha-like patterns and positive SPs
in specific thalamic nuclei and cortex. These dual and
35
seemingly contradictory actions of these drugs can be
accounted for by two assumptions based on experi-
mental results: (1) the functioning of the recurrent
inhibitory GABA-ergic circuits depends on a certain
level of excitatory synaptic pressure and its physio-
logical amplification by the cholinergic ARAS com-
ponent; and (2) this pressure can either be converted
into a desynchronized EEC pattern and negative SPs
or into a hypersynchronized EEG alpha-like pattern
and positive SPs, depending upon the functional state
and "readiness" of the GABA-ergic circuits. If the
latter are tonically inhibited by the ARAS (catecho-
laminergic projections?) e.g. during arousal, the ex-
citatory synaptic pressure can only result in EEG
desynchronization and negative SPs in specific thal-
amic nuclei and cortex. However, if the GABA-ergic
system, e.g. during relaxed wakefulness, is released
from tonic inhibition (slackening of the catecho-
laminergic ARAS component?), the excitatory syn-
aptic pressure in specific thalamic nuclei and cortex
can be readily converted into hyperpolarizing inhi-
bition, bursts of high voltage alpha activity and posi-
tive SPs in specific thalamic nuclei and cortex.
The issues discussed here have several clinical
implications. For instance, it appears that a moderate
(catecholaminergically mediated) inhibitory back-
ground in reticularis thalami (reflected as a positive
SP in this structure) is necessary for the gating of
sensory input by this nucleus. This function is likely
to be impaired in children with MBD. On the other
hand, an excessive hyperpolarizing blockade of this
nucleus by catecholaminergic projections could render
it nonresponsive to cortkofugal modulation and
cause an overload of sensory input and confusion-
characteristic symptoms of schizophrenia. To
account for changes in SPs in schizophrenic patients,
heterosynaptic interaction between dopaminergic and
cholinergic systems is postulated.
-------
REWARD CONTINGENT POSITIVE VARIATION (RCPV)
AND PATTERNS OF NEURONAL ACTIVITY IN THE
VISUAL CORTEX OF THE CAT
T. J. MARCZYNSKI AND G. KARMOS
Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, U.S.A.
The relationship between the firing patterns of
cortical and subcortical neurons and slow potentials
(SP) has been studied by several investigators. Fromm
and Bond (1964) found that in the enclphale isole*
cat preparation, cortical neurons in the visual pro-
jections fire more frequently during surface positive
EEC waves and cease firing during negative waves.
These relationships were reversed, however, when the
visual cortex became more negative with respect to
the frontal sinus. Rebert (1973b)found that flash
stimuli produce in the lateral geniculate body a slow
negative SP associated with increased neuronal firing.
In the chronic cat preparation, under conditions of
nonoperant training, Rowland (1974) found that
surface negative SPs over the visual cortex were asso-
ciated with increased multiple unit activity.
Clemente et al. (1964) observed postreinforce-
ment synchronization (PRS) of EEC in cats trained
to press a lever for milk reward. Marczynski et al.
(1969, 1971a) have shown that PRS (7 to 9 c/sec)is
always associated with an epicortical SP which has
been designated reward contingent positive varia-
tion (RCPV). This phenomenon, like PRS (Sterman
and Wyrwicka 1967), depends on the quality and de-
sirability of reward. The PRS-RCPV responses are
topographically restricted to the primary and second-
ary visual projections and a part of the association
cortex (the posterior marginal and the suprasylvian
gyri). The RCPV usually outlasts the PRS burst by
1 to 2 sec (Marczynski et al. 197la, Rick and Marc-
zynski 1976).
In the present study, the relationship between
patterns of single-unit activity and the PRS-RCPV
phenomenon was investigated. Since PRS-RCPV re-
sponses depend on unpatterned light input, even in
cats trained in the dark (Marczynski et al. 1971b,
Rick and Marczynski 1976), the effect of ambient
light was also tested.
Methods
Eight adult cats were trained to press a lever for
0.8 ml of milk reward. Ag/AgCl electrodes were im-
planted epidurally over the posterior marginal (PM)
and anterior ectosylvian gyri in three cats under pen-
tobarbital anesthesia. Since the latter electrodes were
relatively "neutral" during PRS-RCPV responses
(Marczynski et al. 197la), they served as reference.
In two other cats, the reference electrode was placed
in the white matter of the PM gyms approximately 6
mm below the surface and 3 mm lateral from the
epidural electrode. The subcortical reference con-
sisted of a 0.5 mm Ag/AgCl pellet, enclosed in a glass
tube, which was closed with agar. In the remaining
three cats, no dc recording was attempted: PRS and
unit activity were monitored using standard epidural
stainless steel electrodes in the cats. In all eight cats,
single* or multiple-unit recordings from PM gyms
were obtained by means of bundles of "floating"
platinum-indium or stainless steel wires, 15 to 35/jrn
in diameter, insulated except at the tips which were
cut with scissors. The bundles of wires, stiffened
with sucrose solution, were implanted through a
guide cannula, which was tangentially oriented and
made out of a polyethylene or stainless steel tubing
0.5 mm in diameter. The tip of the cannula was cut at
approximately a 20° angle, and its orifice was pro-
vided with a 1-mm rim. Through a small opening in
the dura, the rim was placed above the pia mater, and
the cannula was fixed to the skull. Wires and epidural
electrodes (including the white matter reference)
were connected to separate miniature sockets. Unit
activity was recorded with a miniature high-input
; impedcnce preamplifier (Sherry et al. 1975), with
wide frequency band responsiveness-(1.0 to 1.5 Hz).
Notch filters and Grass 7-PS 11 amplifiers permitted
simultaneous recording of unit activity and slow
wave ECoG patterns from the electrode tip. Of 52
"floating" wires, 10 yielded good single or multi-
ple unit recording for 2 to 9 days in unrestrained
animals. Data were stored on magnetic tape. An
amplitude discriminator was used for separation of
multiple unit activity. Frequency histograms of unit
firing were obtained with a Computer of Average
Transients Model 1200 and displayed by means of an
X-Y plotter.
-------
RCPV and Neuronal Activity in Visual Cortex
Results
All eight cats showed typical PRS responses in
the presence of ambient light. In the dark, consum-
matory responses were not associated with any sig-
nificant changes in ECoG or SP. In all cats implanted
with Ag/AgCl electrodes, PRS was always associated
with a typical RCPV, as shown in Fig. 1A(S: surface
lead referred to white matter). Steep negative waves
of 7 to 9 c/sec recorded with the intracortical micro-
electrode (D) were always in phase with bursts of
unit activity. During a fully developed PRS response,
these intracortical negative waves were abruptly
terminated by much longer duration (approximately
100 to 130 msec) positive waves. Surface negative
waves were, in most instances, approximately 20 to
35 msec out of phase with respect to intracortical
ones. The duration of surface positive waves was
comparable to that of intracortical waves.
In the presence of light, all 10 successfully stud-
ied neurons showed markedly reduced firing rate
37
during consummatory responses associated with the
PRS-RCPV phenomenon as compared to the time
period immediately prior to, during, or immediately
after the lever press. As shown in Fig. IB (L: fre-
quency histograms obtained in the light), the higher
amplitude unit H and the small amplitude unit S were
maximally suppressed during the time period heuvtvn
2 and 4 sec after reinforcement (R), i.e., during
the consummatory responses and the occurrence of
PRS-RCPV. Since cats performed on a 6-sec fixed
interval reinforcement schedule, the histograms en-
compassed approximately two consummatory re-
sponses and, therefore, were almost symmetrical on
both sides of reinforcement.
Basically, two types of units were encountered:
one type showed no significant change in firing rate
in the dark (D), i.e., when PRSRCPV responses were
suppressed, but showed strong post-reinforcement
inhibition in the light (the histograms S-D and SL,
respectively). The second type of unU, illustrated by
neuron H, showed increased firing rate approximately
REWARDED BAR PRESS
LIGHT
+600
R R
TIME, milliseconds
Fig. I A: Patterns of unit activity in the visual cortex, simultaneously recorded intracortical ECoC from the tip of
the same electrode (D) and surface ECoG(S) during lever pressing performance for 0.8 ml of milk reward The ref-
erence electrode placed in the white matter approximately 3 mm laterally from the intracortical and epicortical
electrodes. B: frequency histograms for higher amplitude (H) and smaller amplitude (S) units during performance
of the cat in the presence of light (L) and in the dark (D). Numbers above the unit channel show discharges for
unit H after reinforcement in light and dark. Bin width in histograms: 100 msec. Each histogram represents 10
rewarded (R) lever presses.
-------
38
Marczynski and Karroos
1.5 sec prior to, during, and 1.5 sec after reinforce-
ment, both in the presence and absence of light (his-
tograms H-L and H-D, respectively). Both types of
units, however, were strongly inhibited during con-
summatory responses in the light i.e., during the
occurrence of PRS-RCPV. As shown by the dashed
line in L histograms, firing rate during PRS-RCPV
reached markedly lower levels than the average firing
rate observed during a relaxed state after satiation.
During sleep onset after satiation, ECoG and SP
patterns were indistinguishable from PRS-RCPV re-
sponses. In contrast to operant behavior, however,
the characteristic 7- to 9- c/sec bursts of discharges
and an overall decreased firing rate were observed in
all units both in the dark and light.
Discussion
The PRS phenomenon and associated suppres-
sion of unit activity in the cortex seem to represent a
typical example of phasing of neuronal discharges
based on recurrent inhibition as postulated for thala-
mocortical relationships by Andersen and Andersson
(1968). The phasing theory that explains recruitment
of larger populations of neurons into alpha-like dis-
charges implies that a certain level of synaptic pres-
sure is necessary to initiate and drive the phasing cir-
cuitry. Hence, neurons that show sustained on-re-
sponses to light (Corazza et al. 1971, Horn 1965,
Jung et al. 1963, MacLean et al. 1968) may be the
main source of "electromotive energy" that could
initiate the phasing mechanism during the brief (but
apparently strong) reward-induced suppression of the
brainstem reticular activating system (Marczynski
1972a, Marczynski and Burns 1976). This suggestion
is supported by the observation that, in the dark,
single and relatively weak electrical stimuli applied to
the optic nerve during consummatory responses trig-
ger in a stimulus-bound manner typical PRS-RCPV
responses whose patterns and topographical distri-
bution are virtually identical with those of spontan-
eous responses in the presence of ambient light (Rick
and Marczynski 1976). The specificity of the effect
of this "noisy" electrical stimulation was demonstra-
ted by the fact that the same, or even stronger, stimu-
li applied during other behavioral states, such as non-
rewarded lever pressing or relaxed wakefulness after
satiation, produced no effect. In conjunction with
previous data on the role of unpatterned light input
in the emergence of PRS-RCPV responses (Marczyn-
ski et al. 1971b), it can be concluded that "noisy"
photic input is effectively utilized in reward-induced
inhibition of neuronal activity in the feline visual cor-
tex, therefore, in the broader sense, in the inte-
gration of input associated with consummatory re-
sponses.
The occurrence of the epicortical positive shift,
i.e., RCPV in association with the PRS bursts, can be
interpreted as resulting from a phasic tendency to-
ward hyperpolarizing inhibition of larger populations
of neurons in the cortex and the electrotonic spread
of IPSPs to apical dendrites, which is reflected as sur-
face positivity (Creutzfeldt et al. 1969). A more de-
tailed analysis of the PRS-RCPV phenomenon, path-
ways involved, pharmacology, and physiological sig-
nificance has been presented elsewhere (Marczynski
and Bums 1976).
Acknowledgment
The help of Dr. C. J. Sherry in the early phase of
this study is appreciated.
-------
ACQUISITION OF SUSTAINED POTENTIALS
DISSOCIATED FROM MASSED ACTION POTENTIALS
IN TEMPORAL CONDITIONING
V. ROWLAND
Case Western Reserve University, School of Medicine, Cleveland, OH, U.S.A.
The CNV may be seen as a sustained, nonoscilla-
tory field potential of the shortest end of the spec-
trum of sustained elec trophysiologic durations. This
spectrum extends from a half second up to several
minutes in duration, as can be shown by conditioning
experiments (Rowland and Goldstone 1963, Sheafor
and Rowland 1974). Also, the potassium-induced
glial depolarization mechanism of genesis of sustained
potential fields may be seen as a possible temporal
integrating or timebinding mechanism, although, to
my knowledge, no direct experimental demonstration
of such a role has yet been offered.
Interest in such a role is enhanced by the failure
to demonstrate actual circulating or reverberatory
iterated fast-decaying transients such as action poten-
tials, short postsynaptic potentials, or wave trains
(oscillating field potentials) to account for identifi-
able electrophysiologic states sustained for more than
a half second. The only known alternative is for the
action of transients to be transformed by other cell
parts or systems to dynamics having much slower
decay-time constants, thereby producing temporal
summation.
In order better to understand the relation of
nontimebinding transients (action potentials) to
the sustained field potentials reflecting the tem-
poral integration of generators of slower decay, we
(Rowland and Dines 1973) developed small hybrid
macroelectrodes and circuitry for simultaneously
registering an artificial integration of massed action
potentials (integrated mass units, or IMU), the con-
ventional oscillatory field potential patterns (electro-
corticogram, or ECoG), and sustained slow potentials
(SP).
Many examples of the expected association of
IMU increments with ECoG and SP activation were
observed in cortex (Rowland and Dines 1973), as
described by Robert (1973b) for the lateral geniculate.
Also IMU decrements were observed with ECoG
synchrony and clear mass unit bursting in phase with
individual high-voltage, low-frequency waves of spin-
dle activity.
By serendipity, in relation to studies of the
IMU-SP relation occurring with food rewards, the
appearance of marked anticipatory SPs without asso-
ciated IMU changes was encountered (Rowland
1974). The same system continued to show the
associated IMP-SP relations formerly seen in reaction
to stimuli or association with an emitted potential,
the lambda wave. The reactive, associated IMU-SP
relation is identified in this paper as SP-1, and the
proactive (anticipatory) dissociated relation (SP
present in the absence of IMU change) as SP-2.
Fig. 1, taken from Sheafor and Rowland 0974),
shows the replacement of SP-1 in the naive animal
by SP-2 after 3 weeks of training. Essential to the
demonstration of SP-2 is a state called quiet
expectancy. This was developed in the cats in this
study by their being trained to restraint in a stock
that permitted them to sit comfortably. They
received food directly into the mouth every 4 min.
They had 5 sec of tone (R) prior to each rein-
forcement, and 8-cm3 feeding. The same tone
was repeated 2 min later at the middle of each 4-fnin
interval but not reinforced (N) in a program called
single alternation (SA). The cat's cortical SP devel-
oped a clear 2-min phase of anticipation of forth-
coming reinforcement while the animal remained
behaviorally quiet. If it spontaneously moved,
a transient SP-1 would appear superimposed on
the sustained ramp of the SP-2,
No evidence was observed in the IMU record of
the graded expectancy or proactive response prior to
either N or R tone, whereas the SP was maximally
positive or least negative prior to the N tone and grad-
ually and regularly became maximally negative prior
to the tone.
Fig. 1 shows, in the course of acquisition, the
development of a proactive SP-2 through an initial
phase at 11 days, interpret able as related to the animal's
-------
40
Rowland
generalizing the N and R tones. The N tone pro-
duces marked change in the IMU and SP. Subsequent-
ly (day 14), both of these disappear, suggesting that
the animal has begun to discriminate the difference at
the same time as the sustained ramp over the second
half of the 4-min interreinforcement interval emerges.
Since N and R tones are the same, the animals have
only their capability of monitoring the lapse of time
(independently of direct cueing) to enable the dis-
crimination between forthcoming reinforcement and
nonreinforcement. This discrimination is not seen just
prior to the tones in the IMU record (Fig. 2). It is
seen clearly in the SP-2 pattern. If further tests sup-
port the interpretation that a true dissociation be-
tween the two variables exists, the conclusion follows
that the SP-2 generating mechanism has access to
stored experience independently of the action poten-
tial generating mechanisms. The proactive response
can only develop in the context of temporal oreinta-
tion arising from the relatively remote memory of
prior days of training and the Fecentf memory of
when the last reinforcement occurred.
Nothing is known from direct experiments
about the mechanisms of genesis of the proactive
SP-2. It appears to be some other mechanism than
the release of potassium generated by mass action
potential activity inducing the presumed glial depo-
larization postulated for reactive SP-1 genesis (Ran-
son and Goldring 1973b). A more extensive con-
sideration of possible mechanisms such as synaptic
potentials operating independently of action po-
tentials, intracellular electrotonus, etc., is presented
in Sheafor and Rowland 0974). A further candi-
date mechanism to be considered is the diffuse
release of a neurotransmitter by the "varicosities"
of axons that originate in cells of median raphe or
other brain stem nuclei.
62
DAYS
2
11
SAIN LIGHT
R
ECoG
r^^^^
y*ti*J5^^
I.M.
14
C$^^^
IjfV^^iMAAAa
19
TONE
FOOD
2 min
I 100/JV
_n
u
Fig. 1. Representative pain of ECoG-IMU tracings for individual trials taken from days indicated illustrate the
SP-IMU relationships observed during SA training in Cat 62. Close SP-IMU association (SP-1) was characteristic
during early acquisition (Day 2) and was obtained with R and during poit-R intervals throughout training (right
half of the figure). As the pre-R (N to R) negative SP was acquired (left half of the figure), it became increas-
ingly dissociated from the IMU measure (SP-2). Multiple unit integrator output is filtered from dc to half-
amplitude frequency response at 1.5Hz in all figures except Fig. 3. Negativity is down for Fig. 1-3.
-------
Dissociation of IMU and SPi During Conditioning
41
62
TRIALS
ACQUISITION
DAY 10
10
12
14
ECoG
100/uV
I • .
t*^^
I.M.
14
TONE
FOOD
Ffr 2. Representative ECoG tracings of seven consecutive trials (28-min continuous recording) illustrate
reliability of the SP pattern (top) acquired in the SA schedule in Cat 62. In relation to corresponding IMU
tracings (bottom), reliability of SP-IMU dissociation (SP-2) during the pre-R (N to R) interval and SP-IMU
association during the post-R (R to N) interval is demonstrated. IMU tracings also show incrementing in
CS-UCS interval of the R trials but little or no change to the same tone in the N trials.
Slope and duration of SP-2 has been shown to
depend on the interval between reinforcements.
Also, it is found to be relatively independent of the
N and R tones. The graded sustained potential
is also of interest as a possible alternative to an
oscillator system as an internal clock, but it remains
to be shown that the SP itself is not dependent on
underlying oscillators.
The above description pertains to SPs of long
duration as dependent variables. Their roles as an in-
dependent variable have only been indirectly implied
in the behavioral studies of Roy Anderson carried out
in our laboratory. Anticipatory SP shifts recorded
without benefit of associated observation of IMU
were seen to appear in cortices of rats on both fixed-
interval and fixed-ratio responding. Again, the slopes
of the expectant portion of the interval were propor-
tional to the time intervals governing the animal's be-
havior. To my knowledge, there has been no specific
test of whether the distribution of SP levels reached
just prior to a timed lever press correlates with the
distribution of times of responding in a specific tim-
ing task in animals; however, Anderson observed a
statistical proportionality between the degree of an-
ticipatory cortical SP developed and the proportion
of lever presses produced in three fixed-interval pro-
grams (Fig. 3). A constant intersection point for the
-------
42
Rowland
30 sec
LM RAV
FI30
-<*^lf
-------
EVENTS CONTINGENT UPON CORTICAL POTENTIALS
CAN LEAD TO RAPID LEARNING
J. S. STAMM, 0. A. GILLESPIE, AND B. B. SANDREW
Department of Psychology, State University of New York, Stony Brook, NY, U.S.A.
Research reported in this volume deals primarily
with HRP parameters as functions of experimentally
controlled conditions—i.e., these potentials are con-
sidered as dependent variables. In the present investi-
gation, a different experimental strategy was em-
ployed: the occurrence of specified electrocortical
events as dependent variables was utilized for training
monkeys on a spatial delayed response (DR) task.
The start of each DR trial was made contingent upon
computer-detection of an endogenous cortical poten-
tial of predetermined magnitude. The dependent
variable-the rate of task acquisition-was then
assessed as a function of the characteristics of the
pretrial contingency.
In previous research (Stamm and Rosen 1972),
macropotentials were recorded from several cortical
areas during performance of a DR task. The averaged
recordings delineated several distinct surface-negative
slow potential (SP) shifts during the course of a trial,
one of which occurred in prefrontal cortex toward
the end of cue presentation and the start of the intra-
trial delay. This shift seemed important in relation to
task performance because its magnitude was signifi-
cantly correlated with the level of correct responses,
but not with the duration of either the cue presenta-
tion or the delay. The physiological significance of
this SP shift is suggested by the finding that pre-
frontal units increase their firing during corres-
ponding epochs of the DR trial (Fuster 1973, Niki
1974).
Investigations of the functional role of prefrontal
cortex in humans and monkeys have provided evi-
dence for its implication in the regulation of attentive
processes (Fuster 1973, Picton and Hillyard 1974,
Pribram and Luria 1973). In accordance with this
view, the occurrence of prefrontal SP shifts and unit
activation during DR performance may be considered
as an expression of a heightened attentive state. At-
tention is especially important during cue presenta-
tion when the monkey must recognize the signifi-
cance of the location of the cue in order to program a
subsequent instrumental response. This interpretation
may be relevant to the general observation that mon-
keys normally learn the DR task very slowly, requir-
ing many hundreds of trials to attain criterion per-
formance. Slow acquisition may be a consequence of
training with constant intertrial intervals because the
spatial cue is then often presented while the monkey
is inattentive. Conversely, if cues are presented during
periods when monkeys are in a state of high atten-
tion, more rapid task acquisition should result.
This hypothesis was examined by using the mon-
key's endogenous prefrontal surface-negative SP shift
for starting the DR trial. Verification that such a
contingency would lead to rapid task acquisition
required control of other factors that could account
for any observed effect. Since enhanced acquisition
rates could result from generalized cortical activation,
monkeys were also trained with pre-cue negative SP
shifts from precentral cortex. In addition, animal
training procedures have shown that the requirement
of a preparatory response for trial initiation, such as
the pressing of a "readiness" lever, leads to more
effective and consistent task performance (e.g., Niki
1974). Therefore, monkeys were also trained under
conditions of trial initiation contingent upon the
occurrence of a behavioral response (lateral eye devi-
ations). This ocular movement was selected because
it is relatively simple, clearly identifiable, and has
been found concomitant with operantly conditioned
prefrontal SP shifts (Rosen et al. 1974).
Methods
Methods have been further detailed elsewhere
(Sandrew et al. 1977). A total of 13 stumptail
monkeys (Macaca speciosa) were trained. Under
sodium pentabarbital anesthesia, pairs of Ag/AgCl
nonpolarizable electrodes (Rowland 1968) were
chronically implanted bilaterally in prefrontal,
precentral, and occipital cortex with one electrode
-------
44
Stamm et al.
of each pair on the cortical surface and the other In
subjacent white matter. Prefrontal surface electrodes
were situated on cortex In the depth of the posterior
third of the principal sulcui. Miniature epoxy resin
electrodes were cemented to the bony orbit to record
electrooculograms (EOGs).
During testing the monkey was placed In a re-
straining chair, and its loft arm was attached by wrist
cuff to the shelf of the chair, The chair was in front
of a vertical panel that contained two circular display
windows, situated at the monkey's eye level, with 12
cm between centers. This separation corresponded
approximately to a 36° angle from the monkey's
nose. Each window served as both projection surface
for the stimuli and manlpulandum for the monkey's
response. A plastic food cup was mounted at the
center, below the windows. The DR trial started with
cue presentation, a 1-sec white illumination of either
the left or right window, followed by a blackout
period-the intratrial delay. Both windows were then
illuminated with blue light, and the monkey's press
on either window started another blackout period,
the intertrial interval (ITI). A correct response (on
the cued panel) was rewarded with delivery of a
sucrose pellet (4'S mg) to the food cup. Each testing
session consisted of 98 trials, with a pseudo-random
sequence for left and right cue presentation.
During testing sessions, the monkey was con-
nected by shielded cables to dc preamplifiers of a
Crass Polygraph. Transcortical electrocorticograms
(ECoGs) and horizontal EOGs were recorded on
seven-channel magnetic tape. Selected channels were
monitored on-line by a PDP-12A computer pro-
grammed to detect SP or EOG events that fell within
a defined voltage change over time. Upon detecting
a criterion event, the program initiated cue presenta-
tion. ECoG, EOG, behavioral data, and trigger pulses
were stored on digital tape.
Prior to surgery all monkeys were adapted to the
testing situation and trained with 8-sec ITIs on 0-sec
DR until they made 88 correct responses in one
session. Following surgery, each monkey was assigned
to one of four training groups (Table 1): (1) Group
FSP (n-4)-cue presentation contingent upon com-
puter detection of a left prefrontal surface-negative
SP shift of 50-100pVand 2.5-sec duration; (2) Group
MSP (n=2)-cue presentation contingent upon detec-
tion of a SP shift of the same parameters from left
precentral cortex; (3) Group LEM (n=2)-cue pre-
sentation contingent upon detection of an EOG volt-
age change that corresponded to an eye movement to
the right of approximately 40° during a 1.5-sec
epoch; and (4) Group YC (n=5)-no pre-cue require-
ments. Each YC monkey was yoked for ITIs to one in
another group (three to FSP monkeys and one each
to an MSP and an LEM). This was accomplished by
recording ITIs for each session and programming
these for the corresponding session with the yoked-
control animal.
Each monkey was first trained under the contin-
gent (on-line) condition on 2-sec DR until 90% cor-
rect response was reached in one session, In order to
aisess performance transfer to noncontlngent (off-
line) conditions, each monkey was then tested (one
or two sessions) with constant ITIs equal to the mean
ITI during the previous on-line session. If perform-
ance fell below criterion, on-line testing was repeated.
This procedure was repeated with successive delays of
4, 8, and 12 sec. The final testing phase was designed
for more direct evaluation of the monkey's attentive
functions by reducing the duration of cue presenta-
tion. Monkeys were retrained under on-line condi-
tions on 12-sec DR and 1-sec cues. During the subse-
quent two sessions, trials were programmed in a
random sequence for cue durations of 0.5, 0.2, and
0.1 sec.
Results
Averaged ECoGs and EOGs for an FSP and an
LEM monkey are presented in Fig. 1. Recordings
for every FSP monkey showed that the large pre-
cue negative SP shift was preceded by a smaller
positive wave that started about 4 sec before cue
onset (Fig. 1A). Criterion SP shifts were localized in
left prefrontal cortex; no concomitant SP events were
observed at right prefrontal, precentral, or occipital
electrode locations. ECoG recordings for MSP mon-
keys indicate a similar sequence of pre-cue SP shifts
localized to the left precentral area. EOGs for LEM
monkeys (Fig. IB) show that the large pre-cue right-
ward eye deviation was preceded by a smaller devi-
ation to the left and was followed by return toward
baseline level. For trials with left cues, these monkeys
attained maximal leftward eye deviations at- approxi-
mately 0.5 sec after cue onset, and their EOGs indi-
cated a subsequent drift to baseline levels. Compari-
sons of ECoGs and EOGs during the pre-cue period
indicated no systematic relationships between SP
shifts and lateral eye deviations. The pre-criterion
leftward eye deviation seen in Fig. 1A was not found
for the other FSP monkeys. During testing under
off-line (constant ITI) conditions, pre-cue ECoG and
EOG traces remained near baseline levels for all
monkeys, including YCs.
Behavioral results (Table 1) show substantially
faster acquisition by FSP than by other groups. Com-
parisons between FSP and YC monkeys show no
overlap of individual scores for either total errors or
sessions required to reach criterion performance on
-------
Cortical Contingencies of Learning
45
R.PREF.ECoG&EOG
Rt.t
12°Rt.llOOj-tVneg
i—i i sec
t Response
Fig. 1. Averaged left and right prefrontal electrocorticograms (solid lines) and concomitant electrooculograms
(dotted lines, superimposed) during criterion performance of 12-sec delayed response for: (A) FSP 297 and (B)
LEM 293. Separate averages (49 trials each) were obtained for trials when the cues were presented to the right
(Cfc) and left (C^j positions. Horizontal lines denote 1-sec cue presentations. Arrows signify the beginning of the
choice response period. Calibrations for ECoGs and EOGs are indicated. Upward deflections indicate cortical
negativity or eye-deviations to the right.
Table 1. Acquisition of 12-sec Delayed Response Task by Groups of Monkeys with Differing
Requirements for Trial Initiation"
Errors at
each delay
2 sec
4 sec
8 sec
12 sec
Total errors
Total sessions
Experimental
295
7
4
4
4
19
4
FSP
297
7
16
5
8
36
5
b
314
14
2
34
10
60
9
298
24
20
34
20
98
7
group
and monkeys
YCC
302
21
8
89
3
121
10
301
78
41
88
24
231
15
315
88
136
95
31
358
19
292
171
84
74
21
350
21
294
337
42
25
76
480
20
MSPd
313 316
32 51
4 86
42 124
7 65
85 326
8 15
LEMe
293 114
59 306
41 7
22 109
2 30
124 452
10 16
"Scores of error* and sessions Include criterion performence of 88 correct responses In a 98-trial session.
bFSP • lurface negative SP ihlft from left prefrontal cortex,
CYC • Intertrlal intervals yoked to those of monkeys In enothar group,
MSP - lurface negative SP ihlft from left precentral cortex.
aLEM • eye deviation to the right
-------
46
Stamm et al.
12-sec DR. Rapid acquisition by the FSP group is
also indicated by the finding that one monkey re-
sponded at 90% correct during every training session
and the others required few additional sessions. Al-
though one MSP monkey (No. 313) acquired the task
almost as fast as the FSP group, the other MSP was
much slower. Since MSP and LEM groups consisted
of only two monkeys each and their acquisition scores
overlapped, they were combined for statistical analy-
ses. Comparisons of total errors indicate significant
differences between FSP and YC (t=3.59; p<.01),
and between FSP and MSP-LEM groups (t=2.19;
p<.066), but not between YC and MSP-LEM groups
(t=0.59). Performance during off-line testing was
evaluated by transfer scores between the last on-line
and first off-line session at each delay setting. Mean
transfer scores were above 92% for every group, indi-
cating that monkeys indeed learned the DR task and
could perform well without pre-cue requirements.
Results for 12-sec DR testing with brief cue pre-
sentations (Fig. 2) also showed better performance
scores by FSP than by other groups. Only FSP mon-
keys continued to respond at the 90% criterion level
during testing with brief cues. Performance differ-
ences between FSP and YC groups were significant
for 0.1-sec cues (t=4.91; p<.01), but the differences
were not significant for 0.2- or 0.5-sec cues. Low
scores by the MSP group were the consequence of
poor response by one monkey (316), which seemed
unable to perform adequately under these conditions.
Low scores by LEM monkeys for 0.2-sec and 0.1-sec
cues may be attributed to an inability to detect cues
in the left position.
100
Sao
ee
oc
o
o
t80
ui
CJ
K
•70
60
v1' N MSP
1.0 O.S 0.2 0.1
CUE DURATION, sec
Fig. 2. Performance on 12-sec DR (two sessions, at
96 trials) with randomly presented cues of 0.5-sec,
0.2-sec, and 0.1-sec duration. The scores with 1-sec
cues were obtained during the previous session. The
testing contingencies for the different groups are
indicated in Table -1.
Discussion
The results show impressive enhancement in
learning the DR task when trial initiation is contin-
gent upon computer-detection of prefrontal surface-
negative SP shifts. Criterion performance to 12-sec
DR by the FSP group was attained with about one-
third the sessions and one-fifth the errors of the
yoked control group. These scores indicate substan-
tially greater facilitating effects on task acquisition
than previously found with either low-voltage stimu-
lation (Stamm 1964) or direct anodal polarization
(Rosen and Stamm 1972) of prefrontal cortex.
Enhancement was more pronounced when training
was made contingent upon prefrontal than when it
was contingent upon precentral negativity, although
further study is needed to establish, clearly, the corti-
cal specificity of effect. The functional significance of
the prefrontal contingency is reflected, furthermore,
by high transfer scores to noncontingent testing con-
ditions. This finding indicates that the monkeys had
indeed learned the task; i.e., their high performance
was no longer dependent upon the contingent
training procedure.
The present results support the view that the
surface-negative SP shift is an important physiological
phenomenon and an expression of neuronal activa-
tion (Fuster 1973, Niki 1974). The hypothesis that
this electrocortical process reflects a heightened
attentive state is supported .by the results of DR per-
formance with brief cues. Cues of 0.1-sec duration
clearly require the monkey to be highly attentive in
order to recognize the relevant cue. The finding that
correct performance with a brief cue presentation
was obtained only by FSP monkeys provides strong
support for the attentive hypothesis.
Facilitated learning may only be possible when
the crucial demands of the task occur during the trial
epoch of maximum prefrontal negativity. This is the
case for DR, which requires the monkey to recognize
the location of the cue and program its choice re-
sponse at that time. For other tasks that require
optimal attention for selection of the choice response
during other epochs of the trial, a requirement of
pre-trial negative SP shifts may not lead to enhanced
acquisition. This prediction was confirmed by an
additional experiment (Gillespie 1977) in which the
present monkeys were trained on a visually delayed
matching-to-sample (DMS) task with the same pre-
trial requirements as for DR. The FSP monkeys did
not acquire the DMS task faster than their yoked
controls.
-------
Cortical Contingencies of Learning
The present investigation demonstrates that the
acquisition of a difficult task can be facilitated by
presenting cues contingent upon the occurrence of a
specific cortical event. The prefrontal negative shift
selected as the criterion event in monkeys is analo-
gous to the CNV in humans (cf. Low et al 1966),
Walter (1966, 1967) demonstrated several years ago
that external stimuli could be triggered by com-
puterized detection of CNV-like negative shifts from
ihumans. With the development of techniques for
scalp detection of single electrophysiological events,
jit may be feasible to apply this method to the study
of human learning and performance. With the detec-
tion of endogenous electrocortical events for trial
47
filiation, it might be possible to enhance a subject's
.performance on attentive and cognitive tasks. The
iputative effects with this method may be of special
benefit to subjects with certain cognitive and emo-
tional disorders, such as mental retardation, learning
'disabilities, or schizophrenia.
Acknowledgments
This research was supported by National Science
Foundation Grant GB 35743X1. We wish to express
our appreciation to Steven Rosen and Richard Reeder
for their technical assistance in all phases of experi-
mentation and data analysis.
-------
SUSTAINED ACTIVATION OF CORTICAL NEURONS IN
STIMULUS-RECOGNITION TASKS1
J. M. FUSTER
Department of Psychiatry and Brain Research Institute, School of Medicine, University of
California at Los Angeles, Los Angeles,CA, U.S.A.
Studies of the effects of brain lesions on be-
havior have implicated certain cortical areas of the
monkey in the integrative processes underlying per-
formance of stimulus-recognition tasks. Delayed
response (DR) and delayed matching-to-sample
(DMS) are prime examples of such tasks. Their
most distinctive feature is a period of delay inter-
posed between a particular stimulus and a parti-
cular behavioral act predicated on the perception,
retention, and recognition of information pertaining
to that stimulus (Fig. 1). Inasmuch as correct per-
formance of these tasks requires the temporary
retention of sensory information, it is appro-
priate to consider them as tests of a certain form of
memory variously designated as short-term memory,
image memory, recent memory, or transient
memory.
In the adult animal, the functional integrity of
the prefrontal cortex is important for short-term
memory. Animals with reversible dysfunction of
the prefrontal cortex show a reversible deficit in
performance of DR and DMS tasks that require
temporary retention of spatial, kinesthetic, or
visual information (Fuster and Alexander 1970,
Fuster and Bauer 1974, Bauer and Fuster 1976).
The deficit is closely dependent on the length of
the delay. When that delay is zero or very brief,
the deficit is not apparent; the deficit appears at
longer delay and increases as a function of its
duration (Fig. 2). Consequently, it seems that
there is a neural process occurring during the delay
for which the functional integrity of the pre-
frontal cortex is important.
In order to investigate that process, the ac-
tivity of nerve cells in the prefrontal cortex and
in related structures during performance of delay
tasks has been explored. This exploration revealed
a large proportion of neurons exhibiting increased
firing during the delay (Fuster and Alexander
1971, Fuster 1973). The discharge of these neurons
is higher on the average during this period than it
is spontaneously, namely, between trials. Inter-
estingly, many units show sustained activation
during the delay but no activation during the pre-
ceding cue or the succeeding response of the animal
(Fig. 3). Concomitant recording of EEC and EOG
indicates that the phenomenon of sustained acti-
vation cannot be simply attributed to arousal or to
eye movements. Both EEC arousal and eye move-
ments are maximal during cue presentation and
during the response period, not during the delay.
Fig. 1. Diagrammatic representation of a monkey
performing stimulus-recognition tasks. Delayed
response (DR): the stimulus (cue) is white light
in one of the two lower stimulus-response buttons,
the animal turns: it off by pressing the button; a delay
ensues, at the end of which both buttons are lit; the
monkey is then rewarded with fruit luice for pressing
the button that has been lit before the delay. De-
layed matching-to-sample (DMS): the stimulus
(sample) is a color, red or green, presented on the
top button; after the delay, both colors appear in the
lower buttons; reward is given for pressing the button
with the sample color. Position of cue (in DR) and
of colors (in DMS) is changed at random from trial
to trial.
'This research was supported by NIMH Research Scientist Award KO5 MH-25082 and NSF grant GB-41867.
-------
Cortical activity and short-term memory
49
:
MATCHING-TO-SAMPLE
DELAYED
RESPONSE
*-»NORMAL TEMP
v~>FRWTAL &•
'-"PARIETAL W
Fig. 2. Effecti of cortical cooling on performance
of DMS and DR. Note the delay-dependent deficit
produced by cooling of lateral prefrontal cortex
on the two tasks. No significant effect Is produced
by cooling parietal cortex.
There are some indications that prefrontal unit
activation during the delay has something to do with
the process of retention of information. A relation-
ship has been seen between the level of activation
of some units and the level of correct performance
of the animal. Furthermore, certain control pro-
cedures Indicate that the phenomenon is determined,
at least in part, by the mnemonic attribute of the
cue (Fuster 1973); however, the role of prefrontal
units in retention is still obscure.
The temporal characteristics of,cellular activation
in the prefrontal cortex are particularly interesting
and may bear on the generation of cortical slow poten-
tials. Many units show the highest levels of discharge
at the end of the cue period and beginning of the
delay, when the information has just been presented
and the waiting period begins. Sharp increases in
firing are commonly observed at that time. Judging
CUE
from individual unit records, there then appears to
be a peak in probability of cell-firing within the pre-
frontal cortex. It ii at that same time that Stamm
and Rosen 0972), using a similar set of behavioral
operations, have found a slow negative surface
potential. This potential, which they relate to
memory formation or registration, may be a mani-
festation of the underlying cellular phenomena men-
tioned above.
The search for the source and function of pre-
frontal unit activity In short-term memory led to
the study of the visual transcortical pathway. This
pathway has been anatomically well demonstrated.
It is composed of a series of interlocking cortico-
cortical connections that originate in the striate
cortex and lead to the prefrontal cortex (Pandya
and Kuypers 1969, Jones and Powell 1970). The
last step of this pathway is constituted by connec-
tions between the inferotemporal and prefrontal
cortices. Histological studies with silver impreg-
nation techniques have established that these
connections are bidirectional: the prefrontal cor-
tex is not only the target of afferent fibers from
the inferotemporal cortex but the source of
efferent fibers running back to the infero-
temporal cortex (Pandya et al. 1971).
This anatomical evidence provided part of the
rationale for investigating the neuronal activity of
the inferotemporal cortex during visual short-
term memory tasks. This research was also encour-
aged by reports in the literature, mostly derived from
ablation studies, indicating that the inferotemporal
cortex is implicated in certain aspects of visual
memory (Gross 1972, Mishkin 1972).
II «:l,111 II 11 111 111 Ml Illl Ill
fCR
llilllll illUM.JllJI.Jl.il
tCL
JJL I 1 I MM II III I I Hill
•fl.iilJJJ.Illl
ii Hiiuinin i
.
5 sec
fCR
II
fCR
*' D'sc*ar8e °J a ce" in! the P™fr°"tal ™rtex during five trials of a direct-method DR task. A t left spon-
taneous discharge between trials Horizontal bars mark the period of presentation of a positional cue-placement
of food ™der one of two Identical objects, one on the right and the other on the left. Between trials and du ing
the mtratrua delay the objects are concealed behind a screen. Arrows mark the termination of delay
R^f^S Dented for choice. Ad,acent notations refettc" £
t. R, right, L, left). Note the increased discharge of the cell during the 32-sec delay.
-------
50
Fuster
A DMS task, using color as the sample or memo-
randum, has been recently utilized as the behavioral
paradigm for examining the activity of inferotemporal
neurons in visual short-term memory. So far, most
of the records have been obtained by microelectrode
penetrations of the anterior inferotemporal region,
including areas of the middle temporal gyrus and
posterior wall of the superior temporal sulcus. Many
color-coded cells have been found in these areas.
Such cells react differently to the sample depending
on its color. When using a task with two colors
(red and green), about the same proportion of units
have been found to be activated preferentially by
one color as by the other.
Again, as in the prefrontal cortex, sustained
activation of discharge has been observed during
the delay. Here, however, the level of activation
is generally more related to the specific information
which is relevant on each trial. This information in
DMS depends exclusively on the wavelength of the
sample color and is not spatially defined by posi-
tion or configuration. This implies that whatever
differences of firing are induced on a unit by the
25 r
sample cannot be attributed or related to differ-
ences in motor activity, including eye movements.
In many inferotemporal units the level of firing
during the delay is different depending on the color
of the sample. In some of the units, differential
firing is in fact only evident during the delay and
not during the sample-presentation period (Fig. 4).
In our view, these observations are presumptive
evidence that at least some units in the infero-
temporal cortex are constituent elements of corti-
cal neuronal assemblies that code and retain visual
information. Because of the mentioned relation-
ships between inferotemporal and prefrontal cortex,
and because of the latter's role in delay tasks, we'
suspect that the retentive function of infero-
temporal units is to some degree dependent on
tonic influences from the prefrontal cortex. We
have obtained some evidence, still sketchy and
preliminary, that supports this hypothesis. Pre-
frontal cooling results in the diminution or dis-
appearance of color-dependent differences in the
discharge of some inferotemporal units during the
delay. This occurs in conjunction with a drop in
performance, which is indicative of poor retention.
21)
GREEN SAMPLE TRIALS
RED SAMPLE TRIALS
FREQUENCY COMPARISONS
POST-GREEN VERSUS BASELINE
POST-RED VERSUS BASELINE
POST-RED VERSUS POST-GREEN
P
3.68 0.001
8.21 <0.001
5.66 < 0.001
Fig. 4. Discharge of an inferotemporal cell during performance of DMS with two colors. S: sample; M: match.
Firing is markedly increased during the delay of red-sample trials.
-------
PRELIMINARY STUDY OF PHARMACOLOGY OF
CONTINGENT NEGATIVE VARIATION IN MAN
J. W. THOMPSON, P. NEWTON, P.V. POCOCK, R. COOPER, H. CROW, W. C. McCALLUM,
D. PAPAKOSTOPOULOS
Burden Neurological Institute, Bristol, England, and University of Newcastle Upon Tyne, England
Although the contingent negative variation
(CNV) was fust described in 1964 (Walter et al.
1964), the electrogenesis of this phenomenon remains
to be determined. The possibility that at least one
putative neurotransmitter is involved in the gener-
ation of the CNV seems likely for at least two
reasons. First, evidence is accumulating from neuro-
physiological, histological, and histochemical studies
which suggests strongly that neurotransmitters are
involved in neuronal transmission within the central
nervous system, and there seems no good reason to
exclude the genesis of the CNV from this possi-
bility. Second, a large number of drugs have been
shown to modify the CNV. These include ethanol
(Kopell et al. 1972), carbon monoxide (Groll-Knapp
et al. 1972), cannabis (Kopell et al. 1972, Low et al.
1973), flurazepam (Hablitz and Borda 1973), caffeine,
nitrazepam, diazepam and cigarette smoking (Ashton
et al. 1973,1974,1976), barbiturate and amphetamine
(Kopell et al. 1974), and chlorpromazine (Tecce
et al. 1975). On the other hand, little attempt has
been made to use drugs as tools to analyse, system-
atically, the neuropharmacological mechanisms that
subserve the CNV. In animals, Pirch (this volume)
has shown that event-related slow potentials can
be recorded (dc) from anterior cortex of the un-
anaesthetised rat and that drugs can be used to study
the neuropharmacological mechanisms of the CNV
under these conditions. The present study appears
to be the first attempt of its kind in man.
The basic principle used in this pilot study was
to examine the effect on the CNV of administering
a drug with well-established selective blocking pro-
perties against a putative central neurotransmitter.
It was predicted that, if any or all of the neuro-
transmitters played a role in the electrogenesis of
the CNV, this fact would be reflected by an alter-
ation in the record, most probably by a reduction
in magnitude. Of several putative neurotransmitters
likely to be involved, three were considered ini-
tially: (1) acetylcholine, (2) noradrenaline, and
(3) dopamine, acting, respectively, on receptors
designated as muscarinic cholinergic, a-adrenergic,
and dopaminergic. Several pieces of evidence sug-
gest that one or more of these neurotransmitters
may be involved in the electrogenesis of the CNV.
First, there is histological and histochemical evi-
dence (Shute and Lewis 1967, Dahlstrom and Fuxe
1964, Ungerstedt 1971) on the distribution and
interconnection of cholinergic, adrenergic, and
dopaminergic systems in the brain. Second, the
case for the role of acetylcholine has been cogently
argued by Marczynski (this volume), while evidence
for the role of dopamine comes from Libet (this
volume).
The blocking drugs (phannacological antag-
onists) used in this study are listed in Table 1. Each
drug acts by competing with the corresponding
neurotransmitter for the appropriate pharmacol-
ogical receptors. A placebo, physiological saline,
was also used.
Methods
Sixteen tests were conducted on 10 healthy,
paid volunteers (6 male and 4 female), aged
18-30 years and of widely different occupations.
Two of the male subjects and one of the female
subjects took part in two, four, and three experi-
ments, respectively; the remaining seven subjects
took part in only one experiment. The project
was approved by the local Hospital Ethical
Committee.
A single-blind and pseudo-random design was
used with one drug administered per experiment.
EEC from the nasion + 2 cm, F3, F4,C3(Cz,C4,
P3,P4 referred to linked mastoids was recorded
with amplifiers modified to provide a 5-sec time
constant. Eye movements were monitored by
recording the vertical EOG. Movements of the
right (button pressing) hand were recorded via the
EMG. Electrocardiogram, respiration, and inter-
mittent blood pressure were also recorded.
-------
52
Thompson et al.
Table 1. Blocking Drugs (Pharmacological
Antagonists) Used in This Study
Neuro-
transmitter
acetylcholine
noradrenaline
dopamine
Antagonist8
atropine sulphate
thymoxamlne
HCI
metoclopramida
HCI
Dose
0.4-0.5 mg
0.08-0.1
mg/kg
5 • 7 mg
a Placebo was physiological saline solution 0.5 ml.
After control responses were obtained, a drug
was injected into the right deltoid muscle, and
the responses repeated. The intramuscular (I.M.)
route was chosen as a compromise between oral
and intravenous methods to avoid, respectively,
the vagaries of gastrointestinal absorption and
the risk of subjective effects of rapid attainment
of blood levels.
CNV tests commenced at times (min): -28, -8,
+2, +8, t]6, +22, +36, and +56; and blood pressure
(BP) at: -34, -22, -2, + 14, +28, +42, and +62 relative
to drug injection. For each set of recordings the sub-
ject received 24 trials. Sixteen trials uncontaminated
by eye movements were selected for off-line compu-
ter averaging. Subjects lay on a bed with eyes open
and fixated throughout.
Results
Atropine
Fig. 1 shows a series of eight CNVs recorded
from one subject who received a dose of atropine af-
ter the second CNV. The figure clearly shows the sub-
sequent decrease in CNV amplitude, which reached a
minimum at 16-22 mln with partial but irregular re-
covery in the CNVs that followed. The mean result
obtained from four subjects is shown in Fig. 3a
(t-test of CNVs at -8 and +22 min, p <.02).
Metoclopramide
Fig. 2 shows the result obtained in one subject.
The mean result obtained in four subjects (Fig. 3b)
shows a steady decrease in CNV amplitude, which
reached a minimum at 36 min (t-test at -8 and t22
min, p <.05 and at -8 and +36 min, p <.01).
Thymoxamine and placebo
Neither thymoxamine (Fig. 3c) nor the placebo
(Fig. 3d) produced a significant change in the mean
CNV in four subjects.
Topographical effects
Corresponding changes in the CNV were observ-
ed in recordings made from adjacent electrode sites.
Preliminary analysis indicated no topographical lo-
calization of drug effects.
Reaction time
RT to the imperative stimulus (S2) showed no
change with atropine or placebo, but it was lengthen-
ed by as much as 30% with metoclopramide and shor-
tened by 15% under the influence of thymoxamine,
in spite of the fact that the latter drug had no detect-
able effect on the magnitude of the CNV. These
changes in RT were statistically significant (t-test
p<.001).
Blood pressure and respiration were not affected
by any of the drugs used in this study.
Subjective effects
With one exception, none of the subjects com-
plained of any subjective effects during the experi-
ments. About 10 min after the injection of atropine,
one subject complained of transient blurring of vis-
ion, making it difficult to see the fixation spot.
Discussion
Preliminary results indicate that the CNV is de-
pressed by atropine and metoclopramide, but is un-
affected by thymoxamine and placebo administra-
tion. It was important that the doses of drugs used
did not produce significant subjective effects which
might have confounded interpretation of the direct
drug-Induced effects on the CNV. Since thymoxa-
mine has a very short plasma half-life (c. 10 min), it
is possible that no effect would be seen with intra-
muscular drug administration. It is important, there-
fore, to study the effects of thymoxamine adminis-
tered by intravenous infusion to maintain more con-
stant blood and brain levels during CNV recording.
These results suggest that both cholinergic
muscarinic and dopaminergic mechanisms are
involved in the generation of the CNV, although
the data do not provide any direct indication of the
neuroanatomical slte(s) involved. The results support
hypotheses that both a cholinergic mechanism
(Marcrynski, this volume) and a dopaminergic
mechanism (Libet, this volume) are involved in the
genesis of the CNV.
The present findings are not incompatible with
Somjen's proposal (this volume) that the CNV may
-------
Pharmacology of CNV in Man
53
EFFECT OF ATROPINE ON CNV
E.B.
- S2=tone
N+2
/2 sec
•28 min.
-8
A
+8
EMG
EOG
tie
V
+22
+36
+56
Cz
EMG
FJ^. 1. Effect ofatropine 0.4 mg I.M. injection (at arrow) in one subject. N+2 refers to an electrode 2 cm above
the nation.
-------
54
Thompson et al.
Si=click
EFFECT OF METOCLOPRAMIDE ON CNV B.H.
EGG
1 ,0 2 sec
-28 mm
N+2
EMG
EOG
+16
+22
+36
+56
Cz
EMG
g. 2. £//ecr of metoclopramtde 7 mg I.M. injection (at arrow) in one subject.
-------
Pharmacology of CNV in Man
55
24 -
22 -
V.
16
<
1
*
B
EFFECT OF ATROPINE
ONCNV
FOUR SUBJECTS 04 osmgiM
©® (D@ cs>
DRUG
-30 -20 -10
0 10 2O 3O 40
TIME.min.
*
b. EFFECT OF METOCLOPRAMIDE
ON CNV
FOUR SUBJECTS5 7ma'M
© ® (D © ©
IG
H
JO -20 -10 0 10 20 30 40 SO
TIME, min.
d. EFFECT OF PLACEBO
ON CNV
FOUR SUBJECTS
05ml physiological saline I M
c. E :ECT OF THYMOXAMINE
ON CNV
FOUR SUBJECTSooe-oimafcgiM
-30 -20 -10
10 20 30 40 SO
TIME.min.
.IO -'0 -10 0 10 20 M 40 50 SO
TIME.min.
Fig. 3. Mean effect in four subjects of (a) atropine (0.4-0.5 mg I.M.), (b) metodopramide (5-7 mg I.M.), (c)
thymoxamine (0,1 mgjkg I.M.) and (d) placebo (physiological saline 1 ml I.M.) on CNV. Drug injected at t0.
be generated by depolarization of glial cells. Somjen
conjectures that glial cell depolarization is deter-
mined by the extracellular potassium concentration
which, in turn, depends upon the activity of adja-
cent nerve fibres. If atropine or metoclopramide
block transmission in a substantial number of nerve
fibres, the reduced neuronal activity would be
accompanied by a decrease in extracellular potassium
concentration and, consequently, a reduced CNV.
Whether or not glial cells are involved in the elec-
trogenesis of the CNV, it is reasonable to postulate
that the generation of the CNV depends upon the in-
tegrity of cholinergic muscarinic pathways in the as-
cending reticular activating system. Dopamine may
enhance cholinergic transmission in these pathways
by inducing a synaptic change in cholinergic receptors
similar to those concerned with slow muscarinic or
s-EPSP responses in ganglia (Libet and Tosaka 1969).
Further experiments in man are planned in which a
range of drug doses will be used to extend the present
pharmacological analysis.
Acknowledgment
The authors wish to thank Dr. B. M. Guyer, William
R. Warner & Co. Ltd., for the donation of thymox-
amine HC1 and Miss D. Mustart and the Department
of Photography and Teaching Aids Laboratory,
University of Newcastle upon Tyne, for preparing the
figures.
-------
EFFECTS OF AMPHETAMINE AND PENTOBARBITAL
ON EVENT-RELATED SLOW POTENTIALS IN RATS1
J. H. PIRCH
Department of Pharmacology and Therapeutics, Texas Tech University School of Medicine,
Lubbock, TX, U.S.A.
Investigations concerning the effects of drugs on
event-related slow potentials (ERSP) in unanesthetiz-
ed, behaving animals are relatively few (Caspers 1963;
Marczynski et al. 1969; Marczynski 1971, 1972b;
Norton and Jewett 1967; Pirch and Norton 1967a,
1967b; Pirch and Osterholm 1975), and studies of
the effects of drugs on the human contingent negative
variation (CNV) have yielded varying results (Kopell
et al. 1972, Low et al. 1973, Braden et al. 1974,
Tecce and Cole 1974, Kopell et al. 1974). Thus, the
effects of different classes of drugs on ERSPs are in-
completely characterized, and, as a result, interpre-
tation of the meaning of drug effects is uncertain.
For example, it appears to be widely accepted that
ERSP amplitude is increased by "stimulant" drugs
and decreased by "depressant" drugs. Tecce and Cole
(1974) reported, however, that amphetamine may
either increase or decrease CNV amplitude and Ash-
ton et al. (this volume) found that nicotine has a
biphasic action on CNV amplitude. Additional know-
ledge of the effects of drugs on slow potentials would
be of value not only for interpretation of drug-in-
duced alterations of ERSP but also as a data base for
evaluating changes induced by toxic environmental
substances. Accordingly, this paper is a brief report
of some of the studies conducted in our laboratory
to characterize drug effects on slow potentials record-
ed from the cortex of rats trained on various behav-
ioral paradigms.
Methods
Female albino rats were housed individually dur-
ing the experimental period. Twenty-two gauge silver
wires were coated with silver-chloride and were im-
planted under pentobarbital and ether anesthesia af-
ter atropine pretreatment. The electrodes were in
contact with the active or reference site via agar-saline
pools (1% agar-1% saline). Artifact due to pulsation
of the brain was reduced by making the bridge with
two pieces of polyethylene tubing filled with the
agar-saline. One piece (PE 90) was fitted onto the e-
lectrode and was inserted into the other (PE 240)
which rested on the recording site. The dura was left
intact over the active recording site. The bone refer-
ence electrode was inserted into an agar-saline pool
formed by the polyethylene tubing placed in a small
depression drilled in the bone. The active electode
was placed over the cortex 2-3 mm anterior to the
bregma and to the right of midline. A reference was
placed approximately 2 mm anterior to the parietal-
interparietal suture on the left side either in bone (in
the discrimination experiment) or on the dura (in the
operant experiment). In other experiments with the
operant paradigm used here, there was little differ-
ence between SP responses when the reference at
this site was in bone, on dura or on lesioned cortex.
On the other hand, if the cortex under the active
electrode was damaged, SP response amplitude was
markedly decreased. EEC was recorded using pre-
amplifers set for dc recording. The 3-Hz half-ampli-
tude high frequency filter on the driver amplifier of
one channel was used to obtain a recording of the
dc potential change without the associated EEC.
Discrimination procedure
For conditioning and recording, animals (n=8)
were placed individually in a clear Plexiglas chamber
10 x 10 x 7.5-in. high with a grid floor. Before elec-
trode implantation, the animals were trained to assoc-
iate the delivery of reinforcement (45-mg food pellet)
with the sound of the delivery device so that they
would approach the feeding dish on hearing this cue,
thereby allowing associative conditioning to other
auditory cues. Two tone bursts of 0.5-sec duration
were employed for discrimination conditioning;
Supported in part by DHEW MH 23653, MH 29653,
by Tarbox Parkinson's Disease Institute at Texas
Tech University School of Medicine, and by the Mul-
tidisciplinary Research Program in Mental Health at
the University of Texas Medical Branch. A portion of
this work was performed in the Department of Phar-
macology and Toxicology at the University of Texas
Medical Branch, Galveston.
-------
Drug Effects on ERSPs in Rats
57
one (Sd) was followed after 3 sec by the delivery of a
food pellet while the other (SA) was not reinforced.
The two stimuli were 400-Hz and 4500-Hz tones at
SOdB. For some animals the 400-Hz tone served as
Sd, whereas the 4500-Hz tone was reinforced in
others. S" and SA were given on alternate trials.
Intertrial intervals varied between 45 and 90 sec.
Thirty trials were given in a single session (IS trials
with each stimulus), and only one session was con'-
ducted per day. The animals had free access to Pur-
ina Laboratory Chow during one hour at the end of
each day.
Voltage changes during the 3-sec period follow-
ing the onset of the conditioned stimulus were meas-
ured at each 0.25-sec interval using a Tektronix 31/53
data acquisition system. The area of the averaged SP
response to each stimulus was calculated and these
values were used for statistical comparisons and ill-
ustrations. '
d-Amphetamine sulfate was dissolved in 0.9% sa-
line and was administered intraperitoneally 30 mln
before trials began. Saline was given before each con-
trol session during the drug testing phase.
Operant procedure
Before electrode implantation, eight animals
were trained to obtain food reinforcement by press-
ing a lever when it extended into the chamber. The
lever was made of nonconducting acrylic. In the final
behavioral schedule, the retractable lever began to
move into the chamber 2 sec following the onset of
a 20-msec auditory warning stimulus (1600 Hz,
90dB). Once the lever was activated (approximately
3.9 sec after the onset of the trial), the rat had 2 sec
to obtain reinforcement. The lever was inactivated
and retracted either when pressed or 2 sec after be-
coming activated. Intertrial Intervals varied between
18 and 70 sec. Sixty to 65 trials were given In a single
session and only one session was conducted per day.
Acquisition of slow potential data began after the
first 20 acclimation trials.
EEC was recorded as described above. Output
from the polygraph was fed into a Nicolet MED-80
Data Acquisition and Analysis System. An additional
channel was used to record the lever-press, and the
signal was also fed to the computer for analysis of
response latencies. The data for each trial (including
500 msec of prestimulus baseline data) were digit-
ized at a rate of 78 samples per second and stored on
a floppy disk. At the end of the session, artifact-free
trials were averaged, lever-press latencies were meas-
ured, and the maximum negative amplitude of the
averaged waveform was determined. The mean of 39
samples obtained during the 500 msec prestimulus
period served as zero baseline.
d-Amphetamine sulfate was administered intra-
peritoneally 30 min before data acquisition began
and pentotarbital sodium (dissolved in distilled water)
was given subcutaneously 15 min before acquiring
data. Results are reported for those animals in which
SP responses remained sufficiently artifact-free for a
long enough period of time to allow administration of
all doses of a drug to an individual rat.
Baseline correlations
In most animals, the recording electrodes were
sufficiently stable that little or no drift occurred dur-
ing the experimental session. During the initial 20 ac-
climation trials the potential difference between the
two electrodes was balanced and no further adjust-
ment was made. Through the use of the data acquired
with the 3-Hz half-amplitude high frequency filter,
the prestimulus dc baseline values obtained for each
trial during the operant schedule were stored, the
most positive baseline for any trial in the session was
found, and this value was subtracted from all baseline
values (i.e., the most positive baseline was adjusted to
zero and all other baselines were negative relative to
this point). The maximum negative amplitude was
also determined for each trial. The Pearson product-
moment correlation coefficient was calculated to
examine the relationship between baseline and amp-
litude. All measurements and calculations were per-
formed by the computer.
Results
When the conditioned stimulus was presented
without reinforcement, Initially observed negative
slow potential (SP) responses decreased in amplitude
after a few sessions. This habltuation developed to
each conditioned stimulus used in these experiments.
When reinforcement was instituted, the amplitude of
the SP responses increased several fold and reached
maximum within a few sessions. Polygraph tracings
of SP responses during four trials in one rat trained in
the operant procedure are shown in the left panel of
Fig. 1. The right panel of Fig. 1 illustrates the aver-
aged SP response of 40 trials in the session. The neg-
ative slow potential response began shortly after the
stimulus and retruned to baseline following the de-
livery of reinforcement. In some cases a positive shift
developed after reinforcement, similar to the postre-
inforcement positive shift observed in cats by Marc-
zynskietal.(1969).
-------
58
Pirch
4-2 »c-*
F& 7. EEC recordings and averaged SP response from
a rat performing the operant task. Left panel: re-
cordings from four single trials; first arrow indicates
onset of warning stimulus; time between arrows is
2 sec; calibration is 250 //K; negative is up. Right
panel: average of 40 trials in session from which
the single trial recordings were obtained; sweep time
is 2 sec; calibration is 50 n V, negative is up.
Discrimination procedure
The first 10 training sessions on the discrimina-
tion schedule demonstrated a phase of stimulus gener-
alization during which large SP responses developed
to both stimuli. By session 12, the responses to the
reinforced stimulus (S") were significantly greater
than responses to the nonreinforced stimulus (S^)
(t-test for paired comparison of SP response areas,
p <.05). This difference increased and persisted
throughout the remaining 25 or more sessions.
Amphetamine produced a dose-related depress-
ion of SP responses to the reinforced stimulus at
doses of 0.25 to 2 mg/kg (Fig. 2a). The effect on
responses to the nonreinforced stimulus was, how-
ever, biphasic and depended upon the dose. The
lower doses (0.25 and 0.5 mg/kg) enhanced the re-
sponses, the intermediate dose (1 mg/kg) produced
no change, while the high dose (2 mg/kg) depressed
the SP responses (Fig. 2b). Examination of the
effects of 0.5 mg/kg clearly shows that this dose
of amphetamine depressed the responses to Sd at the
same time that responses to SA were enhanced. These
experiments illustrate the importance of dose and of
stimulus significance in determining the action of
drugs on event-related slow potential responses.
Operant procedure
Fig. 1 shows samples of single trial SP responses
in one animal, recorded during performance of the
operant task, and Fig. 3 illustrates averaged SP re-
sponses in four different animals, obtained in control
sessions. Mean lever-press latencies for control
sessions ranged from 70 to 750 msec after lever acti-
vation, depending upon the animal.
Both d-amphetamine and pentobarbital caused a
dose-related reduction of the amplitude of SP res-
ponses (Fig. 4). The doses of amphetamine were
0.25, 0.5, and 1.0 mg/kg while pentobarbital was
200 a. RESPONSE TO S
150-
a.
LU
f 100-
111
B
85 50
n.
, b. RESPONSE TO&A
•°,5 <:°1 <.ooi
rl J^T 1
!
JL
1
1
1.
1
D CONTROL
El DRUG
<.06
I
r1!
V,;
[if
<0°5..<.005
1
1
IMS
1 r1!
;
,' P'
1
1,
0.25 0.5 1.0 2.0 0.26 0.5 1.0 2.0
DOSE OF d AMPHETAMINE, mg/kg
Fig. 2. Effect of d-amphetamine on SP responses to
reinforced (Sd) and nonreinforced (S&) stimuli. Each
bar represents the mean of SP responses (calculated
areas) from eight animals. Vertical lines are standard
errors. Open bars show the responses after saline
treatment while shaded bars show the responses after
treatment with various doses of d-amphetamine. Re-
sponses were negative in polarity. P values are based
on paired-t comparisons.
Fig. 3. Averaged SP responses from control sessions
in four different animals performing the operant task.
Average of 40 trials. The time of each response is the
2-sec period following the onset of the warning stimu-
lus. Negative is up.
given in doses of 5,10, and 15 mg/kg. The number of
lever-presses was unaffected by the two lower doses
of amphetamine and there were no consistent changes
in latency. After 1 mg/kg, the four animals shown in
Fig. 4 obtained reinforcement in 98, 93, 63, and
-------
Drug Effects on ERSPs in Rats
59
50% of the trials and the lever-press latencies were
not significantly altered. The three animals treated
with pentobarbital obtained 100% reinforcement
after 5 rng/kg; 98, 88, and 50% after 10 mg/kg; and
38, 10, and 0% after 15 mg/kg. There were no con-
sistent changes in lever-press latencies, with some
animals showing increases and others decreases as
compared with the previous control session. It ap-
pears that if lever presses occur after drug treatment,
they are within the range of control latencies. The av-
eraged SP responses for trials in which the animals ob-
tained reinforcement were larger than the responses
for trials in which no lever press was made.
These experiments indicate that both stimulant
and depressant drugs can suppress event-related slow
potentials recorded from the rat cortex during an
operant task. Under the conditions of these experi-
ments, the slow potential response was a more sen-
sitive indicator of drug effect than the behavioral
measure.
correlations
Slow potential responses to the warning stimulus
were greater in amplitude during those trials in which
the baseline dc level was more positive as compared
with the amplitude of responses in trials with more
negative baselines. Fig. 5 illustrates this relationship
for a session in one animal. Averaged SP responses for
the 20 trials with the more positive (larger response)
and the 20 trials with the more negative baselines are
shown in the insert. Significant inverse correlations
between baseline negativity and SP response ampli-
tude were observed in eight rats in which baseline
75-
50-
o.
Z 25
0 J
0 0.25 0.5 l!o 0 5 10 15
DOSE d-AMPHETAMINE, DOSE PENTOBARBITAL,
mg/kg mg/kg
Fig. 4. Effects of d-amphetamine and pentobarbital
on SP responses associated with the operant task.
SP response amplitude is plotted as percent of the
amplitude of the vehicle control sessions with each
rat serving as its own control. Hach curve represents
an individual animal.
correlations were studied. These experiments indi-
cate that the magnitude of slow potential change in
response to a conditioned stimulus may vary accord-
ing to the dc potential level at the time of stimulus
presentation.
-240 -i
-200 -
UJ
a
t -150-j
a.
a.
w -100
O
5
X
< -50 ^
0-
r = 0.701
p <0.01
0 -50 -100 -150 -200
RELATIVE BASELINE, JUV
Fig. 5. Relationship between baseline dc potential
and SP response amplitude. Data from 40 trials of a
single operant session in one rat. See text for com-
plete description. Averaged SP responses for the 20
trials with the more positive (larger response} and the
20 trials with the more negative baselines are shown
in the insert. Calibration is 25 \lV. Negative is up.
Discussion
The results of these studies indicate that event-
related slow potential responses recorded from the
cerebral cortex of rats are altered by stimulant and
depressant drugs in a dose-dependent manner. Fur-
thermore, the experiments utilizing a discrimination
procedure suggest that the drug effects are also de-
pendent upon the behavioral significance of the elici-
ting stimulus. Thus, with a single drug one may ob-
serve enhancement or depression of SP responses.
With appropriate doses and behavior schedules, drugs
which are members of different pharmacological
classes can produce similar effects on SP response.
The fact that drugs with different modes of action
can cause similar alteration of event-related slow po-
tentials suggests that caution should be exercised in
interpreting the meaning of a drug effect, especially
when based on single-dose or even two-dose studies.
It is clear that chemical agents which affect arou-
sal mechanisms produce changes in ERSP ampli-
tudes. Other factors which alter arousal such as the
-------
60
Pirch
experimental setting or behavioral task can also be ex-
pected to influence slow potential responses. A role
for arousal mechanisms in determining amplitude of
the CNV was proposed by Irwin et al. (1966) and Re-
bert et al. (1967). Tecce (1972) further suggested
that an inverted-U relationship exists between level of
arousal and amplitude of slow potentials. Using
Tecce's model, one might predict that if the arousal
level were optimal for maximum SP amplitude under
the conditions of the experiment, either an increase
in arousal induced by a stimulant drug or a decrease
in arousal produced by a depressant drug could cause
a reduction of the slow potential amplitude. Such a
model might apply to the effects of amphetamine and
pentobarbital in the present experiments using the
operant task. In other studies with rats trained on a
simpler paradigm in which food reinforcement was
automatically delivered, both d-amphetamine and
pentobarbital reduced SP response amplitude (Pirch
and Osterholm 1975). When doses of each agent
which depressed SP amplitude were combined, the
SP response was restored to control levels. Those
results would be consistent with the concept of an
inverted-U relationship between arousal and SP amp-
litude. Arousal is difficult to define, however, and
some other process such as attention may be more
directly related to amplitude of slow potentials.
Although some consistent relationships appear to
exist between arousal and ERSP amplitude, the
effects of amphetamine on the discrimination pro-
cedure suggest that other processes may also play a
role.
An additional factor which has been proposed to
affect ERSP amplitude is the baseline dc potential.
Knott and Irwin (1968) suggested a "ceiling effect"
whereby greater negativity of the dc level at the time
of stimulus presentation results in a limitation of the
negative slow potential change which can develop in
response to the stimulus. The results of the dc base-
line studies reported here are consistent with the
"ceiling" hypothesis. Additional experiments are
under way to determine whether the drug-induced
changes in SP responses are related to alterations of
the baseline dc level.
-------
CHOLINERGIC MECHANISM OF SLEEP ONSET
POSITIVE VARIATION AND SLOW POTENTIALS
ASSOCIATED WITH K-COMPLEXES IN CATS
T. J. MARCZYNSKI
Department of Pharmacology, University of Illinois at the Medical Center,Chicago,IL, U.S.A.
In the cat, sleep onset is characterized by high-
voltage, rhythmic (7 to 9 c/sec), alpha-like bursts
over the pane to-occipital cortex with highest am-
plitude over primary and secondary visual pro-
jections. These electrocorticogram (ECoG) pat-
terns are always associated with large epicortical
positive slow potentials (SPs) the amplitude of which
ranges from 200 to SOO^iV if recorded epidurally with
reference to subjacent white matter or a distant
relatively indifferent electrode located over the
anterior ectosylvian gyrus. Since this localized SP
always occurs during sleep onset, it was termed "sleep
onset positive variation" (SOPV) (Marczynski et at.
1971b).
During slow wave sleep (SWS) mild auditory,
somatosensory, or visual stimuli trigger K-complexes
that are immediately followed by bursts of alpha-
like activity and SPs whose topograpical distributions
are virtually identical with those of SOPV
(Marczynski et al. 1969). The assumption that the
SOPV phenomenon reflects an active process of
internal inhibition in the Pavlovian sense is supported
by the observation that, in a relaxed cat, 7- to 9-c/sec
flash stimuli produce responses indistinguishable from
SOPV and shorten the period necessary for the
emergence of SWS (Marczynski and Sherry 1972).
Hence, the SP associated with K-complex (K-SP) can
be regarded as reflecting a homeostatic mechanism
aimed at maintaining SWS.
In the present study, the effect of mild auditory,
somatosensory, visual, and vestibular stimuli were
investigated in the cat on the emergence of K-SP
prior to and after administration of scopolamine
hydrobromide. In addition, the SOPV phenomenon
was also quantified prior to and after drug adminis-
tration.
Methods
Four adult cats were used. Under pentobarbital
anesthesia, Ag/AgCl electrodes were implanted epi-
durally over the posterior marginal (M), medial
suprasylvian (S) and anterior ectosylvian gyri (E).
The technique of implantation, recording, and
integration of SPs, using Grass cumulative inte-
grators, has been previously described (Marczynski
et al. 1971b). The output of the integrator was ad-
justed to produce two pen deflections in response
to a positive shift of lOO^V lasting 1 sec. This value
was accepted as one unit of SP. Only the SP between
the S and M gyri were quantified and used for
statistical evaluation, using the Student's t-test.
Experiments were conducted in a 1-m sound-atten-
uating Lehigh Valley test chamber provided with
dim light and a one-way window. Auditory stimuli
of approximately 6 dB above background noise were
presented through a loudspeaker attached to the
ceiling. The Grass visual stimulator unit, modified
to produce noiseless flashes, was also attached to the
ceiling. Electric somatic stimulation was delivered
through a pair of stainless steel electrodes implanted
subcutaneously on the cat's back. The electrodes
were connected to a Grass S-8 stimulator and stimu-
lus isolation unit; the parameters of stimulation em-
ployed were 3 - 5V and 0.5 • 0.8 msec duration.
Experiments were conducted between 2 and 5 p.m.
One hour prior to the session, the cat was provided
with food and milk. After satiation, the cat was
allowed to sleep in the basket suspended by strings
from the ceiling of the chamber such that, when
one string was pulled, the basket would sway to
provide vestibular stimulation. K-SPs were quantified
by counting the number of integrator deflections
during a 7-sec time period following stimulus pre-
sentation. At least 10 K-SPs were obtained for
each modality and each dose of scopolamine
hydrobromide. SOPV responses were quantified
by counting integrator deflections from the
moment the cat assumed sleep posture to the
emergence of SWS lasting at least 10 sec. Output
of the integrator was set to zero when the cat
assumed sleep posture. If for any reason the cat
did not develop SWS, raised the head, or left the
basket, the record was disregarded.
-------
62
Marczynski
Results
SOPV responses
In most instances, 4 to 7 SOPVs, each lasting 3
to 12 sec, were observed prior to the emergence of
SWS. Fig. 1A shows three SOPV responses in one cat.
Usually, after the first and second SOPV, a "residual"
positivity was observed, larger over the M gyrus and
smaller over the S gyrus, thus causing a tonic SP shift
below baseline in the S-M lead and above baseline in
the S-E lead. Residual SPs did not continue to accu-
mulate with subsequent SOPVs and tended to dissi-
pate with the onset of SWS (marked with a vertical
dashed line) as shown in Fig. 1A (right) and IB (left)
of the continuous record. The use of the S gyrus as
the reference caused the typical mirror reversal pat-
terns due to the decreasing potential gradient along
the M-SOE line. A detailed description of the topo-
graphical distribution of the SOPV has been report-
ed elsewhere (Marczynski et al. 1971 b).
During control sessions, the sum across cats of
SOPV responses observed from the moment the
animal assumed sleep posture' to emergence of SWS
ranged from 46 to 105 Units (mean 56.7; S.D. + 3.4;
N = 50). In cats treated with scopolamine hydro-
bromide (0.02 mg/kg, i. m. ) 30 min prior to a
session, this value was reduced by 27.6% (S.D. +
0.6; p < 0.01). The dose of 0.04 mg/kg reduced
responses by an average of 55.3% (S.D. + 0.08;
p < 0.0001). After the latter dose, the alpha-like
bursts during SOPV responses never occurred in
long rhythmic trains, but were often interrupted
by irregular delta waves. Despite the conspicuous
reduction in the amplitude of SOPVs, their dur-
ation (6.7 sec per single response; S.D. +_ 1.4) was
not significantly different than that of the control
SOPV (7.1 sec; S.D. +. 1.9;p< 0.05). After higher
doses of scopolamine (0.06 mg/kg, i.m.), the back-
ground amplitude of the ECoG increased and it
was difficult to decide when the SWS emerged.
Choppy alpha-like bursts, if present, were asso-
ciated with small SP shifts (Fig. 1 bottom left).
K-complex SP (K-SP)
The control K-SP in response to an auditory (A),
somesthetic (S), vetibular (V) or flash (F) stimulus
are shown in Fig. IB. The patterns and topographical
distributions of these responses were virtually identi-
cal for all modalities tested and closely resembled
those of the SOPV. In cats treated with scopolamine
(0.02 mg/kg i.m.), K-SPs were reduced by an average
of 32.2% (S.D. ± 0.7; p< 0.01), and doses of 0.04
mg/kg reduced these responses by 67.4% (S.D± 0.9;
p< 0.001). As shown in Fig. 1C (right), a dose of sco-
polamine 0.06 mg/kg almost totally suppressed these
responses and the EcoG and SP remained "fro/en"
within a relatively narrow band of fluctuations.
Discussion
Since scopolamine blocks SOPV and K-SP
responses, it most likely interferes with the
process of internal inhibition. With moderate doses
of scopolamine, the duration of "abortive" SOPVs
did not change, although their amplitude was re-
duced. This indicates that "primary" hypnogenic
influences which trigger SOPV responses are not
affected, but the "execution" of SOPVs is impaired,
most likely at the thalamocortical level. Likewise,
scopolamine suppresses alpha-like postreinforccment
ECoG synchronization (PRS) and the associated
reward contingent positive variation (RCPV) in
cats trained to lever press for milk reward, although
the duration of the choppy PRS and that of the
abortive RCPV responses is not significantly changed
(Marczynski 1971).
The phasing theory of neuronal activity, based
on recurrent inhibitory circuits in the thalamus,
which are reputed to control alpha rhythm, implies
that a certain level of "synaptic pressure" is necessary
to initiate and drive the phasing circuits (Andersen
and Andersson 1968). Numerous microelectro-
phoretic studies of single neurons in specific thalamic
relay nuclei (Steiner 1968, McCance et al. 1968,
Tebecis 1970, Phillis 1971) suggest that the primary
role of chohnergic projections described by Shute
and Lewis (1967) is facilitation of sensory input.
Hence, blockade of cholinergic influences may result
in reduction of synaptic pressure to a level insuffi-
cient to initiate and drive phasing circuits in thalamus
and cortex. Evidence that further supports this
contention and the hypothetical interactions be-
tween cholinergic and monoaminergic projections
that seem to control the phasing mechanisms have
been discussed elsewhere (Marczynski and Burns
1976 and this volume).
The occurrence of SOPV and K-SP in associ-
ation with alpha-like bursts can be interpreted as
resulting from a phasic tendency toward hyper-
polarization of large populations of neurons in
the cortex and electrotonic spread of IPSPs to
apical dendrites which is reflected as surface
positivity (Creutzfeldt et al. 1969). During
bursts of alpha activity in the thalamus (Andersen
and Andersson 1968) and visual cortex (Creutzfeldt
et al. 1969), many neurons show primary IPSPs
(i.e., not preceded by EPSPs) and may remain
silent in a state of hyperpolarization. These
neurons are the most likely source of phasic sur-
face positive SPs associated with alpha-like bursts.
The participation of glia cells may be secondary
to phasic changes in concentration of ions in the
extraneuronal fluid.
-------
Cholinergic mechanism of SOPV
63
The virtually identical patterns and distri-
bution of SOPVs and K-SPs triggered by various
modalities can be explained by the fact that, in
the visual cortex, there are neurons that respond
to auditory, somesthetic, and vestibular stimuli
(cf. Morrell 1972). The equipotential role of various
modalities in generating K-SPs and their localization
over primary and secondary visual projections
indicate that striate and parastriate cortex plays a
dominant role in internal inhibitory processes.
CONTROL
100/iV
INT
SCOPOLAMINE HBr 60 \i g/kg, I. M. 30 min
Fig. 1. Typical SOPV responses and K-SPs during slow wave sleep to auditory (A), somatosensory (S), vestibular
(V) and flash (F) stimuli (top and middle, respectively). Scopolamine hydrobromide blocks these responses
(bottom). For further explanations, see text.
-------
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-------
II. MOTOR CONTROL
Section Editor:
Demetrios Papakostopoulos
Burden Neurological Institute
Bristol, England
-------
THE PRESENT STATE OF BRAIN
MACROPOTENTIALS IN MOTOR CONTROL
RESEARCH - A SUMMARY OF ISSUES
D. PAPAKOSTOPOULOS
Burden Neurological Institute, Bristol, England
The following section is based on preconference
correspondence and on the Motor Control plenary
session. The objectives of this section are to analyze
and evaluate the contributions of macropotential
research to the neuropsychophysiology of movement.
Movements as integral formations
The phenomena encompassed by the term "motor
control" are very broad. The neurologist, neurophysi-
ologist, neuroanatomist, neurochemist, experimental
psychologist, ethologjst, and cybernetician are in one
way or another studying the organization of move-
ment, its various components, executive organs, and
spatiotemporal relationships. Is there need for yet
another approach to the study of motor control
processes?
There is a vast experimental literature characteriz-
ing the electrical activity of single motor units and
muscle discharge patterns. Bernstein (1967) has
observed, however, that unit discharge patterns are far
removed from movements as integral formations. The
limits of most techniques, such as electrical stimula-
tion, used to study movement have been pointed out.
For example, Phillips (1966) remarks that electrical
stimulation does not evoke the natural functioning of
cortex and that movements are intracerebral processes
which are not simply equated with the contraction of
muscles. Although there is increasing realization that
movements are "integral formations" which require
conceptualization in terms of intracerebral processes,
it is less clearly understood that such processes extend
beyond the realm of local brain architectonics. The
concept of movement introduces the need to think in
terms of higher levels of organization than hitherto
accepted forms of anatomical and physiological evi-
dence permit.
Mountcastle et al. (1975) summarized the prob-
lem: "Some of our observations suggest that another
mode of organization is from time to time superim-
posed on the basically columnar pattern and that this
additional set formation is dynamic and conditional
in nature." The study of such dynamic and condition-
al sets has hitherto been the province of psychological
research. McKay (1966), however, has pointed out
that "the entities and paths of the psychologist's mod-
els have classically had few pretentions to anatomical
significance, while those of the physiologist, for rea-
sons of sheer complexity, have been correspondingly
vague in their predictions of gross human behavior."
Macropotential research could supplement classical
methods by offering neurophysiological insight and
precision to those dynamic and conditional intracereb-
ral processes which underlie the highly integrated units
of behavior and internal processing known as move-
ments.
Movement-related brain macropotentials
Electrical brain activities generally referred to as
motor-related potentials include sustained and phasic
changes time-locked to self-initiated actions or to
actions triggered externally with or without forewarn-
ing. Signal averaging techniques have been widely used
to study the Bereitschaftspotential (BP) and CNV,
although this technique has diverted interest from
movement-related brain macropotentials (MRBMs)
which can be observed in scalp recordings without
averaging. The mu rhythm (Gastaut 1952, Chatrian
et al. 1959) is an example of such an event.
Fig. 1 illustrates corticographic analogs of the mu
rhythm recorded from sensorimotor cortex. Note that
sensorimotor response is maximal contralateral to the
active hand, while occipital rhythms are not altered
by movement. The sensorimotor response is less with
iprilateral or sustained contralateral clenching. These
observations suggest both topographical and situation-
al specificity of intrinsic sensorimotor rhythms. The
significance of this specificity and its relationship to
other macropotentials occurring simultaneously are
important questions for future research.
The study of evoked potentials while the organism
remains hi a passive state may also contribute to our
understanding of the organization of movement.
Dubrovsky (this section) discusses the significance of
-------
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L. ARM FLEX. EMO
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CONTINUOUS PRESS R.
flexor* and extensor,
. 6-9). and °"P°f**» (R PREC.). Precentral and tral
-------
Macropotentials and Motor Control
79
visual and cutaneous input to the cortex. Investiga-
tions of somatosensory evoked potentials, further-
more, have suggested specific sensory input to precen-
tral cortex (Papakostopoulos et al. 1974a, 1975;
Papakostopoulos and Crow, in press). Further evidence
concerning afferent pathways to the motor cortex is
contained in neurophysiological (Murphy et al.
1975) and neuroanatomical (Kalil, this section)
studies.
Three factors must be taken into account in any
attempt to classify movement-related brain macro-
potentials. The first is the polymorphism of macro-
potentials which can be recorded from the same corti-
cal area during the same period of time. The second
factor relates to the spatial properties of specific
components. The third factor concerns the temporal
sequence of movement and associated macropotential
patterns. Macropotentials tend to convey a deceptive
static picture of the brain during the organization and
execution of movement unless the temporal sequence
of motor and electrical events is carefully defined.
These factors have been taken into account in
the following classification of movement-related brain
macropotentials.
I. Resting potentials— potentials related with the
state of the motor system at rest (e.g., sensori-
motor rhythm and somatosensory evoked poten-
tial).
2. Preparatory potentials-potentials related with
functions during the preparatory period (e.g.,
BP and CNV).
3. Initiation potentials -potentials related with
the initiation period (e.g., motor potential).
4. Movement execution potentials - potentials
related with the execution of the movement
(e.g., N2 or motor cortex potential).
5. Termination potentials - potentials related with
the termination of the movement (e.g., P2 and
skilled performance positivity).
Serial ordering in movement forms the basis of
this taxonomy which may be viewed as a five-interval
time scale. This classification system has the advantage
of accommodating the fragmented data derived from
movement-related macropotential studies as well as
facts and theories about motor control derived from
other disciplines.
Factors such as spatial coordination, target deter-
mination, holding, and achievement must also be con-
sidered during the unequal intervals of this time
sequence. At any point in the sequence of operations
involved in any motor act, different parts of the body
are subject to different postural states and displace-
ment forces according to the nature or target of the
movement. Brain macropotentials could reflect any
one or combination of these factors.
Functional issues
Three questions arise with regard to the nature
and significance of changes occurring during each time
interval. First, do the macropotential changes reflect
factors related to movement alone, or do other non-
motoric factors contribute? Second, to what extent
do peripheral and central changes involved in every
stage of movement influence the macropotential in
progress? Third, to what extent do movements influ-
ence the sensitivity or selectivity of the organism
toward environmental changes, and what are the
associated effects on brain macropotentials?
The first question, raised briefly by Cohen during
discussion, can easily diverge to a semantic argument
of what constitutes a motor act. On the other hand,
this issue underlies the venerable controversy whether
the CNV and BP are functionally equivalent (cf.
McCallum, this section). The excitability of the spinal
monosynaptic reflex, for example, increases during
the CNV interstimulus interval in the absence of any
overt behavior or EMG activity (Papakostopoulos and
Cooper 1973).
This evidence indicates involvement of motor
structures during the preparatory process but does not
help to differentiate the task-specific operations which
take place during preparation. There is evidence
(Papakostopoulos, this section) that the context within
which similar motor actions are executed is reflected
in the amplitude and wave form of event-related mac-
ropotentials. The evidence suggests that preparation
involves motor structures, even at the spinal cord
level, and that cognitive or contextual elements of
action are reflected in macropotential configurations.
It is probably as misleading to attempt to distin-
guish a particular movement from the purpose for
which it has been organized as it is to suggest a clear-
cut separation of sensory and motor elements within
the nervous system. Magendie pointed out in 1824
that the separation of nerves of feeling and nerves of
motion is arbitrary and of no practical value.
The second question, relating to feedback, was
discussed with reference to the motor potential (MP)
of Xornhuber and Deecke (1965), the N2 component
of Ulden et al. (1966) and Vaughan et al. (1968),
and the positivities which follow it known as reaffer-
ent potentials (Vaughan et al. 1968, Deecke et al.
1969). The first two terms are generally considered to
be interchangeable (cf. McAdam 1973 and Buser
1976). However, Deecke made explicit the position
of the Ulm group that the MP is not equivalent to N2.
Deecke described the MP as an additional negativity
appearing at the precentral cortex contralateral to the
moving finger 54 msec before EMG onset. This com-
ponent is superimposed on an already asymmetrical
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80
Papakostopoulos
BP. The problem is how to distinguish between the
two entities if the BP itself is asymmetrical.
An alternative hypothesis is that the N2 compon-
ent is an index of reafferent activities (Papakostopou-
los et al. 1974a, 1975). Evidence of specific sensory
input to precentrai cortex has been found in man
(Goldring and Ratcheson 1972) and animal (Kalil,
this section). The results of Gerbrandt et al. (1973)
and Papakostopoulos et al. (1975) indicate, further-
more, that N2 follows movement onset. This evi-
dence supports a reafferent view of the N2
component.
In discussing macropotentials associated with
afferent input to the cortex, account must be taken
of the state of the nervous sytem preceding input.
For instance, the configuration of a sensory evoked
response differs when a subject passively receives a
stimulus compared to when the subject is triggered to
action by the stimulus or when the stimulus occurs as
a result of motor action by the subject. Precentrai
and postcentral cortical areas process afferent input
in different modes, depending on the motor contin-
gencies of the situation. Hazemann (this section)
reviews evidence concerning the effect of movement
on sensory evoked potentials.
Vaughan et al.(1968) and Deecke et al. (1969,
1976) suggested that the positive potentials which
follow N2 reflect response reafferent activity. The
response reafferent hypothesis, however, is not consis-
tent with the results of several studies reported in this
section (see Abraham et al., Delaunoy et al., Otto et
al., and Papakostopoulos) which suggest that these
potentials could reflect neurophysiological concomi-
tants of internal afferent feedback or efferent feed
forward processes, possibilities which require experi-
mental verification.
Another related issue is the homogeneity of post-
movement positivities and other late positive compon-
ents described in the ERP literature. For example, is
the P300 functionally related to positive potentials
associated with visual detection of infrequent events
(Cooper et al. 1977) or to skilled performance positiv-
ity (Papakostopoulos, this section)?
Theoretical and experimental integration
Kornhuber and his colleagues (Kornhuber 1971;
Deecke et al. 1973, 1976) have proposed a compre-
hensive theory of motor function which integrates
data from several disciplines including event-related
potential research. According to this theory-, prepara-
tory functions are executed prior to movement in
several regions of the brain such as the cerebellum,
basal ganglia and precentrai and parietal cortex. The
specific loci involved in preparatory functions vary
with the type of anticipated movement. This theory
provides an excellent example of how macropotential
research can contribute to clinical knowledge and
stimulate further experimentation in the area of motor
control.
Another approach seeks to integrate data from
the central, peripheral, and autonomic nervous sys-
tems during the preparation for and execution of
movement. This approach, exemplified by the work
of Lacey and Lacey (1970), Ingvar (1977), McCal-
lum et al. (1973, 1976), Cooper et al. (1975), and
Papakostopoulos and Cooper (1973, 1976, this sec-
tion), is more experimental than theoretical, but has
also contributed substantially to the understanding of
motor control processes. These investigators have
studied changes in cortical 02a, heart rate, and spinal
reflexes during specific phases of movement.
Need for technological and conceptual
innovation
Three methodological issues were discussed: (1)
the effect of experimental artifacts on the reliability
of data; (2) the need to study integrated motor sequen-
ces in place of isolated, purposeless actions; and (3)
the limits imposed by current technology.
Extracranial artifacts such as the large electrical
potentials generated by eye movements (rotation of
the comeofundal dipole) pose serious problems in
most areas of ERP research including motor control.
Despite the ubiquity of the problem and the keen
awareness of most investigators, no foolproof method
has yet been devised to entirely eliminate eye-move-
ment artifact from ERP recordings in all subjects.
Rosen (this section) presents disquieting evidence
from corticographic recordings in monkeys that oculo-
motor processes associated with saccadic eye move-
ments may significantly alter cortical evoked poten-
tials even when the eye is fixated. The contribution
of frontal eye fields to and the effects of different
oculomotor control strategies on ERPs require further
study.
The reports of McCallum and Papakostopoulos
(this section) illustrate the need for refinement of
experimental procedures. Both experiments demon-
strated that the amplitude and spatial distribution of
the CNV and BP were task dependent. Task demands
were found to be a more important determinant of
macropotential configuration than were individual or
group stereotypes. Individual differences do exist, as
discussed by Deecke et al. (1976 and this section),
but the present data suggest that such differences will
be more effectively revealed in experiments which
involve complex patterns of interaction with the
environment where the pattern of response is flexible
rather than stereotyped.
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Macropotentials and Motor Control
81
Naturally, such developments will make Increased
demands on technology in order to study the neuro-
physiological substrate of complex, integrated move-
ment. Otherwise, we will be limited to the study of
simple, stereotyped responses. Improved technology
will not only provide stronger evidence for the existing
range of phenomena, but will reveal more clearly
where fundamental discrepancies exist. For example,
Gerbrandt's attempt (this volume) to determine the
smallest number of scalp electrodes necessary to study
motor processes revealed problems in previous concep-
tualization 01 potentials related to self-paced move-
ments. His data suggest that the BP is far from being
a unitary phenomenon and that its waveform varies
with time in different ways for different areas.
Such approaches underline the complexity of the
issues we face and challenge our traditional methodol-
ogies. Although there may be agreement that the BP
is a preparatory potential, one is obliged to ask how
many types or variants of preparation exist. We are
only at the threshold of a constructive neurophysiolog-
leal analysis of preparatory processes and ideational
components of movement organization in man. The
solution probably lies in understanding the spatiotem-
poral organization of macrostates. The number of
macrostates that can be seen with macroelectrodes
will be determined by the spatial constant (i.e., the
degree of attenuation over distance) of the brain which
is yet unknown for cortical or scalp recordings.
(Methodological details and problems of spatial averag-
ing are discussed extensively in Section IX). Perhaps
spatial sampling techniques already within the bounds
of our technology will enable us to elucidate what
Katchalsky et al. (1974) have called the dynamic
pattern of brain macrostates.
-------
SPINAL CORD STIMULATION AND
EVENT-RELATED POTENTIALS1
P. ABRAHAM, T. DOCHERTY, AND S. SPENCER
Royal Victoria Hospital, Netley, Southampton, England
A. COOK AND A. OYGAR
State University, New York, NY, U.S.A.
L. ILLIS AND M. SEDGWICK
Wessex Neurological Centre, Southampton, England
Cook (1976) reported insertion of electrodes
percutaneously in the thoracic epidural space of the
spinal canal in 185 patients with multiple sclerosis
(MS). Following a period of continuous inductively
coupled electrical stimulation, 69 patients showed
significant improvement in some neurological function
such as speech, bladder function, or locomotor perfor-
mance. Electrodes were implanted permanently in
these patients and stimulation was maintained;
improvement persisted in 51 cases.
The mechanism by which electrical activity in-
duces this benefit is unknown. Symptomatic improve-
ment could be the direct consequence of electrical
stimulation of nonspecific projection systems of the
brain via the midbrain reticular formation. If so, evok-
ed and slow potential changes might provide useful
measures from which to infer the underlying neuro-
physiological mechanism. McCallum et al. (1973), for
instance, found that the shape and duration of SP
changes recorded from intracerebral MRF electrodes
in humans closely resembled the vertex contingent
negative variation (CNV).
Improvement might also be a secondary effect of
the emotional impact of the implantation and stimula-
tion procedure. The drama of surgery and experimen-
tation, the novelty of the techniques, the use of an
electronic device, the encouragement of well-wishers,
and the new-found hope of relief from the distressing
symptoms of progressive disease may all play a part.
If recovery is dependent on a novel state of sustained
excitement, it should be reflected in a postoperative
change-presumably an enhancement-in CNV ampli-
tude, at least when the apparatus is switched, on and
the patient is aware of it.
Methods
Subjects
This preliminary report concerns data obtained
from limited experimentation with five patients who
had spinal electrodes temporarily implanted. Three
patients (RW, CJP, and DHS), aged 34, 36, and 41,
were male and two (SE and EFM), aged 43 and 23
were female. Four had multiple sclerosis and the fifthi
RW, had motor neurone disease. Lesions were judged
clinically to be infratentorial in all patients. In some
cases, the nature and severity of the lesions were
demonstrated by H-reflex recovery curves and audi-
tory evoked response recording. Detailed clinical and
physiological information concerning these patients
appears in Dlis et al. (1976).
Surgical procedures and results
Two electrodes were inserted under X-ray control
in the midthoracic region one or two vertebral widths
apart on the dura surrounding the spinal cord. Elec-
trodes were made of insulated steel with exposed
platinum tips. A battery-operated stimulator/transmit-
ter at the patient's side generated 100-jusec pulses at a
rate of 30 to 40/sec. A receiver located on the skin
surface was attached to the opposite end of the elec-
trodes. The voltage of the pulses could be controlled
by the patient.
'This work was carried out with the support of the Army Department, Ministry of Defense (British).
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Spinal Cord Stimulation and ERPs
83
At normal stimulation levels, the patients reported
paraesthesia throughout the body up to the dermatome
level corresponding to the site of the electrodes. In
view of the electrode positions adjacent to the dorsum
of the dura, it is probable that the dorsal columns
were principally stimulated. Increasing voltage could
induce a painful sensation and muscle fasciculation,
suggesting that stimulation was not confined to the
dorsal columns, at least at high voltage levels.
After a day of continuous stimulation, improve-
ment in function was clinically discernible. Improve-
ment continued with further stimulation over the
next 2 to 7 days, involving extensive areas of the body
and additional functions. Patients also consistently
reported a carry-over effect, i.e., they continued to
feel benefit hours after prolonged stimulation ceased.
Clinical and physiological change are detailed in Dlis
et al. (1976).
Experiment I
To gain insight into the mechanism by which
electrical activity induces the benefits reported and to
evaluate the utility of evoked-response techniques for
such an application, CNV was recorded both pre- and
postoperatively. Postoperative recordings were obtain-
ed under both stimulator-on and stimulator-off con-
ditions. Ag/AgCl electrodes were employed at Fpz,
Fz, Cz, and Pz, with linked earlobes as reference. The
Cz derivation was compensated for eye movements as
described by McCallum and Walter (1968). Skin sites
were abraded with a blunt needle, giving an impedance
of less than 1 k-ohm. EEC was recorded with a 10-sec
time constant. Subjects were seated in a large, quiet,
darkened room kept at a comfortable temperature. In
view of the carry-over effect mentioned above, sub-
jects were asked to switch off the stimulator IS hours
prior to postoperative recording; three of them did so.
Experimental paradigm
A simple CNV paradigm consisting of a distinct
warning click through earphones followed 1 sec later
by a train of light flashes (16/sec) from a stroboscope
25 cm in front of the subject was employed. Subjects
were instructed to terminate the flashes as quickly as
possible by pressing a button. The intertrial interval
varied irregularly between 5 and 15 sec. Performance
was encouraged during short pauses between blocks
of 12 trials. Eight blocks were presented in the follow-
ing sequence: three acquisition, two distraction, one
resolution, and two with eyes open and fixated on
the pupil reflected in a mirror attached to the strobo-
scope. During the first six blocks, subjects were
instructed to keep their eyes closed and still. CNVs
were derived (using a POP 12) from averages of 8 of
the 12 most artifact-free trials. Baseline was computed
from mean EEC activity during the 2.1-sec epoch pre-
ceding SI, and amplitude from the 200-msec epoch
preceding S2.
Distraction trials were included in order to evalu-
ate the possible distracting effect of electrical stimula-
tion (McCallum and Walter 1968). An intermittent
tone was presented through the earphones between
trials during this phase.
Results
Recordings made prior to electrode implantation
showed the form, amplitude, distribution of CNV
components, and effect of distraction to be similar to
those found in healthy subjects. Mean drop in Cz
amplitude during distraction compared to acquisition
was 7 ju V(standard deviation = 3.9).
Averages of pre- and postoperative vertex CNVs
are shown in Fig. 1. Waveforms are indistinguishable
except for a slight increase in postimperative negativi-
ty and a slight increase in the P300 component after
surgery. There was no consistent change in the P300
component, and 75% of the difference was derived
from one subject (RW). Postoperative CNVs with the
stimulator on and off are compared in Fig. 2. Even less
difference is apparent between these two average
waveforms. Neither pre- nor postoperatively were
there large individual differences that might be
concealed by averaging. The largest difference was a
5-uV increase in amplitude after surgery in the case of
EFM, who failed to benefit from the procedure. The
mean computed difference in maximal pre-82 CNV
amplitudes in both Fig. 1 and 2 was 1 /iV. The effect
of distraction after surgery, with or without the
stimulator, was essentially the same as before (6 M'V,
SD=3.9).
Discussion
The absence of any difference between CNVs with
the stimulator on or off could be explained by a
balance between the stimulator's distraction (CNV
reducing) and stimulation (CNV enhancing) effects.
On the other hand, the experience of other CNV
experimenters that a continuous stimulus that does
not intrude on the subject's awareness does not have
a CNV-reducing effect suggests that there was no dis-
traction effect and no compensating CNV enhance-
ment.
It had also been suggested that the drama of the
operation and experimentation and the hope of bene-
ficial treatment might be reflected in a postoperative
increase in CNV in either the stimulator-off or the
stimulator-on conditions. The absence of any substan-
tial change suggests that the benefit derived from
stimulation was not a placebo effect dependent on
the general excitement of the patient. However, it a
possible that the subjects were so highly motivated
that no further increase in CNV was possible (ceiling
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84
Abraham et al.
BEFORE SURGERY
.AFTER SURGERY
10/uV
1 sec
F/& ./. Combined average of CNVs from five subjects after surgery compared with CNVi
from the same subjects before surgery. (Each trace is derived from 320 trials.)
• STIMULATOR OFF
.STIMULATOR ON
10 MV
1 sec
S1
S2
Fig. 2. Combined average of CNVs from five subjects receiving spinal cord stimulation
compared with CNVs from the same subjects not receiving stimulation. (Each trace is
derived from 160 trials.)
hypothesis, Knott and Irwin 1973). The brief op-
portunity available for experimentation did not
permit the rejection of this hypothesis until later
(Abraham et al. 1978 ).
It appears possible that the impulses, although
not susceptible to end-organ habituation or peri-
pheral inhibition since they were generated by a
stimulator in the spinal cord, did not reach the cortex
in sufficient strength to affect the CNV. It also
appears possible, if CNV generation has a primary
subthalamic source (McCallum et al. 1973), that the
spinal cord stimulator, in activating the dorsal
columnar pathway which has few collaterals to the
reticular formation, could virtually bypass the mid-
brain reticular formation and thus have minimal
influence on the CNV. An additional experiment was
carried out to evaluate these possibilities.
Experiment II
The four multiple sclerosis patients took part in
this experiment. A mechanical vibrator was strapped
to the skin overlying the lower end of the right kid-
ney. The purpose of this was to provide a stimulus
comparable to that which the electrical stimulator
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Spinal Cord Stimulation and ERPs
85
was supposed to generate. The kidney site was chosen
so that it did not cause discomfort to the seated
patient, who could nevertheless feel the vibrator
when it was switched on in spite of loss of sensation
in other areas. The patient could not see or hear the
vibrator, since the sound was effectively masked by
70 dB white noise transmitted through earphones.
The current in the vibrator was adjusted to induce the
minimum possible vibration when the circuit was
closed. The patient then adjusted the voltage of the
spinal cord stimulator so that both pieces of apparatus
delivered sensations of roughly equivalent intensity.
This generally involved a reduction in stimulator volt-
age and an accompanying reduction of the paraesthc-
siae, sometimes to a band around the chest. The
current to vibrator and stimulator was controlled by a
PDP 1 2 computer which delivered a 250-msec burst of
stimulation via one or the other apparatus. This burst
was incorporated into the CNV paradigm, replacing
the flashes at S2 for 40 trials and then replacing the
click at SI for 40 trials. The vibrator and stimulator
were alternated after each block of 10 trials. Patients'
eyes were open and fixed on the mirror throughout
this phase of the experiment, and a rest was allowed
after every 20 trials.
Results
Vertex CNVs observed during stimulator and
vibrator conditions are superimposed in Fig. 3 (S2
substitution) and Fig. 4 (SI substitution). CNVs
recorded in S2 substitution trials differed from Experi-
ment I waveforms only in the marked attenuation of
the S2 evoked potential. CNV resolution was equally
rapid in both experiments. In the SI substitution
conditions fast and slow evoked potentials appeared
earlier and were larger when generated by the stimu-
lator than by the vibrator. The increased magnitude
may be an electrical artifact from the stimulator since
a sharp rise appeared at SI onset. The latency differ-
ence is attributable to a mechanical delay in vibrator
response, a tremor transducer attached to the vibrator
indicated a slow rise time to peak.
Discussion
Spinal cord stimulation did not produce any
observable change in CNV amplitude or shape in
Experiment I. The results of Experiment II rule out
the possibility that patients did not perceive spinal
cord stimulation since motor responses were perform-
ed correctly in both S2 substitution conditions. It
should be noted, moreover, that the voltage of the
stimulator had to be reduced in Experiment II to
match the perceived intensity of the vibrator. Percep-
tion of the electrical stimulus should therefore have
been more pronounced in Experiment I than in Exper-
iment II. It is improbable that impulses from the
stimulator were too weak to affect the CNV.
The apparent differences in evoked and slow
potential patterns evoked by electrical and vibratory
stimuli in SI substitution conditions were probably
artifactual. The slow mechanical rise time of the vibra-
tor presumably induced a time lag before the stimulus
level reached the threshold of the sensory end-organ.
Differences in axon length from the sites of vibratory
and electrical stimulation cannot account for the
observed time lag. If latency and amplitude differences
are dismissed as artifact, then one may conclude that
comparable CNVs were elicited by both types of
warning cues. This finding implies either that the
CNV may be initiated by stimulation of the dorsal
column-medial lemniscus-specific thalamic nuclei
pathway, or that the stimulator activated other path-
ways.
Conclusions
The absence of pre- and postoperative differences
in CNV found in this study contrasts with other physi-
ological findings (Illis et al. 1976). A return toward
normal of the H-reflex recovery curve and the fifth
component of the auditory evoked response in some
patients suggested that physiological change had taken
place. Results of these preliminary experiments sug-
gest that the beneficial effects-psychological or physi-
ological—of spinal cord stimulation are not mediated
via cortical excitement as measured by the CNV. The
data, however, do not preclude the possibility that
CNV amplitude reached a ceiling level prior to spinal
cord stimulation in highly motivated patients, though
subsequent experimentation (Abraham et al. 1978)
did so. The similarity of CNV waveforms with and
without dorsal column stimulation suggests, more-
over, that reafferent activity, presumably mediated
by this pathway, does not contribute to the CNV.
Finally, the ability to bypass peripheral nerves
and end-organs provided by spinal cord stimulation
offers a unique opportunity to those investigating
event-related potentials in situations easily confound-
ed by peripheral factors.
Summary
Clinical improvement has been observed in multi-
ple sclerosis patients following spinal cord stimulation,
although the mechanism underlying this effect is not
known. Two brief CNV experiments were undertaken
to investigate possible changes in psychological or
neurophysiological state associated with clinical
improvement. Spinal cord stimulation did not produce
any discernible change in the CNV, suggesting that
therapeutic effects are not mediated by cortical
mechanisms.
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86
Abraham et al.
S2
-VIBRATOR
-STIMULATOR
Fig. 3. Combined average of CNVs from three subjects in whom spinal cord stimulation
was used as the imperative stimulus compared with CNVs from the same subjects in whom
external somatosensory stimulation was used as the imperative stimulus. (Each trace is
derived from 48 trials.)
SI
-VIBRATOR
-STIMULATOR
Fig. 4. Combined average of CNVs from three subjects in whom spinal cord stimulation
was used as the warning stimulus compared with CNVs from the same subjects in whom
external somatosensory stimulation was used as the warning stimulus. (Each trace is
derived from 48 trials.)
-------
FUNCTIONAL SIGNIFICANCE OF CEREBRAL
POTENTIALS PRECEDING VOLUNTARY
MOVEMENT
L. DEECKE
Department of Neurology, University of Ulm, West Germany
It has been established that cerebral activity pre-
ceding voluntary self-paced movement (e.g., index
finger flexion) can be recorded through the intact hu-
man scalp (Kornhuber and Deeckc 1964, 1965). Three
different potentials occur: a slow potential, called the
Bereitschaftspotential (BP)or readiness potential, and
two faster potentials, referred to as the premotion
positivity (PMP), and the motor potential (MP). Cer-
tain methodological requirements are necessary to
record these three potentials. Amplifiers with long
time constants are necessary to record BP. To pick up
the faster potentials and to achieve the necessary
signal-to-noise ratio, exact temporal triggering condi-
tions and a large number of trials are required. Best
results are obtained if the subject is trained to relax
the agonist muscle to the extent of complete silence
m the intramuscular electromyogram (EMG) and then
perform an abrupt and rapid movement. A sensitive
triggering level must be used to ensure triggering from
the very first intramuscular action potential. Deecke
et al. (1976) have shown with index finger flexion
that the earliest activity occurs in the agonist muscle
(M. flexor digitorum communis, pars indicts), al-
though accompanying muscular activity is recorded in
many other arm and neck muscles. Additional meth-
odological requirements are the exclusion of eye
movements (e.g., by gaze fixation) and careful editing
of every trial.
If these precautions are taken, three different
types of subjects are found (Fig. 1). Type A (15%)
shows increasing negativity until movement onset in
all precentral and parietal leads with a steep rise about
60 msec prior to EMG onset in the contralateral pre-
central lead. Type B (41%) shows increasing negativ-
ity until movement onset in the contralateral pre-
central lead but a positive deflection about 90 msec
prior to movement onset in other precentral and
parietal leads. Type C (44%) shows a positive deflec-
tion m all precentral and parietal leads, but a less steep
stope in the contraiateral precentral lead. Both Type
B and Type C (85%) exhibit PMP. Fig. 1 illustrates
that, in the final 150 msec prior to EMG onset, the
waveform is complicated by the superimposition of
the three potentials mentioned above, differing in
polarity and topographical distribution and perhaps
morphology between subjects.
Type A
Type B
Type C
750
'0 msec
Fig. 1. Three different Types of subjects. Schematic
diagram of the potential course in left and right pre-
central and midparietat leads preceding right-sided
finger movement. (Deecke et al., 19 76/
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88
Bereitschaftspotential
The slow premovement potential (Bereitschafts-
potential, readiness potential, or Nl) is a negative shift
of the cortical dc potential, as is the contingent nega-
tive variation (CNV). The principal characteristics of
BP are early onset (commencing up to 1.5 sec or
more-mean 0.8 see-before movement), gradual neg-
ative increase, and bilateral distribution over the pari-
etal and precentral cortex of the two hemispheres.
The BP is bilateral-even if the movement is only uni-
lateral. These characteristics suggest that the early BP
cannot reflect motor command processes, since a
potential reflecting motor command would have to
be faster than motor reaction time. The term early
preparatory process is suggested for BP, meaning a
thalamocortical facilitation process which selectively
excites those cortical areas involved in the intended
movement and inhibits or does not affect other areas.
A negative shift of cortical dc potential is caused by
an increase in synaptic drive in (upper) cortical layers,
since intracellular recordings of cortical neurons reveal
a simultaneous decrease of membrane potential and
an increase in excitatory postsynaptic potential (EPSP)
rate (Caspers and Speckmann, in press). The early
preparatory process of the BP does not reflect simply
general arousal because it can be modified by the
experimental situation. The BPis, therefore, a valuable
indicator for the loci of cortical activity or inactivity.
The literature concerning BP laterality is contro-
versial. The CNV appears to be symmetrical even in
split brain patients responding with their right hand
to stimuli flashed into their right visual field (Gazzani-
ga and Hillyard 1973). Lateralization of the CNV has
been observed only when higher lateralized cortical
functions such as speech (Lowet al. 1976) or numeric
operations (Butler and Glass 1974) are addressed in
the experimental situation. When we first recorded
the brain activity preceding voluntary movement
(Kornhuber and Deecke 1964), we expected that a
unilateral movement would be preceded by unilateral
(i.e., contralateral) cortical activity as suggested by
classical concepts based on stimulation of the motor
cortex. Finding a bilateral negativity preceding uni-
lateral movement was, therefore, a surprise. Bilateral-
ity does not necessarily imply bilateral symmetry, but
this was the case in the initial part of the readiness
potential shown In bipolar recording! of left vs right
precentral and left vs right parietal leads. Only pre-
centrally did a slight contralateral preponderance
occur, commencing about 400 msec prior to EMG
onset and averaging 0.9 juV at a time ISO msec
prior to movement.
In order to extract the three different potentials,
superimposed on each other in the final ISO msec
prior to EMG onset, certain measurement rules were
established (Fig. 2). BP was measured 150 msec prior
-150 0 msec
Fig. 2. Rules for measuring the three different poten-
tials. The Bereitschaftspotential (BP) is measured
(with respect to a prepotential baseline) ISO msec
prior to EMG onset (BP15Q) and at its kinking (if
present) to positivity (BPkn); PQ is the amplitude at
EMG onset. For measurements of the premotion posi-
tivity (PMP), two differences were taken: P0-BPjtft
possible in all the graphs and P0-BPkn (PMP proper)
only possible in graphs with a kink. The motor poten-
tial (MP)-dotted line-was measured in bipolar record-
ings, contralateral vs ipsilateral precentral or contra-
lateral precental vs midparietal, to extract the two
bilateral potentials, BP and PMP. The MP represents
the additional negativity over the contralateral motor
cortex, which occurs on average 54 msec before
EMG onset (Deecke etal, 1976.)
to EMG onset to avoid contamination by other poten-
tials. The contralateral precentral preponderance is
equivalent to Gerbrandt's (1977) asymmetrical Nl
component. Pane tally, however, the BP is absolutely
symmetrical 150 msec before EMG onset (Fig. 3). In
conclusion, whether the BP is symmetrical or lateral-
ized depends on the location and time of measure-
ment. Fig. 3, a three dimensional plot of averages
from 39 subjects, illustrates BP lateralization.
The precentral contralateral preponderance of
the BP and the MP correlates with handedness (Deecke
et. al. 1973). Twenty-five right-handed subjects show-
ed significantly more negativity (2 p<05) recorded
over the dominant motor cortex than the minor one,
both being contralateral to the movement. In 13 left-
handed subjects, an analogous trend (not statistically
significant) toward lateralization was observed, In
accord with sinistrals being more ambidextrous (less
cortlcally lateralized) than right-handed subjects. Simi-
lar results were obtained by Kutas and Donchin
(1974). The BP is subject to psychological factors in-
cluding motivation, and gradually declines with age
beyond the fourth decade of life (Deecke et al., this
volume).
Premotion Positivity
In Type B and C subject! (85% of the test popu-
lation), a positive deflection (premotion positlvity,
PMP, or PI) was observed in the final ISO msec prior
to EMG onset. PMP was maximum over the anterior
-------
Potentials Preceding Movement
89
160 maec
PRECENTRAL
PARIETAL
Fig. 3. Laterally of the readiness potential. Three-dimensional plot of the distribution of negativity preceding
right-sided finger movement (grand averages across 39 subjects), X-axis; electrode positions over the left, mid, and
right precentral and parietal regions. Y-axis: negativity in microvolts. Z-axls: time prior to EMG onset. In precen-
tral leads (left sub figure), the BP is slightly lateralized (contralateral preponderance atBPjso and BP%n). At P0,
pronounced lateralization due to motor potential is seen. In parietal leads (right sub figure), the BP is exactly
bilaterally symmetrical (BPjso an(i BPkn)- Tne sliSnt (insignificant) lateralization atP0 may be due to spread of
the motor potential.
parietal region, Pz (cf. Fig. 1 in Deecke et al., this
volume). PMP was measured as the difference Po-BPjm
or P0-BPj5o (Fig. 2). Since the mean onset time of
PMP is 87 msec prior to EMG onset, which is shorter
than mean motor reaction time, this potential might
reflect cerebral activity associated with the motor
command.
The PMP has also been described by Vaughan et
al. (1968), Shibasaki and Kato (1975), and Cerbrandt
(1977). At present, there seems to be agreement about
PMP phenomenology, but major controversy about its
functional significance. The Ulm group considers the
PMP to be an expression of movement initiation or
motor command, which originates in the parietal area.
Vaughan et al. (1970) suggested that the PMP is associ-
ated with pyramidal tract activity. Shibaski and Kato
(1975) proposed that the PMP is the expression of
unilateral inhibition, unilateral movement being the
result of unilaterally inhibited bilateral movement.
Gerbrandt (1977) has confirmed the existence of the
PMP, but speculates that it may be an epiphenomenon
of movement occurring toward the end of long experi-
ments. The Ulm group demonstrated at Bristol
(McCallum and Knott 1976), however, that the PMP
can be seen after the first few trials (Fig. 4). The
reason for the variable appearance of the PMP in sub-
jects is not known (see discussion above of different
types of subjects), but we have found that a subject
maintains his type in repeated experiments, i.e., there
is high intra-subject constancy of the PMP.
The hypothesis that the PMP reflects a motor
command from the parietal cortex is supported by
several considerations: (l)The PMP is not simply the
resolution of the BP since there is no correlation
between PMP and BP amplitudes (Deecke et al. 1976).
(2) The PMP preceding tactually guided finger move-
ments is maximal over the anterior parietal region of
area 5, which is the sensory association cortex of the
somatosensory modality. The parietal area, whose
destruction causes apraxia, is classically considered to
be the key structure for learned tactually guided
movement and skills. The PMP may, therefore, re-
-------
90
Deecke
0052
EMG ONSET
E06
38
L front
R front
Vertex
L par
R par
EMG
20
1 sec
i
Fig. 4. Premotion positivity in the beginning of an experiment. Typical PMP preceding right-sided finger move-
ment, which is discernible here after 38 trials. Maximum at the vertex.
fleet the activation of a movement program stored in
the parietal cortex. This spatial code must then be
converted to temporal code for the exact timing of
movement parameters. According to the theory of
Komhuber (1971, 1974), conversion is achieved by
subcortical motor function generators of cerebellum
(fast, preprogrammed movements) and basal ganglia
(slow, smooth movements). (3) The 33-msec dif-
ference between PMP and MP mean onset times
permits information transfer and processing via a
cortico-cerebello-motor cortical loop. (4) Thach
(1970) has confirmed in animals that the cerebellum
is activated prior to the motor cortex. The onset time
of frequency changes in cerebellar dentate cells (70
msec before EMG) would fit well between PMP onset
time (87 msec) and MP onset time (54 msec). Thach
(1975) reported that neuronal discharge patterns of
dentate cells changed significantly earlier than cells in
motor cortex (simultaneous recordings in the same
animal). In the thalamic relay of the dentato-cortical
path (ventrolateral nucleus), activity also changes well
in advance of movement onset (Jasper and Bertrand
1966, Evarts 1970). Finally, Mountcastleet al. (1975)
have demonstrated that the anterior parietal region
-------
Potentials Preceding Movement
91
contains so-called "command neurons" that are active
prior to movement
Motor potential
What we call the motor potential (MP) is the
additional negativity that occurs over the contralateral
motor cortex immediately prior to EMG onset. Where-
as the PIVEP and BP are bilateral, the MP is the only
unilateral potential preceding voluntary movements
of one side. A bipolar montage was used to extract
this additional negativity from the BP i.e., contra-
lateral vs ipsilateral precentral and contralateral pre-
cenlral vs midparietal (Fig.2). A definite upward
kinking of the waveform, arising from the slow neg-
ative deflection of the contralateral preponderance,
was discernihle in about 76% of the subjects. Onset
of this kink averaged 54 msec prior to the first intra-
muscular action potential in the agonist muscle.
It is impossible to execute an index finger move-
ment in isolation. There are always accompanying
movements in other hand, arm, and even neck mus-
cles. However, it has been shown that with index
finger flection the earliest activity occurred in the
agonist muscle, from which the trigger pulse was
derived (cf. Deecke et al. 1976, Fig. 2B). Thus, we are
certain that the motor potential recorded in bipolar
leads is a premovement potential.
It should be stressed that the MPis not identical
with the monopolarly recorded N2 component, the
premovement nature of which has been questioned in
epicortical recordings (Papakostopoulos ct al.!974a).
Indeed, this component also occurs with passive move-
ments (Kornhuberand Deecke 1965) and shows phase
reversal between precentral recordings (negative polar-
ity) and postccntral recordings (positive polarity, cf.
Kornhuber and Deecke 1965, Fig.7C).These findings,
obtained with subgaleal needle electrodes, have now
been confirmed in epicortical recordings by Papakos-
topoulos et al. (I974a).
Spatial and temporal characteristics of the MP
immediately suggest its functional significance: its
location is restricted (with unilateral finger movement)
to the hand area of the contralateral motor cortex
and its onset is very close to EMG onset (54 msec on
the average). The MP, therefore, is probably associated
with activity of the motor cortex initiating the des-
cending volley in the pyramidal tract. The motor
cortex is a highly specialized structure, but by no
means the origin of all voluntary movement, as
assumed in classical concepts. According to current
theory (Kornhuber 1971, 1974), only those move-
ments that require the highly sophisticated tactile
analysis provided by the precentral and postcentral
gyri have ascended to motor cortex during phylogen-
esis. Generation of movements which do not require
tactile guidance, such as eye movement, remains in
subcortical structures. Therefore, no motor potential
is found preceding eye movements (Becker et al.
1972). Movements dependent on an intact motor
cortex in the primate are fine finger, toe, lip, and
tongue movements, and manual skills requiring tactile
control. Thesomatotopic representation of these parts
is thus disproportionally large in the motor (and soma-
tosensory) homunculus.
Further experiments with different types of
movements are necessary. Movements can differ in
purpose, speed, context of action, internal needs, and
modality of mediating stimuli, as well as the part of
the body involved in movement. The classical assump-
tion that movements originate in motor cortex is
therefore false. The motor cortex comes into play
later in the course of movement preparation and only
with certain movements. The willful initiation of
movement can arise in many cortical areas of the
so-called "sensory association" fields, depending on
the special type of movement: factually guided move-
ments in the somatosensory association cortex, visual-
ly guided movements in the visual association areas,
speech movements in the speech centers, writing,
music playing, etc., in their respective centers. It
appears that the entire cortex has immediate access to
movement by means of known omnicortical projec-
tions to subcortical motor function generators of the
cerebellum and basal ganglia.
Reafferent potentials
This term has been suggested for potentials that
occur after movement onset (Kornhuber and Deeeke
1965) because the sequence of positive and negative
components after EMG onset closely resembles the
average evoked potential to somatosensory stimuli.
Furthermore, the same components, although some-
what larger in amplitude, occur after passive move-
ments (Kornhuber and Deecke 1965,Papakostopoulos
et al. 1975). The functional significance of this po-
tential complex is probably reafferent activity evoked
by the movement. Thus, this complex could be called
a proprioceptive evoked response. It seems reasonable
to assume that reafferent potentials originate mainly
from peripheral receptors such as cutaneous, deep
somcsthetic, and muscle spindle receptors, but may
also come from feedbackor reentrant activity of lower
motor centers in the brain stem, cerebellum, or
spinal cord. As a result, the reafferent potentials
would not be completely abolished after rhizotomy
(Vaughan et al. 1970). The findings of Vaughan et al.
are therefore not entirely contrary to the reafferent
conception of potentials after movement onset.
The notion that passive movements evoke larger
potentials than similar active movements is of interest
in view of theoretical concepts such as Effernzkopie
or corollary discharge (Hoist ;md Mittelstedt 1950).
-------
EXPERIMENTAL MANIPULATION OF MOTOR
POSITIVITY: A PILOT STUDY*
J. DELAUNOY, A. GERONO, AND J. ROUSSEAU
Department of Medical Psychology and Psychosomatic Medicine, University of Liege,
Liege, Belgium
The slow positive wave that follows movement
onset has generally been attributed to proprioceptive
or kinesthetic afference (cf. Kornhuber and Deecke
1965), although this hypothesis has never been con-
firmed experimentally. Several observations do not
support this hypothesis: (1) postresponse positivity
persists in monkeys after dorsal rhizotomy (Vauahan
et al. 1970), (2) the positivity persists longer 0>500
msec) than the predicted duration of proprioceptive
discharge, and (3) the waveform is frequently absent
in psychopathological patients in whom there is no
apparent proprioceptive deficit.
An alternative hypothesis is that postresponse
positivity may be analogous to the P300 wave (Sutton
et al. 1965) and may reflect the uncertainty or proba-
bility of occurrence of the motor act. The present
experiment was designed to test this hypothesis.
Method
Three normal adults (two men and one woman,
mean age 35 years) were instructed to extend the right
forefinger at regular intervals against a given resistance
of 50g (Rl) or 200g (R2). Each subject completed
two sequences of ISO trials each in which Rl (or R2)
was presented randomly on 1/3 of the trials. The
probabilities were reversed during the second sequence.
EEC was recorded at the vertex with chlorided
silver electrodes referred to the left earlobe and with
a 5-sec amplifier time constant. EOGwas also recorded
for rejection of trials with eye movement artifact.
Averages were triggered from the response mechano-
gram. The averaging epoch was 4 sec (1.5 sec before
the beginning of movement and 2.5 sec after). Two
measurements were made on the averaged waveforms:
(1) the readiness potential (RP) computed as the volt-
age difference between the potential at movement
onset defined by mechanogram, and baseline (initial
500 msec of the average) and (2) the positive wave
measured as the voltage difference between baseline
and the maximum positivity following movement
onset.
Results and comments
RP did not vary as a function of anticipated or
unexpected resistance. The positive wave did not vary
as a function of the expected (2/3) resistance, but
was larger for the unexpected (1/3) resistance, irrespec-
tive of actual level, in two subjects.
These results provide limited support for the pro-
posed hypothesis that postresponse positivity may be
analogous to P300 and may reflect the certainty or
probability of a salient feature of the motor act. Per-
haps this positivity reflects the operation of a central
comparator between a motor program elaborated
before movement and a neural representation of the
executed movement. Observations in eight additional
subjects run under the same experimental conditions
confirm the preliminary results reported here.
This work was supported in part by Grant 20397 - FRSM.
-------
TELERECEPTIVE, PROPRIOCEPTIVE, AND
CUTANEOUS INFORMATION IN MOTOR
CONTROL1
B. DUBROVSKY
The Allan Memorial Institute, Departments of Psychiatry and Physiology, McGill University,
Montreal, P.Q., Canada
Two broad views can be distinguished in the inter-
pretation of mammalian brains. In one, articulated by
Craik (1943), the "fundamental feature of neural
machinery" is the "power to parallel or model exter-
nal events." This model is matched against input from
daily life in order to select the most appropriate line
of action (Young 1971). In contrast to this perspective
which emphasizes perceptual aspects of the central
nervous system, other views emphasize motor control
as the central determinant in the evolution and func-
tion of the brain. This conception can be traced to
S. C. Pierce's pragmatic view that "the evolutionary
increase in man's capacity for perception, feeling,
ideation, imagination, and the like, may be regarded,
not so much as an end in itself but as something that
has enabled us to behave, to act, more wisely and
efficiently" (Sperry 1952). Lashley (1951) encom-
passed both positions: "the neurological problem is in
large part, if not entirely, the translation of the affer-
ent pattern of impulses into the efferent pattern."
This review will summarize recent work on the contri-
bution of proprioceptive, tele receptive, and cutaneous
stimuli in the development of forces and the spatio-
temporal pattern necessary for movements directed
toward the outside world.
The distance receptors of vision, audition, and
olfaction are axial in the development and construc-
tion of the nervous system (Sherrington 1906). Eyes,
by signaling distant events, can provide for the plan-
ning of behavior—not merely reflex responses, but
complex activity in which cortical integration plays a
fundamental role. In recent experimental work, the
relevance of midbrain structures in visually guided
behaviour has been clearly established. Phylogenetic
and physiological data, as well as ablation and depri-
vation experiments,led to the notion that visual local-
ization is primarily associated with activity in the
superior colliculus, whereas visual identification in-
volves the geniculostriate pathway (see review in
Dubrovsky and Garcia-Rill 1971). It is clear, however,
1 Supported by the Medical Research Council of Canada.
that perception of a single unified object or event
includes attributes of quality, intensity, position in
space, and duration in time. The integration of the
output of parallel channels of intermediate sensory
processing is then a necessary condition to the prin-
ciple of parallel processing (Davis 1956).
Phillips (1966) has advanced the concept that
corticofugal neurons in the motor cortex are "common
paths" leading out of the cortex where many differen-
tiated peripheral inputs are integrated. Since planning
of extrapersonal motor strategies requires a properly
defined spatial context, we decided to explore the
possibility of convergence and interaction (a prereq-
uisite for integration, Davis 1956) in the motor cortex
of two distinct neuronal groups related to visual
perception-the superior colliculus and the occipital
cortex.
Experiments with anesthetized cats revealed that
the motor-sensory cortex receives stimuli both from
the visual cortex and from the superior colliculus.
Almost half of the 100 cells studied in this cortical
zone received convergent stimuli from both central
areas. Inhibitory effects, studied by stimulating against
a background of activity induced by iontophoretic
release of glutamate, were observed in 51% of the
neuronal population studied. Analysis of latencies,
duration of inhibitory effects, and following frequen-
cies, indicated that the superior colliculus and occipi-
tal cortex stimuli arrive at the pericruciate cortex by
independent pathways (Dubrovsky and Garcia-Rill
1971).
After establishing that the visual cortex and
superior colliculus may mediate visual information
reaching motor cortex, the response characteristics of
motor-sensory cortex neurons to natural visual stim-
ulation were investigated (Garcia-Rill and Dubrovsky
1971, 1973,1974). Briefly, responses to stimuli with-
in visual receptive fields were of the "on," "off," and
"on-off' type. Most receptive fields were rectangular
and very large. About 75% of the 203 neurons studied
-------
94
Dubrovsky
had receptive fields averaging 72° x 83° and impinged
on both nasal and temporal regions of the visual field;
the rest were limited to the nasal side and averaged
38°x49°.
Latency of excitatory responses to both the onset
and disappearance of stimuli averaged 45 msec. Inhib-
itory effects analogous to the excitatory activity
evoked by discrete retinal stimulation were also
found. The latency for inhibitory responses was long-
er, averaging 75 msec to an "on" stimulus, and 65
msec to an "off" stimulus. A characteristic of the
response of motor cortex neurons to visual stimuli
was the inability to follow recurrent presentations
beyond I/sec.
A majority of units (56%) having visual receptive
fields displayed movement sensitivity. Only 19% of
movement-sensitive cells had a preferred direction for
visual stimuli.
Finally, in examining the relationship between
visual receptive fields and cutaneous receptive fields
of the same units, a topographical distribution of
visual input to motor-sensory cortex became evident.
Essentially, more colonies of cells with input from
the trunk received visual information than those colo-
nies with input from the distal forelimbs. Only 15%
of cells with exclusive input from the distal extremi-
ties received visual input, whereas 75% of neurons
with exclusive and convergent input from proximal
areas received visual information.
The topographical organization of visual afferents
in motor cortex, the large size of visual receptive
fields, the long latency of response, and the poor
frequency-following characteristics of motor cortex
neurons suggest that control of accuracy of move-
ments is not mediated by visual input to motor
cortex. The data do suggest, however that visual
afferents to motor cortex may be related to spatial
aspects of perceptual-motor function. This hypothesis
is further supported by the binocular convergence of
visual pathways in motor cortex. According to Young
(1962), bilateral representation is the basis of "a sys-
tem for representing features of the environment that
are signaled by various receptors in their correct spa-
tial relations."
Although neurons in the motor cortex are char-
acteristically polymodal for cutaneous and deep
modality receptors, visual and vestibular afferents
(spatial information) converge preferentially onto
areas corresponding to the body axis and proximal
limb zones. The latter areas are also richly endowed
with callosal connections, while areas corresponding
to distal extremities are almost devoid of callosal
projections (see Garcia-Rill and Dubrovsky 1973).
Results reviewed here are also consistent with the
differential organization of neural systems controlling
axial musculature of the limbs on one side, and distal
on the other (Kuypers 1963). These data, clinical
observations on the role of vision in postural mechan-
isms for normal and pathological conditions, and
developmental studies emphasize the formation of a
body-centered spatial framework as essential condi-
tions for the development of visually guided behavior
(Garcia-Rill and Dubrovsky 1974) and suggest that
visual afferents arriving at the motor cortex are' re-
lated to tracking functions involved in defining the
spatial context in which movement will take place.
We further proposed that integration of propri-
oceptive, somatic, spatial, and callosal information
converging onto areas of the motor cortex which
correspond to the midline of the body is part of a
neural process related to construction of a reference
axis for limb movement. This axis would form part of
a system of coordinates, essential for the proper local-
ization of physical objects in space. Poincare (1923),
in his classical analysis of the concept of space, recog-
nized that we locate external objects in reference to
our own body and that we apprehend spatial relations
between objects only in relation to our own body.
Interference with the establishment of this referential
body axis results in selective impairment of motor
behavior, as we have shown (Dubrovsky et al. 1974).
Concomitant with the electrophysiological study
of the organization of telereceptive stimuli to motor
cortex, we are analyzing the role of dorsal column
afferents (a proprioceptive and somesthetic path) in a
sequentially organized motor act (Dubrovsky et al.
1971, Dubrovsky and Garcia-Rill 1973). Cats are
trained to jump up to release a piece of raw chicken
liver attached to a vertically oriented, revolving wheel.
The wheel is rotated by a motor of variable speed and
testing is done with constant speed for all animals.
The cats jump from a force transducer platform.
Components of force are recorded in three axes on
magnetic tape and converted for digital computer
processing. The time of jumping in relation to the
position of the rotating wheel is evaluated by attach-
ing to the wheel a small magnet that activates a
switch attached to the rotating axis. Each revolution
is then marked by a pulse generated by the switch
and recorded with the three components of force.
The biomechanical investigation is complemented
by high-speed cinematographic analysis of the move-
ment.
Behaviorally different sequences of the act are
independently analyzed by studying the following
parameters: efficiency, accuracy, tracking, and search-
ing index. Efficiency is evaluated as the percentage of
successful releases of liver, without taking into
account the precision of execution. Accuracy is
-------
Peripheral Input in Motor Control
95
expressed as the frequency with which an animal hits
the holder instead of the target; i.e., an animal is less
accurate the more it hits the holder. Tracking of the
released liver in space is assessed in terms of the abili-
ty of the animal to localize it on the floor within 3
sec after it lands. Finally, the searching index is the
frequency with which an animal attempts to localize
a piece of liver after an unsuccessful attempt to
release it.
After section of the dorsal column above the Cl
level, significant impairment in all behavioral indices
was observed. The following parameters, directly relat-
ed to force, were also significantly decreased (Table
1): (1) height of jump,(2) time in the air, (3) maxi-
mum resolved force, and (4) peak to mean force ratio
(an indication of the speed at which the cat developed
the maximum muscular force).
Film analysis showed that intact cats consistently
extended their limbs in a smooth and progressive way
towards the liver in order to release it. The distance
between the tips of forelimbs remained more or less
constant during flight. Postoperatively, the extension
of the limbs was interrupted by fast flexion move-
ments and the distance between tips increased signifi-
cantly during flight.
Impairment in force development after surgery
may relate, in part, to sectioning fibers from skin
mechanoreceptors conveying information on limb
loading conditions. Marsden et al. (1972) showed the
importance of cutaneous afferents for load compen-
sation in proportion to force and suggested a trans-
cortical mechanism for its development. Furthermore,
we think that section of the dorsal column suppresses
an important path for cutaneous afferents involved
in supraspinal mechanisms of synchronization of
muscle activity (Milner-Brown et al. 1975). These
authors suggested that the mechanisms for exertion of
large, brief forces (e.g., jumping) may result from
strengthening reflex pathways involving a fast, lem-
niscal route to the cortex.
Before surgery, the animals jumped up with a
consistent stereotypic pattern including the direction
of takeoff. After dorsal column section, the initiation
of jumping was delayed and more variable in relation
to preoperative timing, and the cats showed a signifi-
cant change in the direction of takeoff, suggesting a
change in strategy of the animal while on the ground.
The postsurgjcal impairment in reaching the target
may be associated with the fact that the dorsal col-
umns are the exclusive afferent path to brain centers
for muscle spindles and low threshold joint afferents
from the forelimbs. Muscle spindles convey informa-
tion on the length and speed of changes in length of
muscles. Low threshold joint receptors yield informa-
tion on joint position.
Since position sense is necessary for knowledge
of both the spatial and temporal parameters of move-
ment initiation, section of the dorsal columns may
impair the ability of an animal to readily initiate the
sequence by interrupting fibers carrying impulses
from muscle spindles and low threshold joint afferents
from the forelimbs. Both types of information are
involved in kinesthesis. Absence of information from
forelimb musculature on length, and changes in
length, of the muscles can also seriously impair the
accuracy of a motor sequence involving the use of
these extremities. Decreased cutaneous signals
should further reduce the accuracy of forelimb move-
ment because skin sensation is essential for refined
motor acts (Granit 1975).
Table 1. Effect of Dorsal Column Section on Mechanical Performance
Behavioral Index
Preoperative
Postoperative
Probability
Height of jump, meters
H- -
H'2g m
Time in the air, sec
Work, joules
W=mgH
Maximum resolved force, Newtons
Peak/mean force rate
0.3118
0.6139
9.721
82.15
2.417
0.1469
0.5613
4.582
46.914
1.500
p<.001
p<.02
p<001
p<.001
p<.002
' Results Irom one cat representative of a group of three. H * height of jump; 1 = impulse at takeoff; g= acceleration of grav-
ity, 9.81 meters/sec^, x,y,z = axes of rectangular coordinate system (z vertical); m = mass of cat; W = work; F = force.
-------
96
Dubrovsky
Tracking deficits, we believe, are due to the inter-
ruption of proprioceptive signals from the dorsal
neck region ascending through the dorsal columns.
Low threshold muscle afferents from deep and super-
ficial dorsal neck muscles project to zones correspond-
ing to the frontal eye fields of the cat brain (Dubrov-
sky 1974, Dubrovsky and Barbas 1975). These sig-
nals transmitted through the dorsal column may
play an important role in proper coordination of
eye-head-movements in complex motor acts re-
quiring movement of the head relative to the entire
body while the body is in motion. For instance, we
recently found that afferents from extraocular mus-
cles also project to frontal eye field areas in the
feline (Dubrovsky and Barbas 1977).
The bizarre behavior of lesioned cats-frequently
searching for a target that has not been released—may
be a manifestation of the disruption in the organiza-
tion of an integrated serial movement that occurs
when essential information for programming of the
act does not reach higher brain centers. The disturb-
ances in timing of jump behavior after surgery may be
partially related to proprioceptive deficits. "Time"
appears to be a derived concept in the central nervous
system (Piaget 1970). In light of current knowl-
edge of muscle spindle physiology (Matthews 1972),
we suggest that central processes for the construc-
tion of precise timing strategies in movements are
based, at least in part, on information conveyed by
the spindles to telencephalic areas. This would in-
clude information concerning changes in muscle
length (distance traversed by the body) and the
speed at which this change in position took place.
Time can then be derived from this information.
Results of experiments reviewed here support the
preponderant role played by movements of the body
and extremities in the genesis of the concept of space,
as originally proposed by Poincare (1923) and later
developed and extended to the concept of time by
Piaget (1970), With respect to the function of tele-
proprioceptive and cutaneous input in motor con-
trol, our investigations suggest that visual signals
arriving at the motor cortex mainly in zones cor-
responding with axial and proximal body regions,
are probably related to tracking functions, i.e.,
bringing the limbs to a target. Control of accuracy,
precise timing, and force to be developed during
movement appear to be related to information origi-
nating from proprioceptive and cutaneous receptors.
-------
METHODOLOGICAL CRITERIA FOR THE VALIDATION
OF MOVEMENT-RELATED POTENTIALS
L. GERBRANDT
Department of Psychology, California State University, Northridge, CA, U.S.A.
Several scalp-recorded macropotentials, of distinct
functional origins, can become synchronized tempo-
rally with the occurrence of abrupt voluntary move-
ments of the hands or fingers. These movement-
related potentials (MRPs) also superimpose spatially
across the Rolandic region even though most peak
elsewhere. It is not surprising, then, that tight meth-
odological control and extreme caution in measure-
ment are essential to differentiate optimally this
spatiotemporal mixture of MRPs into functionally
distinct components. Moreover, most studies of MRP
and CNV research are probably uninterpretable with
regard to which component was manipulated and
measured, simply because investigators have not used
methodologies shown to be essential for effective dif-
ferentiation of MRP components (Deecke et al. 1969,
Gerbrandt et al. 1973, Deecke etal. 1976,Gerbrandt
1977). Thus, when investigators compare the effects
of an Independent variable on "the readiness poten-
tial," it is uncertain whether a readiness potential or a
compound potential of several functional origins is
being affected by the variable under study. In order
to put known considerations about the possible
sources of "conceptual confounding" into a useful
perspective, this review will be used to derive a
methodological checklist for evaluating MRP results.
Investigators usually assume that there is a unitary
readiness potential (Nl) that can be recorded In isola-
tion, even though MRP research indicates that this
negative sustained potential (cf. Fig. 1, top trace) is
easily contaminated by other movement-adjacent
activities (e.g., PI, N2, N3, P2, and artifacts). This
review will describe procedures regarded to be essen-
tial In distinguishing Nl from these other activities.
Because procedures that are helpful in isolating Nl
from other components include methods for Isolating
these confounding activities, this review should also
be useful to Investigators interested in MRP compo-
nents other than Nl. The methodological considera-
tions discussed here also apply to CNV research
because voluntary movements are Involved in most
CNV paradigms, Evidence suggests, for instance, that
the CNV is enhanced by requiring an overt motor
response (Donchin et al. 1973, Irwin et al. 1966).
Late stimulus (Sl)-llnked SPs are also confounded by
superposition with response-linked negative SPs pre-
ceding movement (Rohrbaugh et al. 1976, Rohrbaugh
et al., in press).
What factors, then, need to be considered to iso-
late Nl, functionally, from confounding components
such as the CNV and other MRPs?
Technical Factors
The history of MRP research began with failures
by several investigators to observe any potentials pre-
ceding self-paced, voluntary movements (Bates 1951,
Caspers et al. 1963, Low et al. 1966, Donchin and
Undsley 1967). The first two failures are attribut-
able, in part, to the fact that an averaging computer
was not used. Since these potentials average about 5
/uV, while background EEC often varies between
10-50 MV (S.D. = 10 nV), a clear and reliable visual
resolution (Signal-to-Notse Ratio = 4) requires at least
64 averaged trials.
FS.N.R. x S.Dl *
[ N1 ampi. ]
vi u rtJ i
Number of trials
To obtain quantitative data, such as onset latencies
and topographic voltage gradients, some investigators
recommend using several hundred (Vaughan et al.
1968), or even a thousand trials (Deecke et al. 1976).
Notice in Pigs. 6 and 8 of Deecke et al. (1976), for
example, that 0.5-1.0 pV of EEC noise still remains
after averaging 630-1082 trials. The inescapable con-
clusion is that, in some subjects, a 10*tV noise esti-
mate Is far too conservative. Therefore, more than 64
trials need to be averaged to resolve, properly, many
of the MRP componenti that may superpose upon Nl
and contaminate its measurement and functional
Interpretation.
Inadequacies in averaging, however, cannot entire-
ly explain these early failures, since premovement
-------
98
P2
512 msec
EMG ONSET
Fig. 1. Top trace: schematic of MRP waveform indi-
cating temporal relationship of each component to
EMG onset (vertical line), using abrupt hyperexten-
sion of the dominant index finger. Traces 2-4: actual
MRPs of a single subject simultaneously recorded in
three amplifiers with different time constants. Each
trace is an average of 64 movements (dominant index
finger hyperextension). Recording site located over
presumed motor cortex (0% site}, contralateral to
movement, as shown in Fig. 3.
potentials such as Nl or PI under some conditions
can be visualized in single trials (Gerbrandt et al.
1973, cf. Fig. 3; Gerbrandt 1977, pi82). Failures to
observe Nl have also been reported when even
smaller signals were apparent in averages (Low et al.
1966, Donchin and Lindsley 1967). The problem in
the latter study may have been the time constant of
the recording system. As Deecke et al. (1976) noted,
if it is assumed that Nl onset averages about 0.8 sec
before the start of EMG activity, Nl amplitudes will
Gerbrandt
be reduced by about one third when a time constant
of 1.2 sec is used:
True amplitude = Recorded amplitude x
[Nl duration of 0.8 sec
2 • TC of 1.2 sec
Fig. 1 (traces 2-4) compares Nl activities as a func-
tion of recording dc versus TCs of 0.80 and 0,45 sec.
At least 22% and 67% of the Nl signal are lost, re-
spectively, by using these shorter time constants. In
this case, Nl onset (in dc recordings) occurred 550
msec before EMG onset so that the attenuation of Nl
by shorter TCs was not as severe as it would have
been with Nls of more typical durations. Neverthe-
less, with a TC of 0.45 sec, this short-duration Nl was
reduced near the EEC noise level. Since the ratio of
Nl to other components of shorter duration becomes
smaller, it is more heavily contaminated by other
components when short TCs are used.
Another problem that could develop when RC
coupling is used is capacitative unloading of Nl be-
fore or during movement onset. Spuriously, "Pis" or
"P2s" would then tend to correlate with Nl in ampli-
tudes, topography, and latencies of onset. Variables
that affect the slope of Nl, such as duration of re-
sponse (Deecke et al. 1976), may differentially
change the temporal locus of this capacitative
unloading.
Instructional Factors
In the study by Low et al. (1966), neither a lack
of averaging nor a problem with time constants ac-
counts for the failure to record Nl in advance of
self-paced button-pressing. What appears to bean Nl
potential was, however, recorded in an average of
only 12 trials when subjects pressed a button to avoid
a loud buzzer (Sidman avoidance tasks). Although
this negative wave may be conceptualized as an
"expectancy" of the buzzer, subjects were so success-
ful in avoiding this stimulus that they should rarely
have expected to hear it.
Nl-like activities have also been recorded in nu-
merous studies where button-pressing was not explic-
itly reinforced (e.g., McAdam and Seals 1969, Rohr-
baugh et al. 1976, Otto et al. 1977). What is more
likely, then, is that the Sidman avoidance schedule
highly involved the subjects in button-pressing, that
subsequent button-pressing alone constituted an
extinction of this involvement, and that involvement
in the action is essential for the appearance of Nl.
Without strong intentional participation (Kornhuber
and Deecke 1965) or incentive-motivation for correct
responding (McAdam and Scales 1969), Nl amplitude
may decrease by more than half.
-------
Criteria For Nl Validation
99
In experiments where Nl activities were reliably
recorded (e.g., Vaughan et al. 1968, Deecke et al.
1969, Gerbrandt et al. 1973), even though reinforce-
ments or instructional sets were not separately manip-
ulated as experimental variables, subjects were explic-
itly instructed what to move, when to move, how
rapidly, and how long to hold the movement. Base-
line EMG activities were continuously sampled to
ensure that subjects followed instructions. This type
of instructional set may demand the involvement of
subjects and thus enhance Nl because the response
form is specified in advance by the voluntary plan of
action, rather than by triggering nonspecific motiva-
tional processes (arousal). Nl onset is earlier and
hemispheric asymmetry possibly greater when a
longer duration response is required (Deecke and
Kornhuber 1977). Papakostopoulos and Cooper
(1976) have also shown that, during the preparatory
interval before a response, the background reflex field
is specifically repaItemed to assist the impending vol-
untary movement. This reduction of stretch reflexes,
which would otherwise antagonize the intended
action, may play an important role in smoothing and
accelerating action sequences.
It appears then, that Nl reflects a process func-
tionally significant in readying the central and periph-
eral nervous systems according to the specific actions
that are intended. Experimenters must ensure, there-
fore, that, during the period of preparation for re-
sponding, subjects attend only to the exact para-
meters of response; e.g., type and extent of move-
ment, force, speed, duration and interval of primary
response, and specific sets to eliminate adventitious
responses. When a movement in MRP or CNV research
is described simply as "button-pressing," too little
attention is probably being paid to motor control by
either the subject or experimenters to know whether
or not Nl functions are being reliably engaged and
sampled.
Spatiotemporal and Triggering Factors
Few MRP investigators have provided evidence
that appropriate steps have been taken to minimize
the Spatiotemporal superposition of Nl and artifact-
ual or other MRP components. A crucial consideration
is whether the Nl distribution is distinct from the dis-
tributions of other components known to encroach
on the spatial and temporal domain of Nl. Since Nl
seems to reflect an action-smoothing function via
specific readiness processes antecedent to specific
actions, Nl asymmetries are differentially focused
over the pyramidal motor system contralateral to the
moving hand in right-handed subjects (Vaughan et al.
1968, Deecke et al. 1969, Gerbrandt et al. 1973,
Deecke et al. 1976).
This topographical feature is illustrated in Fig. 2,
where the asymmetry of Nl is 35% less over pre-
+ 75 percent
1.25/LtV
EMG ONSET
512 msec
Fig. 2. Bipolar derivations (contralateral minus ipsi-
lateral to dominant index finger hyperextension) are
shown representing five paired recording sites. The
waveforms at each recording location are grand aver-
ages (N = 352) over five subjects. The earliest average
EMG onset is indicated by a vertical line. Recording
sites shown in Fig. 3.
sumed sornatosensory cortex (-25% site) relative to
motor cortex (0% site). Electrode locations are de-
fined in Fig. 3. The attenuation of Nl asymmetries
away from motor cortex occurs so rapidly that, in
monopolar comparisons of MRPs contralateral and
ipsilateral to movement, significant asymmetries are
observed only over this pre-Rolandic site (Gerbrandt
et al. 1973, Deecke et al. 1976). It is quite likely,
then, that the C3 and C4 sites used by many MRP
-------
100
S.ORB
S.ORB
1 em
1 cm
Fig. 3. The scalp-recording sites used for the data
presented in Fig. 1, 2 and 4 are shown in relationship
to the 10-20 system.
and CNV investigators are too far posterior for maxi-
mal sensitivity to Nl asymmetries since these sites are
closer to the Rolandlc line on the declining gradient
of Nl. At the same time, these more posterior loca-
tions maximize the chance of mixing attenuated Nl
activities with activities of different functional origin,
as discussed below. Depending upon the method used
to locate the Rolandlc line (Vaughan et al. 1968,
Deecke et al. 1969, Gerbrandt et al. 1973), the pre-
Rolandic electrode should be situated 1-2 cm anterior
to the C3/C4 position.
Even when electrodes are placed optimally for
sampling Nl asymmetries, it may be difficult to re-
cognize them. Although the recording ipsilateral to
movement was about 60% smaller than contralateral-
ly in the study by Vaughan et al. (1968) and 30%
smaller In the study by Gerbrandt et al. (1973), it was
only about 10% smaller (and not statistically signifi-
cant) In the work of Deecke et al. (1969) and 20%
smaller in subsequent work (Deecke et al. 1976).
Indeed, very large asymmetries may Indicate trie
superposition of asymmetrical MRP activities with an
origin other than Nl. Deecke et al. (1976) showed
that the Ipsilateral Nl was 55% smaller than contra-
lateral only when measured from baseline to the
point of EMC onset. They note that the added
asymmetry is largely due to contamination of the Nl
measure by N2 activities that occur 20-100 msec
before EMG onset and are more focused than Nl
over the motor cortex contralateral to movement.
They note further that, If one triggers MRP averages
from mechanograms, photocells, or even skin-surface
Gerbrandt
EMG electrodes (rather than the first intramuscular
EMG activity of the principal effector), N2 activity is
more likely to be confounded with the Nl measure-
ment because (1) the earliest EMG activity is not de-
tected and (2) there is greater temporal jitter between
N2 and movement-estimated onsets compared to
EMG onsets. If total EMG quiescence is not achieved
prior to abrupt movement (documented by multiple-
EMG recordings), and if the most sensitive EMG re-
placement is not used, then N2 activities could begin
as soon as the subject begins to prepare (i.e., as early
as 1.5 sec before the actual movement).
This criticism by Deecke et al. is so lethal that the
validity of most MRP and CNV research is suspect.
Perhaps no research group has succeeded in measuring
Nl free from N2 contamination since it is unlikely
that the same motor units sampled from a given elec-
trode are always the first motor units to fire. Pilot
work by the Kornhuber group shows, however, that
the magnitude of this functional rotation among
motor units and muscle groups is probably not
greater than 100 msec (cf. Fig. 2B of Deecke et al.
1976), at least in the Ulm experiments where the
movement Is simple and abrupt and subjects are all
highly practiced In silencing intramuscular motor
activity across several muscle groups.
Given that the average N2 wave commences 54
msec before the average EMG onset, It may be
assumed that N2 would not be appreciably confound-
ed with Nl more than 154 msec (100 + 54 msec)
before the average EMG onset. No other group has
studied the topography of Nl while systematically
triggering MRPs from the onset of intramuscular
EMG activity, and no other group has estimated the
onset latencies of N2 compared to EMG in a topogra-
phic study. Since only the Ulm group has determined
how early N2 can occur prior to an intramuscular
trigger, and since the extent of functional rotation
has not been estimated, the extent of N2 contamina-
tion elsewhere Is as yet unknown,
Vaughan et al. (1968) triggered averages from a
skin-surface EMG location, a procedure which raises
doubts about the sensitivity of detecting the eurUe&t
EMG onset. However, they used a simple, abrupt
movement (hyperextension of fingers or hand) with a
superficially located principal effector (extensor
dlgttorum communis}, Deecke et al, (1976) found
that estimates of N2 onset latency and amplitude
obtained from intramuscular EMG, skin-surface EMG,
and mechanogram triggering were sufficiently similar
with a simple, abrupt flexion of the Index finger to
conclude that Nl and N2 were not confounded in
this case. Using a simple, abrupt hyperextension of
the Index finger, Gerbrandt (1977) also reported that
intramuscular triggering from the extensor dtgltorum
communts did not change the onset latencies of the
-------
Criteria For N1 Validation
N3 component from earlier estimates obtained with a
photocell trigger and skin-surface EMG electrode
(Gerbrandt et al. 1973). If it can be assumed that the
functional rotation among motor units is similar fora
simple, abrupt hyperextension and flexion of the
index finger, and that EMG silence and sensitivity to
earliest onset were achieved, then the rotation-plus-
N2 onset safety margin of 154 msec estimated by
Deecke et al. (1976) can be used for measuring Nl in
the studies ofVaughan et al. (1968) and Gerbrandt et
al. (1973). Vaughan et al. did not terminate Nl
measurement systematically at 154 msec or more be-
fore EMG onset. Contamination of Nl by N2, there-
fore, probably accounts for the large Nl asymmetries
reported (62% smaller ipsilaterally). Nl measure-
ments in the Gerbrandt et ah work are probably not
contaminated by N2 since measurements were begun
150 msec before EMG onset and the earliest EMG
onset was determined for each subject. Although we
did not report onset latencies for the premovement
N2, reanalysis of the data using bipolar derivations
clearly shows an N2 component arising 46 msec be-
fore EMG onset (cf. Fig. 2, 0% site), whereas Nl
onset occurs at an average of 794 msec before EMG
onset.
Task Factors
Most other Nl experiments (and probably all CNV
experiments involving a terminal motor response) are
uninterpretable with regard to Nl contamination by
EMG-adjacent activities. Complex flexion responses
such as balloon-squeezing, telegraph-keying, button-
pressing, or squeezing a hand dynamometer have
typically been used. Even though some investigators
attempted to sample EMG activities associated with
the movement, an amazing number of principal ef-
fectors are involved in complex responses. Kinesio-
logy tests offer little suggestion as to which effectors
might have the earliest onset. Often, principal effec-
tors are deep muscles that are inadequately sampled
by skin-surface EMG electrodes. Arm and body
positions required to maintain contact with the
apparatus - "ready" to respond — make it difficult
to achieve EMG quiescence. Some devices require the
application of large forces (1-20 kg) that probably
involve functional rotation across an extensive muscle
field.
Subjects must also expect and encounter extra-
kinesic and tactile resistance against the apparatus,
factors that undoubtedly introduce potentials that
would not occur in simple unimpeded movement
situations. The use of oscilloscopes or other on-line
feedback signals may similarly introduce confounding
nonmotoric expectancies. These problems were com-
pounded in many studies by the use of short inter-
movement intervals (34 sec). It is difficult for both
subjects and experimenters to ensure EMG quiescence
101
and stability in such a short interval after movement.
These kinesiological questions require extensive docu-
mentation to show that the earliest EMG activities
have been sampled and that EMG quiescence has been
achieved. Since N2 may be the scalp-recorded integral
of specific commands or initiations of every muscle
group cortically activated during movements, these
methodological errors may introduce N2 confounding
more than 150 msec prior to the arbitrarily deter-
mined EMG onset. The 150-msec estimate obtained
in early work with simple, abrupt movements
(Deecke et al. 1969, Gerbrandt et al. 1973) probably
does not apply to these more complex movements.
Adventitious Movement Factors
Even when the methodologies seem adequate for
attaining good estimates of EMG quiescence and earli-
est EMG onset for the responding limb, adventitious
or occult events (not primarily involved in self-paced
or planned movements) may occur that produce
potentials that summate with Nl. It is essential,
therefore, to place electrodes over all recording loca-
tions where possible contaminating (superimposed)
sources of activity appear differentially compared to
Nl. Otherwise, one cannot verify that the observed
component is behaving as a function of Nl rather
than extraneous factors. Routine placement of elec-
trodes for detection of vertical eye movements
(EOG), for example, is essential for ruling out this
source of artifact (Hillyard and Galambos 1970). Re-
quiring eye fixation on an external reference, denying
subjects view of their own movements, and pretrain-
ing of subjects by having them watch their own eye
movements reduce, but do not entirely eliminate,
artifactual eye movements (Papakostopoulos et al.
1973). Routine monitoring of eye movements is es-
sential (Wasman et al. 1970).
Although horizontal eye movements do not contri-
bute artifactwlly to scalp recordings when a linked-
earlobe reference is used, potentials preparatory to
eye movements may appear over Rolandic and frontal
regions even when averaged EOG recordings may not
indicate artifactual contamination (Becker et al.
1972, Syndulko and Lindsley 1977, Rosen et al. this
volume). These potentials may be functionally related
to Nl in the sense of involving readiness processes,
but not specifically associated with voluntary hand
movement and may thus confound measurements of
the symmetry and topography of components related
to hand movement. Both horizontal and vertical eye
movements should, therefore, be monitored at all
times. Any trials showing orbital-related activities
should be deleted before averaging.
Investigators should also demonstrate that other
extracranial sources of Nl contamination (e.g., glos-
sopharyngeal and neck EMG artifact) have been elimi-
nated. The neutrality of the reference electrode
-------
102
Gerbrandt
Table 1. Electrode Sites and Waveforms Needed to Distinguish N1 Spatiotemporally
from other Components*
Active electrode sites
No.
Waveform derivations
Wo.
Purposes of derivations
External canthus
Supra-orbital(C&l)
+25%(C&I) or F(3&4)
0%(C&I) or modified C(3&4)
-25%(C&l&Z)orP(3&4)
1 EC-LE
2 SO(C&I)-LE, SO(C)-SO(I)
+25%(C&I)-LE,
or or
F(3&4)-LE, F3-F4
0%(C&I)-LE,
or or
MC(3&4)-LE, MC3-MC4
-25%(C&I&Z)-LE, -
or
P(3&4&2)-LE, P(C)-
P4
1 Monitor horizontal eye move-
ments, differentiate eye move-
ments from "asymmetrical and
reversed N1"
3 Monitor vertical eye movements.
confirm differential presence of
"reversed and symmetrical IM1,"
confirm narrowness of N1 distri-
bution
3 Confirm presence of N3, con-
firm narrowness of N1 distribu-
tion and difference from N3 dis-
tribution, confirm narrowness
and difference in N2 vs. N1 and
N3 distributions
3 Confirm focus of asymmetrical
N1, confirm focus of N2
Confirm focus of symmetrical
PI, confirm posterior distribu-
tion of symmetrical INI1, confirm
posterior distribution of P2, con-
firm "reversed" N3 postcentrally
•Abbreviations: C = Contralateral; EC ;= External Canthus; F = Frontal; I = Ipsilateral; LE = Linked Ear Reference; MC = Motor
Cortex; P - Parietal; SO - Supra-orbital; Z = Midline. Electrode sites are illustrated in Fig. 3.
should also he demonstrated with a noncephalic indif-
ferent electrode.
Electrode Derivation Factors
When all these procedures are employed, the proof
of their effectiveness still rests in the demonstration
that Nl is spatiotemporally focused appropriately
and is distinguishable from other MRP components
(PI, N2, N3, and P2) capable of occupying the same
domain. A list ol electrode derivations considered
necessary to analyze Nl is shown in Table 1. Note
(hat bipolar derivations (contralateral - ipsilateral) are
also essential in most subjects to isolate N2 from
superposition with symmetrical PI activities (Deecke
et a!. 1060, compare the 0% sites in Fig. 2 vs. Fig. 4).
Jjipobr derivations are also helpful In distinguishing
Nl from N2 activities because N2 is more symmetri-
cal and differs temporally in slope of amplitude (Fig.
2). Notice, in addition, that Nl has a different distri-
bution with bipolar vs. monopolar derivations. With
monopolar recordings (Fig. 4), Nl is largest post-
centrally, whereas in bipolar derivations (Fig. 2) Nl is
35% larger (at 150 msec before EMG onset) over the
motor cortex.
An even greater contrast between monopolar and
bipolar distributions is obtained when the postcentral
electrode is moved posteriorly over the P3/P4 sites
(Deecke et al. 1076), where Nl shows no asymmetry
at all. The bipolar distribution seems to correspond
more closely to specific readiness processes preceding
specific actions (i.e., it is asymmetrical and focused
over the motor cortex). The fact that motivational
variables may differentially affect symmetrical com-
pared to asymmetrical Nl activities (MeAdam and
Scales 1069, Kutas and Donchin 1077) suggests that
these are functionally different types of readiness
that should be separately measured.
Finally investigators should score records blind
with regard to electrode site, condition, and subject
to avoid experimenter bias about the existence of a
-------
Criteria For N1 Validation
VLr'A/V-vSA^'
+ 75 percent
'
512 msec
Fig. 4. Monopolarly-recorded MRPs (linked ear refer-
ence) for five pairs of electrodes (contralateral to
dominant index finger movement = solid line; ipsi-
lateral = broken line). Waveforms are grand averages
(N = 352) over five subjects. Earliest average EMC
onset indicated by vertical line. Recording sites
located as shown in Fig. 3.
103
component. For instance, random fluctuations in
EEC voltage may inadvertently be identified as Nl
onset, or "PI" or "N2" bumps, even when such com-
ponents may not be present (cf. possible "N2" at
-25% site, Fig. 2). Peak-seeking algorithms which
automatically select a maximum or minimum voltage
point within a specified time window, for instance,
will always provide an output value, regardless of the
quality or nature of the input. Since all MRP analysis
techniques are more or less susceptible to biases or
limits of this type, investigators should explicitly
state the set of measurement rules used (cf. Ger-
brandt et al. 1973, Deecke et al. 1976).
Conclusions
The foregoing methodological considerations are
summarized in Table 2 which is organized as a check-
list for use in planning and evaluating MRP studies.
The specific procedures listed in Table 2 can be re-
duced to three basic criteria for optimizing Nl resolu-
tion: (1) demonstrate clear visual resolution of Nl
(signal-to-noise ratio = 4); (2) demonstrate clear
spatiotemporal resolution of N1; and (3) demonstrate
clear functional resolution of Nl.
If previous MRP and CNV research is evaluated
rigorously in accordance with this checklist, it may be
concluded that Nl has rarely been recorded with suf-
ficient methodological controls to ensure uncon-
founded measurement and interpretation. That is, in
most studies the sustained negative potential associ-
ated with preparation for voluntary movement can-
not be distinguished from other potentials of differ-
ent functional origin. Indeed, so much data are
brought into question that one must ask whether the
criteria are too stringent and why so few investigators
have applied them.
An analogy from the field of neuropharmacology
may be helpful in answering these questions. A neuro-
transmitter is a chemical substance by which informa-
tion is transferred from neuron to neuron. Three
criteria must be met to conclude with certainty that a
particular substance functions as a neurotransmitter
(Julien 1978). These criteria are: (1) the compound
must be contained in, and released from, specific pre-
synaptic nerve endings; (2) control over the rate of
release of the putative compound must mimic post-
synaptic actions (excitation, inhibition) that follow
from presynaptic nerve stimulation; and (3) there
must be a mechanism of inactivation of the com-
pound that shapes the time course of the "natural"
transmitter action.
When students first hear how difficult these cri-
teria are to satisfy in the central compared to the
peripheral nervous system, they question whether it is
"fair" to apply peripherally-devised criteria to the
CNS. In the PNS or CNS, the purpose of the criteria
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104
Gerbrandt
Table 2. Methodological Checklist of Procedures to Optimize Spatiotemporal
and Functional Resolution of IM1
1. EEC Electrode and Recording Factors
(a) Use appropriate electrode montages, including unipolar and bipolar derivations as shown in Table 1 and Fig.
3, to maximize Spatiotemporal resolution.
(b) Use long time constants (> 0.8 sec).
(c) Determine that reference electrode is neutral by use of noncephalic indifferent technique.
2. EMG Electrode and Triggering Factors
(a) Use appropriate recording methods, preferably needle electrodes inserted in principal effector muscles, to
trigger averages from the earliest motor unit discharge.
(b) Determine degree of functional rotation among relevant motor units.
(c) Achieve stable periods of EMG silence (> 4 sec) between successive movements.
3. Task and Instructional Factors
(a) Use a simple, abrupt, unimpeded movement that requires minimal support.
(b) Use long intermovement intervals (> 10 sec).
(c) Use right-handed and left-handed responses (in right-handed subjects) to show lateralized Nl focus.
(d) Carefully instruct subjects to focus attention on relevant parameters of the required response and to inhibit
all other movement. Monitor EMG to ensure compliance.
4. Signal A veraging Factors
(a) Average 64-1082 trials as necessary to achieve an EEG signal-to-noise ratio = 4
(b) Reject high-noise trials and high-noise subjects.
(c) Demonstrate that waveforms are not confounded by art if actual or adventitious potentials that are not
primarily involved in the self-paced movement (e.g., vertical or horizontal eye movements, glossopharyngeal
or neck EMG activity, nonmotoric expectancies).
5. Measurement Factors
(a) Explicitly state the set of measurement rules used in data analysis.
(b) Measure each MRP component at the electrode location and with the particular derivation that maximally
differentiates the component from other components (cf. Table 1 for N1).
(c) Determine the onset latency of N2. Measure N1 from the N2-free terminal point (> longest rota-
tional-plus-N2 onset point).
(d) Score records "blind" to electrode site, condition, and subject to avoid experimenter bias.
is to ensure that the compound in question, rather
than another, is the one that is involved in trans-
neuronal information transfer, rather than some other
function. Application of these criteria in the CNS is
very difficult, but positive identification of a neuro-
transmitter can only be claimed when these criteria
have been met.
This checklist, like the neurotransmitter criteria, is
meant to ensure that a particular functional compo-
nent (Nl) has been demonstrated in isolation. Short-
cuts in applying Nl criteria simply may lead to uncer-
tainty about what is being demonstrated. Hopefully,
this review provides a systematic framework for eval-
uating past Nl research and will encourage a broader
application and further refinement of criteria for
demonstrating Nl and other component functions in
subsequent MRP studies.
-------
EFFECTS OF MOVEMENT ON SENSORY INPUT
P. HAZEMANN
Laboratory of Occupational Physiology, Pitie - Salpetriere Hospital, Paris, France
Sensory input is generally diminished when move-
ment coincides with sensory stimulation if the two
events are not related. This effect can be demonstrated
by the study of evoked potentials in animal and man.
Evidence related to the effects of movement on audi-
tory and somatosensory evoked potentials is reviewed
here. Visual evoked potentials are not considered
because visual inputs are modified by ocular move-
ments and pupillary contraction.
Animal Studies
Starr (1964) studied the influence of motor activ-
ity on click-evoked responses in the auditory path-
way of the awake cat. Responses recorded from the
round window, cochlear nucleus, inferior colliculus,
medial geniculate body, and auditory cortex were of
smaller amplitude when animals were moving. The
extent of attenuation was roughly related to the
extent of movement. When tendons of the middle ear
muscles were sectioned bilaterally, responses recorded
from subcortlcal stations did not decrease during
movement, whereas cortical responses were still atten-
uated. Amplitude of cortical responses to an electric
shock, applied through bipolar electrodes located
along subcortical stations of the auditory pathways,
decreased during motor activity if the stimulation was
subthalamlc, while it was unmodified by medial
geniculate stimulation. This finding suggests that
mechanisms modifying cortical responses do not influ-
ence the cortex directly, but act at intermediate sites.
Chez and Lenzl (1971) studied changes in the
transmission of somatosensory volleys to the medial
lemniscus during a conditioned voluntary movement.
Cats were trained to lift the right paw, press a lever at
the onset of a tone, and then replace the paw on the
ground. The right superficial radial nerve was stimu-
lated, and responses were recorded in the medial lem-
niscui. Responses to stimuli were significantly smaller
during active movement, with depression occurring
between 100 and 200 msec prior to the lifting move-
ment. Responses returned to control levels within
100 to 200 msec after the cat replaced its paw on the
ground. During the period of postural fixation,
responses did not differ from control values.
Ghez and Pisa (1972) attempted to identify the
parameters of movement related to the change in
lemniscal transmission. They found a negative linear
correlation between the amplitude of lemniscal
response and the logarithm of the velocity of the bar,
determined at the instant the stimulus was delivered.
Neither force exerted nor passive movement of the
upper extremity produced noticeable changes. Ghez
and Pisa attributed the attenuation of lemniscal poten-
tials to central influences impinging on the cuneate
nucleus.
Coulter (1974) showed that responses evoked in
the medial lemniscus by stimulation of the contralater-
al forelimb in the awake cat were reduced in amplitude
during gross motor activity. During discrete move-
ments, depression of the lemniscal potential could be
clearly related to the occurrence and duration of
bursts of muscle activity. This depression was observed
about 100 msec prior to EMG activity. Neither move-
ment of the forelimb opposite to stimulation nor pas-
sive movements resulted in depression of the lemniscal
potential.
Human studies
Broughton et al. (1964) noted a decrease in soma>
tosensory evoked potentials (SEPs) during fist clench-
ing, Giblin (1964) also observed a decrease when
fingers were moved either actively or passively.
Coquery (1971) and Coquery et al. (1972) showed
that SEPs elicited by electrical stimulation of a finger
increased during the 200 miec before the beginning
of EMG activity and decreased during contraction
when flexion was performed by the stimulated hand.
SEPs increased when flexion was performed by the
nonstimulated hand, but decreased during active and
passive plantar flexion of both feet. Coquery conclud-
ed that both facilltatory and inhibitory influences act
on the somatosensory pathway and that at least part
of the inhibitory influence has peripheral origin.
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106
Hazemann
Lee and White (1974) studied the effect of repeti-
tive flexion and extension of the fingers on SEPs
elicited by stimulation of the fingers. The most
obvious change during movements of the stimulated
hand was an increase in amplitude and a slight increase
in latency of a late negative component. The enhance-
ment of evoked potentials was specific to movements
occurring in the immediate vicinity of stimulation,
but was not limited to the contralateral area. Enhance-
ment was maximal at the vertex and almost as promi-
nent over the ipsilateral as the contralateral hemis-
phere. Lee and White suggest that the change in evoked
potentials reflects an interaction between central
efferent and afferent systems, a cumulative effect
that probably occurs at several levels.
Papakostopoulos et al. (1975) compared cortical
potentials following passive or externally paced dis-
placement (EPD) to those related to similar but self-
paced voluntary displacement (SPD) of the index
finger. Secondly, evoked responses to brief electrical
stimuli applied to the medial nerve at the wrist during
SPD were compared with similar responses elicited in
subjects at rest. After EPD, a clear evoked response
could be seen from p re frontal, precentral, and post-
central areas, whereas, after SPD, only a diminished
response could be seen in the precentral area. In the
same way, electrical stimulation of the median nerve
evoked clear responses in precentral and postcentral
cortex when the limb was at rest. When stimuli were
timed to occur during self-paced displacement of the
index finger, responses were diminished in the post-
central area, but remained relatively unaffected in the
precentral area. The evoked potentials returned to
resting values 700 msec after the movement onset,
even if the displacement was sustained. Papakostop-
oulos et al. interpreted the results as a movement-
related gating action that selectively affects sensory
input to somatosensory and motor cortex, the latter
being less inhibited.
Hazemann et al. (1975) investigated the temporal
relationship between self-paced movement and pre-
sentation of test stimuli. Evoked potentials were
averaged in 10 successive epochs, extending from 880
msec before to 2.5 sec after movement. Auditory
evoked potentials were attenuated in all epochs, with
the greatest decrease appearing in the epoch just
following movement. Somatosensory evoked poten-
tials were similarly attenuated when movements were
performed by the hand contralateral to stimulation.
In the ipsilateral case, SEP amplitude was attenuated
only when stimulation was administered close to the
active muscle. It appears from these results that move-
ment induces a generalized central modulation of
sensory evoked potentials that reflect the degree of
occupation of a single limited-capacity channel
(Broadbent 1971). The same channel appears to be
used selectively for the transmission of either afferent
input or efferent output signals.
Summary
The amplitude of somatosensory evoked poten-
tials has almost always been found to diminish when
the stimulated part of the limb was moved. Generally,
the decrease commenced prior to movement onset.
The effects of contralateral and passive movements
are not as clear. When studied, the auditory evoked
potentials have also been found to diminish during
movement in both cat and man. Explanations vary,
but most authors suggest that mechanisms of inter-
action between voluntary motor activity and sensory
input may operate at different levels of the central
nervous system.
-------
INFLUENCE OF FORCE, SPEED AND
DURATION OF ISOMETRIC CONTRACTION
UPON SLOW CORTICAL POTENTIALS IN MAN
P. HAZEMANN, S. METRAL, AND F. LILLE
Laboratory of Occupational Physiology, Pitie-Salpetriere Hospital, Paris, France
The first studies on the human cortical motor
potential described the type of movement performed,
but did not take into account the fact that movements
may vary during the experiment. Since that time,
studies have been completed that consider the physi-
cal parameters of movement, although these investi-
gations generally examined only one parameter: force
(Ford et al. 1972, Wilke and Lansing 1973, Kutas and
Donchin 1977) or speed (Becker et al. 1976). Their
results are difficult to compare since, for example,
the movements are performed by segments of differ-
ent limbs.
The present investigation seeks to examine the
systematic influence of force, speed of force variation,
and duration of maintained force on the cortical
motor potentials associated with isometric contrac-
tions of the index finger while a subject regulates his
performance through visual control of the mechano-
gram.
Methods
Thirteen subjects (8 male, 5 female, 2040 years
old) participated in this study. Subjects were comfort-
ably seated in an armchair with forearm support and
index finger immobilized at the last phalango-phalan-
gian joint by a large plastic ring, rigidly fixed to a
strain gauge. The subject was told to make an index
dorsiflexion against this gauge. The apparatus allowed
contraction to occur under practically isometric con-
ditions.
In the three situations defined below, the subject
controlled the mechanograms of his contractions on
an oscilloscope screen 1 meter in front of him. Con-
tractions, timed by the appearance of the oscilloscope
spot, were performed every 4 or 6 sec by the domi-
nant hand and were repeated 300 times for each con-
dition. In the "force" situation, contractions perform-
ed with a great force (GF) (about 500 g) were compar-
ed to contractions of small force (SF) (about 200 g),
achieved in the same time. In the "speed" situation
(speed of force variation dF/dt), high-speed contrac-
tions (HS), done with 500-g force and achieved in
about 160 msec, were compared to low-speed contrac-
tions (LS) in which the same force was achieved in
660 msec. For the "time maintained" situation,
contractions involving 200-g force, achieved in 160
msec, were sustained for 500 msec (BS) or 1000 msec
(CS).
A separate recording session was held for each
situation. Ten subjects participated in the force and
speed situations, and six in the sustained contraction
situation. EEC was recorded from the rolandic area
(C3 or C4) contralateral to movement, with a scalp
electrode referenced to linked ears (Al, A2). The time
constant was 0.7 sec. EMG was recorded by means of
surface electrodes over the extensor digitorum com-
munis muscle. EEC, EMG and mechanograms were
recorded simultaneously on paper and magnetic tape.
The averaged motor potentials of 300 successive
movements were obtained from a CAT 400 with an
analysis time of 4 sec. The averager was triggered
from the mechanogram, with a Schmitt trigger used
to obtain a stable threshold. The lag between reading
and recording heads of the magnetic recorder al-
lowed a 1760-msec delay of the EEC. Motor poten-
tials were displayed on an XY plotter. For each con-
dition, mechanograms were averaged in groups of 100
and 300 to ensure that instructions were observed.
Two subjects participated in supplementary
recordings during which ocular and visual phenomena
were studied. Contractions were performed under HS
and LS conditions with and without visual feedback
from the mechanogram on the oscilloscope in order
to check for ocular tracking movements and visual
afferents. Contractions were averaged, with all trials
preceding, following, or simultaneous with ocular
movement or blinking eliminated, as a test for elec-
trooculogram diffusion. For these experiments, EEC
was recorded from the contralateral Rolandic (C3 or
C4), frontal (Fl or F2), coronal (F3 or F4), and oc-
cipital (Ol or 02) areas, and EOG was recorded with
silver electrodes from the superciliary arch and the
lower rim of the orbit.
The cortical motor potential was analysed in
terms of component latency and amplitude. Latencies
were measured from the beginning of the mechano-
gram to inflexion of the baseline for Nl and peak
latency for all the other components. Amplitudes
-------
108
Hazemann et al.
were measured from the baseline, 200 msec before
the medianogram for Nl, at peak for N2, P2, andP'2.
For PI and P'l, amplitudes were measured from the
preceding peak. Latency and amplitude values for
each condition were compared for individual subjects
and for the entire subject population. Mean values
and standard deviations were compared by student's
test for group data.
Results
Analysis of group data showed that force exerted
(determined by the amplitude of the mechanogram)
was 495 ± 147 g for the GF condition and 222 ± 41 g
for SF, Speed of force variation (measured as rise time
of the mechanogram) was 192 ±46 msec in the HS
condition, 851 ± 106 msec for LS, 200 ± 47 msec for
BS, and 276 ± 58 msec for CS. For conditions BS and
CS, maintenance time (defined as the duration of the
plateau) was 506 ± 122 msec and 956 ±211 msec,
respectively. Therefore, subjects were able to follow
Instructions for force and duration maintenance, but
speed of rise time seemed difficult to control. In every
situation, speed of force achievement was slower than
requested. There was an evident prolongation of rise
time when movements were performed at slow speed
or with sustained movement.
With visual analysis of motor potentials, positive
components were characterized that differed from
those classically described (Fig. 1). The classical motor
potential (using the nomenclature of Gilden et al.
1966) has a premotor negativity Nl, an inconsistent
premotor positivity PI, a negativity N2 culminating
after movement, followed by a positivity P2. As PI
precedes an increase in the slope of negativity (Nl),
the slope inflection was considered to correspond to
PI even when a distinct PI was missing. A second
minor positivity P'l was noted after movement and
preceding or following the N2 peak. P2 was usually
followed by another positivity P'2 and, although P2
was at times a mere notch within P'2, usually two
individual peaks were noted, either of which might be
greater. A double-peaked configuration of late positiv-
ity is also mentioned by Arezzo and Vaughan (1975).
Amplitudes and latencies of components were
measured for the six experimental conditions (Fig. 2).
Mean values and standard deviations for the latencies
are given in Table 1.
Nl latency ranged from -1600 msec to -320 msec,
with an average of -980 msec. Nl was seen in all
subjects for conditions HS, BS and CS, in 8 out of 10
subjects for condition GF, and in only 5 subjects for
condition SF. Its amplitude did not vary significantly
from one condition to another; however, its latency
was significantly longer for sustained contractions
(<.02) and contractions done with little force (<.02).
ONSET OF THE
MOVEMENT
100 muo
Fig. 1, Averaged cortical motor potential. Continuous
line: components described by Gilden et al. (1966);
dotted line: supplementary components described in
this study.
Latency of PI was from 440 msec to -20 msec,
with an average of -204 msec. PI was seen in only
half the subjects for conditions GF, SF, HS, and LS
while it appeared reliably and significantly earlier
(<001) for conditions BS and CS.
P'l latency averaged 85 msec and ranged from 0
to 180 msec. P'l was absent in LS, but appeared fairly
consistently in all other conditions. Amplitude and
latency were not systematically altered by other
manipulations.
N2 latency was from -100 to +320 msec, with an
average of +100 msec. N2 was consistently found for
conditions HS, BS, and CS and was seen nine times for
condition LS, eight times forGF, and seven times for
SF. Its average latency was significantly longer (<.05)
for condition LS compared to HS. N2 amplitude was
significantly smaller (<.05) for condition SF compar-
ed to GF. For all other conditions, there was no signifi-
cant difference in latency or amplitude.
P2 latency ranged from 220 to 500 msec, with an
average of 367 msec. P2 was constant for conditions
GF, SF, and HS, but was missing twice for condition
LS and once for conditions BS and CS. Amplitude for
the three latter conditions was significantly lower
(<.001) than for other conditions.
P'2 was observed in nearly all recordings, but was
missing in one subject for conditions SF and LS. P'2
amplitude was significantly higher (<01) for condi-
tion HS compared to LS and for situation HS (<,05)
compared to GF and SF. Latency was linearly corre-
lated (0.92) with the duration of the mechanogram.
Because of the precocity of Pi in the sustained
situation, the length of time between peak Pi and
-------
Physical Parameters of Contraction
109
Fig. 2. Cortical motor potential (C3-A1A2) recorded in two subjects under six experimental conditions. From
top to bottom: HS = high speed, LS = low ipeed, GF= great force, SF= small force, BS = briefly sustained, and
CS » considerably sustained.
peak N2 was significantly longer (<.01) in the sustain-
ed situation compared to all other situations.
No significant difference in slow cortical poten-
tials recorded from the rolandic area (Fig. 3 A), or in
EEC recordings averaged without ocular artifacts (Pig.
3B) was apparent whether or not visual control of
the mechanogram was provided. These two tests
excluded any contamination of the motor potential
by extracerebral phenomena or by visual evoked
potentials.
Discussion
Most authors who have studied the cortical slow
phenomena associated with movement in man report
high interindividual variability, whereas intraindi-
vidual phenomena for one kind of motor movement
appear stable (Gilden et al. 1966;Deecke et al. 1969,
1973; Gerbrandt et al. 1973). The present findings
and high standard deviations support these observa-
tions. Only Castaigne et al. (1969) report high intra-
individual variability.
Modifications of slow potentials in relation to
the force of movement have been studied previously
by Ford et al. (1972), Wilke and Lansing (1973), and
Kutas and Donchin (1977). In these three investiga-
tions, the amplitude of the motor potential increased
with force exerted, thus affecting either the amplitude
of the readiness potential (Ford et al., Donchin and
Kutas) or negative-positive postmotor deflection
(Wilke and Lansing). Furthermore, Wilke and Lansing
observed the maximum negativity point at a constant
latency from the beginning of EMC activity for a given
subject and suggested that this measure might contain
-------
110
Hazemann et al.
Table 1. Means (m), Standard Deviation (a), and Number (n) of Observations for the Latencies
(msec) of Cortical Motor Potential Components as a Function of Physical Parameters
of Concentration
N1
P1
P'1
N2
P2
P'2
m
0
n
m
a
n
m
a
n
m
a
n
m
a
n
m
a
n
Force
500 g
-858
488
8
-120
87
5
110
47
8
80
97
8
370
62
10
662
133
10
200 g
-1016
454
5
•137
87
5
104
50
9
57
90
7
376
62
10
637
107
9
Speed
160 msec
-855
423
10
-224
144
5
660 msec
-830
298
8
•110
48
5
77
72
8
98
97
10
348
34
10
594
81
10
194
117
9
407
98
8
1104
266
9
Duration
500 msec
-1080
511
6
-326
148
6
70
47
4
106
65
6
336
55
5
1203
268
6
1000msec
-1156
266
6
-288
79
R
64
51
5
108
48
6
356
88
5
1745
296
6
Fig. 3. A : Averaged cortical motor potential (C3-A1A2) for condition HS (left) and condition LS (right), with
(dotted line) and without (continuous line) visual control. B: Averaged cortical motor potential (C3-AIA2) for
condition HS (left) and condition LS (right), from the raw EEC recording (dotted line) and EEC recording with-
out blinking and ocular movement (continuous line).
-------
Physical Parameters of Contraction
111
information about the force exerted during a move-
ment. The only significant differences between GF
and SF noted in the present work concern the ampli-
tude of N2 (p<.05).
The influence of movement speed on motor
potentials has been studied by Becker et al. (1976).
Slow potential modifications affected Nl; the latency
was 800 msec for rapid and 1300 msec for slow move-
ments and the amplitude was greater for slow move-
ments. In the present study, no significant difference
in latency or in amplitude was found, although HS
and LS results tended to corroborate the preceding
authors. The significant N2 latency changes were not
described by previous researchers. The absence of PI
in low-speed movements, although difficult to inter-
pret, is perhaps evidence in agreement with the con-
clusion of Becker et al. that the organi/.ation of slow
movements is different from that of rapid movements.
Gilden et al. (1966) mentioned the influence of
movement duration on the motor potential. They
observed a positive wave beginning 50 to 150 msec
after the start of EMG; the wave persisted, or dimin-
ished slowly, with sustained contraction. The behavior
of this positive wave is similar to the wave P'2 describ-
ed herein. Otto et al,(1977 and this section) have
noted a prolonged positive variation during sustained
motor response. Are/.zoand Vaughan(1975) described
a positive component, P3, at 265 msec, which might
encode information on body position.
There appear to be no major contradictions
between the results of this study and those of authors
cited. Supplementary data, however, have been pre-
sented, allowing the definition of hypotheses and lend-
ing support to the hypotheses of others. The most
important data concern the mobility of PI latency,
the relative stability of N1-P1 duration, the modifica-
tions of P1-N2 duration, and P'2 latency variations.
Apparently, the limits of variation in the motor
potential are influenced by physical characteristics of
contraction and depend upon the interrelations of its
various components. The stable N1-P1 suggests that a
general preparation mechanism is necessary for the
performance of any contraction. The latency of PI
seems to be related to the type of motor contraction.
Gerbrandt et al. (1973) hypothesized that PI alone
might be of motor origin. Deecke et al. (1973) pro-
posed that it might be an electrophysiological expres-
sion of movement initiation by parietal and, perhaps,
other association areas. Groll-Knapp et al. (1977)
attributed PI to processes of thalamocortical control
of the efferent message.
The results tend to relate P1-N2 to the initiation
and contraction control period. In the case of force
control, the period is short but lasts longer when con-
trol affects speed (particularly the low-speed situation)
or both speed of movement initiation and anticipation
of its sustained nature.
Despite the difficulty of relating an animal model
to the present research on humans, animal experimen-
tation shows variations in cell activity according to
force, speed of force variation (dF/dt), and sustained
movement. Evarts (1968, 1969), using the monkey,
demonstrated a relationship between the activity of
certain cells in the pyramidal tract and the magnitude
and rate of change in force, as well as the direction
of displacement. Working with the same species, Smith
et al. (1975) differentiated three cell types in the pre-
central cortex during performance of a sustained grip
between the thumb and forefinger. Some cells behaved
in a dynamic manner (increase or decrease in the
frequency of action potentials related to movement).
Their participation preceded movement by 500 to
750 msec; their activity rate could be related to the
speed of force variation and, less frequently, to force
alone. Other cells were static and came into play 0 to
400 msec after the beginning of movement; their
activity vaguely increased with force and remained
constant until the end ofmovement. Finally, a greater
number of cells were of a mixed type, dynamic and
static at the same time.
The stable temporal link between mechanogram
commencement and P2 peak suggests that this wave
is independent of contraction programming and varia-
bles of performance. This wave may represent the late
component of the somatosensory evoked response, or
the homolog of Sutton's uncertainty wave, as suggest-
ed by Gerbrandt (1977). In contrast, P2, which
occurs at the end ofmovement regardless of its physi-
cal characteristics, varies in latency and becomes larger
with brief contraction. Central and peripheral feed-
back mechanisms have often been proposed to explain
electrical phenomena coming after movement onset.
Papakostopoulos et al. (1974a), studying cortical
potentials related to passive movements, attributed
P2 to articular afferences. Megirian et al. (1974)
observed an amplitude increase in rat motor potentials
after novocainization of the moving paw and deduced
that motor behavior is controlled by peripheral and
central sensory feedback mechanisms. The hypothesis
of a purely peripheral origin seems further weakened
by the findings of Vaughan et al. (1970) that the
ovfdl configuration of the motor potential in the
monkey is unchanged after deafferentation of the
moving limb.'
In conclusion, the physical characteristics of
contraction induce changes in PI latency in response
to temporal program complexity. P'l is absent and
N2 latency increases during low speed contractions.
Lastly, P2 latency changes in relation to contraction
duration.
'Note Deecke's counterargument elsewhere in this
section.
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NEUROANATOMICAL ORGANIZATION OF THE
PRIMATE MOTOR SYSTEM: AFFERENT AND
EFFERENT CONNECTIONS OF THE VENTRAL
THALAMIC NUCLEI.
K. KALIL
Department of Anatomy, University of Wisconsin, Madison, WI, U.S.A.
The ventralis anterior (VA) and ventralis lateralis
(VL) nuclei comprise a major territory of the mam-
malian ventral thalamus, extending forward from the
ventroposterolateral nucleus (VPL) to the rostral pole
of the thalamus. Although the ventral tier nuclei of
the primate thalamus have been carefully parcellated
into cytoarchitecturally distinct sub regions (Olszewski
1952), some boundaries, particularly that between
the VL and the rostral region of the VPL, remain diffi-
cult to define.
It has been demonstrated anatomically and physi-
ologically that the VA and VL nuclei form an import-
ant subcortical region of convergence for a number of
structures related to the motor system. Afferent fibers
to the VA-VL arise from the deep cerebellar nuclei
(Angaut 1970, Mehler 1971, Kievet and Kuypers
1975, Rinvik and Grafova 1974, Chan-Palay 1977,
Kalil 1977), from the globus pallidus (Kuo and
Carpenter 1973), and substantia nigra (Carpenter
et al. 1976). Intracellular recordings show that a single
VL neuron can be influenced by synaptic inputs from
several of these afferent fiber systems (Purpura et al.
1966, Sakata et al. 1966), and there is also consider-
able physiological evidence that VA and VL exert a
strong monosynaptic influence on those neurons of
the motor cortex that give rise to the pyramidal tract.
Amassian and Weiner (1966) reported that pyramidal
tract neurons could be monosynaptically excited by
inputs from both VA and VL (see also Yoshida et al.
1966). Furthermore, by combining antidromic activa-
tion of VL neurons with stimulation of the cerebel-
lum, Sakata et al. (1966) were able to demonstrate
that fibers arising from the deep cerebellar nuclei
synapse directly with VL neurons that, in turn, project
to the motor cortex.
Despite the fact that the VL nucleus has long
been recognized as the principal source of thalamic
affercnts to the primate motor cortex (Walker 1934,
1944), little it known about either the precise top-
ography of thalamocortical connections arising from
the ventral lateral nucleus or their distribution within
cortical laminae. Still less is known about the cortical
projections of VA. While it has been suggested that
VA projects to area 6 (the premotor cortex) (Mettler
1947), large numbers of VA neurons survive hemi-
decortication (Powell 1952), which was thought to
imply that VA sends relatively few axons directly to
the cortex (see review by Carpenter 1967).
The strong influence of VA and VL on pyramidal
tract neurons points to the importance of these thala-
mocortical pathways for the initiation and control of
movement (Evarts and Thach 1969). Thus, it is sur-
prising that so little is known about the detailed
anatomy of these pathways. One of the major reasons
for the paucity of studies on thalamocortical connec-
tions of the monkey VA and VL nuclei is the fact
that, until recently, appropriate neuroanatomical
methods for such studies were lacking. Almost all of
our knowledge of the cortical connections of the VA
and VL is derived from retrograde cell degeneration
studies (Walker 1934, Chow and Pribram 1956), but
these studies give little detailed information about the
topography of this thalamocortical system. More
recent studies (Kievet and Kuypers 1975, Strick
1976b) employed the horseradish peroxidase method
and reported retrograde transport of the enzyme to
the VA, VL, and rostral VPL after injections into the
motor cortex of the rhesus monkey. Though a more
precise topography can be obtained with this method,
it cannot elucidate the laminar organization of thala-
mocortical fibers within the cortex.
Similar problems of methodology have also beset
the detailed study of afferent input to the VA and
VL nuclei, and thus little is known about the precise
organization of cerebellar inputs to the thalamus.
Fortunately, however, the autoradiographic method
for tracing neuronal pathways in the central nervous
system provides a means of studying the connections
of structures deep within the brain without the prob-
lems of damage to fibers of passage in anterograde
studies or resorting to large lesions in retrograde
studies. In this technique, small amounts of radioactive
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Neuroanatomical Organization of Motor System
113
amino acids are injected into the brain and incorp-
orated into proteins by neurons in the vicinity of the
injection site. Labeled proteins are transported soma-
tofugally to axon terminals, where they may be sub-
sequently localized by autoradiographic procedures.
Since axons do not synthesize protein in significant
amounts (Droz and Koenig 1970, Lasek 1970), label-
ed amino acids are not incorporated by fibers passing
through the injection site (Cowan et al. 1972, Cross-
land et al. 1973). Thus, in the present study the auto-
radiographic method was used to trace the afferent
cerebellar connections of the VA and VL thalamic
nuclei and their efferent cortical projections. The
results of these experiments will be described and
related to the functional organization of the primate
motor system.
Methods
Rhesus monkeys were anesthetized with sodium
pentothal and mounted in a Kopf stereotaxic head
holder. The location of target areas within the cere-
bellar nuclei and the VA and VL were determined by
the atlas of Snider and Lee (1961) and by location of
cortical surface landmarks visualized after removal of
a large bone flap and dural incision. Injections of the
gracile and cuneate nuclei were made under direct
vision by incising the a tl an to-occipital membrane.
Small amounts of tritiated proline (0.1 to O.Sml) in a
concentration of 20 to 30 AiCi/pl were injected into
the thalamus, dorsal column nuclei, and deep cerebel-
lar nuclei through a 26-gauge needle, fitted to a 1 jul
Hamilton syringe. In order to prevent cellular damage
and to restrict the size of the injection site, the (3H)
proline was delivered slowly by means of a Harvard
infusion pump. After the injection, the needle was left
in place for at least 20 minutes to avoid contamination
of the cortex when the needle was withdrawn.
The animals were sacrificed at survival times rang-
ing from 48 hours to 1 week in order to visualize
labeled material in both axon terminals and in axons.
The monkeys were reanesthetized and perfused
through the heart with 10% formol saline. After fur-
ther hardening in formalin, the head and intact brain
were placed in the stereotaxic apparatus, and the brain
blocked transversely in the Horsley-Clark plane or
sagittally. The blocks were immersed In sucrose form-
alin and then encased in a gelatin-albumin mixture.
Frozen sections (cut at 30pim) of the entire brainstem,
thalamus, and cortex were mounted on gelatinized
slides, defatted in xylene and individually coated with
NTB-2 (Kodak) emulsion. The slides were exposed at
4°C in light-proof boxes for 6 to 8 weeks, developed
in D-19 at 1S°C, stained through the emulsion with
cresyl violet, and examined with the light microscope
under bright-field and dark-field illumination. Chart-
ings of closely spaced individual sections through the
injection sites and labeled areas of the brain were made
with an overhead projector. Anterior-posterior levels
of the brain sections were numbered to correspond
with the atlas of Olszewski (1952). Surface recon-
structions of the labeled cortical areas were made on
enlarged photographs of the cortex.
Results
Afferent connections of the ventral thalamic
nuclei
Cerebellar Input: Injections of the dentate and
interpositus nuclei of the cerebellum were made in
five monkeys. The preliminary results will be sum-
marized by describing one case in detail. As Illustrated
in Fig. 1, the injection site comprises a 2-mm wide
strip in the center of the nuclei; it encompasses all
but the caudal pole of the dentate-interpositus
complex and extends dorsoventrally throughout the
entire width of the nuclei. Rostrally, after crossing in
the decussation of the superior cerebellar peduncle,
labeled axons enter the contralateral thalamus at levels
shown in the illustration. Two sharply defined "puffs"
of label are located in the central lateral nucleus (CL),
and their consistent location throughout serial thala-
mic sections indicates a precise topography between
the lateral cerebellar nuclei and the central lateral nu-
cleus. By contrast, almost no label is found in the
centromedian nucleus (CM). Cerebellar axons enter
the ventral thalamic nuclei and terminate in VLc
(ventrolateral nucleus, pars caudalls of Olszewski), in
VPLo (ventroposterolateral nucleus, pars oralis), and
in VLo (ventrolateral nucleus, pars oralis). As shown
in Fig. 1, these axonal terminations are concentrated
in a band approximately 2 mm wide and located in
the most lateral part of the ventral nuclei. This ar-
rangement strongly suggests a precise mediolateral
topography in the cerebello-thalamic projections.
There are no projections, for example, to the medial-
ly located VA or nucleus X. Moreover, cerebellar ter-
minations are not distributed evenly in this narrow
strip of thalamus. Rather, silver grains are arrayed in
striking bands and semicircular shapes that surround
the deeply staining cell clusters of the VL nucleus.
It is also noteworthy that the VPLo receives some
of the densest cerebellar terminations. In view of the
fact that this thalamic region projects to the motor
rather than the sensory cortex (see results in next sec-
tion), it is important that this rostral part ofVPLbe
further identified as a motor region of the thalamus
by virtue of its afferent input from the cerebellum.
Dorsal-column input: In several monkeys, injec-
tions of the dorsal column nuclei were made to deter-
mine the precise border between the cerebellar and
lemnlscal recipient regions of the thalamus and to
answer the question of whether these motor and
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114
Kalil
A4.5
P9.0 P10.0 MO. 5
Fig. 1. Series ofchartings of coronal sections through the brain of a rhesus monkey (21), following an injection of
(3/f) proline into the dentate and interpositus nuclei of the cerebellum. Center of injection site represented by
black area; periphery represented by shaded area. Labeled axons represented by broken lines; labeled axonal
terminations by stippling. Note horizontal bands of labeled terminals in the VL and VPLo nuclei. Abbreviations
used in the figures are as follows: Ace. CUM., n. cuneatus accessorius; AD, n. anterior dorsalis; AM, n. anterior
medialis; AV, n. anterior ventralis; CL, n. centralis lateralis; CM, n. centrum medianum; Cun., n. cuneatus;Den, n.
dentatus;Fas, n. fastigii; GM, n. geniculus medialis; Grac., n. gracilis;Int., n. interpositus; LD, n. lateralis dorsalis;
LP, n. lateralis posterior; MD., n. medialis dorsalis; Pul., n. pulvinaris; R, n. reticularis; S.G., n. suprageniculatus;
VA, n. ventralis anterior; VAmc, n. ventralis anterior, pars magnocellularis; VLc, n. ventralis lateralis, pars cau-
dalis; VLo, n. ventralis lateralis, parsoralis; VPI, n. ventralis posterior inferior; VPLc, n. ventralis posterior latera-
lis, pars caudalis; VPLo, n. ventralis posterior lateralis, pars oralis; VPM, n. ventralis posterior medialis; X, area X.
sensory thalamic regions overlapped to any extent. Efferent cortical connections of the ventral
One such case will be described. thalamic nuclei
As shown in Fig. 2, the injection site includes
parts of both the gracile and cuneate nuclei. Lemniscal
fibers are heavily labeled and their terminations are
easily identified in the thalamus. In this and other
cases, the lemniscal terminations in the ventral nuclear
group are confined exclusively to the caudal part of
VPL (VPLc of Olszewski). No silver grains are found
beyond the VPLc-VPLo border region. Thus, there
appears to be no overlap in the cerebellar and lemnis-
cal thalamic inputs.
Thalamo-cortical projects of the VA: A number
of injections of (-^H) proline were made into regions
of the ventral anterior nucleus (VA). Two represent-
ative cases will be illustrated. In case VA 9 R, the
injection site (represented by dark shading) is centered
in the VA nucleus (Fig. 3). As shown by the series of
chartings, the silver grains representing labeled axonal
terminals are found in those regions of the premotor
cortex (area 6) occupying the medial wall of the
hemisphere and the dorsal bank of the cingulate
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Neuroanatomical Organization of Motor System
115
Ace. Cun.
N. Cun.
N. Gruc.
PlO
Fig. 2. Series of charting* of coronal sections through the brain of a rhesus monkey (CB 1 Rj
following an injection of f^ff) proline into the dorsal column nuclei. Injection site represented
by shaded area. Labeled lemniscal fibers shown by broken lines; labeled axon terminations in
VPLc represented by stippling.
-------
116
c C
Fig 3 Series of charting! of coronal sections through
the brain of a rhesus monkey (VA 9 R) following
injection of (3H) proline into the ventral anterior
nucleus (VA). Note terminal labeling in area 6. occu-
pying the medial wall of the hemisphere and the dor-
sal bank of the cingulate sulcus.
sulcus. (This cortical recipient zone will be reconstruct-
ed in Fig. 5.) No fibers from VA terminate in area 4
(,t the motor cortex. These thalamic afferents to area
6 terminate massively in layer 3. Layers 1 and 6 also
contain significant numbers of silver grains.
In another case, VA 3 L, the injection site occu-
pies the VA but also spreads posteriorly into VLc.
As shown by the shaded areas in Fig. 4, there is only
slight spread oflabel into VLo. The resultant axoplas-
mic transport reveals a dense projection to area 6 on
the medial wall of the hemisphere and to the cortical
surface dorsal to the arcuate sulcus (see reconstruction
in Fie 5) The very sparse projections to area 4 most
probably result from the slight labeling of VLo.
When these two cases are compared with other
injections of VA, it appears that this thalamic region
projects exclusively upon the premotor cortical area 6
a rough topography such that more anterior levels
ol the VA project to more anterior regions of area 6.
Moreover, on the basis of its cortical projections, VLc
appears to be a caudal continuation of VA rather
than part of VL, whose cortical association is with
area 4 of the motor cortex.
Kalil
Thalamo-cortical projections of the VL and VPL:
In a large number of rhesus monkey brains, localized
injections were placed in different areas of the VL
and VPL nuclei. In one such case, Monkey VL 1 L
(Fig. 6), the center of the injection site was localized
in VPLo. Labeled axons stream out of the internal
capsule and terminate heavily in the motor cortex
(area 4). When these projections are reconstructed on
an actual photograph of the brain (as illustrated later
in Fig. 9), it is apparent that, although there is some
labeling of the somatosensory cortex, the overwhelm-
ing amount of label is localized in area 4 of the motor
cortex. According toWoolsey's map (1958), the label-
ed regions of the motor cortex correspond primarily
to the face, head, tongue, and a small part of the fore-
limb areas.
In another case, the injection site is concentrated
in VPLo but also extends rostrally into VLo. As shown
in Fig. 7, heavy labeling is found in the motor cortex,
but despite the fact that a considerable portion of the
VPL was labeled by the injection, the somatosensory
cortex contains almost no labeled axons. The surface
reconstruction (Fig. 8) shows that the labeled areas
extend over a broad area of the right precentral motor
cortex (area 4), corresponding to the head, face,
trunk, and forelimb regions (Woolsey 1958). A care-
ful comparison of reconstructions of a number of
VL-VPL injections reveals a topographic projection to
the motor cortex such that medial regions of the
VLo-VPLo project upon the arm and face areas
and lateral regions project upon the leg area.
Precise information was also obtained regarding
the projections of the border zones between various
regions of the VL and VPL nuclei. The results of
many experiments in which small volumes of (3H)
proline were injected into the thalamus reveal that
injections of rostral VPLo and VLo result in labeling
of motor cortex alone, while those centered in VPLc
and caudal VPLo reveal a dense projection to sensory
areas exclusively. The border zone between these
motor and sensory regions is localized in the posterior
region of VPLo and the rostral extremity of VPLc.
When an extremely small volume (approximately a
1-mm sphere) of this transitionary thalamic region is
injected, labeled axons arising from the injection site
terminate exclusively upon area 3a in the floor of the
central sulcus. This cortex, which receives muscle
spindle information (Phillips et al. 1971), is thought
to be transitionary between the sensory and motor
cortex.
The autoradiographic technique gives extremely
precise information regarding the mode of termination
of thalamocortical fibers, particularly when the auto-
radiographs are viewed in dark field illumination. By
far the densest termination of thalamic fibers is in
lamina 3, a layer containing many medium-sized
pyramidal cells and the apical dendrites from the larger
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Neuroanatomical Organization of Motor System
117
Fig. 4. Charting! of a second case in which proline was injected into VA (monkey VA 3 L). The resultant transport
of label to area 6 on the medial wall of the hemisphere and to the cortical surface dorsal to the arcuate sulcus is
shown by stippling.
pyramids of layer 5. However, there is also a substan-
tial projection to layer 6. The termination of thala-
mocortical fibers in layer 1 of the cortex is more varia-
ble. In some cases, particularly in the premotor
regions, this termination is quite dense, but in other
cases (Fig. 9 and 10) there is only sparse labeling of
layer 1. Moreover, there is variability in the pattern of
thalamocortical axon termination within layer 3. The
dark field photo-montage in Fig. 9 shows that the
distribution of label in layer 3 of the arm area motor
cortex forms a continuous dense band. By contrast,
Fig. 10 shows a striking series of columns or patches
of label in layer 3 of the face area motor cortex. The
bands are about 1 mm in width and are separated by
relatively grain-free spaces, about 0.5 to 1 mm wide.
These columns also extend into layer 6 of the cortex.
Discussion
The results reported in these experiments reveal
that the motor and sensory regions of the monkey's
ventral thalamus are separate and discrete. The sensory
fibers arising from the dorsal column nuclei terminate
primarily upon VPLc and do not extend beyond the
VPLc-VPLo border region, which sends efferent fibers
to area 3a. This thalamic region corresponds precisely
to the areas of VPL in which Poggio and Mountcastle
(1963) recorded classical lemniscal responses follow-
ing stimulation of the periphery. Rostral to this
lemniscal recipient zone (i.e., in the region designated
by Olzsewski as VPLo), Poggio and Mountcastle
described neurons with properties very different from
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118
Kalil
VA9
VA3
Fig. 5. Surface reconstructions of the medial wall of
the hemisphere to show areas of terminal labeling in
area 6 of cases charted in Fig. 3 and 4.
the modality-specific lemniscal cells, with their precise-
ly localized peripheral receptive fields. These VPLo
neurons were described as having very large or even
bilateral receptive fields and were activated only by a
heavy or prolonged stimulation of deep tissues. Our
experiments reveal a dense topographic termination
of efferent fibers from the deep cerebellar nuclei in
VPLo, VLc and VLo. These thalamic areas thus repre-
sent the motor region of the ventral nuclei. Recent
physiological evidence (Strick 1976a) confirms this
view since some of these neurons, which are related
to arm movements performed by awake monkeys,
could not be driven readily by peripheral afferent
input. Thus, the present anatomical findings show
that motor and sensory inputs to the thalamus do not
overlap, and these results are strongly supported by
physiological experiments.
Similarly, the efferent thalamocortical connec-
tions of the ventral nuclear complex reveal a topog-
raphy and clear-cut demarcation among (1) VA and
VLc projecting to the premotor cortex (area 6), (2)
VLo and rostral VPLo projecting to the motor cortex
(area 4), (3) a VPLo-VPLc border zone projecting to
area 3a, and (4) caudal VPLo-VPLc projecting to the
somatosensory cortex. Again, there is no overlap in
the motor and sensory thalamocortical fiber systems.
These results are supported, in part, by the retrograde
horseradish-peroxidase method used by Strick (1976b),
who also found that a large rostral zone of VPL(i.e.,
VPLo) projects not to sensory but to motor cortex.
This finding raises the question as to whether this
region of the thalamus is actually part of the VPL
receiving peripheral afferent input or whether it is, in
fact, a caudal region of VL that has heretofore not
been identified correctly. The issue of whether the
motor cortex receives somatosensory input directly
from the thalamus is especially significant in view of
the recent observations by Rosen and Asanuma (1972)
that cortical efferent zones in the monkey's motor
cortex, which influences distal forelimb muscles,
receive a projection from cutaneous afferents. These
authors concluded that cooling of the postcentral
gyrus showed that sensory cortex was not involved in
transmitting peripheral input to the motor cortex and
that "the thalamic region of origin for the fibers sub-
serving peripheral afferent input to the motor cortex
is obscure." Our anatomical results clearly show,
however, that VPLo does not receive lemniscal input
from the dorsal column nuclei but is, instead, a cere-
bellar recipient zone. Thus, physiologically demon-
strated peripheral afferent input to the motor cortex
must travel by routes other than the classical lemniscal
pathway.
More recently, Lemon and Porter (1976) and
Lemon et al.(1976) have reinvestigated the correlation
between peripheral afferent input and movement-
related neurons in the motor cortex of awake behav-
ing monkeys, rather than in the anesthetized prepar-
ations used by Rosen and Asanuma. Lemon and Porter
found that the most powerful peripheral input to the
motor cortex was generated by joint movement. This
input probably originates in muscle, tendon, or joint
receptors, but the receptors could not be specifically
identified in these experiments. The brevity of the
latencies reported in these studies argues for a fairly
direct projection from the periphery to the motor
cortex, but the authors conclude that neurons in VL
are unresponsive to peripheral inputs or have poorly
localized responses and that VPL and its fast afferent
pathways are a more likely route for peripheral affer-
ent input to the motor cortex. This conclusion accords
well with the anatomical data reported here, i.e., that
the VPLo receives a massive cerebellar input that is
then relayed directly to the motor cortex. However,
the "fast afferent pathways" to VPL must come from
the cerebellar nuclei and not the dorsal column nuclei.
Regarding the columnar organization of the
motor cortex, Rosen and Asanuma (1972) suggested
that afferent input is topographically organized such
that each motor cortical "column" receives a specific
-------
A 13
V
U
A TO 5
c c c c
Fig. 6 A series of charting! of coronal sections through the brain of a rhesus monkey (VL 1 LJ following infections of f H) proline
into VPLo of the thalamus. Terminal labeling (represented by stippling) is heaviest in the motor cortex, area 4, and is concentrated i
layer 3. Labeled axons also terminate in the somatosensory cortex.
I
SL
|
1'
-
I
c
c
—*
c
I
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Fig. 7. Charting* of coronal sections of a brain with injection of(3H) proline into VPLo and VLo. Heavy labeling is found in the motor
cortex but almost none in the somatosensory cortex.
-------
Neuroanatomical Organization of Motor System
121
peripheral input from the same anatomical zone to
which the column projects. By contrast, the experi-
ments of Lemon and Porter (1976) on awake behaving
monkeys suggest a less rigid arrangement of the affer-
ent projection since a local region of the motor cortex
may receive inputs from entirely different joints.
These authors conclude that "there is no highly speci-
fic columnar organization of cells within the motor
cortex, divided and separated one column from the
other, either from the point of view of the afferent
input to these cells, or from the point of view of the
motor activities with which the discharges of the cells
are associated."
On the basis of the physiological data of Lemon
and Porter, it seems unlikely that "puffs" of label
found in layer 3 of the face area of the motor cortex
after injection of the VPLo represent physiological
"columns." It seems more likely that "puffs" of high
grain density represent the terminations of thalamo-
cortical projection fibers and that the grain-free spaces
are filled in by commissural fibers from the other
hemisphere. If this interpretation is correct, the corti-
cal areas representing the arm and leg receive a con-
tinuous band of thalamocortical fibers since cortical
regions serving distal extremities would not receive
commissural fibers.
Fig. 8. Surface reconstruction of cases plotted in Fig.
6 and 7. Dots on brain photographs show labeled areas
extending over broad areas of the precentral motor
cortex (area 4), with relatively little labeling of the
somatosemory cortex from injections of the VL-VPL
nuclei.
-------
122
Kalil
Fig. 9. Dark field photo-montage shows distribution of label in layer 3 of the arm area motor cortex. Note
that the label forms a continuous dense band, which appears white in dark-field.
-------
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2
FJ^. 10. Dark field photo-montage shows series of columns or patches of label in layer 3 of the face area motor cortex
in width and are separated by relatively grain-free spaces about 0.5 to 1 \im wide.
The bands are about 1mm
-------
RELATIONSHIPS BETWEEN
BEREITSCHAFTSPOTENTIAL AND
CONTINGENT NEGATIVE VARIATION
W. C. McCALLUM
Burden Neurological Institute, Bristol, England
The Bereitschaftspotential (BP), or readiness
potential, and contingent negative variation (CNV)
were discovered independently, and first reported in
1964. The term BP is generally reserved for cerebral
slow potential changes preceding a voluntary action,
while the term CNV is most frequently applied to slow
potential changes occurring in the interstimulus inter-
val of a foreperiod reaction time situation. Both are
electrically negative phenomena at the surface of the
cerebral cortex, over which they are widely distrib-
uted, and both appear in circumstances involving
preparation for action or decision. The tendency in
the past to speak of the CNV as if it were a simple
unitary phenomenon may have been misleading. Two
or more relatively independent components emerge in
certain circumstances. Loveless and Sanford (1973)
and Loveless (1976) suggest that the late negativity of
the CNV-i.e., that part which immediately precedes
the imperative stimulus-may be identical with the BP
and distinct from earlier negativity associated with
the warning stimulus, a view supported by Rohrbaugh
et al. (1976). Others suggest that the two effects may
be manifestations of activity in the same underlying
systems. Before such issues can be resolved, it is neces-
sary to take a closer look at what relationships can be
observed between the BP and CNV.
As a result of collaborative work between the
groups responsible for the discovery of both potential
changes, an experimental paradigm and computer
program's were evolved to examine the form and
distribution of the two potentials separately and joint-
ly. This procedure was demonstrated by Deecke and
his colleagues at Bristol (McCallum and Knott 1976).
This paradigm has been modified and extended in the
present experiment to further investigate the rela-
tionship involved.
Method
Scalp recordings were made from 12 normal sub-
jects (8 female, 4 male) using Ag/AgCl electrodes.
Similar cortical recordings were made from 12 patients
(9 female, 3 male) in whom gold electrodes had been
implanted in connection with clinical procedures.
Recording was by a modified 16-channel Elema
Schonander Mingograph linked to a PDF-12 com-
puter. Time constants of 5 sec were used for normal
controls and, where possible, for the patient group In
the latter group, however, it was necessary in rive
cases to reduce the time constant to 2.5 sec and in
five cases to 1.2 sec to offset the effects of high-
amplitude infraslow activity, to which the intracere-
bral electrodes become increasingly sensitive. Scalp
electrodes were located at 2 cm above the nasion
F3, F4, C3, Cz, C4, P3, and P4, and referred to a
common reference consisting of the linked mas-
toids. Cz was compensated for eye movements as
described by McCallum and Walter (1968). Individual
trials contaminated by eye movement or other
artefacts were rejected on-line. Recording in the
patient group was from eight selected subdural
gold electrodes, each 150 jum in diameter and 4 mm
long, extending in an anterior-posterior line over
the right cerebral cortex from the prefrontal re-
gion to the postcentral gyrus. Surface Ag/AgCl
EMG electrodes were located over the flexor muscles
of the right and left forearms in normal subjects and
patients.
The basic task consisted of pressing, with the
index finger, a 1-cm-diameter metal stud, housing a
pressure transducer, set in a flat wooden base. All
subjects reclined on a bed with eyes open and fixated.
The experimental procedure consisted of a BP condi-
tion in which subjects made brief, voluntary finger
presses with a minimum interval of about 10 sec
between presses. Twenty-four presses were sampled
from the left hand and 24 from the right. For all con-
ditions, the epoch sampled was 4 sec at a rate of 128
Hz. Two seconds were sampled before and 2 sec fol-
lowing each trigger pulse. The trigger pulse was initiat-
ed from the output of the pressure transducer. The
second, or CNV, condition consisted of a foreperiod
reaction time (RT) situation in which a single warning
-------
BP and CNV
125
click, delivered 2 sec after the start of the sampled
epoch through headphones at approximately 70 dB,
was followed 1.5 sec later by a 700-Hz tone terminated
as rapidly as possible by pressing the metal stud with
the index finger of the preferred hand (or the left
hand in the case of the patient group). RT was auto-
matically recorded by the computer. Finally, in a
BP/CNV condition, the two situations were combined,
the click stimulus being removed. Subjects made a
series of voluntary button presses with the preferred
hand (normals) or left hand (patients). Each press was
followed 1.5 sec later by the tone which subjects
were required to terminate as rapidly as possible by a
second button press, with the same finger. BP and
CNV amplitudes were measured with respect to a
baseline calculated as the mean amplitude of activity
recorded during the first 300 msec of the sampled
epoch.
Results
Both BPs and CNVs were present in all subjects
and patients and, superficially, showed a similarity of
distribution. Both were largest at the vertex, the
mean scalp amplitude for Cz being - 12.5 juV for CNV
and -5.0 juV for BP. As in previous studies, scalp CNV
showed no consistent asymmetry in its distribution.
Individual differences between bilateral pairs of elec-
trodes could be up to 3/uV, but these were not consist-
ent in direction across the group, nor did they appear
to be related to handedness or to the task involved.
Scalp BP showed a small asymmetry, amplitude values
over the hemisphere contralateral to the hand used
for pressing being slightly higher than those over the
ipsilateral hemisphere (Table 1). Differences for left-
hand presses failed to reach significance, but those for
right-hand presses were significant for central (p<.05)
and parietal (p<.01) locations using a t-test for corre-
lated samples.
Both BP and CNVs were smallest over the frontal
and pre frontal regions, and the BP frequently could
not be observed at all in these areas. The CNV, how-
ever, was almost invariably observable frontally, if
only at low amplitude. In the combined BP/CNV con-
dition (Fig. 1), scalp CNV diminished by up to 30%
over central and 20% over parietal areas compared
with the standard CNV condition (Table 1), but
remained relatively unchanged over frontal areas. In
the same condition (BP/CNV), scalp BP showed
increases of 30% or higher over all areas (including
frontal) compared with the simple voluntary press
condition. Fig. 2 presents cross-subject vertex averages
for the four conditions.
Anterior-posterior CNV distribution over the right
cortex of patients was similar to scalp recordings in
normal subjects with the largest amplitudes found
precentrally. In some patients the most anterior elec-
trodes showed no CNV, while in others the CNV was
quite prominent there, but varied somewhat in form.
BP amplitudes were markedly diminished when the
ipsilateral hand was used for pressing. Fig. 3 shows
this asymmetry in one patient. In the one left-handed
patient, this difference between contralateral and ipsi-
lateral hand presses was even more pronounced. BP
distribution also spread more anteriorly in this patient.
Fig. 4, which illustrates waveforms from the eight
selected electrodes averaged across patients shows the
consistency of the asymmetry. Fig. 5 provides similar
across-patient averages for the CNV and BP/CNV
conditions. The locations of electrodes varied to some
extent from patient to patient, although the most an-
terior electrode was always over prefrontal cortex; the
second electrode was always over frontal cortex; and
the remaining electrodes extended posteriorly from
precentral cortex, the most posterior electrode usual-
ly being over the postcentral gyrus. The distance of
electrodes from the midline also varied considerably.
This variability and time constant differences are ig-
nored in Fig. 4 and 5 to obtaining a broad picture of
hemispheric differences. Therefore, these summary
averages should not be taken as a reliable indication
of localized differences of waveform or amplitude,
although individual records clearly indicate that such
differences exist.
Table 1. Mean Amplitude (/uV) of the Bereitschaftspotential and CNV
on the Scalp in Different Tasks
Measure (task)
BP deft)
BP (right)
BP (combined)
CNV (simple)
CNV (combined)
Above
nasion
-1.82
0
-1.1
-0.7
-1.3
F3
-1.55
•0.91
-2.9
-4.1
-4.3
F4
-1.36
+0.45
-1.7
-4.5
-4.0
Electrode
C3
-3.18
-3.64
-4.8
-8.2
-6.7
position
C4
-3.45
-1.45
-2.7
-8.2
-6.4
Cz
-5.27
-4.55
•6.0
-12.5
-8.5
P3
-2.0
-1.3
-2.6
-6.1
-5.4
P4
•2.09
0
-1.4
-6.1
-5.0
-------
126 McCaDum
VOLUNTARY BUTTON PRESS (RIGHT INDEX FINGER) TONE (TERMINATED BY BUTTON)
-20 u
1 sec
»w
' U
EYE
V^^4AU^» J
F3
Ffc /. 5ca/p distribution of the combined BP/CNV condition from one normal subject. Averages of 24 trials in
which subject made a voluntary right index finger press, followed 1. 5sec later by a tone, terminated by a second
press using the same finger. •
Mean RT to the imperative stimulus in the stand-
ard CNV condition was 160 msec (SD 40) in normals
and 185 msec (SD 50) in patients. In the BP/CNV
condition, these values increased to 185 msec (SD 52)
tor normals and 224 msec (SD 71) for patients. Differ-
ences between the conditions were significant for
both groups on at-test forcorrelated samples (p<.05).
Discussion
Results indicate that BP is maximal at the vertex
and is weakly asymmetrical, showing increased nega-
tivity «ver tne hemisphere contralateral to the opera-
tive musics, the largest values occurring prerolandical-
ly. The asymmetry appears most marked when the
dominant hemisphere is the one primarily involved in
the movement. This finding is consistent with that of
Kutas and Donchin (1974) and is in general agreement
with that of Deecke et al. (1973), although the latter
liiilhuis wish to differentiate between several separate
components in the activity preceding motor move-
Intracerebral data confirm the distribution pat-
tern that emerges from scalp data. The fact that corti-
cal electrodes in any one patient were restricted to
one hemisphere prevented bilateral comparisons, but
the differences seen in response to left- and right-hand
pressing reveal the contralateral predominance of the
BP more clearly than scalp data.
As indicated in Table 1, mean CNV amplitudes
for the normal group were remarkably symmetrical.
This finding is consistent with those of McCallum and
Cummins (1973), McCallum (1976), and Marsh and
Thomson (1973). Isolated reports of CNV asymme-
tries under special conditions have appeared, which
might seem to contradict the established view (Low
et al. 1966, Cohen 1969) that CNVs are bilaterally
symmetrical. Otto and Leifer(1973b)reported larger
negative shifts over the motor cortex contralateral to
the movement, but the measure used was total CNV
area and the differences only reached significance
when pooled to include a condition in which a motor
response was initiated during the S1-S2 interval. Butler
and Glass (1974) have observed larger CNVs over the
dominant hemisphere during numeric operations, but
the findings have not been replicated. Low et al.
-------
BP and CNV
127
VOLUNTARY BUTTON PRESS
RIGHT HAND
LEFT HAND
12
D
-10
t
PRESS
(OR SI-CLICK)
S2
(TONE)
1 sec
Fig. 2. Averages (12 subjects) of vertex (Cz) channel
for each of the four experimental conditions. A:
Voluntary press, left index finger; B: Voluntary
press, right index finger; C: CNV-click, tone, button
press with index finger of preferred hand; D: BP/CNV
(as in Fig. 1).
^
-
(1976) also reported mean CNV area asymmetries
related to hemispheric dominance for language pro-
duction in patients and to handedness in normals.
The extent to which they apply to "late" negativity,
however, is not clear. So far, the balance of evidence
does not substantiate any claim for consistent asym-
metry of CNV amplitude measured prior to the
imperative stimulus.
Although superficially similar, the BP and CNV
are independent in terms of distribution and the
balance between the two distributions varies with the
situation. Results of the present study further suggest
that, as task involvement increases, frontal areas
make a relatively greater contribution, as reflected
in the distribution of both types of slow poten-
tial change. In planning future ERP experiments
to examine the role of different cerebral regions in
the context of planned motor actions, the value of
adding levels of task complexity or involvement to
the simple press or warned foreperiod situation should
thus be considered. (See also Papakostopoulos, this
section.)
t
-20
2 sec
Fig. 3. Anterior-posterior cortical distribution of BP
over the right hemisphere of one patient, recorded
from gold subdural electrodes extending from pre-
frontat (electrode 12) to postcentral (electrode 6)
regions. Averages of 24 trials.
While this study underlines the inappropriateness
of speaking of the CNV as if it were immutable in
form and distribution, it lends little support to those
who, rejecting a "unitary phenomenon" theory of
-------
128
McCallum
RIGHT-HAND PRESS
LEFT-HAND PRESS
20 pV
1 sec
(h)
Fig. 4- Averages (eight patients} from an anterior-posterior line of gold subdural electrodes over the right hemis-
phere for BP conditions involving left and right voluntary finger presses. Note: The diagram showing electrode
placement gives only a general indication of their distribution. Exact locations of equivalent electrodes varied
from patient to patient. These differences have been ignored in averaging.
-------
BP and CNV
129
CNV
BP/CNV
ELECTRODE
EMG
jKr^^V^^v-^^jlv Vr
20 vV
1 sec
(h!
Fig. 5. Averages (eight patients) from an anterior-posterior line of gold subdural electrodes over the right hemis-
phere for CNV and BP/CNV conditions. See note on Fig. 4.
-------
130
McCallum
CNV, seek to replace it with a two-, three-, or multi-
component theory. To equate early CNV negativity
with an orienting response when it can be seen to
occur-albeit slightly diminished-when SI is replaced
by a voluntary button press, is at best an oversimplifi-
cation. To equate late CNV negativity with the BP is
also an oversimplification because a clearly lateralized
BP and symmetrical CNV can be demonstrated at
the same electrode sites.
Mounting evidence points to slow potential
changes as a function of an extensive mosaic of corti-
cal neuronal domains. Which domains are active during
a particular process of preparation for action or deci-
sion and at what time during the course of that pre-
paration they are active will depend upon innumerable
factors inherent in both the individual and the situa-
tion. Intracerebral recording reveals some of the result-
ant subtle changes and local differences. Few of these
subtleties, however, survive the spatial averaging that
takes place in the transition through skull to scalp.
Variations in the distribution of waveforms seen at
the scalp can hopefully provide information on broad
areas of function and can indicate cortical regions
primarily involved at given points in time. However, it
seems unwise to be lured into a process of component
labelling on the basis of sparsely sampled scalp data
'p.d. note: See D. Papakostopoulos, "Macropotentials as a
Source for Brain Models." Section X, this volume.
acquired in a limited range of circumstances. Hastily
applied labels, particularly those derived from broad
psychological constructs, add little to our understand-
ing of brain events and may even impose constraints
on our thinking and interpretation. It would be wiser
to review some of the constructs concerned in the
light of recent event-related potential data than to
squeeze the physiological data into ill-fitting psycho-
logical or behavioural categories.1
Summary
Bereitschaftspotential and contingent negative
variation were recorded independently and in associa-
tion with one another from multiple scalp electrodes
in a group of normal subjects and from subdural elec-
trodes over the right hemisphere in a group of patients.
The distribution of the two phenomena was similar,
but not identical. CNV was slightly more prominent
anteriorly than BP, and BP showed some asymmetry-
largest over the hemisphere contralateral to the hand
used in pressing. In the situation in which BP and
CNV were combined, BP appeared frontally and
increased in amplitude at all electrodes, whereas CNV
decreased over central and parietal areas.
Acknowledgment
The help of Philip Newton in recording data and
Philip Pocock in development of the computer pro-
gram is gratefully acknowledged.
-------
SLOW POSITIVE SHIFTS DURING
SUSTAINED MOTOR ACTIVITY IN HUMANS
D. OTTO AND V. BENIGNUS
U. S. Environmental Protection Agency, Research Triangle Park, and Department of
Psychology, University of North Carolina, Chapel Hill, NC, U.S.A.
Bates (1951) was the first to report slow cortical
potentials associated with movement onset. He describ-
ed a negative shift commencing about 20 msec after
EMG onset and attributed the wave to the "arrival of
afferent impulses from the periphery." Bates failed to
detect any cortical potentials preceding movement.
Kornhuber and Deecke(1965), using improved averag-
ing techniques, observed a slow negative shift before
movement, followed by a positive shift after move-
ment onset. Vaughan et al. (1968) designated this late
positive wave as the P2 component of the motor poten-
tial. Since the late positive wave appears to follow the
initiation of motor activity, Komhuber and Vaughan
both hypothesized a peripheral afferent origin. The
evidence, however, is inconclusive.
Otto et al. (1977) observed a prolonged positive
shift, maximal postcentrally, during sustained motor
response. In that study, subjects were required to esti-
mate the duration of a 1-sec holding interval without
external cues. It is possible, therefore, that the positive
shift reflected a central timing mechanism, rather
than afferent input from peripheral muscles. This
hypothesis may be tested by estimating time without
sustained motor response. On the other hand, if the
positive shift represents incoming afference, one
would expect to see larger shifts over the sensorimotor
region corttralateral to response. Further, one would
expect to find the amplitude of positivity directly
proportional to the force of contraction. The present
study was undertaken to test these hypotheses.
nize signal averages. Each subject's maximal pressing
force, with the dominant hand, was determined with
a Jamar PC5033 hand dynamometer. Each subject
then completed a series of 3-sec contractions at force
levels of 10, 25, and 50% maximum, as monitored
visually on the gauge of the dynamometer. Subjects
were instructed to initiate and terminate contractions
briskly and to relax responding muscles as completely
as possible between presses.
Two additional conditions were run to determine
the effect of estimating time without tonic contraction
and the corollary effect of tonic contraction without
estimating time. The estimation task consisted of
squeezing the dynamometer briefly to indicate the
lapse of 3-sec after presentation of a tone pip. In the
nonestimation task, subjects initiated and maintained
contraction until presentation of a tone pip.
Results
Prolonged positive shifts were observed during
hand pressing in most subjects in most conditions.
Averaged waveforms recorded in six subjects during
the 50% condition are shown in Fig. 1. Positive shifts
during pressing were easily discernible in the raw data
of many subjects, as shown in Fig. 2. This sample
illustrates, however, that the positive shift is not invari-
ably present, nor is the onset and termination clearly
time-locked to activity in the brachioradialis muscle.
Method
EEC recordings, referred to linked ears, were
obtained from nine young adult male subjects at C3,
C4, P3, and P4 using amplifiers with 2.25-sec time
constants. EOG and rectified EMG from the brachio-
radialis muscle were also recorded. A Schmitt trigger,
adjusted to fire at EMG onset, was used to synchro-
Fig. 3, averaged across subjects, illustrates that
the magnitude of positivity is not directly related to
pressing force at C3 and C4. Larger shifts were observ-
ed during the 10% and 50% conditions than during
the intermediate 25% force level. Only at P3 was
there a suggestion of a linear relationship between
amplitude and force. No consistent lateraliry differ-
ences were observed in any condition.
-------
132
Otto and Benignus
DY01
DY03
EMG
DY07
DY09
EMG
EOG
.3 O J 4 6 8
TIME (SECONDS)
Fig I. Slow potential shifts observed in six subjects
during 50% isometric contraction. Averages of 6 to
11 trials were triggered from onset of brachioradialis
muscle EMG and digitized at 48 msec/point by means
of a PDP-12 computer. EOG was recorded diagonally
from above the inner canthus to below the outer can-
thus of the right eye. Baseline was computed from
the initial 400-msec segment in each average.
Fig 2- Single trials from one subject during 50% con-
tractions. Note that positive shifts are not present in
all trial* "r clearly time-locked to the firing onset or
• i/fifi »f the brachioradialis muscle. Trial 5 was trig-
gered fram a transient KMG spike. Trials with im-
proper F.MG triggering, or EOG artifact, during or
preceding contraction were excluded from averages.
EMG
C3
C4
EOG
.:
-rEEG:IO/uV
EOG: SO/iV
RELATIVE FORCE
OF CONTRACTION
-10%
25%
50%
8 SECONDS
Fig 3. Composite averages from seven subjects during
10%, 25%, and 50% contractions. Positive shifts do
not appear to be proportional to force of contraction.
Results of the delayed response task 0abeled SR)
provide evidence that the positive shift during sustain-
ed motor activity is not the reflection of a central
timing mechanism. Time estimation in the absence of
tonic motor response yielded a slowly incrementing
negative shift, similar to CNV, as shown in Fig. 4.
When subjects initiated a hand press voluntarily, but
released upon presentation of a tone pip (condition
HS), no consistent positive or negative shifts were
observed (Fig. 4).
EOG
SLJ
64
][ l
HS
EEG: 10ATV
~
EOG: 50;UV
EMG
•101 234
TIME (SECONDS)
i
-101234
TIME (SECONDS)
Fig. 4. Summary averages (eight subjects) during
time estimation without contraction (SRj and con-
traction without time estimation (HS). Negative shifts
were observed during SR, but no consistent shifts
were found during HS.
Discussion
Results of this experiment confirm our previous
report (Otto et al. 1977) of a prolonged positive
potential over the centroparietal region of the brain
during tonic motor activity. Similar motor-related
positive shifts have been noted previously (Gilden et
-------
Positive Shifts during Motor Activity
133
al. 1966, Jones and Beck 1975), but never studied
systematically.
Other investigators report conflicting evidence.
Vaughan et al. (1970) observed a prolonged negative
shift in epidural recordings over the contralateral
motor cortex of monkeys during sustained wrist con-
tractions. Robert et al. ( 1976) also observed sustained
negative shifts at the vertex in humans during tonic
weight pulling. Rebert's experimental design was con-
founded, however, by external stimuli and a secondary
reaction-time task which bracketed the weight-pulling
within an extended CNV interval.
Ottoet al. (1977)have shown that negative antici-
patory and positive response-related processes sum
linearly on the scalp when tonic motor activity is
superimposed on a CNV-eliciting interval. Since the
negative potential tends to be larger than the positive
potential in this situation, the observed effect of sus-
tained key-pressing is a reduction in CNV amplitude.
Papakostopoulos and Cooper (this volume) have con-
firmed this phenomenon.
Further evidence of the interaction on the scalp
of negative and positive slow potentials occurs in this
study. When subjects were asked to briefly squeeze
the dynamometer 3 sec after presentation of a tone
pip (time estimation without tonic contraction),
a slow negative shift was observed consistent with
McAdam's (1966) report.When subjects were instruct-
ed to initiate and maintain contraction until presenta-
tion of the tone pip, however, no consistent positive
or negative slow potentials were observed. The sim-
plest explanation of this finding is that negative
anticipatory and positive response-related potentials
summed to zero at the scalp recording sites.
Is the slow positive shift during motor response
an extracerebral artifact? All trials containing signifi-
cant eye movements as indicated in EOG tracings were
carefully excluded from averages. Picton and Hillyard
(1972) and Corby et al. (1974) have described a
cephalic skin potential artifact which could conceiv-
ably contribute to the observed waveforms. This arti-
fact was not observed, however, by Picton or Corby
when linked ear references were used, as in the present
study. The small amplitude of positive shifts (5 to 10
also is inconsistent with a cephalic skin potential.
Another possibility is that the baseline is biased
in a negative direction by the readiness potential that
precedes movement. The baseline measure was com-
puted from the initial 400 msec of data in each aver-
age. The baseline epoch terminated 2.3 sec prior to
the EMG trigger and appeared to precede the onset of
the readiness potential in most cases. The precise onset
of the readiness potential, is, however, difficult to
determine since it is an internally generated event not
necessarily time-locked to the initiation of movement.
A closely related problem concerns the selection
of an appropriate trigger event. EMG onset of the
brachioradialis muscle was chosen since this large
superficial muscle discharges prominently and reliably
during fist clenching. Many other muscles of the fore-
arm also participate in this complex motor response.
A transducer attached to the handle of the dynamom-
eter might have provided a more reliable trigger index
of movement onset.
The question of the functional significance of the
prolonged positive shift remains unanswered. Results
of the delayed response-time estimation task argue
against the central timing hypothesis. If the positivity
reflects afferent input from peripheral muscles, one
would expect the amplitude to increase directly with
the force of pressing. One would also expect the wave-
form to be larger over the somatosensory region con-
tralateral to response. The fact that neither effect was
observed casts dcubt on the peripheral afference
hypothesis.
Considerable evidence reviewed by Hazemann
(this section) indicates that afferent input is inhibited
during movement. Marczynski (this volume) concludes
from an extensive review of behavioral, electrophysio-
logjcal, and pharmacological data that slow surface-
positive brain potentials, including the P300, RCPV,
and other motor-related positivities, reflect cortico-
fugal suppression (inhibitory modulation) of the
ARAS. Papakostopoulos and Cooper (this section)
propose a similar explanation of the CNV reduction
observed during the Jendrassik maneuver. Slow posi-
tive shifts described in this study ate presumably
related, functionally and neurophysiologically, to
these other ERP phenomena. Further research is need-
ed to evaluate the corticofugal inhibitory hypothesis
of Marcyznski and Papakostopoulos, and to clarify
the relationship of the expanding family of slow
positive ERPs.
Summary
A prolonged positive shift was observed at central
and postcentral recording sites during tonic contrac-
tion of the hand. No consistent hemispheric differ-
ences or linear relationship with the force of contrac-
tion were found. It appears unlikely, therefore, that
this waveform reflects proprioceptive or kinesthetic
feedback from responding muscles. CNV-like negativi-
ty during simple time estimation suggests, further-
more, that the positive waveform does not reflect a
central timing mechanism.
Acknowledgment
The authors thank J. H. Knelson for support and
L. Ryan and J. Bedrick for technical assistance.
-------
ELECTRICAL ACTIVITY OF THE BRAIN
ASSOCIATED WITH SKILLED PERFORMANCE
D. PAPAKOSTOPOULOS
Burden Neurological Institute, Bristol, England
Self-paced and externally triggered movements
are preceded by sustained negative brain potential
changes known respectively as Bereitschaftspotential
(BP) (Deecke et al. 1969) and contingent negative
variation (CNV) (Walter et al. 1964). The movements
employed are usually simple brisk flexions or exten-
sions of a finger with no other demand imposed on
the subject. In the case of the CNV, reaction time to
the imperative signal is usually measured and a con-
troversial literature has developed (McCallum and
Knott 1973, Papakostopoulos and Fenelon 1975).
When studied in isolation, reaction time, limb dis-
placement, or development of muscular force, how-
ever important they may be for movement, contrib-
ute little to our understanding of the organization
and development of skillful action. An experimental
paradigm was devised in which brain activity was re-
corded during a manipulative task demanding pre-
cision and improvement of performance by providing
the subject with real-time information on the out-
come of his action. Comparison was made with
more conventional situations where only a brisk
motor action was required.
Method
Seven subjects, aged 18 to 34 and including five
male and two female, were investigated. Four were
left-handed and three were right-handed.
The subject sat in a comfortable chair facing the
10-cm screen of a cathode ray oscilloscope (CRO).
In each hand, he held a plastic ball 3 cm in diameter
fitted with a button that could be pressed. The
excursion of the button was Smm. Pressing with the
left thumb initiated a single sweep of the oscilloscope
spot; pressing with the right thumb stopped the
sweep. The spot velocity was I m/sec. The subject
was told to initiate the sweep using the left hand
and stop it with the right within ±1 cm of the center
of the CRO screen, i.e., within a 40- to 60-msec in-
terval following sweep initiation. The above pro-
cedure will be referred to as the skilled performance
test (SPT). A PDP-12 computer was programmed to
acquire EEC and EMG data for 1.2 sees preceding
and 0.8 sees after the initiation of the trace. The
sampling rate was 250 points/sec. The latency be-
tween left and right-hand press was also computed.
For each trial, six EEC and three EMG channels
were recorded and stored on digital magnetic tape.
EEC electrodes were placed at Fpz, Cz, and 5 cm
lateral to the midline 2 cm anterior (precentral) and
2 cm posterior (postcentral) to the central sulcus of
both hemispheres. EMG was recorded from left fore-
arm flexors and extensors and right forearm flexors.
The time constant and high-frequency response
(-3 dB) were 5 sec and 70 Hz for EEC and 0 03 sec
and 3000 Hz for EMG.
The experimental procedure included 24 trials
with left-hand press (LHP), 24 trials with right-
hand press (RHP), 24 trials with both-hand press
(BHP), and 100 trials of the skilled performance
test, all self-paced.
Stored data were analysed either as single trials
or averages. Averaging was done with two different
criteria according to the temporal order or precision
of responses. In order to examine temporal effects
three averages of 24 trials of LHP, RHP, and BHP
conditions and four averages of 24 successive trials
of SPT were computed. To classify data in terms of
performance, the time following initiation of the spot
by the left-hand press was separated into successive
20-msec intervals. Correct performance was defined
as right-hand press in the interval between 40 and
59 msec. Trials in which the right-hand press was
early (20 to 39 msec) were called -wrong (-W) and
late (60 to 79 msec) were called +wrong (+W).
Mean amplitude measurements were computed
for three different 200-msec epochs for individual
trials and averages as follows: (1) immediately pre-
ceding left EMG onset-termed Bereitschaftspotential
(BP), (2) immediately following left EMG onset-
-------
Skilled Performance Positivity
135
termed motor cortex potential (MCP) as suggested
by Papakostopoulos et al. (1975), and (3) commenc-
ing 350 msec after left EMG oaset. The baseline for
measurements was the mean amplitude of the initial
200 msec of data. The Wilcoxon matched-pairs
signed-ranks test and the paired t-test were used to
evaluate findings.
Results
Subjects averaged 42.4 correct trials (range: 23-
57). The 700 total skilled performance trials in-
cluded 155 early (-W), 297 correct, and 131 late (+W)
trials; 117 trials occurred outside these intervals.
The longest latency to right-hand press was 150 msec.
Early presses significantly decreased (N=7, t=5,
p < .05) while late presses significantly decreased
(na7, t=0, p=.02) in the latter part of the experiment.
The frequency of correct presses increased slightly,
but not significantly, across trials.
Measurements of brain potentials, eye artifact
(Fpz) and EMG averaged across subjects for each ex-
perimental condition are shown in Table 1. Note
that vertex HP and MCP measures for LHP, RHP, and
BHP conditions were very similar, although lateral
measurements were differentially affected by the
responding hand. For all four lateral electrodes for
all subjects combined, the difference between the
measures using the contralateral hand and those using
the ipsilateral hand was significant both for the BP
(n=14, t=4.64, p < .001) and for the MCP (n=14,
t=4.85, p<.001). This result suggests lateralization of
both the BP and MCP components. Table 1 also in-
dicates different antero-posterior distributions of
these components. BP was maximal at central and
postcentral locations, while the MCP was maximal
precentrally. Values of the third measure were small
and inconsistent at all recording sites in conditions
LHP, RHP, and BHP. Typical waveforms from one
subject are shown in Fig. 1A.
Engagement in the skilled performance test pro-
duced marked increases in the amplitude of BP and
MCP components and the emergence of a large, slow
positive component peaking about 400 msec after
left EMG onset. This positive component was maxi-
mal at the vertex and averaged 14.2 juV (range: 4.5
to 21 t*V) across subjects. Since this large positive
component appeared only during the SPT, it was
called skilled performance positivity (SPP). This
waveform is illustrated for one subject in Fig. IB.
In order to assess the electrophysiological effects
of performance, BP, MCP and SPP measurements
were pooled across all electrode sites to derive the
mean voltage of correct and wrong (±W combined)
trials for each subject. BP (n=7, t=2.55, p< .05) and
MCP (n=7, t=2.2, p <.l) measures were greater for
correct than wrong trials. SPP and EMG amplitude
did not vary consistently as a function of correct/
wrong response (Fig. 2).
No significant temporal order effect was ob-
served in any electrophysiological measure.
Discussion
EEG, EMG, and behavioral data were collected
during two types (skilled and unskilled) of self-
paced motor activities. Unskilled actions consisted
of initiating the sweep of an oscilloscope beam with
either or both hands. The outcome of this action
was invariant. Skilled actions entailed the initiation
and termination of the sweep within very narrow
limits (40 to 60 msec), a paradigm that permits the
study of movement-related brain macropotentials
(MRBMs) during skilled manipulative performance.
Considerable changes were observed in MRBM
patterns when self-paced movements were direct-
ed toward a specific objective as opposed to stereo-
typed movements without any apparent purpose.
Both the Bereitschaftspotential (BP) and motor cor-
tex potential (MCP) were larger in amplitude during
skilled compared to unskilled performance. The
major finding, however was the emergence during
skilled actions of a broad positive component that
peaked about 400 msec after EMG onset. This
component was observed only in the skilled task
and, therefore, has been termed skilled perform-
ance positivity (SPP).
Since scalp data reflect a spatial average of
underlying brain activity (Cooper et al. 1965), the
increase in BP amplitude during skilled performance
could reflect either increased cortical synchroni-
zation or increased cortical negativity. The sig-
nificance of this finding is not clear, although the
BP ratio of skilled/unskilled tasks could conceiv-
ably provide a useful electrophysiological index of
brain efficiency.
Kutas and Donchin (1974) have shown that BP
varies as a function of contractile force. BP differ-
ences observed in this study cannot be attributed
simply to the force applied in the two tasks because
significant differences in BP amplitude were observed
when correct and wrong trials were selectively aver-
aged. Rectified EMGs were the same for both sets of
trials.
The MCP has been interpreted elsewhere (Papa-
kostopoulos et al. 1975) as an index of peripheral
-------
136
Papakostopoulos
Table 1. Mean Voltage (and S.D.) in pV of Bereitschaftspotential (BP),
Motor Cortex Potential (MCP), and Skilled Performance Positivity (SPP)
During Self-paced Tasks
Left-Hand Press
Electrode
Fpz
Cz
Prec L
Prec R
Postc L
Postc R
EMG FL
EMG FR
BP
+0.4(3.7)
-3.1(0.9)
- 1.0(1.3)
-3.4(1.9)
-2.1(1.2)
- 3.9(0.9)
+ 2.8(3.6)
0
MCP
+ 0.4(2.7)
- 6.0(2.4)
- 3.7(2.2)
- 6.9(1.6)
- 3.6(2.0)
- 5.9(2.5)
+26.4(21.2)
0
SPP
+2.1(6.5)
+1.3(2.0)
+1.1(2.5)
+0.6(2.7)
+1.3(1.9)
+0.4(2.5)
+1.2(2.0)
0
Both-Hands Press
Fpz
Cz
Prec L
Prec R
Postc L
Postc R
EMG FL
EMG FR
+3.0(2.8)
-3.0(4.1)
- 2.0(3.6)
-3.2(3.5)
-4.7(2.6)
-4.7(2.6)
+6.0(5.2)
+4.8(3.6)
+ 3.5(4.2)
- 7.2(3.9)
- 6.0(4.8)
- 8.0(2.2)
- 8.0(3.7)
- 7.5(2.5)
+68.8(47.6)
+ 50.8(15.2)
+0.2(8.6)
+2.5(2.5)
+0.2(2.6)
0.0(3.0)
-2.0(3.4)
-0.7(8.5)
+4.0(5.6)
+6.8(11.6)
Right-Hand Press
BP
+ 0.0(3.0)
- 3.4(4.0)
- 3.9(2.8)
- 2.9(2.5)
- 5.0(3.5)
- 3.1(2.3)
0
+3.6(6.0)
MCP
+0.0(2.6)
-6.3(4.1)
-7.3(3.4)
-4.3(2.5)
-6.7(3.4)
-3.3(2.2)
0
+41.6(20.8)
Skilled Performance
+1.4(3.2)
- 10.2(4.7)
-6.9(4.0)
-8.9(3.2)
-8.8(3.7)
-9.7(4.1)
+3.2(3.6)
+2.8(3.6)
+0.5(4.2)
-14.9(5.6)
-12.7(5.7)
-15.2(4.1)
-13.1(5.0)
-13.6(5.3)
+63.2(46.4)
+54.6(22.0)
SPP
+ 0.6(2.8)
+ 3.0(3.7)
+ 0.4(3.0)
+ 1.4(3.1)
+ 0.6(3.5)
+ 2.1(3.5)
0
+1.2(2.8)
Test
+ 3.7(3.6)
+ 14.2(6.0)
+10.9(4.0)
+ 9.7(4.9)
+ 10.4(4.5)
+ 9.5(5.7)
+3.6(2.8)
+7.2(9.6)
reafferent activity from skin, joint, and muscle
receptors during movement. The change in MCP am-
plitude observed in this study could reflect an in-
crease in cortical excitation and, therefore, increased
responsivity to peripheral input during skilled actions.
Such increased excitability has been observed in a
CN'V task (Papakostopoulos et al. 1970). Alterna-
tively, the MCP increase could reflect relaxed gating
(disinhibition) or selective subcortical facilitation of
peripheral input (Frigyes et al. 1972; Papakosto-
poulos et al. 1975; Ha/emann, this section) during
skilled performance.
The SPP is a new component in the constellation
ol movement-related macropotentials. It is distinct
in waveform, amplitude, and latency from the P2
component that occurs in averages of unskilled press-
es (Fig. 1). Since there is little apparent difference
in EMG patterns for the both-hand press and skilled
performance conditions, the SPP cannot be account-
ed for in terms of increased reafferent activity.
The time course of the SPP suggests that it may
coincide with the realization by the subject that
his actions succeeded or failed, i.e., when informa-
tion concerning the consequences of performance is
being processed. Although the task was self-paced,
instantaneous visual feedback was available from the
oscilloscope to evaluate performance. It is likely,
therefore, that the SPP is related to the P300 wave'
which has been associated with similar concepts
of information delivery, resolution of uncertainty,
and feedback (see Tueting, this volume, for an ex-
tensive review of the P300 literature).
Few data are available concerning the neural
substrate of the SPP or P300. Marczynski (1972 and
this volume) has described similar slow positive
shifts in cats associated with the delivery of appetitive
reinforcement. Otto et al. (1977 and this section)
have described prolonged positive shifts associated
with sustained motor responses. The association and
-------
Skilled Performance Positivity
BpMCP
137
MCP
Fig. AX. Superimposed averages of brain and EMG
potentials during left-, right-, and both-hand presses
of a button. B. Data from the same subject and lo-
cations during the skilled performance test. Horizon-
tal bars indicate measurement epochs.
significance of these various movement- and rein-
forcement-related slow positive macropotentials re-
main to be elaborated in future studies.
Summary
Movement-related brain macropotentials
(MRBMs) were compared during skilled and unskilled
self-paced motor tasks. Engagement in a task that re-
quired precisely coordinated movements of both
hands yielded increased amplitude of the BP and
MCP and the emergence of a new component called
skilled performance positivity (SPP). The BP, MCP,
EYE
Fig. 2. Comparison between wrong (-W) and correct
(C) trials during the skilled performance test. Hori-
zontal bars as in Fig. 1.
and SPP can be differentiated in terms of topograph-
ical distribution and functional significance. The BP
seems to be related to the organization of prepro-
grammed action, the MCP to movement-generated
reafference, and the SPP to the evaluation of per-
formance outcome.
Acknowledgments
The author wishes to gratefully acknowledge
the assistance of P. Pocock in computer programming
and statistical analysis and of P. Newton in experi-
mental support.
-------
THE ELECTROMYOGRAM, H REFLEX,
AUTONOMIC FUNCTION, AND
CORTICAL POTENTIAL CHANGES
DURING THE JENDRASSIK MANEUVER
D. PAPAKOSTOPOULOS AND R. COOPER
Burden Neurological Institute, Bristol, England
During the foreperiod of a simple reaction time
(RT) experiment, when sustained potentials known as
the contingent negative variation (CNV) develop
(Walter et al. 1964), the excitability of the spinal
monosynaptic reflex increases (Papakostopoulos and
Cooper 1973, 1976). However, the relationship
between the development of cortical sustained nega-
tivities and increase in the excitability of the spinal
monosynaptic reflexes, as measured by the H reflex
technique (Paillard 1955), is not a simple one as the
two phenomena show a different time course. It has
been proposed, therefore, that these two phenomena,
and heart rate deceleration which accompanies them,
are not causally related but are mediated through a
common mechanism in the brain stem that integrates
the whole body reaction to the stimulus and response
situation (Papakostopoulos and Cooper 1973). To
test this hypothesis further, we decided to study the
time course of H reflex excitability and CNV develop-
ment in two situations with similar stimulus condi-
tions, but different response requirements. The first
situation was the simple RT experiment (situation 1),
the second was the Jendrassik maneuver (situation 2).
This maneuver is a classical clinical procedure
designed to increase spinal monosynaptic reflexes. It
involves clenching the fist to an external command
and relaxing it to another. By replacing the verbal
commands with two stimuli, 2 sec apart, and appropri-
ate instructions to press a button to the first stimulus
and release it to the second, the situation is similar to
a simple RT experiment (situation 1) with the addition
of initiation and sustainment of a continuous motor
output during the foreperiod.
Previous data by Donchin et al. (1973),
McCallum and Papakostopoulos (1972), and Otto et
al. (l''73a, 1977) where motor action has been sus-
tained during the foreperiod, suggest that the CNV
during such a procedure should be smaller in com-
parison with the CNV to similar external cues in the
sample RT experiment.
Method
Five female and four male volunteers (mean age,
24 years) were paid to participate in the study. Mono-
synaptic reflexes (H reflex) were electrically elicited
at various times during and after the 2-sec foreperiod
of a simple RT experiment with a click as SI and a
tone as S2 and an average intertrial interval of 29+ 11
sec. The H reflex was elicited once per trial in pseudo-
random order 0.2, 1,1.5,1.8,1.9 sec after SI and 0.2,
0.5, 2, 5, 10 sec after S2 by a 0.5-msec electrical'
pulse applied to the tibial nerve in the popliteal fossa.
Five sequences each of 10 trials were presented
in which the subject responded to S2 by pressing a
button with his left thumb (task 1) and five sequences
in which he responded to SI by a press that had to be
maintained until release after the presentation of S2
(task 2). Either of these actions to S2 caused the
cessation of the tone. The occurrence of stimuli for
eliciting the CNV and H reflex was controlled by the
PDP-12 computer which was also sampling and display-
ing data. RT was measured and printed out on-line.
Before initiating the trigger pulse for each trial, the
computer measured and stored the R to R interval for
5 heart beats. The fifth beat initiated the stimulus
sequence and SI appeared 1 sec later. This procedure
was used to establish EEC, EMG, and heart rate base-
line before SI. EMG of forearm flexors, gastrocnemius
and tibial anterior muscles from surface electrodes
were each sampled at 1-msec intervals until 1 sec after
S2. Respiration (chest expansion) and heart beat inter-
vals continued to be stored for 6 and 10 sec after S2,
respectively. Electrodermal resistance (EDR) was also
monitored.
For the H reflex, the total sampling time was 50
msec. The CNV, examined during a 4-sec epoch, was
recorded from the vertex, C3, and C4 referred to'link-
ed mastoid process. Anasion + 2-cm electrode referred
to the same reference was used to monitor eye move-
ments and also served for compensation of the vertex
channel. A modified 16-channel Elema-Schonander
-------
Cortical Potential during Jendrassik Maneuver
139
electroencephalograph acted as the main amplification
system. For EEC, respiration, and EDR, a time con-
stant of 5 sec was used. Special Ag/AgCl electrodes,
selected to have less than 1-mV potential between any
pair in distilled water, were used. Separate amplifiers
with 10-Hz bandwidth were used for recording the
H reflex. Individual trial data were stored for further
off-line analysis.
Results
RTs to S2 in tasks 1 and 2 were very similar
(267 ± 60 msec and 255 ± 54 msec, respectively).
RTs to SI in task 2 were consistently slower (391 ±
91 msec) than those to S2 in both situations.
EMG activity from the forearm muscles in task 1
was absent or just detectable during the S1-S2 period.
After S2 the phasic EMG activity leading to the action
of pressing was recorded (Fig. 1 left). The EMG in
situation 2 was characterized by an initial phasic
increase followed by a diminished and sustained activi-
ty until after S2, when a new phasic increase appeared
(Fig. 1 right). The latency of the phasic EMG increase
after S2 in both situations was similar. This latency
was always shorter than the latency of the phasic
EMG increase following SI in task 2. No EMG activity
was recorded from leg muscles at any stage of task 1
or 2. The consistent appearance of phasic EMG activi-
ty after S2 in task 2 suggests that the button release
was an active manipulative action that involved flexor
and extensor forearm muscle groups. In other words,
the button release was not a passive concomitant of
the cessation of action by the forearm flexors.
CNV from the vertex and two central areas for
all subjects tested was always smaller during the
press-wait-ielease situation (task 2) compared with
task 1. This is illustrated in Fig. 2 where the grand
averages obtained from all subjects for each condition
at the vertex and central areas are shown. The possi-
bility of differences due to eye movements can be
excluded as the activity at Fpz during the interstim-
ulus period was very similar for the two situations.
0.2 mV
1 sec
EMG1
The H reflex elicited during the S1-S2 period was
larger than H reflexes elicited 2 to 10 sec after S2 for
both situations. This increase during the foreperiod
was larger in task 2 than in task 1. This is shown for
the whole group in Fig. 2 and for one subject in Fig.
3. A further increase of the H reflex was recorded
200 msec after S2 in both situations and 200 msec
after SI in task 2. This additional increase coincided
in time with the phasic EMG increase leading to press
or release after S2 and to press after SI in task 2 (Fig.
2). No consistent changes in electrodermal potentials
were recorded in the two situations.
The heart rate during the foreperiod of task 1
decreased in all subjects; this decrease was not observ-
ed in task 2. The deceleration during the foreperiod
in task 1 and the absence of it in task 2 for all subjects
tested is graphically represented in Fig. 2.
Discussion
Data from task 1 confirmed previous findings
(Papakostopoulos and Cooper 1973, 1976) that
increased excitability of spinal monosynaptic reflexes
and heart rate deceleration accompany CNV develop-
ment during the foreperiod of a simple RT experiment.
A very different pattern emerges in task 2, where a
further increase of H reflex excitability occurs in
association with diminished CNV and no heart rate
deceleration. RT to the second stimulus is similar in
both tasks.
The EMG and H reflex data provide clues con-
cerning the possible mechanism and significance of
the neurophysiological difference observed between
the two tasks. Two basic types of motor action were
involved in these tasks, phasic pressing or releasing in
responses to stimuli, and tonic pressing during the
interstimulus interval of task 2. Of all the variables
measured, only the H reflex from the leg extensor
muscles paralleled the EMG changes in forearm
flexors. That is, phasic increases in H reflex excitability
were observed with each phasic action of forearm
muscles, while a tonic increase in monosynaptic excit-
ability occurred with sustained pressing.
EMG 2
SI (CLICK)
S2 (TONE)
PRESS
t
SI
PRESS
t
82
RELEASE
Fig. 1. Averaged rectified EMG from the forearm flexors in task 1 (left) and task 2 (right) from one subject.
-------
140
Papakostopoulos and Cooper
C4
EMG
0.2mV
SI
t
S2
1 sac
RESP.
S2+0*2 0*5
Fig. 2. Grand averages (nine subfects) of the CNV, rectified EMG of the left forearm flexors (EMG), respiration
(RESPI, H reflex (HI, H2), and heart rate changes. The CNV, EMG, and RESP of task 1 are shown as thin traces,
those of task 2 as thick traces. The H reflex (upper graphs) and heart rate (lower graphs) of task 1 are shown as
continuous lines and these of task 2 as lines with squares. Measures were obtained at points indicated by dots.
Time calibration in RESP, 1 sec. Arrows indicate the time of SI and S2 presentation. Time after S2 is nonlinear
for H reflex and heart rate.
Gottlieb et al. (1970)and Pierrot-Dcseilligny et al.
(1971) attribute phasic increases in H reflex excitabil-
ity during arm flexion to involvement of the cortico-
splnal or pyramidal system. Phasic actions in this
itudy were presumably mediated by pyramidal path-
ways. Other observed cortical and autonomic changes
may also relate to pyramidal function. The CNV
decrease associated with sustained pressing, for
example, could result from direct corticofugaJ action
on bruinitem structures. It is conceivable that the
corticabulbar component of the pyramidal system
selectively excites descending tracts of the reticulo-
spinal system and simultaneously inhibits ascending
retkular pathways. Selective Inhibition and facilitation
of subcortical pathways by corticofugal action have
been demonstrated In animals (Frlgyesi et al. 1972;
Skinner, this volume) and probably in man (Papako-
stopmilos ct al. 1975). Moreover Steriade (1969) has
shown that reactivation of motor-sensory (precentral)
cortex, in contrast to other cortical regions, diminishes
with reticular activation. Diminished cortical activa-
tion, therefore, is not necessarily inconsistent with
Increased motor output.
If this is the case, CNV reduction in task 2 should
be selective for motor sensory areas. Otto et al.(1973b,
1977) have shown, however, that sustained motor
activity during the S1-S2 interval yields a generalized
decrease in CNV over anterior (Fz) and posterior (Pz)
areas, as well as central regions.
Dimished CNV could be attributed alternatively
to reafferent feedback from peripheral receptors that
discharge during tonic motor activity (of. Matthews
1972). Several strands of evidence are inconsistent
with this hypothesis. McCallum and Papakostopoulos
-------
Cortical Potential during Jendrassik Maneuver
1 2
141
IN
2mV
OUT
10 msec
Fig. 3. Superimposed single H reflexes in task I (left) and task 2 (right) elicited 5 and 10 sec after S2 (lower
traces-Out) and during the period when the CNV develops (upper traces-In). Note that H reflexes during CNV
(upper traces) are larger than those elicited out of the CNV period. Yet Ms H increase is consistently larger for
task 2 (upper right) than for task 1 (upper left).
(1972) have shown that CNV amplitude is not affected
if the button is depressed continuously and released
momentarily in response to S2. This finding suggests
that the initiation of action at the beginning of the
interval, rather than sustained response, is the critical
factor. This initiation should be followed by feedback
from phasic receptors in the periphery. If such feed-
back can be seen with scalp electrodes, it should appear
as short duration negativity (Wilke and Lansing 1973;
Jones and Beck 1975; Papakostopoulos et al. 1975;
Papakostopoulos, this volume). One might expect
such negativity to summate with the CNV and appear
as an increase of the sustained potential. The results
of this experiment are clearly contrary to this argu-
ment. Two other papers in this section (Hazemann et
al., Otto and Benignus) also present evidence incon-
sistent with the reafference hypothesis.
Another approach is to assume that the reduction
in CNV during tonic motor activity is phenomenal
rather than real. For instance, if another positive
potential occurred during the foreperiod in parallel
with the CNV, the true CNV amplitude might be
masked. The existence of a prolonged positive shift
during sustained contractions has, in fact, been
demonstrated by Otto et al. (1977 and this section).
Prolonged positivity following skilled performance
has also been described (Papakostopoulos, this
section). Otto et al. (1977) showed, moreover, that
the decrease in CNV amplitude when sustained motor
activity was superimposed could be accounted for by
the simple linear combination of anticipatory negative
and response-related positive components.
The neuronal generators and functional signifi-
cance of such positivities are as yet unknown. If these
potentials are related to the reinforcement contingent
positive variation (RCPV) reported by Marczynski
(1972), increased rhythmicity of the sensorimotor
areas during task 2 could be expected. This possibility
seems remote in terms of present data, which suggest
that motor activity, phasic or tonic, is accompanied
by suppression of sensorimotor rhythms (Chatrian
1959; Papakostopoulos, this volume).
Summary
During the 2-sec interval between a warning
stimulus SI and a second stimulus S2 that requires a
motor action by the subject, the brain develops sus-
tained potential changes, known as the contingent
negative variation (CNV), the H reflex increases in
amplitude, and heart rate decreases. During the same
period, EMG of relevant muscles is silent or only
moderately active. To assess the significance of myo-
graphic activity during the S1-S2 period, nine subjects
pressed a switch with the left thumb when SI occurred
and released it at S2.
In both situations, the reaction times for releasing
or pressing the switch to S2 were similar. However,
the CNV was significantly smaller and the heart rate
-------
142 Papakostopoulos and Cooper
deceleration during the S1-S2 interval did not occur spinal excitability extending to autonomic function
when motor action was required during this interval. and behavioral output. The effect of the motor action
At the same time, there was a significant increase of on subcortical centres that underlie cortical negativity
the H reflex amplitude beyond that normally seen in can be seen as a result either of reafferent activities
the simple S1-S2 preparatory situation. A dissociation generated by the action itself or, most probably, as a
has thus been demonstrated between cortical and direct inhibition by cortical efferents.
-------
OCULOMOTOR COMPONENTS OF
EVENT-RELATED ELECTROCORTICAL
POTENTIAL IN MONKEYS.
S. ROSEN, J. ROBINSON, AND D. LOISELLE
Department of Psychology, State University of New York at Stony Brook, Stony Brook, NY,
U.S.A.
This report concerns the extent to which event-
related cortical macropotentials, particularly those
time-locked to sensory stimuli, reflect oculomotor
processes. Cortical structures have long been implicat-
ed in oculomotoi functions as a consequence of the
findings of electrocortical stimulation and single unit
recording studies. Stimulation of the frontal and
occipital eye fields in the monkey (Brodmann's area 8,
18, and 19) result in eye deviations generally contra-
lateral to the hemisphere stimulated (Crosby et al.
1952, Ferrier 1875, Wagman 1964). Moreover, brief
pulse stimulation of the awake monkey's frontal eye
field (FEF) elicits single saccades of specific amplitude
and direction with latencies of 15 to 25 msec (Robin-
son and Fuchs 1969). The latter finding strongly sug-
gests that the FEF serves an oculomotor command
function. This view is challenged, however, by reports
indicating that the vast majority of FEF cells, which
indeed discharge in relation to saccadic and pursuit
eye movements, fire during, or following, the move-
ments, but never before them (Bizzi 1968, Bizzi and
Schiller 1970,Mohleret al. 1973).
Despite the evidence of cortical involvement in
the control of eye movements, event-related cortical
macropotentials have rarely been examined in relation
to the oculomotor processes they may reflect. This
has been due in part to the difficulty in dissociating
between potentials of cortical origin related to eye
movements and those artifactually generated poten-
tials arising as a consequence of the rotation of the
corneofundal dipole with eye movements (Hillyard
and Galambos 1970, Peters 1967). Furthermore, in
animal studies in which eye movement artifacts can
be reduced by means of bipolar recording electrodes
placed directly on the cortex equidistant from the
eyes and use of differential amplifiers affording
common mode rejection of eye potentials, great diffi-
culty is encountered in the behavioral control of eye
fixations and the elicitation of eye movements of
specifiable amplitude and direction. The present
report presents the results of investigations in which
many of these difficulties have geen successfully over-
come. Our findings indicate that significant com-
ponents of prefrontal electrocortical potentials
evoked by visual stimuli upon which a monkey must
fixate reflect cortical mechanisms of oculomotor
control that both precede and follow accompanying
saccadic eye movements.
Methods
Subjects
Nonpolarizable Ag/AgCl electrodes were chroni-
cally implanted in prefrontal (bilateral), precentral,
and occipital cortex and also subcutaneously across
the eyes for horizontal electrooculogram (EOG) re-
cording in two stumptail monkeys. Cortical elec-
trodes were implanted in pairs with one electrode of
each pair on the pial surface and the other in subjacent
white matter (5- to 10-mm tip separation). The pre-
frontal surface electrode was located on cortex within
the posterior half of the principal sulcus, and the
depth reference was in white matter of the lateral
bank of the sulcus. EOG electrodes, of the type de-
scribed by Bond and Ho (1970), were cemented to
the nasal and temporal sides of the bony orbit. All
electrode leads were soldered to the Amphenol con-
nectors, which were then fixed to the skull with stain-
less steel screws and dental cement. Embedded in
the resulting cement cap were two parallel brass tubes
(oriented perpendicular to the saggital plane) for head
immobilization in the testing apparatus.
Apparatus
During testing, the monkey was seated in a
restraining chair containing a response lever within
easy reach. The lever had a 5-mm stroke, and 120 g
force was required to depress it and activate a micro-
switch. The chair was positioned in an electrically
shielded soundproof chamber so that the monkey's
head was between two parallel plates rigidly fixed to
the chamber. The plates contained slots which permit-
ted attachment of metal rods that were inserted
through the tubes in the monkey's skull cap to the
plates. Once the monkey's head was immobilized in
this manner, the tip of an adjustable brass tube for
injection of liquid rewards was brought to the
-------
144
Rosen et al.
monkey's mouth. For the presentation of visual stim-
uli, a perimeter containing five light-emitting diodes
(1-1.l>s) 20°apart was situated at eye level in front of
the monkey at a distance of 1 meter. Onset arid dura-
tion of IJJJ illumination (equated for intensity and
color), as well as the sequence of light presentations,
was controlled by an external program panel.
The chamber also contained connectors and low-
noise cables for recording EOG and electrocortico-
gram (hCoG) events. Inputs were led to low-level
preamplifiers outside the chamber, and amplified sig-
nals were stored on FM magnetic tape for off-line
analysis with a PDP-12A computer. A videotape sys-
tem also permitted simultaneous recording of electro-
graphic and eye movement events.
Procedures
In order to obtain steady fixations and saccadic
eye movements of known amplitude and direction,
monkeys were trained on a difficult reaction time
(R I) task. A single fruit juice reward was delivered if
the animal pressed the lever twice, once during the
0.75-sec dimming of a central (0°) fixation light and
again during the dimming of a peripheral test light
that was illuminated immediately following the first
press. Both fixation and test lights were of variable
duration (1.5 sec minimum), and the order of test
light presentations was random from trial to trial. A
DHL schedule was used to eliminate presses during
the light-on, but not the dimming, periods. Animals
were tested daily until their performance resulted in
consistent patterns of lateral eye movements.
In another experiment involving operant condi-
tioning of unilateral cortical slow potential (SP) shift,
rewards were made contingent upon on-line computer
detection of 3-sec surface-negative SP shifts of 50- to
100- iiV amplitude. Conditioned SP events were then
correlated with records of eye movements.
Data analysis
During testing, hori/ontal EOGs and ECoGs from
left and right prefrontal, left precentral, and left
occipital cortex were recorded with dc amplifiers
and the data were stored on FM magnetic tape. Corti-
cal evoked potentials and HOG events resulting from
test-light presentations were computer-averaged
off-line, with separate averages obtained from each
area for each of the five test lights. Each average repre-
sented the data from 40 similar stimulus presentations
with a time base of 2 sec. Pcak-to-peak amplitudes of
the evoked cortical potentials and peak latencies were
computed. These in turn were related to the ampli-
tude, duration, latency, and direction of averaged
laieral eye movements.
Results
Stimulus-triggered eye movements
EOG and videotape recordings made during suc-
cessful RT task performance by two monkeys (i.e.,
when 90% or more of the monkey's paired presses
were rewarded) indicated that the animal's gaze was
directed towards the Fixation light when presented
and that appropriately directed saccadic eye move-
ments followed test light onset. Computer-averaged
EOG activity time-locked to the different test light
presentations confirmed the existence of characteris-
tic patterns of eye movements to each of the test
lights (Fig. 1). The averaged recordings appear similar
to records of individual saccadic movements, with
mean latencies of the averaged movements ranging be-
tween 240 and 3 18 msec (Table 1). The amplitude of
the averaged saccades (both initial and final) were
linearly related to the angular displacement of the
visual targets (Fig. 2A).
Potentials evoked by test stimuli
Prefrontal: Components of averaged electrocor-
tical potentials evoked in prefrontal cortex by test
light presentations were observed 22 to 750 msec fol-
lowing test light onset. Generally, two negative (Nl,
N2) and two positive (PI, P2) peaks could be identi-
fied in a N1-P1-N2-P2 sequence (Fig. l).TheNl,Pl
and N2 components preceded initiation of saccadic
eye movements to the test target by 20 to 150 msec.
The rise of the P2 component coincided with the sac-
cadic movement, although its peak amplitude was at-
tained some 100 to 150 msec after the initial saccade
was completed. Prefrontal components could only be
consistently identified in the hemisphere contralateral
to the direction of the stimulus-triggered saccade
i.e., right prefrontal EP components were reliably
seen with left movements to the 2Qo and 40° left
targets, whereas the left prefrontal components were
seen with right movements elicited by the corre-
sponding right targets (Fig. 1). Amplitudes were sig-
nificantly larger for more peripheral targets (Fie
2B and 2C).
Precentral: As many as eight peaks could be iden-
tified in averages of precentral events time-locked to
onset of the test target. Unlike prefrontal components,
these could be identified in averages associated with
each test light presentation. The amplitude of these
components, some of which preceded (Nl and Pi)
and the remainder which followed saccadic eye move-
ments, did not vary systematically with test lights in
different locations. Mean amplitudes of the first four
components (Nl, PI, N2, and P2) associated with
each test light location were not significantly different
(Fig. 2D). These results were not surprising in light of
-------
Oculomotor ERP Components
145
HORIZ. EOG
4O°L
Table 1. Mean Latencies3 (msec) of Averaged
Saccadic Eye Movements and Prefrontal
Evoked-Potential Components for Two
Monkeys
4O*«
Fig. 1. Averaged horizontal EOG and left and right
prefrontal ECoG events time-locked to test light
onset. Individual traces represent the average of 40
responses evoked by each test light during a single
testing session with Monkey 297, Left (L) and right
{R} test lights are indicated to the left of the tracei.
The time base equals 2048 msec and calibration bars
show 100 i*V. The minimum test light duration was
1.5 sec, indicated by the horizontal bar at the bottom
of the figure.
Averaged
waveform b
Monkey 297
HEOG
RFpNI
P1
N2
P2
LFp N1
P1
N2
P2
Monkey 293
HEOG
RFp N1
P1
N2
?2
LFp P1
N1
P2
N2
Test light
40° L
257.6
143.6
176.8
219.2
499.6
292.4
85.6
161.2
221.6
401.2
20° L
240.8
144.0
177.6
221.2
509.2
318.4
106.8
158.4
210.4
382.8
0°
293.2
20° R
285.2
296.0
40° R
297.2
60.0
103.2
187.1
339.2
312.4
22.4
101.2
316.8
747.6
aLatencies were obtained for only those tett lights that pro-
duced consistently identifiable waveforms. The mean latencies
are comprised of 8 to IS measures of the time intervals be-
tween test light onset and the initial averaged EOG deflection
(for saccadic tye movements), and the peak amplitude of
each of the averaged EP components.
* HEOG • horizontal electro-oculognm; RFp • right perfrontal
cortex; LFp - left prefrontat cortex.
the dear implication of precentral areas in the initia-
tion of skeletal motor responses. Since the motor
response, namely the lever press, Is the same re-
gardless of which test light is presented, no differ-
ences in averaged potential would be expected.
Occipital: Evoked-potential components from
occipital cortex were observed 40 to 1500 msec after
test light onset. The rise of an initial negative com-
ponent was observed some 40 to 60 msec after target
onset, and it attained peak amplitude at about ISO
to 200 msec. This was followed by somewhat more
variable positive and negative waves with peak laten-
cies of about 300 to 900 msec. The amplitudes of the
initial negative wave (Nl) and the final positive wave
(P2)were greater for the centrally located test targets,
i.e., the 0 (fixation) test target and the 20° left and
the 20° right test lights (Fig. 2E). However, the differ-
ences in the mean amplitudes of these components
were not statistically significant.
-------
146
Rosen et al.
U
u
J
-0.2
u ;
ISO
100
H
I
tso
_J
<25
1°
100
A
SO
26
200
ISO
100
#297
0.4
0.2
0
0.2
ISO
100
so
I
I
75
SO
25
0
)
300
22S
ISO
75
E
SO
N
40
20
K
•A
TEST LIGHT
Fig. 2. Mean amplitudes of averaged EOG and ECoG
components as functions of test light location. Data
for Monkeys 297 and 293 are shown. Amplitude
measures are of (A) horizontal EOG, (B) right pre-
frontal, (C) left prefrontal, (D) left precentral, and
(E) left occipital averaged responses. Mean values rep-
resent measurements of components seen in eight to
fifteen 40-trial averages obtained during consecutive
days of testing. Amplitudes are in microvolts except
for the EOG, which is in millivolts.
Operantly conditioned slow potential shifts
Reinforcement of unilateral surface negative SP
shifts in prefrontal cortex resulted in an increase in
the incidence and amplitude of these spontaneously
occurring cortical events. Reinforced shifts of 50 to
100 juV amplitude and 2.5 to 3.0 sec duration were
accompanied by a series of contralateral saccades and
sustained conjugate eye deviations until reward was
delivered (Fig. 3). Delivery of reward resulted in rapid
centering eye movements, but no marked change in
the cortical SP. Contralateral prefrontal SP shifts
were completely unrelated to eye movements or
reward delivery.
Discussion
This investigation provides clear evidence of
electrocortical potentials in prefrontal cortex of
monkeys that encode amplitude and direction of
stimulus-triggered saccadic eye movements. These
potentials are time-locked to the onset of a visual
stimulus that the animal is required to fixate upon
and appear in the hemisphere contralateral to the
direction of the saccade. Moreover, components of
these potentials both precede and arise coincidentally
with the initiation of horizontal saccades. The dura-
tion of the preceding components is less than 100
msec, whereas that of the following components
often exceeds several seconds. The recording methods
employed do not permit specification with any degree
of certainty that the potentials arise from the posteri-
or half of the principal sulcus, or more posteriorly
from the traditionally defined FEF (area 8) as a
consequence of volume conduction to the recording
electrodes in the principal sulcus. However, these
potentials are clearly specific to the prefrontal region
since averaged recordings of precentral and occipital
cortical activity were not consistently related to eye
movements. Moreover, it is unlikely that the observed
potentials reflect eye movement artifacts. Clearly the
issue pertains not to the components preceding the
eye movements but to those arising concomitantly
with eye movements. The finding that the latter com-
ponents appear only in the hemisphere contralateral
to the direction of the saccade is inconsistent with an
eye movement artifact interpretation since saccadic
movements involve both eyes and significant poten-
tials of opposite polarity would be expected at
homologous locations in the other hemisphere. These
were not observed. Furthermore, in the procedure
involving operant conditioning of unilateral prefrontal
SP shifts, concomitant contralateral saccades were
observed during the increase of cortical surface nega-
tivity, but subsequent centering eye movements were
completely independent of cortical SP shifts, a find-
ing that could not be explained if rotation of the
corneofundal dipole was the source of the potentials.
With regard to the functional significance of pre-
frontal potentials related to eye movements, it would
-------
Oculomotor ERP Components
1 2
147
^^A/$\!^^
4. MEG
J
1sec
Fig. 3. An operantly conditioned surface-negative cortical steady potential shift in left prefrontal (LFp) cortex
and concomitant right (Rt) oculomotor responses indicated in both horizontal EOG and drawings of stop-action
videotape recording of eye position. The vertical bar indicates time of food reward. Vertical lines indicate times
during bioelectric recordings when eye positions were photographed. Note the lack of response in the homo-
logous right prefrontal (RFp) ECoG recording.
appear that those accompanying and following sac-
cades reflect the sustained activity of FEF neurons,
which reportedly discharge during saccades and steady
fixations (Bizzi 1968, Mohler et al. 1973). Insofar as
the components preceding eye movements are con-
cerned, the finding that the amplitude of these com-
ponents increases with more peripherally placed visual
targets argues against the notion that they simply
reflect a visual sensory input to the prefrontal area via
known cortical-cortical afferents from areas 18 and
19 (Jones and Powell 1970). Mohler et al. (1973)
have reported that FEF cells with visual receptive
fields have extremely large fields, and individual cells
tend to discharge minimumly, not maximally, when
spots of light are presented in the periphery of the
field. It is possible, however, that prefrontal poten-
tials preceding saccadic eye movements reflect an en-
hanced sensory response of FEF neurons that has
been observed when the visual target for an impend-
ing saccade falls within the receptive fields of a sub-
population of FEF cells (Wurtz and Mohler 1976).
Alternative explanations include the possibility
that presaccadic potentials reflect attempted head
movements and possible feedback from neck muscles.
These views are suggested by the findings of FEF cells
that discharge prior to head turning (Bizzi and Schiller
1970) and FEF neurons in the cat that respond, with
short latencies, to stimulation of the neck muscles
(Dubrovsky and Barbas 1975, Mandl and Guitton
1975). Another possibility is that the observed poten-
tials reflect a corollary discharge mechanism (Teuber
1964) or a motor command system for voluntary
saccadic movements, perhaps related to search behav-
ior or attention.
It should be noted that the present data are not
the only indication of cortical events preceding eye
movements. Lynch et al. (1977) have recently found
cells in parietal cortex (area 7) that discharge prior to
stimulus-triggered saccades and appear to encode
direction of movement, and Schlaget al. (1971) have
found cells in the internal medullary lamina of the
cat that similarly discharge preceding eye movements.
This region is known to receive input from the FEF
(Orem and Schlag 1971).
-------
148
Rosen et al.
In conclusion, the results of this investigation
strongly suggest that significant components of corti-
cal potentials evoked by sensory stimuli can reflect
oculomotor processes, particularly if attention to
these stimuli by the subject involves saccadic eye
movements and eye fixations.
Summary
In order to examine the extent to which poten-
tials evoked in monkeys' dorsolateral prefrontal cortex
by visual stimuli reflect oculomotor functions, mon-
keys with chronically Implanted nonpolarizable elec-
trodes in prefrontal, precentral, and occipital cortex,
and also subcutaneously across the eyes, were trained
on a reaction time task for liquid rewards. The task
required that the monkey detect the dimming of a
centrally located fixation light and then fixate upon
one of five test lights in order to detect its dimming.
The test lights were perimetrically presented in
random order at 20° and 40C to the left and right of
center. Computer averages of cortical potentials time-
locked to 40 presentations of each test light, within a
daily testing session, revealed prefrontal components
that preceded and followed saccadic eye movements.
These components were of maximal amplitude for
the most peripherally located test stimuli in the con-
tralateral visual field. By contrast, the largest occipital
evoked potential components were observed with cen-
tral stimuli, and precentral potentials showed no vari-
ations in amplitude with different test light presenta-
tions. The data indicate the evoked potentials in pre-
frontal cortex elicited by peripherally presented visual
stimuli, upon which an animal must fixate, reflect
oculomotor processes related to saccadic eye move-
ments.
Acknowledgments
This research was supported by National Science
Foundation Research Grant GB 35735X1 to Dr. John
S. Stamm. The authors wish to thank Richard Reeder
for technical assistance, and Michele Parker for help
In preparation of the manuscript.
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III. INFORMATION PROCESSING AND COGNITION
Section Editor:
Patricia Tueting
Maryland Psychiatric Research Center
University of Maryland Medical School
Baltimore, Maryland, U.S.A.
-------
EVENT-RELATED POTENTIALS, COGNITIVE
EVENTS, AND INFORMATION PROCESSING1
P. TUETING2
Department of Psychophysiology, New York State Psychiatric Institute, New York, NY, U.S.A
This review is based on pre-Conference correspon-
dence among the members of the EPIC IV Information
Processing Panel; additional comments from discus-
sion at the conference have also been included. Con-
tributors were: P, Tueting (chairman), New York
State Psychiatric Institute, New York, NY; E. Don-
chin, University of Illinois, Champaign, IL; J. Ford,
Stanford University, Palo Alto, CA, D. Friedman,
New York State Psychiatric Institute, New York,NY;
M.R. Harter, University of North Carolina, Greens-
boro, NC; S. Hillyard (co-chairman), University of
California, San Diego, CA, W. Ritter, Lehman Col-
lege, Bronx, NY; J. Rohrbaugh, University of Califor-
nia, Los Angeles, CA, W.T. Roth, Stanford Universi-
ty, Palo Alto, CA; D. Ruchkin, University of Mary-
land, Baltimore, MD, K. Squires, University of Illi-
nois, Champaign, IL, N, Squires, University of Illi-
nois, Champaign, IL, S. Sutton, New York State Psy-
chiatric Institute, New York, NY, and R.T. Wilkin-
son, Medical Research Council, Cambridge, England.
The papers in this section are divided into two
categories: (I) issue-oriented reviews and (2) data
papers. The review papers developed out of the corre-
spondence and discussion at the conference and are
presented first. Roth considers the issue of how many
late positive waves can be defined. Ritter discusses
the relationship of ERPs to decision latency, and
Ruchkin explains the importance of the concept of
equivocation in interpreting ERP data. The relation-
ship of ERPs to orienting is discussed by Friedman.
Ford presents template and match/mismatch theory.
Sutton and his colleagues document P300 studies
relevant to feedback issues. The research reports that
follow the review papers relate to one or more of these
issues and are representative of current research in the
area. Research reports germane to information
processing were submitted by R. Cooper, Burden
Neurological Institute, Bristol, England; N. Lesevre,
Salpetriere Hospital, Paris, France; and JJ. Tecce,
Tufts University School of Medicine, Boston, MA, as
well as by members of the Information Processing
Panel.
Background
New evoked potential (EP) components are
emerging so rapidly that it is difficult to determine
their validity, let alone their function in information
processing. Temporal sequences of components have
traditionally been evaluated within a "stages of infor-
mation processing" framework. However, it is becom-
ing increasingly clear that EPs also reflect parallel
processing. Serial decisions may be accompanied by
parallel memory storage, memory retrieval, set adjust-
ments, and motor processing. Parallel processing is
indicated by the occurrence of components overlapped
in time at a single electrode location and by observa-
tion of independent components occurring at the
same time but with different scalp distributions.
High-frequency far-field components, thought to
originate in auditory nerves and various levels of brain-
stem, can be recorded at vertex for an auditory stim-
ulus. These potentials originate mainly from the high-
frequency end of the cochlea and carry information
concerning stimulus intensity. Woods and Hillyard
(this volume) failed to find evidence of peripheral gat-
ing in brainstem potentials evoked by probe stimuli in
a dichotic listening task demanding selective attention.
There are, however, animal EP data that suggest effer-
ent gating at the brainstem level.
Components related to the initial registration of
stimulus information at the cortex have been identified
lThis project received support from NIE Grant No. 6-74-0042 awarded to Dr. Samuel Sutton. The assistance
of Dr. Steven Hillyard and Dr. Sutton is gratefully acknowledged.
^Dr. Tueting is now at the Maryland Psychiatric Research Center, Department of Psychiatry, University of Mary-
land Medical School, Baltimore,MD. Dr. Tueting organized the correspondence, wrote the narrative summary,
and edited this section. She was, however, unable to attend the Congress. Dr. Hillyard chaired the panel discus-
sion in her absence.
-------
160
Tueting
in the somatosensory and visual modalities. These
components also carry basic information related to
stimulus parameters such as intensity, wavelength,
and spatial location, and are affected very little by
the attention state of the organism, by the arousal-
sleep continuum, or by decisions regarding stimulus
input.
The primary registration of information at cortex
is only the beginning of the perceptual-cognitive eval-
uation involved in the ultimate use, nonuse, or storage
of stimulus information. The task of the Information
Processing group of the EPIC IV Congress was to con-
sider some of these later information processing deci-
sions in a realm that is often referred to as cognitive.
Early components and selective filtering
At the conference, Hillyard defined a selective
attention experiment as one involving a situation in
which there are at least two stimulus categories. Selec-
tivity is demonstrated when the subject processes one
of these stimulus categories more effectively than the
other, as indicated by a behavioral measure. For
example, selective attention is demonstrated when
the subject makes more accurate and more refined
discriminations in one stimulus category than in
another, reacts faster to one category than to another,
or is able to retrieve from memory one stimulus cate-
gory better than another. McCallum pointed to the
unfortunate tendency to use the term selective atten-
tion without defining a specific operational context.
Behavioral validation in EP experiments of selective
attention is often nonexistent or inadequate.
Hillyard and his colleagues are now using concur-
rent signal detection measures of attention in their
dichotic listening tasks. In a dichotic listening task,
the amplitude of N100 is larger for relevant stimuli
possessing easily identifiable characteristics such as
pitch or spatial position toward which the subject's
attention has been directed-usually by instructions
and task. N100 amplitude is correspondingly smaller
for stimuli occurring in irrelevant, rejected channels
(Hillyard et al. 1973, Schwent and Hillyard 1975).
These findings have been most clearly demonstrated
when channels are separated by both pitch and spatial
attributes (Schwent et al. 1976) and when subjects
are exposed to information overload, i.e., when a sub-
ject is placed in a situation where there is difficulty in
processing all of the input effectively in the time avail-
able.
Based on a study by Wilkinson and Lee (1972)
involving auditory channels differing in stimulus
frequency, Wilkinson has expressed the hypothesis
that N100, and possibly N100-P200, of the auditory
evoked response reflects selective filtering only for
bade stimulus attributes like modality and location in
space and time, but not for other attributes like pitch
and linguistic distinctions. According to the hypo-
thesis, contingent negative variation (CNV) resolution,
rather than N100 itself, may reflect these latter cate-
gories of stimulus selection. However, Schwent et al.
(1976) reported that selective effects on N100 could
be obtained with either pitch or spatial location. Larg-
er effects were found when both pitch and spatial
cues were used. These results do not seem to be inter-
pretable in terms of CNV resolution.
The conclusion that N1 is correlated with between
channel (i.e. stimulus set) selection is based primarily
on the work discussed above on the auditory vertex
N100. At the conference, Hillyard proposed that the
vertex Nl may index a cortical process related to an
initial selection of a source of information for further
processing regardless of modality-auditory, visual, or
somatosensory. Hillyard's proposal assumes that an
Nl component with a frontocentral distribution is
elicited by stimuli in all three modalities. Measurement
of Nl across modalities is complicated, however, by
latency changes and component overlap. It is unclear
whether auditory Nl has a frontal source, a temporal
source, or both a frontal and a temporal source
(Arezzo et al. 1975). Vertex Nl may be represented
in occipital recordings at reduced amplitude, but Nl
of the auditory evoked potential (recorded from ver-
tex) and Nl of the visual evoked potential (recorded
from occipital) may not be directly comparable. In
the somatosensory modality, there is evidence that
there may be an overlap of components originating in
primary somatosensory cortex and in association cor-
tex in recordings over either the vertex or the somato-
sensory region (Donald 1976).
Harter described selective attention in the visual
modality. In the Eason et al. (1969) study, selective
attention to spatially separate stimuli (light flashes
presented to either the left or right visual field) was
found to influence the amplitude of the first negative
deflection of the occipital EP beginning 120 to 130
msec after the eliciting stimulus. These findings are
consistent with Hillyard and Wilkinson's proposal that
selective filtering is reflected by early components
only when easily identifiable stimulus attributes are
being discriminated. Harter and Salmon (1972), how-
ever, have reported selective attention effects on the
earliest components of their visual EPs when the rele-
vant and irrelevant stimuli were different colors with
identical spatial attributes (but not when the relevant
and irrelevant stimuli were in different orientations or
were different shapes). Color is represented neuro-
physiologically in the peripheral visual system, while
orientation and shape are represented at higher levels.
Harter therefore suggested that it is the presence of
peripheral representation of stimulus attributes, rather
than the complexity of the attributes per se, that is a
prerequisite to selective filtering.
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ERPs and Information Processing
161
A vertex negative component elicited by somato-
sensory stimulation has been described by Debecker
and Desmedt (1971) and Desmedt and Debecker
(1978). The findings with respect to the somatosen-
sory vertex Nl are similar to the findings described
above for the auditory and visual Nl.
The P300 component
By far the most controversy and discussion in
relating psychological variables to EPs has been gener-
ated by the P300 component, first described by Sutton
et al. (1965). The P300 component is not modality
specific and has been shown to be endogenous by the
fact that it can be elicited in the absence of stimulation
by an apparently internal trigger if (1) stimulus
absence is significant and (2) stimulus absence is time-
locked either by a prior stimulus or by some other
time-marking aid.
A modality-specific negative component preced-
ing the emitted P300 is elicited when stimulus omis-
sions are rare in comparison to stimulus presentations
(Simson et al. 1976), Therefore, this component is
also an endogenous component. Mystery surrounds
the question of whether the stimulus-elicited P300 is
always preceded by a negative component or not-
N2?, N190?, N250?, NX?-but it is clearly evident in
the waveforms of Harter and Salmon (1972), N.
Squires et al. (1975) and others, and has emerged in
principal component analysis (K. Squires et al. 1977).
Part of the ephemeral nature of the negative compon-
ent may be due to the fact that it is overlapped with
other components known to occur in the same latency
range when a stimulus is actually presented. If the
latency variability of the negative component is the
same as the latency variability for P300, then it would
not be seen as easily as P300 because of the negative
component's relatively small amplitude (Ritter, this
volume). It is also possible that the negative com-
ponent does not always accompany P300 but that the
exact variables, subject or otherwise, necessary and
sufficient for its elicitation have not been specified.
So far, however, the N190 component seems to be
affected by probability in the same way as P300 is, at
least when both components are clearly elicited in
target-identification situations (cf. K. Squires et al.
1977).
Karlin (1970) expressed the opinion that P300
represents a nonspecific reactive change of state sub-
sequent to cognitive evaluation of significant stimuli.
This opinion was originally prompted by the fact that
P300 components tend to be elicited in situations
where a slow negative expectancy process (CNV) pre-
cedes stimulus presentation. The CNV frequently
resolves into a slow positive-going poststimulus process
with recording, and this CNV resolution appears simi-
lar in some respects to P300. It was argued that any
nonspecific state prior to the stimulus, a state indexed
by EEC desynchronization (Naatanen 1967), or by
nothing recordable from the scalp, could be associated
with a nonspecific change of state subsequent to
stimulus presentation and reflected in P300 (see also
Naatanen 1975).
The existence of an independent P300 related to
specific cognition and stimulus identification is no
longer the issue. P300 components have been elicited
under conditions of uncertainty when .the stimulus
delivers feedback concerning the accuracy of a guess
or of a judgment, in situations where the subject is
required to make a choice response as soon after stim-
ulus presentation as possible, and in situations where
low probability targets are presented against a back-
ground of more probable nonsignals. It has been
shown by factorial experimental design and by scalp
topography (e.g., Donchin et al. 1975) that CNV and
P300 are dissociable components. However, the issue,
in slightly different form, remains. It is probable that
in some situations a distinct P300 and a positive CNV
resolution (or "resident potential resolution") may be
overlapped. Wilkinson suggests that baseline-to-peak
measurements of P300 would ordinarily be confound-
ed in these cases of overlap. (Random presentation of
experimental conditions, although it does not elimin-
ate overlap, does preclude differential prestimulus
states, and should always be used in experiments aimed
at poststimulus processing.)
How many "PSOOs"?
It would be more parsimonious if one unifying
psychological construct could be found for the P300
component. A search for such a construct began sever-
al years ago after it was observed that P300 was elici-
ted in a wide variety of situations. Uncertainty, infor-
mation delivery, significance, salience, orienting, inhi-
bition, selective recognition involving response set,
and awareness have all been postulated as candidates
for the one unifying construct for P300. (See Sutton
et al., this volume). Donchin has postulated that P300
reflects the activity of a specific processor that can be
invoked in a wide variety of situations. In this formu-
lation (and most others), P300 latency would be
determined by the time at which the processor is in-
voked (see Kutas and Donchin, this volume).
The trend now, however, is to search for more
than one P300. Two is the current vogue in some cir-
cles, but three or more (P3a, P3b, P3 visual frontal,
P3 no-go, P3 vertex) have been proposed. It is difficult
to say at this point whether the seeming multiplicity
of P300& simplifies the search for cognitive correlates
of P300 or increases the complexity. Donchin, at the
conference, argued for stricter criteria for admission
to the P300 "club."
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Tueting
The criteria that have been used for isolating
P300 components are scalp distribution and wave-
form characteristics such as latency and amplitude.
Separation has been made on the basis of differences
obtained in these measures for different psychological
situations and for different modalities of stimuli. A
P300, "P3a" is elicited by low-probability auditory
stimuli presented while subjects are engaged in another
task (e.g., reading) and "ignoring" the stimuli (Roth
1973, Ford et al. 1976, N. Squires et al. 1975, K.
Squires et al. 1977). "P3a" has an early latency, rela-
tively small amplitude, and a frontocentral scalp distri-
bution. A P300, "P3b," elicited by low-probability
signals in a vigilance task is later in latency, larger in
amplitude, and has a centroparietal distribution.
"P3b" has a virtually identical scalp distribution in a
wide variety of target-detection tasks involving
threshold-level stimuli, omitted stimuli, and auditory
and visual discriminations (Hillyard et al. 1976; Pic-
ton and Hillyard 1974; Ritter et al., in press).
Courchesne et al. (1975) reported a P300 to novel
visual stimuli that were not task-related. This fron-
tal P300, which had a relatively long latency, habit-
uated quickly as novelty decreased. Although this
P300 was also elicited by low-probability stimuli un-
related to the subject's main task and had a fronto-
central distribution, it was not necessarily considered
to be equivalent to the auditory "P3a." The "P3b"
may or may not be identical to the original P300 de-
scribed by Sutton et al. (1965), which is elicited in
guessing situations and tends, if anything, to be a
little larger at vertex than at parietal loci. The "de-
tection potential" described by Cooper et al. (this
volume) is also similar to "P3b."
There is speculation that the frontal P300 to
both auditory and visual irrelevant stimuli may be
related to orienting. The idea is that subjects will
orient to low-probability stimuli even though they are
told to ignore them and are involved in a task with
other stimuli. The parietal P300 on the other hand
has been related to delivery of relevant information,
"response set," and decision. It is elicited by low-
probability target stimuli to which a specific response
such as counting has to be made. Ford has distinguish-
ed the two P300s within an active-attention versus
passive-attention framework. The term "passive atten-
tion" might apply to the frontal P300 since attention
is drawn involuntarily by a low-probability stimulus
that is irrelevant to the subject's main task. The parie-
tal P300, however, seems to require active attention,
being obtained mainly when subjects are actively en-
gaged in a task in relation to the eliciting stimulus.
A frontal P300, which may be related to response
inhibition rather than orienting, was proposed by
Papakostopoulous (Donchin 1976) for the Bristol
Congress on Event Related Slow Potentials. A P300
with a frontocentral distribution similar to that of
"P3a" (but much longer in latency) is elicited to the
no-go stimulus in a go/no-go reaction time task (Tuet-
ing and Sutton 1976; Ritter et al., in press; McCallum
1976). The P300 elicited by the go stimulus has a
more parietal distribution, reminiscent of the task
related "P3b." In a choice-reaction time (RT) task,
the subject is prepared to react as fast as possible to a
stimulus, and the no-go stimulus can be considered to
set up a red flag, i.e., an inhibition of the go. However,
extending the construct of inhibition for P300 beyond
choice-RT situations requires viewing motor function-
ing as a largely covert activity that is closely intertwin-
ed with cognitive processing (cf. Sokolov 1972 or
McGuigan and Schoonover 1973).
The group generally agreed that latency by itself
should not be used to dissociate P300 components.
More information about the range of responsiveness
of the P300 component to experimental variables and
about the implications of component overlap at vari-
ous electrode locations is needed before latency alone
can be used to dissociate P300 components. Some of
the problems involved in interpreting scalp distribution
data are reviewed by the Scalp Distribution group
(Donchin, this volume).
Moreover, it is still unclear whether several inde-
pendent P300 components truly exist, and the issue
of one versus several P300s was a focal point of discus-
sion at the conference. The issue is reviewed in detail
by Roth (this volume). The concept of only one P300
is still viable. Some of the findings interpreted as indi-
cating multiple P300s could be interpreted as indicat-
ing one P300 whose anterior-posterior amplitude dis-
tribution varies with task demand. In addition, the
amplitude of "P3a" is often small, and K. Squires et
al. (1977) reported that "P3a" is an elusive compon-
ent relative to "P3b." A further problem for the
multiple P300 theory is that differences in anterior-
posterior distribution could be a result of differences
in the overlapping slow wave component as suggested
by N. Squires in the correspondence. The slow wave
has been reported to be negative-going frontally and
to become progressively more positive-going pane tal-
ly. Conceivably, P300 latency could also be affected-
P300 could be truncated in latency frontally by the
negative slow wave and lengthened posteriorally by
the positive slow wave.
A note of caution should be mentioned in com-
paring observations of P300 latency from different
laboratories. A lower cutoff frequency may influence
P300 latency. In the correspondence, Rohrbaugh
pointed out that P300 peak latency is sometimes
shortened appreciably with a 1-Hz cutoff compared
to a dc recording, reflecting phase shifts at frequen-
cies near the low edge of the bandpass; its amplitude
may also be reduced. However, it is unclear whether
raising the low-frequency cutoff decreases the appar-
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ERPs and Information Processing
163
ent P300 latency because of phase shifts of the P300
itself or because the concurrent slow wave is not
passed by the filter.
P300 and orienting
The construct most frequently associated with
the frontal P300 at present is orienting (see review by
Friedman, this volume). The frontal P300 that follows
novel visual stimuli may be a stronger candidate for
an orienting correlate than the auditory "P3a" since
it increases with the complexity/nonrecognizability
of the stimulus and habituates rapidly (Courchesne et
al. 1975). Friedman pointed out in the correspondence
that orienting is reduced or absent in patients with
frontal lobe damage (Luna 1966), and this is consis-
tent with an orienting construct for the frontal P300.
One way to assess the validity of this hypothesis
will be to record traditional autonomic measures of
orienting such as heart rate, galvanic skin response,
vasodilation of the skin, pupil, etc., in conjunction
with EPs. Friedman et al. (1973) have studied event-
related potentials (ERPs) and pupil dilation concur-
rently. They found situations in which dilation and
ERPs correlated in response to psychological variables.
For example, both vertex P300 and peak dilation of
the pupil were monotonic inverse functions of stim-
ulus and guessing probability. Roth et al. (this volume)
have recorded auditory EPs and skin conductance
concurrently, but their results were equivocal.
A significant methodological problem in record-
ing ERPs concurrently with autonomic measures is
that autonomic measures have a much longer latency
than most ERPs. Only certain paradigms involving
long interstimulus intervals may be used. Another
problem is that the relationship of autonomic variables
to orienting is not completely clear, and complexities,
particularly variations in recording techniques and
individual differences in autonomic responsivity, arise.
The data overload and complexities are increased
even further when ERPs (latency, amplitude, and scalp
distribution measures of several components) are
added to the picture.
P300 and decision latency
One conceptual framework implicates the P300
and decision-making. Unfortunately, the exact nature
of the presumed decision is not thoroughly worked
out, but a common thread running through the differ-
ent tasks that elicit P300 seems to indicate that a
comparison of stimulus input against representations
in memory (templates) is involved either directly or
indirectly. P300 is not directly involved in the decision
regarding the selection of a specific motor response to
a stimulus, as the large P300 obtained in choice-RT
studies might imply, since large P300s are routinely
obtained in a guessing task where subjects are not
required to choose one overt response over another in
the immediate poststimulus period. Similarly, specific
poststimulus response selection is not involved when
P300s are obtained with stimuli delivering feedback
concerning accuracy in a discrimination trial or with
non-task-related low-probability or novel stimuli.
However, Hillyard pointed out in the correspondence
that a theory relating decision-making to P300 must
take into account the finding of Karlin and Martz
(1973) that low-probability responses, as well as low-
probability stimuli, are associated with larger P300s.
The appeal of the term "decision" is its general-
ity, but a useful feature is that a decision is made at a
precise point in time that is measurable, at least theo-
retically. Both N. Squires et al. (1975) and Roth
(1973) found that P300 evoked in an orienting
response situation occurs earlier than the P300 evoked
in a signal-detection paradigm. It seems reasonable
that the decision to orient is easier and faster than the
decision that the target signal just occurred, and
P300 latency could be reflecting that difference in
decision time, a possibility suggested by Ford in the
correspondence. However, since there is no voluntary
intention when P300s are elicited by low-probability
events presented while subjects are reading, Roth
pointed out that it might be clearer semantically in
this case to use the term "reaction" instead of "deci-
sion." Thus, the term decision may be more appropri-
ate for the parietal task-related P300 than for a frontal
orienting P300.
In the correspondence, Donchin pointed to find-
ings relating P300 latency to an internal trigger, which
varies with stimulus evaluation time (e.g., Kutas and
Donchin, this section). The fact that P300 can be elici-
ted without a stimulus also supports the idea that the
latency of P300 is related to the latency of a cognitive
event. Assuming that the trigger for P300 is basically
internal, considerable variability in P300 latency
across conditions in averages time-locked to stimulus
presentation should be expected, and has been observ-
ed. Variability from trial-to-trial within a single con-
dition, and variability among subjects in P300 peak
latency distribution has also been noted. "Inexplica-
ble" results when conditions that are stimulus time-
locked (e.g., "hits" in threshold signal-detection para-
digms) are compared to conditions that are not time-
locked (e.g., "false alarms" in signal-detection para-
digms) are also to be expected. Threshold signal-
detection data become more interpretable when time
marking aids are used (K. Squires et al. 1975).
Validity of latency measures: A first consideration
in relating P300 latency to decision latency should be
whether a difference in P300 latency is a valid measure.
It is relatively simple to say that at a given latency
there is an amplitude difference, but more assump-
tions may be involved in concluding that a component
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164
Tueting
of assumed amplitude, shape, and approximate latency
shifts peak latency as a function of condition or elec-
trode location. Donchin has repeatedly pointed out
that it may be misleading to identify components
with the appearance of visible peaks in the waveform,
and it may be preferable to define components in
terms of the effects of experimental variables on volt-
age measurements.
Most of the group felt that, despite considerable
problems, latency can be a valid measure. In fact,
amplitude measures may also be invalid or confound-
ed. For example, a condition with greater variance in
peak latency distribution may result in smaller aver-
age amplitude because of high latency variability and
not because of a real decrease in amplitude (Ruchkin
and Sutton, 1978). One solution to the problem of
the validity of amplitude and latency is to obtain
amplitude distributions and latency distributions on a
triaJ-by-trial basis. This, although more difficult to do
for small components, is a possibility for P300, which
can be fairly large on individual trials in some subjects.
The technical problems involved in defining P300
latency in individual trials are considerable however
(see correspondence summary on Alternatives to Sig-
nal Averaging, by Weinberg). The problems develop
from the low signal-to-noise (S/N) ratio for P300 at
the scalp, which may be so low for some subjects and
for some experimental conditions as to make single
trial analysis an impossibility.
Typical single-trial analysis procedure for obtain-
ing P300 peak latency and amplitude distributions
involves setting a latency search window for a comput-
er instructed to select the most positive peak within
the time span specified. The selection of the search
window is critical-too wide a search window may
result in loss of the peak in some trials. A painstaking
visual inspection of the data (and often of individual
trials) before selecting a latency search window is
often necessary. Ruchkin is now using Woody filter
analysis (Woody 1967), which requires an iterative
correlation procedure as a basis for realigning single
trials before latency-corrected averaging. This proced-
ure is more quantitative and objective than visual
inspection or peak selection within search windows.
Other single-trial techniques do not yield peak
latency information, although the latency at which
there is an amplitude difference may be identified
and experimental trials classified. For example, K.
Squires and Donchin are using the value of a discrimi-
nant score on each trial. Researchers unable to deal
with single-trial analysis may nevertheless obtain
tome information from additional measurements like
breadth of P300, area of P300, rise and fall of P300,
and onset latency ofP300. Specific post-hoc clustering
of the data may be helpful, e.g., clustering EP trials
on the basis of differing ranges of reaction time.
Despite problems involved in single-trial analysis,
the initial findings are intriguing. Ritter et al. (1972)
found that variation in parietal P300 latency from
trial to trial correlated with trial-to-trial variation in
RT. Ruchkin and Sutton (1978) found that P300
varied in latency from trial to trial in a guessing task.
In their study, latency variability was considerably
greater when stimulus omission rather than stimulus
presence delivered information concerning the sub-
ject's guess. Presumably, the point in time at which
the subject decides whether a guess is correct or not
(and hence P300 latency) is more dependent upon
time-estimation ability in the omitted-stimulus case
than in the present-stimulus case.
Validation of decision latency: Donchin pointed
to a significant problem, namely that a method has
not been developed to independently determine the
time of invocation of the processor that P300 presum-
ably represents. For example, Ruchkin found a ten-
dency, not statistically significant, for emitted P300
latencies to be longer for incorrectly guessed single-
click trials than for correctly guessed single-click trials.
(Subjects guessed whether a single or a double click
would be presented on each trial, and a P300 was
emitted at the point in time of omission of the second
click in a single-click trial.) One possible inference is
that subjects may wait longer to acknowledge the
absence of a second click when they have predicted
that it would be present. Testing this plausible infer-
ence directly is a difficult problem, as Ruchkin pointed
out. (A similarly delayed P300 for feedback that dis-
confirmed a prior judgment was found by K. Squires
et al. 1973a.)
Psychologists have traditionally made inferences
about cognitive events via behavioral measures, and
the traditional behavioral measure of decision latency
has been RT. The correspondents all agreed to take
seriously the caution to record physiological and beha-
vioral data in the same set of trials; Sutton (1969)
outlined the very good reasons for doing this. A major
problem arises, however, because potentials preceding
and following the response may be overlapped (espe-
cially in the centroparietal area) with potentials related
to stimulus evaluation (decision). These "motor"
potentials consist of a slow premotor negative poten-
tial, a higher frequency complex associated more
directly with response initiation, and then a large and
slow postresponse positive wave peaking about ISO
msec after response (thought by some to be related to
somatosensory feedback from muscle and joint recep-
tors). InanRT task, premotor potentials overlap evok-
ed potential components up to the point of the reac-
tion, and for fast RT, the postresponse positive wave
could overlap P300, N350, and P400.
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ERPs and Information Processing
165
A further complication emphasized by Roth and
by Wilkinson is that motor involvement increases the
size of the CNV, and they point out that the timing
of decision may be more closely associated with the
latency of CNV resolution than with the latency of
P300. In any case, it is likely that in some instances
the latency and amplitude of CNV resolution and the
latency and amplitude of P300 will be confounded by
the overlap of these two components.
Some correspondents emphasized that it may
prove impossible to disentangle decision-related com-
ponents like P300 from motor components associated
with a required reaction. Simple linear addition of
motor components when an RT task is added to a
situation is unlikely. However, the advantage of having
an independent behavioral measure of decision latency
is so important that investigators are compelled to use
a number of strategies that converge on this issue.
Several techniques considered in this context follow:
1. Choice of response measure in RT studies. The
judicious choice of response measure in RT studies
may help in reducing motor potentials and movement
artifact. In a study of the relationshp of EPs and RT
to uncertainty, Tueting and Sutton (1976) found
that a lift no-lift response task gave cleaner response-
evoked potentials than a key press response. Rohr-
baugh suggested that systematically varying force
and excursion of the responding member may aid in
partialling out motor responses, and that, in many
experiments, keeping force and distance at a mini-
mum may reduce motor potentials. Stretching this
strategy even further, it may be possible to train
subjects to make an extremely small response that
can still be picked up by EMG recording. Covert
verbal reactions such as counting to onself should be
throughly investigated to see if minute muscle or
laryngeal responses can be picked up reliably, since
counting should be considered a motor response and
may be accompanied by motor potentials and motor
artifact. Whatever the response elected, it should be
absolutely silent and should produce as little tactual
and visual sensation as possible to avoid inadvertent-
ly adding sensory EPs to the already complex picture.
2. Differential topography. In come cases, motor
potentials can be separated from stimulus-evoked
responses by precise delineation of topography
(Vaughan et al 1965, Vaughan et al. 1968) and some
motor potentials have been identified by their asym-
metry (Kutas and Donchin 1974). Possibly a factor
analysis approach using data from several recording
sites could separate "motor" and "cognitive" effects,
but factor analysis assumes an underlying linearity,
which according to Ruchkin may not exist in this
situation
3. Delayed response control. A delayed-response
task (or a task requiring no motor response) can be
compared to an otherwise identical RT task (Vaughan
et al. 196S,Karlinand Martz 1973, Picton et al. 1974,
Courchesne 1975). However, Roth pointed out that
delaying or omitting motor responses is likely to
change the nature of the decision and other cognitive
features of the task. A delayed-response control
would be better than a no-task control, as long as
anticipatory reactions are prevented.
4. Self-paced motor response control. Another
strategy is to collect self-paced motor responses in a
separate control condition. Potentials obtained in the
self-paced condition can be inspected and inferences
drawn (Ritter et al. 1972), or the motor potentials
obtained in the self-paced task can actually be subtrac-
ted from the potentials obtained in the RT task. Pre-
sumably, subtraction would leave potentials related
to stimulus evaluation (decision) without motor con-
founding. The subtraction procedure assumes, how-
ever, that the motor potentials in RT situations are
similar to motor potentials recorded in self-paced
response tasks. Several correspondents pointed out
that self-paced tasks may differ in a number of ways
from the task for which they are being used as con-
trols. For example, Ruchkin et al. (1977) used self-
paced motor responses as a control in a time-estima-
tion study.
5. Comparison of stimulus versus response-locked
potentials. Averages time-locked to the response can
be compared to averages time-locked to the stimulus
(Ritter et al. 1972, Karlin et al. 1971). Presumably,
decision time would be more closely related to actual
response time that to stimulus onset time; there-
fore P300 should be more precisely time-locked to
response time. The experimental findings to date are
equivocal (Karlin et al. 1971), indicating that P300
may actually be smaller in response-locked averages
than in stimulus-locked averages. However, motor
potentials are more closely time-locked to response
time, and motor potentials can be seen more clearly
in response-locked averages than in stimulus-locked
averages.
6. The go/no-go reaction time task. Still another
technique is to use a go/no-go choice-RT task, and to
counterbalance conditions (usually within subjects)
so that every condition has a replicate (one go and
one no-go). The assumption is that no-go evoked
responses are not confounded with motor potentials
since a motor response is not required. However, it
seems likely that there is motor involvement in the
no-go case in a choice-RT task. For example, motor
response inhibition in the no-go case could be reflected
in a motor potential related to motor inhibition.
Specifically, frontal P300 is a candidate (Donchin
1976; McCallum 1976; Ritter etal.in press; Tueting
and Sutton 1976).
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Tueting
P300 latency and RT: If P300 occurs in precise
temporal relation to a cognitive decision, an indepen-
dent behavioral measure of decision latency such as
motor RT ought to correlate with P300 latency.
Hillyard, for the correspondence, reviewed studies in
which P300 and RT were recorded concurrently.
Only two of the studies indicated that RT variations
paralleled changes in P300 latency (Ritter et al. 1972,
Picton et al. 1974). A few other studies provided less
direct support for a positive P300 latency-RT corre-
lation (Bostock and Jarvis 1970, Rohrbaugh et al.
1974, Routh et al. 1975, Posner et al. 1973). On the
other hand, many studies showed a dissociation of
P300 latency and RT (Karlin et al. 1970, Karlin et
al. 1971, Karlin and Martz 1973, Donchin et al.
1973, Donchin et al. 1975, Parasuraman and
Davies 1975,Courchesne 1975, Ford 1975).
Admittedly, these studies suffer from problems
discussed above, such as confounding from component
overlap, and from problems in comparing mean RT to
peak latencies obtained from evoked potentials averag-
ed over trials (rather than from single trials). Despite
these shortcomings, the inconsistencies are too great
to dismiss. The dissociation between RT and P300
latency seems to be separable into the two following
categories.
1. P300-reaction time correlations in relation to
discrimin ability and equivocation. Ruchkin and Sut-
ton (this section) have formulated the concept of
equivocation in relation to P300. Equivocation refers
to a loss of information related to the subject's
a posteriori uncertainty, and can be thought of in
terms of the "immediacy and ease" with which a
decision can be made. An increase in equivocation
leads to a decrease in P300 amplitude. The equivoca-
tion concept is in some ways similar to the "confi-
dence of the decision" concept proposed by K.
Squires etal. (1973b).
Dissociation between P300 latency and RT seems
to occur when discriminability, or equivocation, is
the variable. Both P300 latency and RT increase as
equivocation increases, but the magnitude of the
change appears to be three to five times greater for
RT than for P300 latency. For example, Ford et al.
(1976) varied the degree to which rare target tones
differed in frequency (pitch) from more probable
background stimuli. As the frequency difference
decreased (increasing equivocation), P300 latency
increased by an average of 26 msec while RT increas-
ed by an average of 81 msec. Parasuraman and Davies
(1975) found that P300 latency and RT were greater
for false alarms as compared to hits in a vigilance task,
but the magnitude of the difference was greater for
RT than for P300 latency.
2. P300-RT correlations in relation to uncertainty
and probability. The second kind of dissociation is
more serious for the hypothesis that P300 latency is a
measure of decision latency. This kind of dissociation
seems to come about whenever equivocation is low
but uncertainty or probability is the variable. (In in-
formation theory, a low-probability stimulus has
greater uncertainty than a high-probability stimulus.)
As uncertainty increases, P300 latency remains the
same (or it may even decrease), while RT increases by
a considerable amount (Hyman 1953). The situation
is further characterized by the fact that the increase
in RT often is accompanied by an increase in P300
amplitude. For example, when comparing a condition
where the subject does not know in advance what
stimulus will occur next to a condition where the sub-
ject does know, RT increases considerably with the
added uncertainty, but P300 latency does not. P300
amplitude may increase (Tueting and Sutton 1976) or
not (Donchin et al. 1973), apparently depending
upon other factors such as pressure for fast RTs.
Hillyard suggested that these dissociations between
RT and P300 latency when uncertainty (or probabil-
ity) is the variable could represent a disruption of
motor processing as a result of the emotional con-
comitants of the added uncertainty or by some other
confounding of decision latency with probability.
The theory that P300 is directly related to a
decision involving response selection encounters still
another obstacle. It has been reported that the peak
of the parietal-occipital P300 component in a partic-
ular trial can occur, under certain circumstances, after
the subject's reaction in that trial (Eason et al. 1969,
Ritter et al. 1972, Rohrbaugh 1973). The finding that
P300 latency can occur after the reaction indicates
that the correlation between parietal P300 latency
and decision latency is not a causal one. Ritter (this
section) concludes that even P300 onset cannot be
causal to reaction when the time between the initia-
tion of motor processes in the brain and RT is precise-
ly considered.
In summary, the theory that P300 latency is
directly related to an independent RT measure of
decision latency runs into trouble. There are reports
that P300 latency and RT can be dissociated, that
response-locked averaging can result in a smaller P300
than stimulus-locked averaging, and that the peak of
P300 can occur after the reaction.
A casual relationship between P300 and reaction
can probably be excluded, but P300 may still be
indirectly related to response selection. Hillyard sug-
gested that RT-P300 latency dissociatons could
be explained if P300 reflects an early decision such as
"the stimulus belongs to a relevant class" rather than
to a later decision such as "which stimulus it is and
what response is required"; subjects may hold off a
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ERPs and Information Processing
167
"one of a relevant class decision" until a target is
detected with low-probability targets, but not hold
off with frequently occurring targets. Alternatively,
the P300 could simply represent a phasic arousal pro-
cess related to the consequences of the decision.
Simson et al. (1976) have proposed that P300 could
be related to "conscious awareness of the outcome of
the decision." Finally, P300 could reflect adjustments
of memory representations and set that are conse-
quent to the decision on the current trial but may be
reflected in decisions on future trials (see section
below on Feedback and P300).
Ritter concluded that P300 does not reflect the
selection of a particular target within a class of stimuli
in vigilance tasks because (1) P300 follows rather than
precedes reaction time and (2) stimulus probability
appears to be a more potent variable than whether or
not the stimulus is a "target." Ritter (this section)
proposes that the earlier negative component may be
more directly related to decision latency than isP300.
P300 and template match/mismatch
Decision processes are no doubt different for the
different tasks that elicit P300 (guessing, feedback,
detection). An underlying feature, however, could be
a match/mismatch judgment (Ritter and Vaughan
1969, K. Squires et al. 1973a, Posner et al. 1973,
Thatcher 1977) involving comparison with a template
stored in memory. One proposal is that mismatch
involves extra processing time compared to match.
RT is shorter for match than for mismatch judgments,
and Posner et al. (1973) have reported that P300 for
match judgments occurs earlier than P300 for mis-
match judgments. A second proposal is that match
judgments are accompanied by a larger P300 because
the stimulus fits a representation stored in memory.
The fact that P300 amplitude is larger for match than
for mismatch judgments in auditory threshold tasks
(Hillyard et al. 1971) and in semantic tasks (Thatcher
1976) supports this latter proposal.
The problem is that the above match/mismatch
premises do not hold when probability is the variable.
RT results are consistent in that RT is shorter for a
high-probability stimulus (match) than for a low-prob-
ability stimulus (mismatch). However, P300 results
do not flt-P300 components recorded for a high-
probability stimulus (match) in identical tasks are
smaller in amplitude and equal, or even later, in laten-
cy than for a low-probability stimulus (mismatch)
(Tueting 1968, Friedman et al. 1973, Ritter et al.
1968, Ford 1975).
According to orienting response theory, the tem-
plate is inferred to be for a high-probability stimulus
because of its greater frequency and familiarity (Lynn
1966). In an orienting response framework, a low-
probability stimulus is viewed as a mismatch because
it is unexpected, and Ritter and Vaughan (1969) have
proposed that P300 represents additional perceptual
and cognitive processing called in to evaluate the sig-
nificance of.a mismatch. Mismatches in orienting
response theory usually involve low-probability stim-
uli that are also novel. With the exception of Cour-
chesne et al. (1975), however, low-probability stimuli
in EP studies have not necessarily been novel.
In summary, RT results are consistent in that RT
is longer for mismatch, which corresponds to the
hypothesis of longer processing time for a mismatch.
However, there seems to be a paradox for P300 ampli-
tude and latency. For threshold and semantic-meaning
tasks, a match is related to a larger amplitude, ear-
lier latency centroparietal P300. However, for proba-
bility situations, a match is related to smaller ampli-
tude and equivalent (or later) latency P300 (frontal
and parietal).
Donchin proposed that some of the critical ques-
tions concerning match/mismatch theory are "How
do we infer what the template is?" and "Why are some
templates singled out for association with P300 while
others are not?" One way out of the paradox is to
postulate two different match/mismatch processes for
P300, one for probability (frontal P300?) and one for
more complex target-detection tasks (parietal P300?).
In addition, low-probability events are inherently
more significant to the organism than high-probability,
familiar events, even if the task does not specify them
as targets. Some developmental theorists have pro-
posed that infants learn by attending more to events
that are lower in probability and slightly discrepant
(e.g., Kagan 1972). In a certain sense then, low-prob-
ability events are target-like, and it is clear that P300
is elicited by target events. The inference of a template
for low-probability events on the basis of their inher-
ent target-like nature would have the advantage of fit-
ting all of the P300 results into the same match/mis-
match logic. Note, however, that RT results would
not fit the notion of a template for low-probability
stimuli-RT is longer for low-than for high-proba-
bility events.
Because inferring what the template is, or how
many templates there are, may be difficult, as the
above discussion demonstrates, progress may be
made in using experimental designs specifically aimed
at memory search (cf. Roth et al. 1975, Posner et al.
1973, Thatcher 1976, Poonetal. 1976). Roth's design
involves storage of specific templates with subsequent
probing of memory for the template. An analysis of
the relationship between P300 and template match/
mismatch has been made by Ford (this section).
P300 and feedback
Dissociation between P300 latency and RT, the
finding that P300 can occur after the response, and
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168
Tueting
the fact that response-locked averages can attenuate
P300 bring into question the generality of the decision
construct for P300. The decision concept can be
reconstructed, as Donchin has done, if the argument
is made that P300 may not be so much related to
decisions of response selection in the current trial as
to modifications that will be reflected in decisions in
future trials. This view of P300 is supported by the
fact that large PSOOs are obtained to stimuli delivering
feedback concerning guessing outcome or discrimina-
tion-task accuracy, and to low-probability or novel
stimuli requiring no task whatsoever. Response selec-
tion is not required immediately following stimulus
presentation in these situations. However, stimulus
information in these cases may influence future gues-
ses, future judgments, or future reactions to the same
novel or low-probability stimulus. In this conceptual-
ization, stimulus presentation elicits a readjustment
of templates or relative probabilities, reevaluation
of relative costs of subsequent decisions, etc. For
example, Donchin suggested that the sensitivity of
P300 to probability could reflect the greater need for
readjustment following the presentation of a rare
event.
In a guessing task, response selection occurs
before stimulus presentation; therefore, the fact that
a large and reliable P300 is elicited implicates P300
involvement in feedback. Feedback can be inferred
here in terms of its information properties, i.e., the
subject finds out whether his guess was right or
wrong. If he made a high-risk guess, the feedback may
be interpreted differently than if he had made a low-
risk guess (Tueting and Sutton 1973).
In a guessing situation, P300 is larger to sound
after light (crossmodal) than to sound after sound
(ipsimodal), and the same is true for light (Levit et al.
1973, Zubin and Sutton 1970). These results corre-
spond to RT data; crossmodal sequences yield longer
RTs than ipsimodal sequences (Waldbaumetal. 1975).
Pilot data also suggested that P300 amplitude in the
current trial depends upon whether the subject's
guess in the previous trial was right or wrong (Sutton,
unpublished data).
Tueting (1968) and Tueting et al. (1970) reported
that P300 in a guessing task was large for a low-prob-
ability event whether the event was determined in
terms of stimulus probability, sequential probability
(probability of alternation or of repetition), or proba-
bility of the outcome of the subject's guess. These
effects were strongest for correct guess outcomes, and
there was some indication that probability of outcome
was an additional relevant factor. The fact that the
probability effect held for probability of repetition as
well as for probability of alternation and the fact that
the probability effect differed for right and wrong
outcomes indicates that sequential effects for P300
are not a simple function of time separating identical
stimuli in a sequence, and hence are not a result of
recovery or simple habituation. These sequential
effects, however, could be related to cognitive varia-
bles such as the subject's running calculation of absol-
ute and sequential probabilities of events and of the
calculated risks involved in making one guess rather
than another. The right-wrong dimension in the gues-
sing task can be interpreted within a match/mismatch
framework, and templates for probability and analysis
of risk can be inferred to develop in probability
learning tasks (Leifer et al. 1976).
K. Squires et al. (this section) have investigated
sequential P300 effects in a random program of rare
target stimuli and frequent background stimuli. These
effects go back in sequence at least 10 stimuli (or
11.7 sec) when the probability of the target is 10%
and the probability of the background stimulus 90%.
The results indicate that a stimulus elicits a larger
P300 if preceded by more of the same than if preceded
by different stimuli. A similar result has been reported
by Barrett et al. (1975) in a threshold situation.
A more complete discussion of the relationship
of P300 to feedback can be found in Sutton et al.
(this section).
Summary
Conference discussion confirmed the fact that
evoked potentials (EPs) reflect a number of cognitive
variables in a systematic manner. Discussions revolved
around three EP components: Nl, P300, and a nega-
tive component preceding P300. The latter negative
component is similar to P300 in that it too is endog-
enous, but unlike P300, it is modality specific.
Evidence is accumulating that Nl is related to
stimulus set, an early stage of selective attention, in
auditory, visual, and somatosensory modalities. How-
ever, most data have come from studies using auditory
stimuli. The level of attenuation or gating in the
nervous system, whether central or peripheral, and
the amount of attenuation in terms of the complexity
of the information being processed were debated.
One aspect emphasized was the importance of precise
definition of selective attention based on behavioral
measures, preferably obtained on the basis of signal
detection theory.
The relationships of P300 to response set, selec-
tive attention, decision, feedback, expectancy, orient-
ing, uncertainty, etc., were discussed. The focus was
on the proper methods for relating two sources of
data-on one hand, behavioral data on cognition, and
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ERPs and Information Processing
169
on the other hand, EP data. One important behav-
ioral paradigm for measuring the time required for
various mental operations, reaction time (RT), was
discussed at length. Certain methodological issues
arise when comparing RT data to EP data. Conse-
quently, there is considerable difficulty in making
sense of the relationships between RT, P300 latency,
and P300 amplitude that have been obtained to date.
Much theorizing in the area of cognition involves the
notion of a comparison of stimulus input against
stored memory representations. In this context, the
usefulness of the match/mismatch logic for interpret-
ing P300 was assessed, and the difficulty of defining
the template was pointed out.
The negative component preceding P300 received
a great deal of attention. At the present time, data
related to this new component are limited, but dis-
covering where this component fits in human cogni-
tion is an important challenge for future study.
There is considerable data and theory in cogni-
tive psychology that EP researchers could use to
advantage in designing experiments and interpreting
results. EP data may well prove fruitful for an increas-
ed understanding of the area of cognition as well. EPs
may serve to validate inferences made on the basis of
behavioral measures concerning what intervenes
between stimulus input and response output. In any
case, it seems likely that these two areas of investiga-
tion-cognition and evoked potentials-should even-
tually mesh. For the time being, any contradictions
are likely to be particularly fruitful areas of research.
-------
HOW MANY LATE POSITIVE WAVES ARE THERE?'
W. T. ROTH
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine,
Stanford, and Veterans Administration Hospital, Palo Alto, CA, U.S.A.
Three variables define the relatively faceless phe-
nomena to which our research efforts are devoted:
voltage, time, and location. The interactions of volt-
age and time that create peaks with various latencies
and polarities give a name to the topic of this discus-
sion late positive waves (LPWs). This family of waves
has also been called collectively P3 or P300jThe lat-
ter term, which implies a mean latency of 300 msec,
is increasingly less descriptive as later and later LPWs
are reported. If the term LPW is reserved for waves
after P2, a rather flexible minimum latency must be
accepted for LPWs. The P2 component in the auditory
mode has mean latencies that vary at least from 170
to 205 msec, depending in part on task parameters
(Roth et al. 1976a). Visual P2s are later, extending to
around 280 msec. Thus, the earliest LPW, P3a, is some-
times hard to distinguish from P2. The P3 a component
may merge with P2 or it may be as late as 300 msec
(Roth 1973; N, Squires et al. 1975; Snyder and Hill-
yard 1976; Ford et al. 1976). It is seen most clearly
when stimuli are rare and task-irrelevant. The P3b
component usually occurs in the 300- to 400-msec
range for rare task-relevant stimuli. P3b is the stan-
dard P300 described in many earlier papers by Sutton,
Donchin, Tueting, Hillyard, and others. A "positive
missing stimulus potential" appears when stimulus
omissions from a regular ?3imulus train are rare and
when these omissions are targets (e.g., Simson et al.
1976). In the Simson et al. experiment, this wave had
a mean latency of 465 msec for auditory stimuli and
565 msec for visual stimuli. A peak termed "P4" with
a latency of 650 msec has been reported by Picton et
al. (this volume). It was elicited by an auditory feed-
back stimulus that gave information as to the correct-
ness of a choice in a visual concept learning task.
Finally, Courchesne (1976) found that rare task-rele-
vant visual targets that evoked a positive wave at 417
msec in adults, evoked a similar wave with a mean
latency of 702 msec in 5- to 8-year olds. Equally rare
but nontarget stimuli evoked a positive wave with a
mean latency of 448 msec in adults and 982 msec in
the children.
The components listed above can be called "peaks"
since they rise and fall in a few hundred milliseconds.
A late slow positive wave at Pz has been observed to
follow rare task-relevant stimuli. It begins some time
after 300 msec and lasts for more than 1 sec (N.
Squires et al. 1975, K. Squires et al. 1977, N. Squires
et al. 1977). Either CNV resolution or skin potential
artifacts at the reference electrodes can produce pro-
longed shifts, but these are unlikely explanations for
the origin of this slow wave because of its scalp dis-
tribution.
Of the three variables that characterize the phe-
nomena, location has become the most favored in
arguments for the distinctness or unitary nature of
the various LPWs. At least four different anterior-
posterior scalp distributions have been described for
these waves: (1) A predominantly parietal-central dis-
tribution (Fz < Cz < Pz > Oz) is characteristic of
most peaks in the P3b latency range and missing stim-
ulus potentials. (2) A predominantly frontal-central
distribution (Fz = Cz > PZ > Oz) is said to be charac-
teristic of the P3a component, or P3s to task-relevant
stimuli to which no motor response is required (Hill-
yard et al. 1976, Tueting and Sutton 1976), and of
unfamiliar rare task-relevant nontarget visual displays
in adults (Courchesne et al. 1975), or of all rare task-
relevant, nontarget visual displays in children (Cour-
chesne 1976). (3) A parietal-occipital distribution
(Fz < Cz < Pz = Oz) was found for "P4." (4) A distri-
bution in which the polarity differs by lead was found
for the slow wave. This wave is positive at Pz, almost
absent at Cz, and negative at Fz.
If there are four topographic distributions of
LPWs, does it follow that there are four different pro-
cesses? If "process" is considered to be an explanatory
framework that brings order to our observations, the
distinctness of phenomena observed in a particular
experiment cannot be considered sufficient evidence
for the distinctness of the processes underlying them.
preparation of this paper was supported by NIMH Grant DA 00854 and the Veterans Administration.
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How Many Late Positive Waves?
171
Although there is an inherent ambiguity in grouping
things as "like" and "unlike," an ambiguity similar to
that of defining figure and ground for a pattern recog-
nizer, certain guidelines are implictly followed in
classify ing evoked potential phenomena. First, distinct
processes should be represented by phenomena that
can be varied independently. Statistical procedures
such as principal component analysis are of value here,
but there are many pitfalls in determining the inde-
pendence of phenomena. Some of these pitfalls are
discussed by Weiskrantz (1968) in his critique of the
concept of "double dissociation." Suffice it to say
that processes related to each other in a hierarchical
manner may appear to be dependent until just the
right experimental manipulation is discovered. Second,
processes are often thought of as distinct only if they
are discontinuous and intermediate processes are never
encountered. Whatever combination of voltage, time,
and location define the two processes, phenomena
should not fall into a continuous spectrum between
the two definitions.
The criterion of discontinuity for distinctness can
be made clearer by reference to a few examples. If
four different auditory stimulus intensities resulted in
four significantly different Nl amplitudes, no one
would be misled into thinking that this was evidence
that four different processes were operating, since Nl
is known to be a continuous variable related to sensa-
tion level by a reasonably simple monotonic function.
Thus, the four distinct amplitudes only represented
the experimental parameters chosen. Or if LPWs of
four distinct latencies were created, principal com-
ponent analysis might yield four orthogonal compon-
ents. It might even be possible to vary the amplitudes
independently from the latencies. Yet, since available
data suggest that latency is a continuous function of
speed of stimulus evaluation, latency differences are
not considered sure-fire evidence for distinct proces-
ses. For example, Kutas and Donchin (this section)
found that LPW latency varied more than 200 msec,
depending on how visually displayed words were to
be evaluated. More complex evaluations that took
more time, such as deciding whether one word was
synonymous with another, resulted in later LPWs
than simpler evaluations, such as identifying a fixed
target word. Similarly, target stimuli that are more
easily discriminable give shorter latency LPWs than
less discriminable targets (N. Squires et al. 1977).
Children probably take longer than adults to process
stimuli, which could explain some of the longer laten-
cy LPWs for children found by Courchesne (1976).
Even if age has an independent effect on LPW latency,
it is likely to act continuously in that older children
would have latencies intermediate between those of
younger children and adults. The realization that
LPW latency is a continuous variable makes it easy to
accept the conclusion of N. Squires et al. (this section)
that P3bs elicited by rare target stimuli of various
intensities and by the omission of stimuli in a train
are part of the same process or "functionally equiv-
alent." These two LPWs have the same scalp distribu-
tions, are affected in the same way by manipulations
of probability, and show discrepancies in amplitude
and latency that could be explained on the basis of a
continuous variable such as amount of time jitter or
latency of recognition.
P3a presents more difficult detection and classifica-
tion problems. It would be convenient if P3a were
simply a very early LPW consistently elicited when
stimulus-processing demands are minimal. Unfortu-
nately, LPW latency is not always shorter when sub-
jects are told to ignore stimuli or given a reading task
(Roth et al. 1976b; and this section). K. Squires et al.
(in press) had difficulty finding P3a in a replication of
N. Squires et al. (1975). K. Squires et al. (in press)
did find a factor that had peak loadings in the 250
msec range, but it accounted for only 2.6% of the
variance and the factor scores were not consistently
related to experimental variables. However, in spite of
ah1 these difficulties in specifying the exact circum-
stances under which positive waves with latencies
between 200 and 300 msec can be produced, it is
impossible to disregard the evidence that such peaks
exist.
Evidence for the distinctness of P3a and P3b de-
rives primarily from the different topographic distri-
butions of the two components. This raises a question
of the validity of topographical differences as criteria
for establishing the distinctness of a process.2 There
is no logical priority for topographic distribution over
amplitude and latency as a criterion of distinctness.
The power of distribution as an argument for essential
differences comes from the concreteness of being able
to imagine generators at spatially distinct locations in
the brain. In fact, different amplitudes and different
latencies, even without different .scalp distributions,
may also be produced by different physical generators
in the sense of different pathways and different selec-
tions of single units. However, these mechanisms are
so poorly understood that they are not even a topic
of speculation in the LPW literature. Just as differen-
ces in amplitude or latency do not necessarily imply
different processes, neither do different distributions
and different generators. Take, for example, the
experiment of Kutas and Donchin (1974) in which
the readiness potentials of right-handed subjects were
larger over the hemisphere contralateral to the respon-
ding hand. Two distinct distributions occurred, each
undoubtedly produced by spatially separated neural
masses. The authors, however, never claimed that
they had fractionated the readiness potential into two
*See the Scalp Distribution section of this volume for an extended discussion of related issues.
-------
172
Roth
distinct processes, RPr and RP1, because the mapping
of motor ar. J sensory processes on the cortex relates
asymmetry and task parameters in a fairly simple
manner. The relationship is not completely continuous
given the neuroanatomy of the cortex, although inter-
mediate distributions might be obtained if the sub-
jects pressed foot pedals. That is, the unity of a proc-
ess may depend on structural and developmental
considerations rather than the continuity of mathe-
matical descriptors.
Similarly, a unitary LPW process that changes
smoothly in latency and distribution depending on
stimulus at processing time might be hypothesized.
For instance, P3a and P3b could simply represent two
samples of this function at different points in time.
At early latencies, the process would be more frontal,
and at later latencies, more parietal. Thus, latency
and distribution would be dependent. Unfortunately,
there is insufficient evidence to claim continuity.
Ford et al. (1976) did find distributions intermedi-
ate between P3a and P3b in an experiment where an
attention variable had three levels. These results would
have been more convincing if the amplitude of P3a
had been larger. The flat anterior-posterior distribution
obtained when attention was not directed to the stim-
uli may have been a floor effect related to the effect
of noise on their measurement method. They located
peaks as the maximum or minimum voltage in a speci-
fied latency range and, as the signal-to-noise ratio de-
clined, noise peaks rather than signal peaks may have
been detected. Thus, the peaks located would never
be smaller than the "floor" of fluctuations produced
by the noise.
Also damaging to the hypothesis of a single genera-
tor for P3a and P3b is the fact that, even within a
single experiment, latency and distribution may be
independent. Courchesne et al. (1975) reported the
same latencies for LPWs with a frontal distribution
elicited by complex visual displays and for LPWs with
a parietal distribution elicited by simple visual displays
(digits). However, these results do not justify postal-
lating two distinct processes. Instead, these results
suggest that experiments could be devised to test the
distributional continuity of LPWs by varying stimu-
lus familiarity. If a parameter were discovered that
controlled LPW distribution continuously, a good
cue could be made for considering LPWs part of a
single process.
Another type of implicit evidence for the distinct-
ness of processes is the presence of visually distinct
peaks in an evoked potential tracing. However, P3a
and P3b are so close together, and P3a is so close to
P2, that visual separation is not convincing. Even if
two peaks were discontinuous in latency (i.e., never
overlapping), multiple peaks could represent a single
process that requires the repetition of a mental oper-
ation or a single process that yields multiple peaks
because of its specific neuroanatomy (e.g., multiple
parallel pathways). In these cases, principal compon-
ent analysis would be helpful.
Even peaks that differ in both latency and distri-
bution could represent the same process. This may be
the case for theP4 wave of Picton et al. (this volume),
which appears in their Fig. 5 to occur in the same
tracing as an earlier P3. Both peaks are affected iden-
tically by the experimental variables. The authors
conclude that "this distinction" (i.e., latency and
scalp distribution differences) "makes it possible to
hypothesize that the two waves reflect separate pay-
chophysiological processes, possibly the appreciation
of feedback information (P3) and its utilization in
conceptual learning (P4)." Based on the available evi-
dence, the authors' conclusions seem to be unwar-
ranted. The peaks are highly correlated in appearance.
The most logical argument would be for the authors
to contrast their findings with those of the many
other studies that have reported P3s without P4s. At
best, this would open the possibility that the two
peaks represent separate processes.
In general, the case for multiple LPW processes is
unproven. More data are needed, particularly on the
experimental parameters that affect late wave distri-
bution. If other ERP processes play an interactive
role, such processes may not be positive onw-i.e.,
interactions of slow negative processes with LPWs
may change LPW distributions as well as latencies.
For example, N. Squires et al. (in press) observed a
0.7S correlation between distributional differences in
P300 amplitude and slow wave size, and a correlation
of 0.86 between latency differences and slow wave
size. Other negative phenomena have been reported
by Loveless and Sanford (1974), Rohrbaugh et al.
(1976), and Roth et al. (1976a). Rohrbaugh et al.
described a frontal negativity that increased over time,
a finding that could explain the observation by
Courchesne et al. (1975) of LPWs that initially show-
ed a frontal distribution, but shifted in a posterior
direction across trials. The nature of these negative
processes and their interactions with LPWs remain to
be clarified.
-------
LATENCY OF EVENT-RELATED POTENTIALS
AND REACTION TIME
W. RITTER
Lehman College, City University of New York, New York, NY, U.S.A.
Of the various event-related potentials (ERPs)
elicited by target stimuli in reaction time (RT) experi-
ments, the P3 component (hereafter assumed to have
a parietal maximum) is the only one previously known
to have a range in latency great enough to be related
in time to RT. Depending on the experimental con-
dition, the peak latency of P3 based on averaged ERPs
has been found to vary anywhere from 250 to 600
msec. The range in latency for single-trial P3s for an
individual subject within a single condition can be as
great as 300 msec (Ritter et al. 1972). The large varia-
bility in P3 latency both within and across conditions
is consistent with most theories concerning the func-
tional significance of physiological activity underlying
P3, such as information delivery, target selection,
decision-making, sensory discrimination, and match-
mismatch processes. (For review, see the summary of
preconference correspondence, this section.) In
addition, these theories tacitly or explicitly presume a
correlation between P3 latency and RT. As Hillyard
pointed out in preconference correspondence, some
studies have found a correlation (e.g., Ritter et al.
1972, Picton et al. 1974), while others have not(e.g.,
Karlin et al. 1970, Karlin and Martz 1973). Kutas
and Donchin (this section) have shown the correla-
tion between P3 latency and RT is affected by the
trade-off between speed and accuracy of response,
a finding which may account for some of the dis-
crepant results.
There is a more serious problem for most of the
theories of P3 function than whether or not the
latency of P3 correlates with RT. Ritter et al. (1972)
concluded that P3 onset could occur early enough to
be causally related to RT. That conclusion was based
on estimated average delays for each subject between
P3 onset and the initiation of motor activity in motor
cortex. For one subject (WR), the estimated average
delay was 20 msec; for other subjects, it was longer.
It therefore appeared possible forP3 onset to precede
motor activity, though it was suggested that the N2
component, which peaks about 100msec earlier than
P3, may reflect a significant factor in the timing of
RT. In retrospect, it appears likely that a large pro-
portion of motor responses must have begun be-
fore the onset of P3. Otherwise, the distribution of
delays between P3 onset and the initiation of motor
activity on single trials would have been surprisingly
small in variability (an unlikely possibility since the
correlations between P3 and RT latencies were
generally in the 0.70s or were quite skewed). There
is certainly no justification in hypothesizing that P3
reflects such processes if subjects can make discrim-
inative motor responses prior to P3.
Several investigators have recognized that P3
occurs too late to reflect the processes usually attrib-
uted to it and have accordingly suggested that P3
reflects sequalae to task-related decisions and respon-
ses, such as registration of pertinent information in
memory, resetting of perceptual analyzers, or other
processes associated with preparation for future trials
(Donchin et al. 1973, Picton and Hillyard, 1974).
Since P3 apparently occurs too late to reflect target
selection or information delivery, we turned our at-
tention to N2, a component that occurs early enough
in time to be causally related to motor responses,
appears to be elicited in the same kinds of situations
that elicit P3, and, like P3, is endogenous in nature.
There seem to be two reasons for the late arrival
of N2 on the ERP scene. First, N2 is smaller in ampli-
tude than P3 and is often obscured by P2 because of
overlapping latencies of the two components. Second,
since N2 is smaller in amplitude than P3, less variabil-
ity in latency from trial to trial is required for N2 to
be observed in averaged ERPs. Klinke et al. (1968)
resolved both of these difficulties with one stroke by
randomly omitting stimuli in a train of stimuli deliver-
ed at a steady, fast rate. The omitted stimuli elicited
clear N2 and P3 components. The use of a steady,
fast rate of stimulation presumably permitted subjects
to develop internal rhythms that produced excellent
time-locking of N2 to stimulus omissions. The circum-
stance that P2 (an exogenous potential) is not elicited
by omitted stimuli prevented P2 from obscuring N2.
Two reports support the time-locking explana-
tion. Picton et al. (1974) found that increasing the
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174
Ritter
interstimulus interval in a train of stimuli which con-
tains randomly omitted stimuli resulted in smaller
and eventually unobservable N2 components associat-
ed with stimulus omissions. (A similar result occurred
for P3, but it could still be observed at the longest
interstimulus interval used because of its greater
amplitude.) Ruchkin and Sutton (in press) have con-
cluded that the failure to observe N2 for omitted
stimuli that elicited P3 in Sutton et al. (1967) was
due, at least in part, to the degree of trial-to-trial varia-
bility in the latency of N2.
Although the Klinke et al. report appeared in
1968, P3 continued to hold center stage in theories
concerning target selection and related processes, pre-
sumably because it was not clear that P3 latency was
too long to reflect those processes. When the impor-
tance of N2 became clear because of RT data, it was
hypothesized that N2 and P3 were both components
of a complex waveform emanating from the same
brain tissue. Topographic analyses of ERP associated
with omitted stimuli (Simpson et al. 1976), however,
showed that N2 and P3 had different intracranial
sources. Furthermore, N2 was modality-specific in
its distribution, whereas P3 was not.
Similar results were obtained in a vigilance experi-
ment in which the targets consisted of random changes
in physical parameters (Simson et al. 1977). The
modality specificity of N2 suggested that different
neural ensembles accomplish auditory and visual dis-
criminations. The circumstance that N2 preceded P3
in latency for ERPs elicited by stimulus omission
indicated that N2 reflected the detection of omitted
stimuli and P3 some other process. Results of the vigil-
ance study suggested that N2 reflected target selection
whether the target was an omitted stimulus or a
change in parameter of a physically present stimulus.
These results are detailed elsewhere (Ritter, this
volume).
As pointed out earlier P3 is the only component
with a range in latency hitherto known to be great
enough to be related to RT. If N2 reflects target selec-
tion or related processes, then N2 latency should vary
as a function of the difficulty of target selection and
correlate with RT. Recently completed data analysis
supports that conclusion (Ritter et al,, in preparation).
Reanalysis of the data of Ritter et al. (1972) indicates
that, in single-trial measurements of N2 elicited by
the targets of the vigilance task, the mean latency of
N2 increased across conditions as a function of the
difficulty of the discrimination of the targets within
conditions. Furthermore, the single-trial analysis yield-
ed somewhat greater product-moment correlations
within conditions between N2 and RT than was pre-
viously found between P3 and RT.
On the basis of these considerations, it seems
appropriate to propose that the earlier hypotheses
relating P3 to information delivery, target selection,
and related processes be shifted from P3 to N2. In
this case, the only relevant hypotheses concerning the
functional significance of the physiological activity
underlying P3 would be those associated with prepar-
ation for future events. Since there are no published
studies of these alternative possibilities, there is a
clear need for experiments that examine new hypo-
theses concerning the functional significance of P3.
Hillyard (personal communication) has raised the
possibility that, although P3 is too late to directly
reflect target selection, it might nevertheless indirectly
reflect selection by virtue of a delay between critical
neural activity and the manifestation of P3 at the
scalp. Somjen (this volume) indeed mentions the
possibility that some late components could be due
to glial potentials (with a delay of as much as 100
msec between neural activity and the detection of a
glial potential at the scalp), Thus, Hillyard (personal
communication) points out: "Suppose, for instance,
that the P3 was generated by the depolarization of
glial cells consequent upon the release of K + ions by
the active neurons which do the selecting. The delay
between the neural activity and its direct glial 'reflec-
tion' could account for the delay of P3 re the selective
response."
Although this possibility must be considered, it
opens a Pandora's box. At present neural and glial
potentials at the scalp cannot be distinguished, except
for early potentials with a latency presumably too
short to reflect glial potentials. The sequence with
which the neural activity associated with various late
potentials would thus be unknown. Imagine, for
example, that either P2 or N2 (or both) reflect neural
activity directly and P3 reflects glial potentials gener-
ated by neural activity that precedes the neural activi-
ty of either P2 or N2 (or both). Some glial potentials
might be associated with a delay of 50 msec and
others with 100 msec or values in between. Thus, the
neural activity of P2, N2, and P3 could occur in any
sequence imaginable, including the possibility of their
simultaneous occurrence. In view o f the havoc these
possibilities entail, and the variety of post hoc specula-
tions open to the whim of a given investigator's theo-
retical inclinations, the following is suggested: until it
is established empirically that scalp-recorded ERP
components can reflect glial potentials, all ERP com-
ponents (with the possible exception of dc potentials)
should be considered to be directly related to neural
activity and, therefore, the latency of a component
should indicate the time of occurrence of the neural
events that produce that component. These assump-
tions appear to provide the most parsimonious frame-
work currently available for the interpretation of
ERPs.
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EQUIVOCATION AND P300 AMPLITUDE
D. S. RUCHKIN
Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD, U.S.A.
S. SUTTON
Department of Psychophysiology, New York State Psychiatric Institute, New York, NY, U.S.A.
The purpose of this paper is to briefly review
evidence for the concept that the information received
by a subject from the occurrence of an event deter-
mines, in part, the amplitude of the P300 component
elicited by the event. We do not mean to imply, how-
ever, that other variables are not also relevant in deter-
mining P300 amplitude or that the P300 wave is a
unitary phenomenon.
Review
In the framework of classical information theory
(Shannon and Weaver 1949), the amount of informa-
tion provided by an event is related to the subject's
a priori uncertainty of the event's occurrence; the
lower the a priori probability of occurrence, the great-
er the information provided. However, the amount of
information received by the subject equals the infor-
mation provided by the event minus an information
loss related to the subject's a posteriori uncertainty of
having correctly perceived the event; the greater the
a posteriori uncertainty, the greater the information
loss. In information theory terms, this loss is referred
to as equivocation.
The role of a priori event probability was explicit-
ly recognized in the initial investigations of P300
(Sutton et al. 1965). Sutton et al., Tueting et al.
(1970), Friedman et al. 1973), and Ruchkin et al.
(1975) have used a paradigm in which the subject
guessed what the ensuing stimulus would be. When
stimulus probability was manipulated, P300 amplitude
varied inversely with the joint probabilities of the
stimulus and guess (outcome probability). Donchin et
al. (1973) modified this procedure by varying the
complexity of the sequence in which stimuli were
presented. P300s were smallest when simple, easily
predictable sequences were used and became progres-
sively larger as the sequences became more complex
and thereby more difficult to predict. Karlin and
Martz (1973) investigated the P300 component in
choice-reaction time and delayed-choice paradigms.
They reported that stimulus and response probability
jointly influenced P300 amplitude, with the least
probable combination eliciting the largest P300. Paul
and Sutton (1972) and Squires et al. (1975b) varied
the probability of occurrence of the signal in auditory
signal detection experiments. The P300 elicited by
detected signals was largest when signal probability
was lowest.
Squires et al. (1973) used a paradigm in which
the subject performed an auditory intensity discrimi-
nation. In each trial, the subject indicated the degree
of confidence in his decision. This was followed by a
visual stimulus that gave feedback on accuracy. It was
found that when the stimulus confirmed a high-confi-
dence decision, P300 was smallest. When the stimulus
discontinued a high-confidence decision, P300 was
largest.
A common element of the experiments described
above is that the stimulus provided information that
resolved the subject's uncertainty with respect to a
prior expectation. As the subject's estimate of the a
priori probability of the occurrence of an event de-
creased, the amplitude of the P300 elicited by that
event increased. To the extent that the information
content of an event may be viewed as being inversely
proportional to its a priori probability, the amplitude
of P300 can be interpreted as reflecting, in part, the
amount of information provided by the event.
There also have been several reports of the effect
upon P300 amplitude of the subject's a posteriori
uncertainty of perception. Mast and Watson (1968),
Hillyard et al. (1971), Paul and Sutton (1972), and
Squires et al. (1975b) have investigated the behavior
of P300s elicited by auditory stimuli near sensory
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176
Ruchkin and Sutton
threshold. Mast and Watson utilized a signal-counting
procedure. Their results suggested that P300 ampli-
tude was related to the subject's criterion for detect-
ing presence of a signal. Hillyard et al, Paul and
Sutton, and Squires et al. utilized standard signal-de-
tection paradigms (Green and Swets 1966). Hillyard
et al. (1971) investigated the relationship between
discriminability (d;) and P300 amplitude. They re-
ported that P300 increased as discriminability in-
creased, up to a level of about 90% correct responses.
Paul and Sutton (1972) used a fixed stimulus inten-
sity and varied the subject's criterion by manipulating
pay-off contingencies. P300 amplitude elicited by
correct detections increased as the criterion became
more strict. Squires et al. (1975b) also used a fixed
stimulus intensity. Their subjects responded with a
numeric confidence rating. P300 amplitude was
largest when the subject was most confident of his
decision.
The common finding of these investigations is
that P300 amplitude increased as the subjects were
more certain of their perceptions and hence the infor-
mation loss due to equivocation was less. Hillyard et
al. demonstrated this by direct variation of discrimina-
bility of the stimulus, while Paul and Sutton in effect
varied the degree of certainty required of the subjects,
and Squires et al. segregated the data into different
levels of certainty. Donchin (1968) reported similar
findings in a visual perception experiment involving
threshold flashes. P300s were large when the subjects
were certain of their judgments and small when the
subjects were uncertain.
Further evidence for the role of equivocation in
determination of P300 amplitudes is provided by dis-
crimination experiments reported by Ritter et al.
(1972), Adams and Benson (1973), Lang et al. (1975),
and Ford et al. (1976). Ritter et al. investigated the
relationship between P300 latency, reaction time, and
auditory pitch discrimination in a go-no go paradigm.
Two conditions were used. In one, the discrimination
was relatively easy; in the other, it was difficult.
While the authors did not specifically report the effect
of discrimination difficulty upon P300 amplitude,
inspection of their published waveforms indicates that
P300 amplitude was lower when the discrimination
was more difficult. Langet al. (1975) instructed sub-
jects to rank five different equi-intensity tones. The
tones, presented individually, were 700, 1000, 1100,
1200, and 1500 Hz. There were relatively few errors
for the 700- and 1500-Hz tones, while errors were
relatively numerous for the 1000-, 1100-, and 1200-Hz
tones. Peak-to-peak amplitude from NlOO to P300
was significantly larger for easily ranked tones than
for tones that were difficult to rank.
Adams and Benson (1973) used a relatively high-
intensity (30 dB SL) auditory stimulus to signal cor-
rect performance of a difficult psychophysical task.
Incorrect performance was indicated by presentation
of a lower intensity stimulus. Objective intensity con-
trast between the two alternative stimuli was manip-
ulated by varying the intensity of the stimulus that
indicated incorrect performance (from 0 to 24 dB).
As the contrast was reduced, amplitude of the P300
elicited by the fixed-intensity stimulus was reduced,
although the stimulus provided the same a priori infor-
mation. Increased equivocation as stimulus contrast
decreased is a parsimonious explanation of this find-
ing. However, Adams and Benson did comment that
subjects were able to readily distinguish between the
two stimuli, although the investigators did not deter-
mine whether there were any objective differences in
the ease with which the distinction could be made.
The fact that the subjects apparently readily distin-
guished between two stimuli does not necessarily
vitiate the equivocation argument.
Thurmond and Alluisi (1963) demonstrated, in a
choice-reaction time experiment, that as dissimilarity
between two signals was reduced, reaction time in-
creased, even though discriminability remained high.
This indicates that although a relatively small degree
of equivocation may not significantly interfere with
the ultimate accuracy of a decision, it will delay it,
due to increased difficulty in processing the signal.
Ford et al. (1976) have provided further support
for this interpretation. They presented subjects with a
sequence of tone pips at a fixed loudness level and
frequency. Occasional mismatch tone pips were pre-
sented on a random basis, there being three levels of
frequency mismatch: (1) a 5% frequency shift (2) a
25% shift, (3) an octave shift. Subjects were required
to respond to the mismatch tones with a button press.
P300s elicited by the mismatch tones increased in
amplitude and reaction time decreased as the degree
of mismatch increased, despite the fact that subjects
responded correctly to 89% of the 5%-frequency-
shift trials and to 96% of both the 25%-shift and
octave-shift trials. Ford et al.'s results provide a fur-
ther demonstration of the effect of equivocation
upon P300 amplitude. Their results also directly
demonstrate that P300 amplitude may reflect the
degree of difficulty in reaching a decision rather than
the final accuracy of the decision-making process, as
indicated by the accuracy (which did not vary), reac-
tion time (which increased), and P300 amplitude
(which decreased) for the octave and 25%-shift con-
ditions.
Reduction in average P300 amplitude with in-
creased equivocation may be due to a direct decrease
in amplitudes in individual trials and/or to increased
latency variation of P300 in individual trials. The lat-
ter possibility seems particularly likely if one assumes
that equivocation leads to variability in decision time
and that P300 latency is linked to the time at which a
decision is made.
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Equivocation and P300 Amplitude
177
An opportunity to examine these alternatives
was afforded by investigations of the emitted poten-
tial. An emitted P300 may be elicited by the non-
occurrence of a relevant stimulus that may or may
not occur at a given point in time. Emitted P300s
have been observed in guessing experiments (Sutton
et al. 1967, Ruchkin and Sutton 1973) and some
signal detection experiments (Squires et al, 197Sb),
Average emitted P300s in guessing experiments
are smaller than corresponding evoked P300s elicited
by stimulus occurrences. Ruchkin and Sutton (in
press) demonstrated that the lower average amplitude
was due partly to increased latency variation of emit-
ted PSOOs and partly to a direct amplitude difference.
The direct amplitude decrement as well as the in-
creased latency variability may be due to temporal
uncertainty and hence increased equivocation asso-
ciated with identification of the nonoccurrence of a
stimulus, There have been several reports of the occur-
rence of clear evoked P300s in correct detection trials
of signal-detection experiments, but the evidence for
the occurrence of emitted P300s in signal-absent trials
is more limited. Hillyard et al. (1971) and Paul and
Sutton (1972) were unable to observe emitted P300s.
Squires et al. (1975b) reduced temporal uncertainty
through the use of a cue light and sorted their data
into high and low decision-confidence trials. They
observed emitted PSOOs in high-confidence correct
rejection and false-alarm trials. They further demon-
strated that emitted P300 amplitude in correct rejec-
tion trials increased as stimulus intensity increased.
Squires et al.'s results suggest that latency variations
may in part contribute to the lower amplitudes of
average emitted P300s. However, the effect of de-
cision confidence and stimulus intensity upon emit-
ted potentials in signal-absent trials suggests that
equivocation also has a direct effect upon P300
amplitude.
The results of the investigations cited in this paper
can be most parsimoniously described as follows:
P300 amplitude is in part determined by the total
amount of information received, i.e., the greater the
reduction in uncertainty, the greater the P300. P300
can vary as a function of information received in two
ways: (1) for a fixed level of prior uncertainty, P300
amplitude will be determined by equivocation-de-
creasing as equivocation increases; (2) for a fixed level
of stimulus equivocation, P300 amplitude will be
determined by prior uncertainty-increasing as uncer-
tainty increases. The latter relationship is subject to
the provision that equivocation is not so large that
a priori probability effects are "swamped" by the
high degree of a posteriori uncertainty (Squires et al.,
1975 b). What seems to be at issue in the former
relationship is not necessarily outright discriminability
or correctness, but the immediacy and ease with
which a decision can be made. This suggests that
P300 amplitude may reflect processes involved in the
early stages of decision making rather than the final,
conscious step.
Summary
Evidence for the concept that the amount of
information received by a subject from the occurrence
of an event determines, in part, the amplitude of
P300 is reviewed. The amount of information received
depends upon the a priori uncertainty of the event's
occurrence minus an information loss, refe&ed to as
equivocation, due to the a posteriori uncertainty of
having correctly perceived the event. Support for this
concept is provided by the results of experiments in
which either or both a priori probability and equivo-
cation were variables.
Acknowledgments
This work was supported in part by U.S. Public
Health Service Grant NS11199 to D. S. Ruchkin and
U.S. Public Health Service Grant MH14580 to S.
Sutton. We thank Dr. E. M. Glaser of the University
of Maryland for his criticism and advice.
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THE LATE POSITIVE COMPONENT AND
ORIENTING BEHAVIOR
D. FRIEDMAN
New York Psychiatric Institute, Department of Medical Genetics, New York, NY, U.S.A.
Review
The concept of orienting is an old one, dating
back to the work of Pavlov, who noted (at first, in
annoyance) that his experimental animals directed
their attention to any novel or unusual stimulus in
the experimental chamber. He thus termed it the
"investigatory" or "what is it?" response. The orient-
ing response consists of a series of physiological chang-
es including heart-rate deceleration (Graham and
Clifton 1966), pupillary dilation (Shakhnovich 1965),
increments in galvanic skin response (GSR) (Lovibond
1969) and EEC desynchronization (Lynn 1966). It
has been shown to be elicited by such stimulus charac-
teristics as novelty and uncertainty (see Lynn 1966),
some of which have also been shown to influence the
ubiquitious P300 wave. The orienting response has
received much experimental attention with the use of
electrodermal variables, heart rate, and pupillary dila-
tion, but it is only within the last decade that the late
positive component has been added to the list of
"components of the orienting response."
Ritter et al. (1968) were the first to use the classi-
cal orienting response paradigm to elicit averaged
evoked-potential components of this response. They
presented a series of 1000-Hz tones at 2-sec intervals.
There were 30 stimuli per run and 24 runs. In order
to look at habituation within the stimulus train, Ritter
et al. averaged by stimulus position within the train,
across the 24 runs. A substantial decrement in P200
was observed as a function of stimulus position, but
in a second experiment where stimulus presentation
was changed to one every 10 sec, no decrement in
P200 was seen, so that refractoriness (Davis et al.
1966) and not habituation seemed to be the cause of
the decrement. In a third experiment, 1000-Hz
tones, one every 2 sec, were delivered with a pitch
change to 2000 Hz at the 21st stimulus. Stimulus
position averaging revealed a short-term decrement in
P200, but the pitch change did not restore the ampli-
tude of P200. The change in stimulus quality produced
a change in the evoked-potential waveform, with a
parietal-maximum, late positive component at 350
msec. In a fourth experiment, the paradigm was
changed to include the unpredictable onset of a run
(temporal uncertainty) and an unpredictable pitch
change within a run. Both of these unpredictable
changes produced parietal-maximum late positive
components at 350 msec. Thus, Ritter et al. (1968)
demonstrated that P300s were elicited in situations
identical to those used to elicit autonomic compon-
ents of the orienting response.
Support for P300 as a component of the orienting
response could be strengthened by concomitant
recording of autonomic measures. Evidence from a
variety of laboratories had indicated that heart rate
(Higgins 1969), GSR (Lovibond 1969), and pupillary
dilation (Levine and Hakerem 1969) were similarly
affected by manipulations of stimulus uncertainty,
one of the early postulated psychological correlates
of P300. Tueting et al. (1970) had shown that P300
varied markedly in amplitude with changes in stimulus
probability in an uncertainty paradigm. We (Friedman
et al. 1973) followed these lines of evidence by
recording both evoked potentials and pupillary dila-
tions in a modification of the Tueting et al. (1970)
probability paradigm. Pupillary dilation is easily time-
locked, with an approximate 1-sec latency to peak
and, when averaged, can be distinguished from noise
with approximately the same N as P300 (Hakerem
1967). We found that pupillary dilation followed the
same lawful relationship to probability of occurrence
as did P300: the lower the probability, the larger the
amplitude of dilation. In addition, a component of
the dilation response, prestimulus slope, followed a
similar time course and was closely related to CNV
amplitude, tending toward dilation when subjects
were guessing upcoming events (CNVs were more
negative) and toward constriction (CNVs were less
negative and some were positive) when they were
told which stimulus would occur next (Friedman
1972). This paradigm was not the traditional "ori-
enting" paradigm. In informational terms, however,
both P300 and pupillary dilation were larger in am-
plitude when an infrequent event reduced uncer-
tainty. The concept of uncertainty reduction has
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Late Positive Components and Orienting
179
been used before within an orienting framework
(Pribram 1967,Sokolow 1960).
Roth et al. (this section) recorded GSR and evok-
ed potentials in an orienting response paradigm where
chords unpredictably and continuously (unlike the
Ritter et al. 1968 paradigm) replaced background
noise bursts. They used GSR as a criterion measure
for sorting PSOOs to the chords into high- and low-
amplitude averages. During attend conditions (respond
to the change), GSR and P300 showed similar ampli-
tude changes. During read (i.e., ignore) conditions,
there was a dissociation of the two measure, with
small-amplitude PSOOs associated with large-amplitude
GSRs. Roth et al. (1976) speculated that direction of
attention affected P300 and GSR differently, with a
larger GSR orienting response when attention is not
directed towards the stimulus train. This result holds
only for the "read" condition.
In both the Tueting et al. (1970) and Friedman
et al. (1973) "certain" conditions (subjects told what
stimulus to expect), P300 amplitude was still a mono-
tonic function of stimulus probability even though
stimuli were "task-irrelevant." Roth (1973) and Roth
and Kopell (1973) also demonstrated that infrequent,
task-irrelevant stimuli produced reliable P300s, but in
the case of Roth's investigation (1973), P300s were
of much earlier latency (mean of 210 msec) than pre-
viously reported. In further support of this "early
P300" as an orienting potential, these investigators
found a decrement in amplitude across quarters of
the experimental run. Response decrement is to be
expected as the novelty of a repeated change in stim-
ulation diminishes. Habituation of the orienting
response with repetition is one of the key postulates
of orienting response theorists (Lynn 1966).
Theoretically, an orienting response is expected
whenever background stimulation (to which subjects
are assumed to habituate) is changed in any manner-
hence, the use of prolonged runs of standard stimuli
with infrequent changes. The finding that P300s were
present for task-irrelevant, nonattended stimuli (Ritter
et al. 1968, Roth 1973) as well as for attended, task-
relevant stimuli (Ritter et al. 1972) poses a problem
for any unified theoretical interpretation of the P300
wave. On the other hand, if there are two P300s, one
elicited when variables that produce orienting are
used and the other when task-relevance is the key
feature of the experimental design, then interpretation
is easier.
Squires etal. (1975)distinguished the "orienting"
from the "attend" P300 by both latency and scalp
topography. They utilized a paradigm in which sub-
jects either attended or ignored infrequent background
stimuli and infrequent intensity or pitch changes.
During the attend condition, subjects counted changes
and during the ignore condition, they read. The ignore
condition produced P300s only to the lowest proba-
bility stimuli (p = 0.10). This P300 varied in latency
from 220 to 280 msec (similar to that of Roth 1973),
and had a frontocentral topographic distribution.
When subjects attended, this "P3a" wave was present
but was overridden by a later (310-380 msec), more
posteriorly distributed "P3b" wave. Squires et al.
(1975) concluded that the presence of the "P3a"
wave reflected a "mismatch to an ongoing stimulus
train, whether or not it is being attended" (p. 399).
This conclusion is in accord with Sokolov's (1960)
theoretical model, which postulates that any changes
in background stimulus conditions leads to a mismatch
with the neuronal model and results in an orienting
response.
Courchesne et al. (1975) studied the influence of
novelty on the late positive component of the visual
evoked potential, using easily recognizable and com-
pletely unrecognizable novel stimuli. Novel stimuli
were interspersed (each with 5% probability of occur-
rence) among frequent nontarget stimuli (the number
2) and infrequent task-relevant target stimuli (the
number 4). The subject had to count the target stim-
uli, which occurred with 10% probability. Evoked
potentials for the counted 4s and the task-irrelevant,
completely unrecognizable novel stimuli contained
late positive components that differed in scalp top-
ography, but not in latency. Novel stimuli produced
a more anteriorly oriented distribution, while the
counted 4s produced a more posterior scalp topog-
raphy. When evoked potentials elicited by the first,
second, and third presentations of these novel stimuli
were averaged separately, there was a large decrement
(50% for the second stimulus) in P300 amplitude,
thus demonstrating habituation of the response and
supporting an "orienting" interpretation of this front-
ally distributed wave.
The more frontal distribution of the potential for
novel visual stimuli reported by Courchesne et al.
(1975) supports the data of Squires et al. (1975) for
the auditory modality, but differences in latency and
task mitigate against an association between the audi-
tory "P3a" wave and the late P3 to novel visual stim-
uli. It is possible, however, that the two waves are
part of the same orienting potential, but differ in
latency and amplitude, depending upon stimuli and
task conditions. This latter possibility may well be in
accord with another of Sokolov's postulates that the
amplitude of the response varies with the degree of
mismatch from the neuronal model. For example,
Sokolovian theory would predict a larger amplitude
response to a more novel visual stimulus (Courchesne
et al. 1975) than to a less novel pitch change (Squires
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180
Friedman
et al. 1975). Comparision of these two studies, in fact,
confirms this prediction: PSOOs to unrecognizable
novel stimuli (Courchesne et al.) were larger in ampli-
tude than PSOOs to easily recognizable novel stimuli
(Squires et al.).
This latter postulate was directly tested by Ford
et al. (1976), who parametrically varied the degree of
disparity of infrequent pitch changes from standard,
frequent background tones. Mismatch tones were 5%
(one-half musical step), 25% (major third), and 100%
(an octave) discrepant and were interspersed during
read (ignore) and respond (button press to mismatch)
conditions. Under both read and respond conditions,
the amplitude of P300 varied with the degree of mis-
match, although this relationship was much clearer
and stronger under respond conditions. P300 latency
was longer during respond (mean of 336 msec) than
during read (mean of 287 msec), and the topographies
were different as well. The read P300 was more uni-
formly distributed, while the respond P300 was largest
at Pz. These data support an interpretation of P300 in
terms of orienting dependent upon the degree of mis-
match and support the hypothesis that more than one
P300 generator exists, producing PSOOs of different
latency and amplitude.
Summary and conclusions
Enough evidence has accrued to suggest that
P300 does reflect orienting, since it is elicited in the
same situations and by the same variables that elicit
the classical autonomic components of the orienting
response. The fact that late positive components of
different latencies and scalp topographies have been
elicited under similar orienting paradigms presents a
problem in attempting to draw general conclusions
about situations that produce an "orienting P300." In
general, early and more frontally distributed late posi-
tive components have been reported to occur when
subjects were ignoring the stimuli, while longer latency
late positive components have been found when they
were attending the train of stimuli, even though the
stimuli were task-irrelevant (i.e. Courchesne et al.
1975). Fitter et al. (1968) found a late (350 msec)
P300 that had a posterior focus, while Squires et al.
(1975) reported an early (220-280 msec), frontally
distributed "P3a" and Ford et al. (1976) observed an
early (287 msec), but more uniformly distributed
P300 to auditory stimuli during "ignore" conditions.
It has been suggested by Roth (1973) and Squires et
al. (1975) that the late P300s reported by Ritter et al.
(1968) were "target-detect" P300s, since their
subjects were practiced and were expecting the pitch
change, thus accounting for the longer latency and
posterior topography.
In any event, it is likely that one of the various
P300 waves will occur when experimental operations
designed to induce orienting behavior are employed.
The conditions, stimuli, and tasks under which the
production of these waves can be wholly attributed
to orienting remain to be parametrically investigated.
The addition of autonomic measures to these same
paradigms might aid in the interpretation of orienting,
and use of single-trial analysis (Ritter et al. 1972,
Courchesne et al. 1975), especially in the case of large
amplitude autonomic signals (e.g., GSR), might pro-
vide information that is "washed out" when the tech-
nique of averaging is used.
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DOES P300 REFLECT TEMPLATE
MATCH/ MISMATCH?
J.M.FORD
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine,
Stanford, and Veterans Administration Hospital, Palo Alto, CA, U.S.A.
The mentalistic concept of template matching
has been used by psychologists to explain pattern
recognition. When used by psychologists, template
means a standard or a prototype. A stimulus is iden-
tified by noting its congruence with the template
(Neisser 1967). Although the concept has some appeal
at first blush, it loses strength when it becomes appar-
ent that in order to explain much of perception, it is
necessary to make the definition much more flexible,
ultimately making template-matching theories indis-
tinguishable from feature-analysis theories. For
example, if the task is to detect any letter A, then the
template will be a composite of block A's, script A's,
tilted A's, etc. Regardless of these definitional prob-
lems, evoked potential researchers often think in
terms of templates to explain the P300 phenomenon.
To do this, a flexible notion of how a match or mis-
match is made is adopted. The template is some kind
of memory of stimulus events. New stimuli are com-
pared with this template, and a match or mismatch
occurs. Depending on task or environmental demands,
the template will be more or less fuzzy.
A number of variables affect P300. Two of them,
task relevance and probability, are discussed in this
paper. Since these variables interact in a complex
manner, studies in which only one is manipulated, the
other being held constant, are considered. The success
or failure of template matching and mismatching in
explaining existing P300 data is examined, after first
defining template matching and mismatching in terms
of task relevance and probability.
Definitions
Task-relevant stimuli are stimuli that a subject
needs to make a decision. They are either stimuli
requiring a response (a target) or stimuli having some
bearing on the decision regarding the target, perhaps
affecting performance. In experiments where the
subject is instructed to detect a particular signal,
some researchers assume the subject leams what the
target is and develops a template (neural representa-
tion) of it in memory. When a signal occurs that
matches the template, the subject decides that the
target has occurred. This template will be referred to
as the target template. It has been suggested that it is
a match of the sensory input with the target template
that elicits the P300.
Probability has also been shown to affect P300
amplitude. P300 amplitude has been manipulated by
varying the probability of ongoing events, either the
global or the sequential probability, or by varying the
outcome probability. These events are psychological
events manipulated by the contingencies between
physical events. Templates of these events may be the
environmental templates ofSokolov (1963). To deter-
mine the effect of any type of probability on P300, it
is important to establish that both the probable and
improbable events are task relevant and equally dis-
criminable. In experiments where the subject grows
accustomed to hearing or seeing a certain background
signal or experiencing a certain event, some researchers
assume that the subject develops a template for the
probable event. When another event of a different
pitch, configuration, or psychological value occurs,
the input mismatches his template. This template will
be referred to as a probability template; and when the
observed event mismatches the probable event, a
P300 results. The probable stimulus could be con-
sidered a probability template match; and unless it is
also task relevant, it does not elicit a large P300
(Squires et al. 1975). Expectancy is a term often used
interchangeably with probability. Since the subject is
rarely asked what he really expects in these experi-
ments, it is better to use the more operational term of
probability.
Target template matching
The most direct attack on the issue of target
matching was made by Posner et al. (1973). The
experiment was a match-to-target design where sub-
jects were shown a target letter followed 1 sec later
by another letter. The second letter either matched or
mismatched the target. A match elicited an earlier
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182
Ford
and larger P300 than did a mismatch, but the mis-
match elicited a larger N2 than did the match. Match-
es often have faster (Posner and Boies 1971) and less
variable (Nickerson 1969) reaction times (RTs) than
do mismatches. The psychological process underlying
this phenomenon is unclear. Nevertheless, inferring
from RT data, it seems reasonable that P300s to mis-
matches would be later and the onset of individual
P300s would be more variable. These factors could
explain the late, shallow appearance of P300 to mis-
matches, and had they been averaged with respect to
RT (keeping RT and RT variability equal for both
matches and mismatches), the PSOOs might have look-
ed quite similar. However,since the difference between
standard deviations in RT is usually less than 25 msec
(Sternberg 1969), it is unlikely that this could explain
the difference in broadness of P300 seen in Posner's
data.
Another example of target matching and mis-
matching, when matches and mismatches were equi-
probable, is an experiment by Courchesne et al. 1976.
Seven subjects saw 80% background slides (2's), 10%
targets (4's), and 10% novels (colorful, unrecognizable
pictures). Subjects were required to count the targets.
For the moment, assume that the subject has a tem-
plate for the target so that its delivery results in a
match and the delivery of a novel results in a mismatch.
The match evoked a large parietal P300 and the mis-
match evoked a large frontal-central P300 (and N2).
In another condition, where subjects counted the
novel slides, the novel stimuli evoked a large parietal
P300, as did the target 4's in the other condition.
Since no novel slide was ever presented more than
once, it is difficult to imagine a template of a partic-
ular novel slide. In order to make these data fit the
notion of template matching, we must think of a
general template for any complex stimulus (Tueting,
this volume).
The relationship between target template-match-
ing and P300 has been studied extensively by the
Hillyard/Squires group (Hillyard et al. 1971; Squires
et al. 1973a, 1973b, 1975). On the basis of signal
detection experiments, these authors suggest that sub-
jects establish two templates in memory-one for sig-
nal presence (a template of the signal itself) and one
for signal absence. P300 is triggered by a match to
either template, and the closeness of the match is
measured by decision confidence. The closer the
match, the larger and earlier the P300 (Squires et al.
1973b). One interesting result in the 1975 study was
that detections of signal presence (hits) are associated
with larger PSOOs than are detections of signal absence
(correct rejections) made at the same level of confi-
dence. To explain this result, a second variable, related
to stimulus probability, was suggested and tested.
This variable was the outcome probability of a trial.
The more improbable the outcome, the larger the
P300. That is, when signal absence is improbable,
correct rejections also become improbable and evoke
larger P300s than do correct detections. Squires et al.
1975 pointed out that, when a signal is well above
threshold, when subjects are confident that a signal
has been delivered, and when task relevance is not
varied, improbability of outcome seems to play a
more dominant role than target template-matching.
Probability template mismatch
Throughout the literature, P300s evoked by
improbable events are reported. In two separate
experiments, Tueting et al. (1970) varied the sequen-
tial and global probabilities of stimulus occurrence.
When subjects were asked to guess which of two
stimuli would occur next, Tueting et al. found that
P300 amplitude was predicted by the interaction of
the stimulus probabilities and the guessing behavior
of the subject. The interaction was called the outcome
probability; the more improbable the outcome, the
larger the P300.
K. Squires et al. (1976) also investigated the
effect of both sequential and global probability on
the ERPwaveform. Instead of probability, they called
the variable expectancy. Expectancy was defined as a
mathematical function of decaying memory for events
within the prior sequence. For target stimuli, P300
(as well as N200 and slow wave components) varied
inversely with stimulus expectancy.
An improbable event can also be response-related.
Karlin and Martz (1973) have shown that, when a
response is rare, the stimulus associated with the
response elicits a larger P300 than when the response
is frequent regardless of stimulus probabilities.
When improbable feedback is delivered, a large
P300 is elicited (Squires et al. 1973a, 1975; Tueting
et al. 1970); when an infrequent pitch or intensity
change occurs, large P300s are elicited (Ritter et al.
1968, Ford et al. 1976, Squires et al. 1975); when an
infrequent line drawing occurs in a series of letters, a
P300 is elicited (Courchesne et al. 1975); and so on.
Thus, it appears that improbable events associated
with stimulus, response, or outcome evoked larger
amplitude P300s. Many reports can be reinterpreted
in terms of a mismatch with the probability template
eliciting a P300, although few investigators have
used these terms.
In summary, the largest P300s are elicited in two
fairly disparate situations-target template matching
and probability template mismatching. To reconcile
this disparity may not be possible within the frame-
work of template matching and mismatching, but
some of the possible ways are suggested below.
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P300 Latency and Template Match/Mismatch
183
Tueling (this section) suggests that target tem-
plate-matching and probability template-mismatching
might be pulled together under a unitary concept by
assuming, in the probability case, that the subject
establishes a template for improbable or novel events.
Another speculation is that the two processes can be
considered component parts of a serial process where
probability mismatches are registered first, followed
by an evaluation of whether the event matches the
template. When an event mismatches the expectancy,
an early P300 should result; when it matches a target,
a later P300 should result. This concept fits the data
of N. Squires et al. (1975) and Roth et al. (1976), but
is inconsistent with the data of E. Courchesne et al.
(1978) showing that probability mismatches elicit
later P300s than do targets in the visual system. Rotli
cl al. (in preparation) have obtained similar inconsis-
tent data in the auditory system. Furthermore, this
concept docs not deal with the occurrence of target
mismatches as in Posner's work (1973), or with how
P300 amplitude and latency might change with the
degree of match or mismatch.
Squires et al. (1975) formulated a way in which
P300 could be affected by the degree of target match-
ing. They suggested that template matching may in-
volve a series of comparisons of the signal against a
list of templates that vary from the most target-like
to the least target-like. P300 would be elicited when a
match is satisfactorily encountered, causing P300
latency variations. The confidence in the decision
that a match actually occurred would be reflected in
P300 amplitude. The same logic can presumably be
extended to the probability situation, in which the
list of templates is ordered from the most expected to
the least expected. N. Squires et al. (1975), however,
adopted a different strategy. Instead of trying to unite
target matching and probability mismatching under
one rubric, they suggested that the P300s elicited
under these two situations are separate components
(P3b and P3a) that have different latencies and scalp
distributions and reflect different processes. P300
data at the present time do not permit the unequiv-
ocal evaluation of the different template match-mis-
match hypotheses discussed in this paper.
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EVOKED POTENTIALS AND FEEDBACK1
S. SUTTON, P. TUETING2, M. HAMMER, AND G. HAKEREM
Department of Psychophysiology, New York State Psychiatric Institute, New York, NY, U.S.A.
More than 10 years ago, Sutton et al. (1965)
reported that subjects had larger P300s on discovering
that a guess was wrong than on discovering it was right.
However, in subsequent experiments, this pattern was
noted to be inconsistent. In some experiments, no
statistical difference was found. In one experiment,
most subjects had larger PSOOs associated with feed-
back that informed them their guess was right (Levit
et al. 1973).
On noting how sensitive P300 amplitude was to
the interaction of stimulus and guessing probabilities
(guessing probabilities were not examined in the earli-
er experiments), the assertion that being wrong gave
greater amplitude than being right was temporarily
withdrawn, and it was suggested that the issue of
right-wrong differences could not be resolved until it
was disentangled from the effects of probability
(Tueting et al. 1970). At about this time, Squires et
al. (1973) looked at feedback that told a subject that
his discrimination was correct or incorrect, and found
that P300 was larger when feedback indicated an in-
correct discrimination. These differences remained
even after probability effects were statistically partial-
led out. Poon et al. (1974) used a guessing procedure
in which subjects could learn the correct sequence of
stimuli to a fairly high degree of accuracy. Again,
they found that P300 was larger for incorrect than
correct feedback.
In contrast to studies reporting larger P300s for
incorrect feedback, a recent study by Leifer et al.
(1976), also a guessing situation, found larger PSOOs
associated with correct feedback. But an inkling of
the complexity of the problem is given by their analy-
sis of changes over successive blocks. P300s associated
with feedback following predictions that the high
probability event would occur became smaller in am-
plitude over successive blocks. However, P300s asso-
ciated with feedback following predictions that the
low probability event would occur did not alter over
successive blocks. On the other hand, in a simpler 50-
50 probability situation not involving probability
learning, Tueting and Levit (unpublished data) found
that incorrect guesses had larger P300s at the begin-
ning of the experiment, but this reversed as the ex-
periment progressed so that correct guesses had larger
P300s in later trials.
More recently, we attempted a reanalysis of the
feedback concept and have completed some prelimi-
nary experiments based on that reanalysis. We devel-
oped the following formulation: Whether stimuli pro-
vide feedback with respect to a guess or with respect
to a discrimination, they have the following cross-cut-
ting properties:
1. Confirmation-disconfirmation — The feedback
stimulus tells the subject that a guess or discrim-
ination was correct or incorrect.
2. Degree of value-This can be illustrated by
experimental designs in which the experimenter
places different degrees of monetary reward or
loss on being correct or incorrect.
3. Direction of value-We are used to thinking of
being right as a good thing and being wrong as a
bad thing. But it is not always so, as illustrated
in the statement, "Damn it! I knew it was going
to rain!"or when one is sure that some symp-
tom means cancer and then discovers that it
indicates only a minor ailment.
4. Information-A feedback stimulus delivers infor-
mation relevant to future guesses or judgments
(e.g., it may indicate that the last judgment was
wrong, and that the subject should try to find
some other basis for the next response). We
have, however, generally only assumed that
feedback influences the subject's guessing and
discrimination strategies on future trials and
that these changes are reflected in P300. A
somewhat different approach is to construct
'This investigation received support from Grant No. N1E-G-74-0042. The assistance of Stuart Steinhauer, Marion
Hartung, and Robert Youdin is gratefully acknowledged.
2Now at the Maryland Psychiatric Research Center/Department of Psychiatry, University of Maryland Medical
School, Baltimore, Maryland.
-------
EPs and Feedback
185
experimental designs in which one controls the
information provided by the feedback stimulus
in order to study more directly the degree to
which it affects the subject's behavior and evok-
ed potentials on future trials. An interesting
experimental design is one arranged so that the
subject's being correct or incorrect on a given
trial is used by the experimenter to determine
the subsequent probability with which different
stimuli will be presented.
In a recent set of experiments, we attempted to
disentangle two of these properties of feedback, con-
firmation-disconfirmation and direction of value.
The direction of value concept is more familiarly
known as the win-lose dimension.
In one experiment, 12 subjects guessed in each
trial whether the next stimulus would be a high-pitch-
ed click or a low-pitched click. Thus, in each trial, as
the click occurred, the subject discovered whether the
guess was correct or incorrect. This single outcome,
however, did not determine whether the subject won
or lost. The subject had been instructed that winning
or losing was based on performance in each pair of
trials, according to the following rules: the subject
won a quarter if both members of the pair were right
or if both members of the pair were wrong. The sub-
ject lost a quarter if one member of the pair was right
and the other was wrong. Note several things about
this design. Being right on the first member of the
pair did not in itself determine the payoff. If the sec-
ond was also right, the subject won; if the second was
wrong, the subject lost. Likewise, being wrong on the
first member of the pair did not determine payoff. If
the second was also wrong, the subject won; if the
second was right the subject lost. Furthermore, with
respect to the second member of the pair, the subject
could win on right or on wrong guesses or could lose
on right or on wrong guesses. Thus we experimentally
separated confirmation-disconfirmation from winning
and losing. (With some subjects, we played the
game with opposite rules.)
The overwhelming finding was that P300 to the
second member of the pah- was much larger than to
the first member of the pair, as shown in Rg. 1. This
difference in amplitude might be attributed to the
fact that the response to the second stimulus involved
completion of the pair; however, related data suggest
that this was not the basis for the finding. Another
interpretation is that the larger P300 for win-lose
reflects a value dimension that is often forgotten in
formulations with respect to P300; winning or losing
a quarter is more important than simply having a
guess confirmed or disconfirmed.
Other findings were less dramatic. For the second
member of the pair, P300 was usually larger and later
for lose than win. A more general finding was greater
S1
400 800
RIGHT
WRONG
S2
RIGHT
WRONG
400 800
400
800
WIN
LOSE
Fig. 1. Vertex auditory evoked potentials for one subject in a guesting paradigm. Negative at vertix is up with respect
to a linked earlobe reference. The flrst stimulus of the pair (SI) confirmed or disconflmed the subject's guess. The
second stimulus of the pair (SI) also confirmed
-------
186
Sutton et al.
negativity in the P2-N2 region for the lose waveform
for the overwhelming majority of subjects. On the
whole, these differences between lose and win wave-
forms held whether they occurred in experimental
formats where the subject lost by being wrong or lost
by being right and correspondingly won by being right
or won by being wrong. This is the direction of value
concept mentioned earlier. Identification of more
subtle interactions must wait until all data have been
retrieved from the computer. Data for all scalp loci
also have not been fully examined; only vertex has
been analyzed at this time.
In the confirmation-disconfirmation waveforms-
responses to the first member of the pair—consist-
ent differences were again in the P2-N2 region.
The discon firm a tion wave form, for almost all subjects,
was more negative in the P2-N2 region. Unlike the
win-lose comparison, there were no differences in the
P300 region.
Summarizing, then, in feedback designs the P300
is very sensitive to the importance or value of the
stimulus to the subject, as reflected by the fact that
win-lose P300s were much larger than confirmation-
disconfirmation P300s. On the other hand, differences
between winning and losing, as well as between confir-
mation and disconfirmation, were reflected most con-
sistently in the P2-N2 region.
In the correspondence group discussion, preced-
ing this symposium, Squires reexamined earlier data
from Squires et al. (1973), which compared confirm-
ing and disconfirming feedback in a discrimination
situation. The earlier data appear remarkably similar
to ours. The statement that there was more negativity
in the P2-N2 region summarizes what was most con-
sistent over all of our subjects. We also saw evidence
for: (1) a latency shift, particularly in the N1-P2
arm-later for lose; (2) truncation of P2 for lose; (3)
sometimes a development of a clear N2 for lose; and
(4) sometimes a later, more peaked, and larger am-
plitude P300 for lose than for win.
In another set of guessing experiments involving
eight subjects by Steinhauer of our laboratory, sub-
jects decided before each trial whether they would
bet 504, 254, or nothing, for that trial. Again, only
vertex data have been analyzed. P300 was found to
be larger the greater the value of the bet, as shown in
fig. 2. Even more interestingly, in otherwise identical
sessions with the same subjects, a random-number
program selected the value of the subject's bet and
the subject was informed of that value prior to each
trial. The whole level of P300 amplitude was shifted.
When the computer selected the value of the bet, all
P300s were half the size of those obtained when the
subject selected the value of the bet. In the computer-
bet condition, order tended to be preserved-larger
stakes yielded larger PSOOs than smaller stakes-but
less consistently than in the subject-bet condition.
The concept that the feedback stimulus may pro-
vide different degrees of information needs further
elaboration. We have not limited the term feedback
to those cases where it can be shown that the feed-
back provides information that alters data obtained in
subsequent trials. Partly, this is because it seems
reasonable to infer that systematic feedback almost
always affects future evoked potentials and behavior,
and when the question is examined directly, one finds
that indeed it does. For example, in a guessing situa-
tion without telling subjects about the relative prob-
abilities of two events, but simply letting the stimuli
indicate whether guesses are right or wrong, most sub-
jects will match the event probabilities. In discrimina-
tion situations, the story is more subtle, but evidence
exists that feedback results in improved discrimination
(Jenness, 1972a).
Tueting et al. (1970) and Friedman et al. (1973)
have shown that in situations in which subjects match
event probabilities, P300 is larger the smaller the
obtained outcome probability. Outcome probability
is a term that takes into account both stimulus proba-
bilities and the subjects' guessing probabilities. The
relationship was clearest for confirming feedback, but
seemed to hold for disconfirming feedback as well.
More recently, Campbell and Picton (1976), using
feedback stimuli in a time estimation task, reported
that P300 amplitude was more systematically related
to the meaningful information content of the feed-
back stimulus than to the information content defined
classically in terms of surprisal value (probability) of
the stimulus.
Subtle sequential effects, particularly in P300,
have been noted and related to the inferred sequen-
tial expectancy of the subject. In some studies, data
have been averaged as a function of type of sequence
(Levit et al. 1973; Sutton et al. 1978; Tueting et al.
1970). In other studies, single trials have been con-
sidered as a function of type of sequence (Squires et
al., this volume).
Levit (1972) compared normal subjects, schizo-
phrenic patients, and depressive patients in a guessing
situation in which clicks and light flashes had a 50:50
probability. Normal subjects and depressive patients
developed what we called ipsimodal expectations. In
other words, when they received a light on a given
trial, they more often guessed that on the next trial
they would also receive a light; having received a
sound, they more often guessed that on the next trial
they would receive a sound. Schizophrenic patients
were about 50:50 in their expectation. When P300
was examined as a function of modality of the stim-
ulus in the previous trial, normals and depressives had
-------
EPs and Feedback
SUBJECT BET
COMPUTER BET
1000
WINO
WIN 25 c
WIN 50 c
0
1000
SUBJECT BET
COMPUTER BET
1000
10
1000
LOSEO
LOSE 25 c
LOSE 50 c
Fig. 2. Vertex auditory evoked potentials for one
subject in a guessing paradigm. Negative at vertex is
up with respect to a linked earlobe reference. Win
and lose waveforms are compared as a function of
the monetary value of the bet. Waveforms are al-
so compared in a situation where the subject de-
cided on the monetary value of the bet and in a situ-
ation where the computer decided on the monetary
value of the bet.
larger P300s when the stimulus in the previous trial
was in the other modality-just what one would
expect on the basis of the notion that P300 is larger
when the stimulus is relatively unexpected. For schiz-
ophrenics, no such difference was found. Admittedly,
such evidence is indirect, but it is in the right direc-
tion, and it was inferred by examining both the
behavioral and evoked potential data (see Sutton et
al. 1978). Unfortunately, few studies have system-
187
atically related feedback to changes in both behavior
and P300 (with the exception of Jeness 1972b and
Leifer et al. 1976). More study of the effect of feed-
back on both behavior and P300 on future trials is
greatly needed.
We would like to conclude by focussing on the
concept of value or importance as an explanatory
dimension in interpreting P300 findings. While we
have no intention of suggesting that this variable pro-
vides an explanation of all P300 findings, the concept
of the importance of the information provided by the
stimulus appears to cross-cut a number of experimen-
tal designs that affect P300 amplitude. Perhaps target
stimuli, in a sense by definition, are more important
than nontarget stimuli. Perhaps, because of the way
organisms are biologically constructed, rare events,
novel events, or unexpected events may be inherently
more important than n on orienting events. In the data
presented here, winning 50tf is more important to the
subject than winning nothing. Placing a bet oneself is
more involving, and in that sense more important,
than observing the computer's luck, even if the subject
collects the winnings or pays the losses. Perhaps the
reason why P300 is sometimes larger for confirm and
sometimes larger for disconfirm is that we have inad-
vertently made it more important for the subject to
focus on either right or wrong outcomes in determin-
ing guessing strategy. An interacting variable may be
variation among subjects. For personality reasons,
some individuals may focus on winnings and others
on losses. Experiments would need to be directed at
these issues. Such an approach to the experimental
analysis of P300 in the win-lose paradigm may be use-
ful for other P300 paradigms as well.
Summary
The literature on whether P300 is larger when a
feedback stimulus informs a subject that performance
on a task is correct as opposed to incorrect was
reviewed. We concluded that the relationship between
P300 amplitude and direction of feedback continues
to be inconsistent. Based on a re-analysis of the prob-
lem, a new experiment that yields more consistent
findings was performed. Losing money yielded greater
negativity in the P2-N2 region than winning money,
no matter whether the rules were such that a correct
guess resulted in losing or an incorrect guess resulted
in losing. However, when the experimental design
dissociated being correct or incorrect from winning or
losing, in the sense that correctness or incorrectness
could not influence the monetary outcome directly,
being incorrect showed greater negativity in the P2-N2
region than being correct. With respect to P300, the
effects were relatively weak; for more subjects P300
was larger for losing than for winning. But there was
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little difference in P300 for correctness and incorrect-
ness when the experimental design isolated this varia-
ble from winning or losing.
In another experiment, P300 amplitude was larger
the greater the size of the monetary bet placed on the
guess. However, in a design in which the computer
selected the monetary value of the bet to be placed,
P300 amplitude was half the size obtained when the
subject selected the monetary value of the bet to be
placed. It should be noted that even when the com-
puter selected the value of the bet, the subject pock-
eted the winnings or paid the losses.
It was suggested that the importance of informa-
tion provided by the stimulus may be a key variable
influencing P300 amplitude. A possible source of
inconsistent findings with respect to P300 amplitude
and right-wrong feedback might be that different
experiments have inadvertently steered subjects into
focussing on either being wrong or being right in guid-
ing their strategy.
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POTENTIALS ASSOCIATED WITH THE
DETECTION OF INFREQUENT EVENTS IN A
VISUAL DISPLAY
R. COOPER, P. V. POCOCK, W. C. McCALLUM, AND D. PAPAKOSTOPOULOS
Burden Neurological Institute, Bristol, England
As part of a project to investigate changes in vigi-
lance over extended periods of time.electrophysiolog-
ical events that accompany detection of infrequent
events occurring in a continuously observed visual
display were studied.
Method
The observer was seated 2 meters away from a
25-inch television monitor (16-deg angle subtended in
the horizontal plane), on which a picture of a land-
scape was displayed from video tape (Cooper et al.
1977). At infrequent, irregular intervals (average 4
min) a vehicle-car, van, or lorry-crossed the display
along any of four roads starting from left or right or
from behind bushes in the centre. The observer was
instructed to press a switch with his left thumb when-
ever he saw a vehicle and press another switch with
his left index finger using a prearranged code to indi-
cate the type of vehicle. The angle subtended by the
vehicles was between 0.5 and 0.25 deg. The contrast
of the picture was about 20%, and the brightness was
set for comfortable viewing in the darkened room. A
total of 24 events occurred during a 1.5-hr watch
period.
In six subjects, recordings were taken from Fpz,
Cz (compensated for eye movement), and Oz referred
to commoned electrodes on the two mastoid processes
and from bipolar montages 01-P3 and 02-P4. EEC
and horizontal and vertical oculograms were recorded
using amplifiers with an 8-sec time constant. In three
additional subjects, electrodes were placed at Fpz, Fz,
Cz, Pz, Oz, F3, F4, C3 C4, P3, P4.01.02, and 3 cm
posterior to Oz. In these subjects, recordings of the
oculograms were obtained. The upper frequency limit
was 70Hz (-3dB). Respiration, EKG, galvanic skin
response switch presses, and EMG of operant muscles
were also recorded. Data channels were sampled at
100 points/sec and stored on digital tape of aPDP-12
computer. The sampling started shortly before the
vehicle entered the display and ended 16 sec later.
Results
Detection time-i.e., the time between the entry
of the vehicle onto the display and the switch press
indicating detection—varied greatly across subjects,
vehicles, and routes, with an average of 4.3 sec and a
range of 0.4 to 25 sec. A further 2.4 ± 2 sec was
required to recognize the vehicle.
Recordings of eye movements showed that up to
1 or 2 sec before detection (indicated by switch press)
subjects were scanning the display as shown in a
two-dimensional plot of eye position in Fig. 1. In this
trial the vehicle was moving on a right to left track.
At the start of this trial, the eyes were scanning near
the vehicle, which had already entered the display,
but the eyes then moved to the left at AB without
seeing it. About 1 sec later (D) the eyes returned to
the left and scanned the area of the display just below
the vehicle. The eyes then moved upward, overshot
the track at EF, and then locked onto the vehicle.
The vertex EEC shows a large positivity at time EF,
followed by the switch press indicating detection.
Multichannel recordings of the same event are
shown in Rg. 2. Large positive potentials occur at the
vertex and occipital midline electrodes. EMG begins
to increase immediately after the positivity culminat-
ing in the button press 5.4 sec after the vehicle has
entered the display.
All nine subjects developed this large positive
potential between the time when an eye movement
brought the gaze to the region of the vehicle and the
switch press indicated detection. In 90% of the trials
of all subjects, the potentials were identified in single
trials stored on digital tape. The average amplitude at
the vertex of this detection potential across nine sub-
jects was 38 juV; mean amplitudes for individual sub-
jects ranged from 20 to 63 /iV. The field distribution
is such that Cz and Pz are more or less equipotential
and the field falls to about 60% at electrodes Fz, Oz
P3,P4, C3 andC4 (Cooper et al. 1977).
The occurrence of this potential was not time-
locked to the eye movement taking the eye into the
target area, nor was it at a fixed time before the switch
press that indicated detection. The frequency distri-
bution of the times of occurrence of eye movements
and switch press with respect to the positivity are
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Cooper et al.
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