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The role of synaptic inhibitory mechanisms in neuropsychological systems
Neuropsychologia,
1969,
Vol. 7,
pp.
217 to 233.
Pergamon Press.Printed in England
THE ROLE OF SYNAPTIC INHIBITORY MECHANISMS IN NEUROPSYCHOLOGICAL SYSTEMS* RICHARD F. THOMPSON
In collaboration
with :
LEWIS A. BETTINGER~, HERMAN BIRCH, PHILIP M. GROVES
and KATHLEEN S. MAYERS Department
of Psychobiology,
University of California, Irvine, California, U.S.A.
Abstract-Possible synaptic mechanisms that could produce “inhibition” of the output of a limited neural system, such as the response of a given pool of neurons, are considered. A particular example of inhibition, the reduction in amplitude of the gross evoked cortical It polysensory association response that occurs during behavioral attention, is analyzed. appears that when the animal (cat) attends to a novel stimulus, the ongoing level of activity of individual neurons in association cortex increases markedly. The concomitant reduction in amplitude of the gross response evoked by a repeated peripheral probe stimulus (click, light flash, or forepaw shock) appears to be proportional to the degree of increase in ongoing unit activity. Electrical activation of frontal cortex in the anesthetized preparation is shown to replicate effects of attention in the waking animal on gross and unit activity in association cortex. IN PREPARING this paper I jotted down a few ways in which the term “inhibition” has been used. I stopped when the list reached about twenty. It is clear that the word can be used to refer to virtually anything in relation to a change in almost any type of measure or phenomenon. There are at least four different levels of common usage in neurobiology: (1) behavioral, (2) generalized brain state, (3) interactions of systems within the brain, and (4) specific synaptic actions. All four levels are illustrated by the papers of this symposium. WARREN is concerned with the role of frontal cortex in behavioral response inhibition in go-no go situations; KIMBLE considers the neural substrates of generalized internal inhibition; RHODES discusses inhibitory interactions among brain systems as they influence the EEG, and I will include consideration of inhibitory synaptic actions. Interrelations among these various levels of “inhibition” are not predictive. Thus, if we consider behavioral response inhibition in relation to synaptic actions on motoneurons, it is clear that both making a response and withholding a response involve excitatory and inhibitory synaptic actions. Synaptic inhibition can lead to the presence or the absence of a response and occurs in both. It is to be assumed that interactions among systems within the brain, in the context of generalized internal state, determine the patterns of
* Supported in part by Research Grant NB-02161 from the National Institutes of Health and Research Scientist Award MH-06650 from the National Institute of Mental Health. The technical assistance of Sarah Beydler and Margaret Westwell is gratefully acknowledged. t Present address: Department of Psychology, Vanderbilt University, Nashville, Tennessee. 217
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synaptic actions that lead to a given behavioral response. However at present this is more an assertion of faith than a statement of fact. If we restrict usage of the term “inhibition” to synaptic processes of inhibition in the mammalian central nervous system, there are perhaps two basic types, postsynaptic inhibition and presynaptic inhibition. (“Remote” inhibition, to the extent that it occurs, is probably a special case of postsynaptic inhibition.) Postsynaptic inhibition is the best known, involving a chemical synaptic action resulting in a temporary hyperpolarization of the postsynaptic membrane. Presynaptic inhibition is actually a case of postsynaptic excitation acting on presynaptic terminals to produce a partial depolarization which in turn results in a smaller postsynaptic response. A virtually unlimited number of possibilities occur if we attempt to relate these two neural processes of inhibition to the output of even a limited neural system, e.g. the response of a given pool of neurons measured as nerve discharges or a gross evoked response. A few examples of inhibition are indicated schematically in Fig. I. The large circle represents the output neurons. (A) shows direct inhibition, (B) indicates inhibition acting on an excitatory interneuron, (C) shows presynaptic inhibition, (D) indicates excitatory input acting on an inhibitory interneuron, (E) shows inhibition of an inhibitory
Fiti. I. Highly simplified schematics of a few possible excitatory and inhibitory synaptic interconnections in simple input-output systems (A-F). The large circle represents output neurons and the vertical arrows indicate increased or decreased output lo the excitatory (E) input when the inhibitory input (I or “E” or “1”) is also activated. G illustrates two excitatory inputs producing facilitation or occlusion.
interneuron, which results in a net increase in cxcitabilily, and (F) indicates inhibition of an excitatory interneuron that itself acts to produce presynaptic inhibition for a net excitatory effect. Finally, (G) indicates that it is even possible to inhibit the output of a system by purely excitatory synaptic processes, e.g. occlusion. If two excitatory inputs act on a pool of neurons, an evoked output from one input may be reduced to the extent that the cells are being fired from the other input, depending on the timing of the two inputs. In our own work we have been interested in the decrease or inhibition of evoked responses in nonspecific association areas of the cortex of cat during behavioral attention [l-4]. We will use this effect as an example of inhibition and describe some of our work attempting to track down the underlying processes responsible for the inhibition. Figure 2 shows examples of gross evoked association responses to repeated click, light Ilash :111d skin shock recorded as superimposed individual traces from chronically implanted
TIIE ROLE OF SYNAPTIC’
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FIG. 2. Examples of evoked responses recorded from association cortex in normal waking cats. Each response is approximately 50 superimposed individual traces. A-E, responses to click stimulatidn; A, C,area PMSA: R, 6, area AMSA: E. area ALA. F-J, responses to iusilateral forepaw shock stimulation: F, area AMSA: G-J. area PMSA. K-O. responses t; light Bash siimulation; K-N, areaPMSA; 0, area AMSA. Data presented here are from ten different animals. Amplitude calibration line to left of each multiple trace represents 100 pV. Stimulus presentation, indicated by dot below each multiple trace, occurs 10 msec after beginning of trace. In this and subsequent figures, upward deflection represents positivity.
gross bipolar surface to depth electrodes in posterior association areas (middle syprasylvian and anterior lateral gyri) in the normal waking cat. The animals were sitting quietly with eyes open. Effects of novel stimuli on evoked association responses to repeated peripheral probe stimuli are illustrated in Fig. 3. In all cases there is a marked inhibition of responses to the repeated probe stimulus during novel stimulation, regardless of modality. The effects of novel stimuli of all three modalities on cortical association responses evoked by probe stimuli of all three modalities are summarized in Fig. 4. Data are from a total of eight cats. In all cases there is a significant reduction in evoked response amplitude during novel stimulation, independent of modality. The time course of recovery of a click evoked association response following novel stimulation is shown for three different novel stimuli in Fig. 5. It would appear that food is most interesting and the experimenter least interesting to the cat. Note that recovery of the response amplitude to control level requires one ot more minutes. Nonspecific association responses are at some points dependent on degree of activity in primary sensory systems. The simplest hypothesis would be that the attentive inhibition of association responses is secondary to decreased responsiveness in primary sensory systems, perhaps of the sort described by HERNANDEZ-PEON [5]. In the auditory system, for example, evoked activity could be reduced by alterations in sound field intensity (as described by MARSH et al. [6]), middle ear muscle contractions, perhaps by efferent control systems, central actions of reticular formation, etc.
R. F. THOMPSON, I_.A. BETTINGER, H. BIRCH. P. M. GROWS
TEST
CONTROL A.
FOREPAW SHOCK
B.
CLICK
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LIGHT
0.
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and K. S. MAWRS
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Fro. 3. Effects of behavioral arousal and attention on evoked cortical association responses. A, suppression of association response following increase in bodily activity (control -sitting quietly, eyes open, test=standing quietly, eyes open); response evoked by ipsilateral forepaw shock stimulus. B, suppression of association response by “novel” visual stimulus (controlsitting quietly, eyes open, test-same posture during sight of food); response evoked by click stimulus. C, suppression of association response by “novel” auditory stimulus (control-z sitting quietly, eyes open, test-same posture during growling sound); response evoked by light flash stimulus. D, suppression of association response by sight of experimenter (control -=sitting quietly, eyes open, test=samc posture during sight of experimenter); response In each case the test response was recorded from the same electrode evoked by click stimulus. in the same animal within four minutes following recording of control response. Each pair of responses recorded from different animal; all records from area PMSA. Amplitude calibration 100 pV.
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IN NEUROPSYCHOLOGICAL
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during
SYSTEMS
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FIG. 4. Summary of mean evoked response amplitudes to “probe” stimuli before (Control) and during (Test) presentation of “novel” stimuli (auditory=growling sound; visual=rat in jar; tactile=air jet delivered on back vs away from back).
experlmenteL-x
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food
60 after
80 novel
120
100 stimulus
140
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stimulus
FIG. 5. Time course of recovery of evoked response amplitudes to a click probe stimulus following 10 set presentations of various novel stimuli. (Each point during recovery is the average of 20 successive responses.)
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These possibilities were evaluated by comparing changes in evoked responses in posterior association and primary auditory areas of the cortex using a free field click and a click delivered through an earspeaker implanted in the contralateral eutcrnal ear (Fig. 6).
FIG. 6. EFects of novel stimulalion (rat in jar) on amplirt&x of asxxiation and primary evoked responses to click stimulation as a function of method of stimulus presentation. A.
Mean amplitudes of association responses recorded from supt asylvian gyrLls (dot on inset drawing) before (control) and during novel stimulation. Responses are significantly dep-essed for both free field and earspeaker sound presentations. B. Mean amplitudes of primary auditory evoked responses (dot in inset drawing) before (control) and during novel stimulation. The response is significantly depressed with a free field click presentation but significantly etrhonrerl with carspeaker presentation.
Note there is a significant and comparable decrease in the association response under both types of stimulus presentation during novel stimulation. However, the primary evoked potential (amplitude of initial surface positivity) decreases only slightly under free field conditions and increases slightly (but significantly) with earspeaker click during novel stimulation. Consequently, the decrease in association responses during attention is not due to changes in primary sensory systems. This also rules out changes in general cortical excitability such as generalized arousal. A general cortical factor ought to influence both primary and association cortical responses. A train of shocks to frontal cortex in the chloralosed cat produces the same differential effects on cortical evoked responses to subsequent peripheral stimuli as does attention in the waking animal [7, 81. Figure 7 illustrates these effects of a prior frontal shock train (40 pulses at 200/set delivered through two wire electrodes of 2 ~11~11separation 3 mm anterior to the cruciate sulcus) on light flash evoked cortical association responses (area PMSA) and primary visual (area VI) responses. Note that as shock intensity is increased the association response amplitude decreases and the amplitudes of the various components of the primary visual response, particularly the later components, increase. Figure 8 illustrates the effects of frontal shock on a polysensory cell recorded from association cortex in the chloralosed cat (glass coated tungsten microelectrode). Note that the cell fires to all stimuli, singly and in combinations, in the absence of frontal shock, but does not respond to any stimuli following frontal shock (shock train terminated
THE
RO1.E OF SYNAPTIC
INHIBITORY
?LASIl ASSOC.
COQTICALsrlocK IITBSITI
(ALA)
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FIG. 7. Effects of prior frontal shock train on cortical association (area PMSA) and primary visual (area VI) responses evoked by light flash in chloralosed cat.
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AT
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FIG. 8. Response of polysensory unit in suprasylvian gyrus of chloralosed cat to auditory (A), visual (V), and tactile (T) stimuli alone and in combination with and without shock train to precruciate area prior to stimulus presentation (train of pulses at 300/set, 40 msec duration, terminating 50 msec before peripheral stimulus). Peripheral stimuli occur at beginning of trace.
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50 msec prior to presentation of peripheral stimuli). Enhancement of the responses of a single neuron in primary visual cortex following frontal shock train is shown in Fig. 9. The numbers to the left of each trace indicate the probability of occurrence of that particular response to light flash (i.e. no spike, one spike, two spikes, etc.).
NO
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FIG. 9. Responses of unit in primary visual cortex of chloralosed cat to flash with and without prior frontal shock train (see Fig. 8 caption). Numbers to the left of each trace indicate probability of each type of response illustrated (i.e. the proportion of times each type of response occurred during a series of flash presentations).
A recent study by GOLDRING et aE. [9] suggests a rather unfortunate alternative explanation for the inhibition of association responses during attention in the waking cat: They were unable to record association responses in normal waking cats under any conditions using computer averaging techniques. In order to investigate this question further we have completed a series of experiments on normal waking animals recording both gross and single cell responses in association cortex using a chronic micromanipulator system of the same general type described by HUBEL [lo] and EVARTS [l 11. A permanent receptacle chamber was affixed to the skull; during a recording session glass coated tungsten microelectrodes of l-3 p tip diameters with impedances ranging from 2-20 megohms were inserted. Recording was monopolar against a distant indifferent. On-line averages of gross evoked responses and single and multiple unit poststimulus histograms were obtained using a Fabri-Tek Model 1062 and a Nuclear-Chicago Model 7100 computers. All unit data were also recorded on tape for subsequent computer analysis. Unless otherwise noted, all data were obtained when the cats were awake but “inattentive,” i.e. sitting quietly or lying down head on forepaws with eyes open. Examples of computer averaged gross evoked responses to click, light flash and ipsilateral forepaw shock recorded monopolarly from association area PMSA are shown in Fig. 10. Surface responses (Fig. 10, Al, Bl, Cl) show the moderately long latency initial surface positivity characteristic of association responses in the normal waking and chloralosed preparations [12, 41. As the microelectrode is passed down through the cortex, the polarity of the initial component reverses and exhibits a clear initial negativity in the depths of the cortex (Fig. 10, A2, B2, C2). An example of the depth distribution of the evoked association responses to light flash stimulation is shown in Fig. Il. The depth distributions of the responses closely resemble the depth distributions of association responses in the chloralosed preparation [12]. This reversal of polarity through cortex is characteristic of a locally generated intracortical field (i.e. a cortical dipole).
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FIG. 10. Averaged gross evoked association responses recorded from the surface (Al, Bl, Cl) and approximately 2.4 mm below the surface (A2, B2, C2) of cortex in association area PMSA m waking cat to click (Al, A2), light flash (Bl, B2) and ipsilateral forepaw shock (Cl, C2). Each tracing is the average of 256 successive responses.
FIG. 11. Depth distribution in cortex of area PMSA of averaged association response to light flash in waking cat. Responses (A-F) are recorded at successive 0.4 mm intervals from surface (A) to a depth of 2.4 mm (F). Each tracing is the average of 256 responses.
Individual examples of unit activity in area PMSA evoked by various peripheral stimuli are shown in Fig. 12. These data are illustrative of the multiunit data used for computation of poststimulus histograms. The majority of units tended to fire at relatively slow and variable spontaneous rates in the absence of stimulation. Note that the largest unit in Fig. 12 tends to fire within a given restricted latency range for each type of stimulus. However, the smaller units appear to have much broader latency ranges. In fact, in many cases it is not possible to distinguish between spontaneous unit activity and unit responses evoked by the stimulus on the basis of this type of individual response data.
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THOMPSON,L. A. BETTINGER,FI. BIRCH,
50
H
m set
P. M.
GROVES and
K. S. M.\ut-ws
I iooyv
FIG. 12. Examples of unit responses in area PMSA in waking cat to click (A), light flash (V), ipsllateral forepaw shock (T) and simultaneous combinations of these (AV=click-flash, AT=click-shock, VT--flash-shock, AVT=click-flash-shock). Spontaneous activity is indicated in tracings with no stimuli (NS).
Comparisons of averaged gross evoked potentials and unit poststimulus histograms in association area PMSA to peripheral stimuli are shown in Fig. 13. Each of these were direct, simultaneous on-line averages of 1024 successive gross responses and the corresponding unit discharges recorded from a depth of approximately 1 mm below the surface of the cortex. Only the two or three largest unit responses were passed by the discriminator for this analysis. Note that the periods of maximum probability of unit discharge (peaks of poststimulus histograms) tend to occur just after the peaks of the negative components of the evoked responses. Effect of stimulus repetition rate is illustrated in Fig. 13A (Lsec interstimulus interval) and 13B (O-5-see interstimulus interval) for light flash. Note that the faster repetition rate results in a marked depression of the amplitude of the gross response and the amplitude of Response to click stimulation is illustrated in Fig. 13C the poststimulus unit histogram. and response to a simultaneous light flash-click stimulus is shown in Fig. 13D. Note that the post stimulus histogram shows a later peak corresponding to a later negativity in the averaged In all cases there is a close and gross response to the combined visual-auditory stimulus. consistent relationship between the gross evoked response waveforms and the periods of maximum unit activity following the stimulus, the histogram peaks occurring at (Fig. I3B) or more commonly just beyond (Fig. 13, A, C, D) the negative peaks of the gross responses when only the largest amplitude spikes are included in the analysis. The averaged gross evoked responses illustrated in Fig. 13 are essentially identical in latency and waveform to gross responses recorded from the same depth in area PMSA in the chloralosed cat [12]. Currently there is some controversy concerning the form of the relationship between the gross evoked cortical potential and the probability of unit discharge to a peripheral stimulus.
THE
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BI
50 msec FIG. 13. Comparisons of simultaneously recorded averaged gross evoked responses (upper tracings of each pair) and unit poststimulus histograms (lower tracings of each pair) from area PMSA in normal waking cat; microelectrode approximately 1 mm below surface of cortex. Al, 2, response to light flash with an interstimulus interval of 2 sec. Bl, 2, response to light flash with an interstimulus interval of 0.5 sec. Cl, 2, response to click (2 set intervals). Dl, 2, response to simultaneous click-flash (2 set intervals). Only the largest spikes were in&ded in the unit analysis. Each tracing is the average of 1024 successive responses.
Thus, Fox and O’BRIEN [13] reported a close correspondence between the peak of the unit histogram and the positive peak of the evoked potential in visual cortex. More recently, Verzeano and associates have presented evidence indicating that in lateral geniculate body
228
K. F. THOMPSON, L. A. BETTINGER, H. BIRC~I, P. M. Gaovrs
and
K. S. MAYERS
FIG. 14. Comparison of gross evoked association response (A), first derivative of gross response (B) and poststimulus unit histogram CC) to light flash. Both larger and smaller spikes included in unit analysis. Each tracing is the average of 1024 successive responses.
and visual cortex, if only the largest amplitude spikes are included in the analysis, the unit histogram peaks occur a few milliseconds after the negative peak of the gross potential. sometimes on the negative peak of the gross response, but most frequently on its positive slope; however, if both larger and smaller amplitude spikes are included in the unit analysis, the histogram peaks correspond closely to the negative peaks of the first derivative of the gross potential [ 14, 151. We completed a comparable analysis for unit activity in association area PMSA to light flash stimulation. Data were obtained under identical conditions to those for the data of Fig. 13, except that the discriminator level was lowered to include both smaller and larger spikes. Figure 14 illustrates the gross evoked response (A), the first derivative (B), and the poststimulus histogram (C) obtained. Note that the region of maximum unit response probability corresponds to the region of maximum negative peak of the first derivative of the evoked potential. Note also that there is a more pronounced and Iongel duration decrease in unit activity following the period of maximum response under these conditions. So far we have demonstrated that there appears to be a relatively invariant relationship between amplitude of the gross evoked potential and probability of cell discharge following a peripheral stimulus in association cortex. The more important question concerns the effects of behavioral attention on gross and unit activity. Figure 15 illustrates a comparison of gross evoked responses and multiple unit poststimulus histograms recorded from area PMSA in the normal waking cat in the inattentive and attentive states. In this experiment the peripheral stimulus was a repeated earspeaker click. Figure 15A is the surface gross association response to click (indicated by arrow) in the normal inattentive cat. Figures 15B
THE ROLE
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IN NEUROPSYCHOLOGICAL
SYSTEsMS
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FIG. 15. Effect of attention on averaged earspeaker click evoked gross responses and unit poststimulus histograms in association cortex (area PMSA) in normal waking cat. A, surface gross response; B, gross response 1 mm below surface of cortex; C, multiple unit poststimulus histogram corresponding to B; A, B, C, control condition, animal sitting quietly with eyes open. D, gross response and E, poststimulus histogram under same conditions as B, C Except that animal given series of novel visual stimuli. Note marked increase in level of ongoing “spontaneous” unit activity during attention (arrcw from baseline to tracing in E) in contrast to control state (arrow from baseline to tracing in C). Each tracing average of 256 successive responses.
and C are the depth gross response and corresponding unit poststimulus histogram under the same conditions. Figures 15D and E illustrate the marked reduction in both the gross evoked response and the unit poststimulus histogram during attention to novel visual stimuli. Note the marked increase in baseline activity in cells during attention (arrows from baseline to spontaneous level of unit activity in C (inattentive) and E (attentive) states). The gross evoked and unit activity to the repeated probe stimulus are reduced in proportion as the ongoing level of discharge of cells increases during attention to novel stimulation. The initial depth negativity, which corresponds to the initial surface positivity, probably represents summed extracellularly recorded EPSPs. Thus the decrease during attention is a genuine instance of inhibition in that it is a reduced synaptic excitation. The cells in association cortex of cat behave very much like SOKOLOV’S hypothetical novelty cells [16]. They respond a great deal to the first few presentations of a novel stimulus, but habituate rapidly. During this time they respond very little to a long repeated peripheral probe stimulus. In the absence of a novel stimulus, certain of the cells fire fairly regularly to the repeated probe stimulus. Assuming common underlying generators for gross and unit responses, the increased ongoing activity of cells during attention may result in fewer cells being available to respond to the repeated probe stimulus and hence a marked reduction or inhibition of the gross evoked association response. As a control procedure, it is necessary to show that this type of “novelty” effect is not general to both association and primary sensory systems. Figure 16 illustrates a comparable experiment recording evoked gross and unit activity in the depths of the auditory cortex of the normal waking cat in the inattentive (A) and attentive (B) states to earspeaker click. Note that, in contrast to the inhibition of the association response, there is a small increase in the initial large negative component of the evoked response and a small increase in the
230
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THOMPSON:
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A.
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H. BIRCII. I’. M. Gkovrs and K. S. hl,~v~.ns
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H 50 mle‘ FIG. 16. Effect of attention on averaged earspeaker click evoked gross responses and unit poststimulus histograms in primary auditory cortex (dorsal portion of area AI). A, gross response (1) and unit histogram (2) recorded 1 mm below surface of cortex during control state (animal sitting quietly with eyes open). B, gross response (1) and unit histogram (2) under identical conditions to A except that animal given series of novel visual stimuli. Each tracing average of 256 successive responses.
poststimulus histogram during novel visual stimulation, but HO clear churge in the level of ongoing unit activity under the two conditions. The increase in primary sensory evoked response amplitude described here for cat is consistent with recent data on monkey reported in this volume by PRIBRAM [17]. Returning to the effects of frontal stimulation, Fig. 17 illustrates the changes in the gross response and multiple unit poststimulus histogram evoked in association cortex by a light flash stimulus following a shock train to frontal cortex in the anesthetized preparation. Figure 17A is control responses and Fig. 17B shows reductions following frontal stimulation. Note that here, in contrast to effects of attention on units in waking cat, there is no change in baseline activity. Figure 18 shows the enhancement of the gross response and a corresponding increase in the evoked poststimulus histogram in primary visual cortex to light flash stimulus following frontal stimulation. Again, there is no obvious change in ongoing level of cellular activity. Finally, Fig. 18 illustrates the same finding for response to click in the primary auditory cortex. To summarize, when an animal attends to a novel stimulus, there is a marked and selective increase of cell firing in association cortex. Concomitantly, there is a substantial inhibition or reduction in evoked gross and unit responses to a long repeated probe stimulus. In contrast, in primary sensory areas of the cortex there is little or no change in ongoing cellular activity during novel stimulation but small increases in evoked gross and unit responses. Shock to frontal cortex mimics effects of attention on evoked gross and unit responses in association and primary areas of the cortex but, at least in the anesthetized preparation, does not seem to influence the level of spontaneous activity of cells.
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A
‘v B
PIG. 17. Effect of frontal shock train on gross responses (Al, Bl) and unit poststimulus histograms (A2, B2) in association cortex (area PMSA) of chloralosed cat; light flash stimulus. A, control state; 8, following frontal shock train. Each tracing average of 16 successive responses.
FIG. 18. Effects of prior frontal shock train on gross responses (Al, Bl) and unit poststimulus histograms (A2,82) in primary visual cortex (area VI) to light flash stimulus. A, control state: B, following frontal shock train. Each tracing average of 16 successive responses.
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C~ROVES
and K. S. MAY~KS
FIG. 19. Effects of prior frontal shock train on gross responses (Al, Bl) and unit poststimulus histograms (AZ, B2) in primary auditory cortex (area AI) to click stimulus. A, control state; B, following frontal shock train. Each tracing average of 16 successive responses.
REFERENCES of evoked cortica! association responses on behavioral I. SHAW, J. A. and THOMPSON, R. F. Dependence variables. P.rq’chonom. Sci. 1, 153-l 54, 1964. responses and 2. SHAW, J. A. and TFIOMPSON. R. F. Inverse Ielation between evoked cortical association behavioral orienting to repeated auditory stimuli. P.~~chonom. Sci. 1, 399400, 1964. of attention. In Atfention: ,4 Behaviornl 3. THOMPSON, R. F. and BETTINGBR, I.. A. Neural substrates Anahsis. D. MOS~OFSKY (Editor). Appleton-Century-Crofts, New York, 1969. In press. correlates of evoked activity recorded from association 4. THOMPSON, R. F. and SHAW, J. A. &havioral areas of the cerebral cortex. J. conm. phvsiol. Psvchol. 60, 329-339, 1965. correlates of habituation and other manifestations of plastic 5. HERNAN~EZ-PENN, R. Neurophysidlo$al inhibition. Electroenceph din. Newophysiol. 12, 41-58, 1960. on evoked auditory 6. MARSH, .I. T., WORDEN, F. G. and HICKS, L. Some effects of room acoustics potentials. Science 137, 280-284, 1962. control of specific and nonspecific sensory 7. TIIOMPSON, R. F., DFNNEY, D. and SMITH, 11. Cortical projections to the cerebral cortex. P.syc/zononr Sri. 4, 93-94, 1966. 8. BET.CINGER.L. A.. BIRCH. H.. GROVES. P. M.. MAYER% K. S. and THOMPSON, R. F. Effects of stimulation of frontal cortex on neuronal activity in association and sensory areas of the cortex. Psychonow. Sri. 12, 167-168. responses from association areas in waking 9. GOLDRING. S.. SHEPTAK. P. and KARAHASHI. Y. Averaged cat. Electroenceph. din. Nerrroph)~siol. 23, 241-247. cats. J. Physiol. 147, 226-238, 1959. 10. HUBEL. D. H. Single unit activitv in striate cortex of unrestrained and evoked discharge of single units in I I. EVARTS, E. V. Effects of sleep and waking on spontaneous visual cortex. Fe& Proc. Fe&. Am. Sots. esp. Biol. 19, 828-837, 1960. of auditory, somatic sensory, and II. THOMPSON, R. F., JOHNSON, R. H. and HOOPES J. Organization visual projection to association fields of cerebral cortex in cat. J. Newoph),sio/. 26, 343-364, 1963. of evoked potential waveform by curve of probability of 13. Fox, S. S. and O’BRIEN, J. H. Duplication firing of a single cell. Science 147, 888, 1965. and 14. VERZEANO, M., DILL, R. C., VALLEC~I.I.E. E., GROVES, P. and THOLIAS. J. Evoked responses neuronal activity in the lateral geniculate. E.rperientiu 24, 696-698, 1968. neuronal activity and stimulus 15. DILL, R. C., VALLECALLE. E. and VERZEANO, M. Evoked potentials, intensity in the visual system. Phvsiol. Behav. 3, 1968. E. N. Neuronal modelsand the orienting reflex. In The Cenfrnl Nervous System am/ Behavior. 16. SOKO&. M. A. B. BRAZICIC (Editor), Vol. 111. Macy Foundation, New York, 1960. 196’). Il. PRIBRAM, K. H. The primate frontal cortex. Neurop.~ycho/ogia 7, 259-266,
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INHIBII-ORY
MLCHANISMS
IN NEUROPSYCliOLOGlCAL
SYSTEMS
Resum&On considtre les mecanismes synaptiques possibles qui pourraient prod&-e 1’“inhibition” de la sortie d’un systeme nerveux limit& telle que la reponse d’une assemblee don&e de neurones. On analyse un exemp!e particulier d’inhibition, la reduction d’amplitude des reponses evoquees globales du cortex d’association polysensorielle qui survient durant le comportement d’attention. 11apparait que lorsque I’animal (chat) recoit un nouveau stimulus. le niveau preexistant d’activite des neurones individuels dans le cortex d’association s’accroit de facon marquee. La reduction concommittante d’amplitude de la reponse Cvoquee globale dfie a un stimulus ptripherique rep& tel que click, flash de lumiere, choc sur la patte semble etre proportionnelle au degre d’augmentation de I’activite preexistante des unites. On montre que l’activation Clectrique du cortex frontal dans les preparations anesthtsiees a les memes effets que l’attention chez I’animal eveille sur I’activitd aussi bien globale que cellulaire au niveau du cortex d’association. Zusammenfassung-Katzenexperimente an frei beweglichen Tieren mit Oberflachen und Tiefenableitungen des EEG und von einzelnen Zellen des Gehirns a) aus Assoziationsfeldern (Gyrus suprasylvius und Gyrus anterior lateralis) und b) aus den spezifischen primlren (akustischen, optischen, somatosensiblen) Areae. Wenn ein Tier sich einem ne~en Reiz zuwendet, nimmt die Zelltltigkeit im Assoziationscortex selektiv zu. Gleichzeitig tritt eine deutliche Verminderung der corticalen Reizantworten und der Antworten von einzelnen Zellen auf, wie sie vorher und wlhrend des ganzen Versuches gegeniiber einem eintiinig wiederholten Reiz bestanden, der wlhrend der PrIsentierung des neuen Reizes weiterlauft. In den primlren sensorischen Rindenfeldern dagegen findet sich unter denselben Redingungen keine Anderung in der St&kc der spontanen Zelltltigkeit wlhrend eines neuen Reizes, lediglich eine kleine Zunahme der corticalen Reizantworten und der Einzelzellantworten auf die fat tlaufende eintonige Reizung. Elektrische Reizung det Stirnhirnrinde (bei narkotisierten Tieren) fuhrt ZLI einem Bhnlichen Effekt wie Aufmerksamkeitszuwendung auf corticale und Einzelzellantworten in assoziativen Rindenfeldern und primaren sensorischen Rindenfeldern; sie scheint aber die spontane Zelltltigkeit nicht ZLI beeinflussen. Del- Autor mochte die Wirkung eines neuen Reizes auf die corticalen Antworten im Assoziationscortex auf emen aktiven Hemmungsvorgang zuriickftihren; der Versuch mit der etektrischen Reizung der Stirnhirnrinde, bei der eine allgemeine Zunahme der Zelltltigkeit im assoziativen Cortex nicht auftritt spricht jedenfalls dafiir, da’3 cs sich nicht urn einen Okklusionseffekt handelt.
‘33
1969,
Vol. 7,
pp.
217 to 233.
Pergamon Press.Printed in England
THE ROLE OF SYNAPTIC INHIBITORY MECHANISMS IN NEUROPSYCHOLOGICAL SYSTEMS* RICHARD F. THOMPSON
In collaboration
with :
LEWIS A. BETTINGER~, HERMAN BIRCH, PHILIP M. GROVES
and KATHLEEN S. MAYERS Department
of Psychobiology,
University of California, Irvine, California, U.S.A.
Abstract-Possible synaptic mechanisms that could produce “inhibition” of the output of a limited neural system, such as the response of a given pool of neurons, are considered. A particular example of inhibition, the reduction in amplitude of the gross evoked cortical It polysensory association response that occurs during behavioral attention, is analyzed. appears that when the animal (cat) attends to a novel stimulus, the ongoing level of activity of individual neurons in association cortex increases markedly. The concomitant reduction in amplitude of the gross response evoked by a repeated peripheral probe stimulus (click, light flash, or forepaw shock) appears to be proportional to the degree of increase in ongoing unit activity. Electrical activation of frontal cortex in the anesthetized preparation is shown to replicate effects of attention in the waking animal on gross and unit activity in association cortex. IN PREPARING this paper I jotted down a few ways in which the term “inhibition” has been used. I stopped when the list reached about twenty. It is clear that the word can be used to refer to virtually anything in relation to a change in almost any type of measure or phenomenon. There are at least four different levels of common usage in neurobiology: (1) behavioral, (2) generalized brain state, (3) interactions of systems within the brain, and (4) specific synaptic actions. All four levels are illustrated by the papers of this symposium. WARREN is concerned with the role of frontal cortex in behavioral response inhibition in go-no go situations; KIMBLE considers the neural substrates of generalized internal inhibition; RHODES discusses inhibitory interactions among brain systems as they influence the EEG, and I will include consideration of inhibitory synaptic actions. Interrelations among these various levels of “inhibition” are not predictive. Thus, if we consider behavioral response inhibition in relation to synaptic actions on motoneurons, it is clear that both making a response and withholding a response involve excitatory and inhibitory synaptic actions. Synaptic inhibition can lead to the presence or the absence of a response and occurs in both. It is to be assumed that interactions among systems within the brain, in the context of generalized internal state, determine the patterns of
* Supported in part by Research Grant NB-02161 from the National Institutes of Health and Research Scientist Award MH-06650 from the National Institute of Mental Health. The technical assistance of Sarah Beydler and Margaret Westwell is gratefully acknowledged. t Present address: Department of Psychology, Vanderbilt University, Nashville, Tennessee. 217
218
rt.
F. THOMPSON,
L.
A.
RElTINC;EK,
El.
hX
P.
M.
GKOVtS
aid
K.
s.
hdAYF.KS
synaptic actions that lead to a given behavioral response. However at present this is more an assertion of faith than a statement of fact. If we restrict usage of the term “inhibition” to synaptic processes of inhibition in the mammalian central nervous system, there are perhaps two basic types, postsynaptic inhibition and presynaptic inhibition. (“Remote” inhibition, to the extent that it occurs, is probably a special case of postsynaptic inhibition.) Postsynaptic inhibition is the best known, involving a chemical synaptic action resulting in a temporary hyperpolarization of the postsynaptic membrane. Presynaptic inhibition is actually a case of postsynaptic excitation acting on presynaptic terminals to produce a partial depolarization which in turn results in a smaller postsynaptic response. A virtually unlimited number of possibilities occur if we attempt to relate these two neural processes of inhibition to the output of even a limited neural system, e.g. the response of a given pool of neurons measured as nerve discharges or a gross evoked response. A few examples of inhibition are indicated schematically in Fig. I. The large circle represents the output neurons. (A) shows direct inhibition, (B) indicates inhibition acting on an excitatory interneuron, (C) shows presynaptic inhibition, (D) indicates excitatory input acting on an inhibitory interneuron, (E) shows inhibition of an inhibitory
Fiti. I. Highly simplified schematics of a few possible excitatory and inhibitory synaptic interconnections in simple input-output systems (A-F). The large circle represents output neurons and the vertical arrows indicate increased or decreased output lo the excitatory (E) input when the inhibitory input (I or “E” or “1”) is also activated. G illustrates two excitatory inputs producing facilitation or occlusion.
interneuron, which results in a net increase in cxcitabilily, and (F) indicates inhibition of an excitatory interneuron that itself acts to produce presynaptic inhibition for a net excitatory effect. Finally, (G) indicates that it is even possible to inhibit the output of a system by purely excitatory synaptic processes, e.g. occlusion. If two excitatory inputs act on a pool of neurons, an evoked output from one input may be reduced to the extent that the cells are being fired from the other input, depending on the timing of the two inputs. In our own work we have been interested in the decrease or inhibition of evoked responses in nonspecific association areas of the cortex of cat during behavioral attention [l-4]. We will use this effect as an example of inhibition and describe some of our work attempting to track down the underlying processes responsible for the inhibition. Figure 2 shows examples of gross evoked association responses to repeated click, light Ilash :111d skin shock recorded as superimposed individual traces from chronically implanted
TIIE ROLE OF SYNAPTIC’
INHIBITORY
I.
1
r
FOREPAW SHOCK
IN NEUROPSYCHOLOG1CAL.
SYSTEMS
219
.
A
CLICK
MECMANISMS
I
I
I
I
I
I
I
.
I
t
IO0
Ins.<
FIG. 2. Examples of evoked responses recorded from association cortex in normal waking cats. Each response is approximately 50 superimposed individual traces. A-E, responses to click stimulatidn; A, C,area PMSA: R, 6, area AMSA: E. area ALA. F-J, responses to iusilateral forepaw shock stimulation: F, area AMSA: G-J. area PMSA. K-O. responses t; light Bash siimulation; K-N, areaPMSA; 0, area AMSA. Data presented here are from ten different animals. Amplitude calibration line to left of each multiple trace represents 100 pV. Stimulus presentation, indicated by dot below each multiple trace, occurs 10 msec after beginning of trace. In this and subsequent figures, upward deflection represents positivity.
gross bipolar surface to depth electrodes in posterior association areas (middle syprasylvian and anterior lateral gyri) in the normal waking cat. The animals were sitting quietly with eyes open. Effects of novel stimuli on evoked association responses to repeated peripheral probe stimuli are illustrated in Fig. 3. In all cases there is a marked inhibition of responses to the repeated probe stimulus during novel stimulation, regardless of modality. The effects of novel stimuli of all three modalities on cortical association responses evoked by probe stimuli of all three modalities are summarized in Fig. 4. Data are from a total of eight cats. In all cases there is a significant reduction in evoked response amplitude during novel stimulation, independent of modality. The time course of recovery of a click evoked association response following novel stimulation is shown for three different novel stimuli in Fig. 5. It would appear that food is most interesting and the experimenter least interesting to the cat. Note that recovery of the response amplitude to control level requires one ot more minutes. Nonspecific association responses are at some points dependent on degree of activity in primary sensory systems. The simplest hypothesis would be that the attentive inhibition of association responses is secondary to decreased responsiveness in primary sensory systems, perhaps of the sort described by HERNANDEZ-PEON [5]. In the auditory system, for example, evoked activity could be reduced by alterations in sound field intensity (as described by MARSH et al. [6]), middle ear muscle contractions, perhaps by efferent control systems, central actions of reticular formation, etc.
R. F. THOMPSON, I_.A. BETTINGER, H. BIRCH. P. M. GROWS
TEST
CONTROL A.
FOREPAW SHOCK
B.
CLICK
C.
LIGHT
0.
I .
.
I FLASH
and K. S. MAWRS
4 .
CLICK
Fro. 3. Effects of behavioral arousal and attention on evoked cortical association responses. A, suppression of association response following increase in bodily activity (control -sitting quietly, eyes open, test=standing quietly, eyes open); response evoked by ipsilateral forepaw shock stimulus. B, suppression of association response by “novel” visual stimulus (controlsitting quietly, eyes open, test-same posture during sight of food); response evoked by click stimulus. C, suppression of association response by “novel” auditory stimulus (control-z sitting quietly, eyes open, test-same posture during growling sound); response evoked by light flash stimulus. D, suppression of association response by sight of experimenter (control -=sitting quietly, eyes open, test=samc posture during sight of experimenter); response In each case the test response was recorded from the same electrode evoked by click stimulus. in the same animal within four minutes following recording of control response. Each pair of responses recorded from different animal; all records from area PMSA. Amplitude calibration 100 pV.
THE
ROLE
OF SYNAPTIC
1NHIBITORY
MECHANISMS
Novel
IN NEUROPSYCHOLOGICAL
stimulus
modality
Auditory Cortical evoking
during
SYSTEMS
test Toct~le
Visual
response
F-----l
stimulus
8. 60 40
CLICK
20 r
z-
LIGHT
FOREPAW
n Control
Test
Control
Test
Control
Test
Control
Test
Control
Test
Control
Test
Control
Test
FLASH
SHOCK
FIG. 4. Summary of mean evoked response amplitudes to “probe” stimuli before (Control) and during (Test) presentation of “novel” stimuli (auditory=growling sound; visual=rat in jar; tactile=air jet delivered on back vs away from back).
experlmenteL-x
20 : g
CitrolNo;ey
40 Time
food
60 after
80 novel
120
100 stimulus
140
kec)
stimulus
FIG. 5. Time course of recovery of evoked response amplitudes to a click probe stimulus following 10 set presentations of various novel stimuli. (Each point during recovery is the average of 20 successive responses.)
221
R. F.
_77-l ._-
TtIOMI5ON,
L. A. Br ~1 tmt-R,
H. Bm(‘tI. I’. h/l. GROWS
and t;. S. MAYERS
These possibilities were evaluated by comparing changes in evoked responses in posterior association and primary auditory areas of the cortex using a free field click and a click delivered through an earspeaker implanted in the contralateral eutcrnal ear (Fig. 6).
FIG. 6. EFects of novel stimulalion (rat in jar) on amplirt&x of asxxiation and primary evoked responses to click stimulation as a function of method of stimulus presentation. A.
Mean amplitudes of association responses recorded from supt asylvian gyrLls (dot on inset drawing) before (control) and during novel stimulation. Responses are significantly dep-essed for both free field and earspeaker sound presentations. B. Mean amplitudes of primary auditory evoked responses (dot in inset drawing) before (control) and during novel stimulation. The response is significantly depressed with a free field click presentation but significantly etrhonrerl with carspeaker presentation.
Note there is a significant and comparable decrease in the association response under both types of stimulus presentation during novel stimulation. However, the primary evoked potential (amplitude of initial surface positivity) decreases only slightly under free field conditions and increases slightly (but significantly) with earspeaker click during novel stimulation. Consequently, the decrease in association responses during attention is not due to changes in primary sensory systems. This also rules out changes in general cortical excitability such as generalized arousal. A general cortical factor ought to influence both primary and association cortical responses. A train of shocks to frontal cortex in the chloralosed cat produces the same differential effects on cortical evoked responses to subsequent peripheral stimuli as does attention in the waking animal [7, 81. Figure 7 illustrates these effects of a prior frontal shock train (40 pulses at 200/set delivered through two wire electrodes of 2 ~11~11separation 3 mm anterior to the cruciate sulcus) on light flash evoked cortical association responses (area PMSA) and primary visual (area VI) responses. Note that as shock intensity is increased the association response amplitude decreases and the amplitudes of the various components of the primary visual response, particularly the later components, increase. Figure 8 illustrates the effects of frontal shock on a polysensory cell recorded from association cortex in the chloralosed cat (glass coated tungsten microelectrode). Note that the cell fires to all stimuli, singly and in combinations, in the absence of frontal shock, but does not respond to any stimuli following frontal shock (shock train terminated
THE
RO1.E OF SYNAPTIC
INHIBITORY
?LASIl ASSOC.
COQTICALsrlocK IITBSITI
(ALA)
itgSPoHSE
MECHANISMS
IN NFUROPSYCHOLOGICAL
223
SYSTEMS
SfmuLIJS ?RIJlARY
(VI)
RKSPUWE
(VOLTS)
0
5
10
20
FIG. 7. Effects of prior frontal shock train on cortical association (area PMSA) and primary visual (area VI) responses evoked by light flash in chloralosed cat.
NO A-
FRONTAL
SHOCK
SHOCK
Am
AT
rtreJpl
AVT
IV
AT
-
AVT
-
25
-
m set
FIG. 8. Response of polysensory unit in suprasylvian gyrus of chloralosed cat to auditory (A), visual (V), and tactile (T) stimuli alone and in combination with and without shock train to precruciate area prior to stimulus presentation (train of pulses at 300/set, 40 msec duration, terminating 50 msec before peripheral stimulus). Peripheral stimuli occur at beginning of trace.
224
R. F. THOMPSON,L. A. BETTINGER,H. BIRO{, P. M. GROVES and K. S. MAYORS
50 msec prior to presentation of peripheral stimuli). Enhancement of the responses of a single neuron in primary visual cortex following frontal shock train is shown in Fig. 9. The numbers to the left of each trace indicate the probability of occurrence of that particular response to light flash (i.e. no spike, one spike, two spikes, etc.).
NO
.3
-
.5
-
SHOCK
FRONTAL
.2
SHOCK
-
25
m set
FIG. 9. Responses of unit in primary visual cortex of chloralosed cat to flash with and without prior frontal shock train (see Fig. 8 caption). Numbers to the left of each trace indicate probability of each type of response illustrated (i.e. the proportion of times each type of response occurred during a series of flash presentations).
A recent study by GOLDRING et aE. [9] suggests a rather unfortunate alternative explanation for the inhibition of association responses during attention in the waking cat: They were unable to record association responses in normal waking cats under any conditions using computer averaging techniques. In order to investigate this question further we have completed a series of experiments on normal waking animals recording both gross and single cell responses in association cortex using a chronic micromanipulator system of the same general type described by HUBEL [lo] and EVARTS [l 11. A permanent receptacle chamber was affixed to the skull; during a recording session glass coated tungsten microelectrodes of l-3 p tip diameters with impedances ranging from 2-20 megohms were inserted. Recording was monopolar against a distant indifferent. On-line averages of gross evoked responses and single and multiple unit poststimulus histograms were obtained using a Fabri-Tek Model 1062 and a Nuclear-Chicago Model 7100 computers. All unit data were also recorded on tape for subsequent computer analysis. Unless otherwise noted, all data were obtained when the cats were awake but “inattentive,” i.e. sitting quietly or lying down head on forepaws with eyes open. Examples of computer averaged gross evoked responses to click, light flash and ipsilateral forepaw shock recorded monopolarly from association area PMSA are shown in Fig. 10. Surface responses (Fig. 10, Al, Bl, Cl) show the moderately long latency initial surface positivity characteristic of association responses in the normal waking and chloralosed preparations [12, 41. As the microelectrode is passed down through the cortex, the polarity of the initial component reverses and exhibits a clear initial negativity in the depths of the cortex (Fig. 10, A2, B2, C2). An example of the depth distribution of the evoked association responses to light flash stimulation is shown in Fig. Il. The depth distributions of the responses closely resemble the depth distributions of association responses in the chloralosed preparation [12]. This reversal of polarity through cortex is characteristic of a locally generated intracortical field (i.e. a cortical dipole).
THE
ROLE
OF SYNAPTIC
1NHIBITORY
MFCHANISMS
IN NEUROPSYCHOI.OGICAL
SYSTEMS
225
FIG. 10. Averaged gross evoked association responses recorded from the surface (Al, Bl, Cl) and approximately 2.4 mm below the surface (A2, B2, C2) of cortex in association area PMSA m waking cat to click (Al, A2), light flash (Bl, B2) and ipsilateral forepaw shock (Cl, C2). Each tracing is the average of 256 successive responses.
FIG. 11. Depth distribution in cortex of area PMSA of averaged association response to light flash in waking cat. Responses (A-F) are recorded at successive 0.4 mm intervals from surface (A) to a depth of 2.4 mm (F). Each tracing is the average of 256 responses.
Individual examples of unit activity in area PMSA evoked by various peripheral stimuli are shown in Fig. 12. These data are illustrative of the multiunit data used for computation of poststimulus histograms. The majority of units tended to fire at relatively slow and variable spontaneous rates in the absence of stimulation. Note that the largest unit in Fig. 12 tends to fire within a given restricted latency range for each type of stimulus. However, the smaller units appear to have much broader latency ranges. In fact, in many cases it is not possible to distinguish between spontaneous unit activity and unit responses evoked by the stimulus on the basis of this type of individual response data.
226
R. F.
THOMPSON,L. A. BETTINGER,FI. BIRCH,
50
H
m set
P. M.
GROVES and
K. S. M.\ut-ws
I iooyv
FIG. 12. Examples of unit responses in area PMSA in waking cat to click (A), light flash (V), ipsllateral forepaw shock (T) and simultaneous combinations of these (AV=click-flash, AT=click-shock, VT--flash-shock, AVT=click-flash-shock). Spontaneous activity is indicated in tracings with no stimuli (NS).
Comparisons of averaged gross evoked potentials and unit poststimulus histograms in association area PMSA to peripheral stimuli are shown in Fig. 13. Each of these were direct, simultaneous on-line averages of 1024 successive gross responses and the corresponding unit discharges recorded from a depth of approximately 1 mm below the surface of the cortex. Only the two or three largest unit responses were passed by the discriminator for this analysis. Note that the periods of maximum probability of unit discharge (peaks of poststimulus histograms) tend to occur just after the peaks of the negative components of the evoked responses. Effect of stimulus repetition rate is illustrated in Fig. 13A (Lsec interstimulus interval) and 13B (O-5-see interstimulus interval) for light flash. Note that the faster repetition rate results in a marked depression of the amplitude of the gross response and the amplitude of Response to click stimulation is illustrated in Fig. 13C the poststimulus unit histogram. and response to a simultaneous light flash-click stimulus is shown in Fig. 13D. Note that the post stimulus histogram shows a later peak corresponding to a later negativity in the averaged In all cases there is a close and gross response to the combined visual-auditory stimulus. consistent relationship between the gross evoked response waveforms and the periods of maximum unit activity following the stimulus, the histogram peaks occurring at (Fig. I3B) or more commonly just beyond (Fig. 13, A, C, D) the negative peaks of the gross responses when only the largest amplitude spikes are included in the analysis. The averaged gross evoked responses illustrated in Fig. 13 are essentially identical in latency and waveform to gross responses recorded from the same depth in area PMSA in the chloralosed cat [12]. Currently there is some controversy concerning the form of the relationship between the gross evoked cortical potential and the probability of unit discharge to a peripheral stimulus.
THE
ROLE
OF SYNAPTIC
INHIIlITORY
MECHANISMS
IN NEUROPSYCHOLOGICAL
SYSTEMS
227
BI
50 msec FIG. 13. Comparisons of simultaneously recorded averaged gross evoked responses (upper tracings of each pair) and unit poststimulus histograms (lower tracings of each pair) from area PMSA in normal waking cat; microelectrode approximately 1 mm below surface of cortex. Al, 2, response to light flash with an interstimulus interval of 2 sec. Bl, 2, response to light flash with an interstimulus interval of 0.5 sec. Cl, 2, response to click (2 set intervals). Dl, 2, response to simultaneous click-flash (2 set intervals). Only the largest spikes were in&ded in the unit analysis. Each tracing is the average of 1024 successive responses.
Thus, Fox and O’BRIEN [13] reported a close correspondence between the peak of the unit histogram and the positive peak of the evoked potential in visual cortex. More recently, Verzeano and associates have presented evidence indicating that in lateral geniculate body
228
K. F. THOMPSON, L. A. BETTINGER, H. BIRC~I, P. M. Gaovrs
and
K. S. MAYERS
FIG. 14. Comparison of gross evoked association response (A), first derivative of gross response (B) and poststimulus unit histogram CC) to light flash. Both larger and smaller spikes included in unit analysis. Each tracing is the average of 1024 successive responses.
and visual cortex, if only the largest amplitude spikes are included in the analysis, the unit histogram peaks occur a few milliseconds after the negative peak of the gross potential. sometimes on the negative peak of the gross response, but most frequently on its positive slope; however, if both larger and smaller amplitude spikes are included in the unit analysis, the histogram peaks correspond closely to the negative peaks of the first derivative of the gross potential [ 14, 151. We completed a comparable analysis for unit activity in association area PMSA to light flash stimulation. Data were obtained under identical conditions to those for the data of Fig. 13, except that the discriminator level was lowered to include both smaller and larger spikes. Figure 14 illustrates the gross evoked response (A), the first derivative (B), and the poststimulus histogram (C) obtained. Note that the region of maximum unit response probability corresponds to the region of maximum negative peak of the first derivative of the evoked potential. Note also that there is a more pronounced and Iongel duration decrease in unit activity following the period of maximum response under these conditions. So far we have demonstrated that there appears to be a relatively invariant relationship between amplitude of the gross evoked potential and probability of cell discharge following a peripheral stimulus in association cortex. The more important question concerns the effects of behavioral attention on gross and unit activity. Figure 15 illustrates a comparison of gross evoked responses and multiple unit poststimulus histograms recorded from area PMSA in the normal waking cat in the inattentive and attentive states. In this experiment the peripheral stimulus was a repeated earspeaker click. Figure 15A is the surface gross association response to click (indicated by arrow) in the normal inattentive cat. Figures 15B
THE ROLE
OF SYNAPTIC
INHIBITORY
MECHANISMS
IN NEUROPSYCHOLOGICAL
SYSTEsMS
229
FIG. 15. Effect of attention on averaged earspeaker click evoked gross responses and unit poststimulus histograms in association cortex (area PMSA) in normal waking cat. A, surface gross response; B, gross response 1 mm below surface of cortex; C, multiple unit poststimulus histogram corresponding to B; A, B, C, control condition, animal sitting quietly with eyes open. D, gross response and E, poststimulus histogram under same conditions as B, C Except that animal given series of novel visual stimuli. Note marked increase in level of ongoing “spontaneous” unit activity during attention (arrcw from baseline to tracing in E) in contrast to control state (arrow from baseline to tracing in C). Each tracing average of 256 successive responses.
and C are the depth gross response and corresponding unit poststimulus histogram under the same conditions. Figures 15D and E illustrate the marked reduction in both the gross evoked response and the unit poststimulus histogram during attention to novel visual stimuli. Note the marked increase in baseline activity in cells during attention (arrows from baseline to spontaneous level of unit activity in C (inattentive) and E (attentive) states). The gross evoked and unit activity to the repeated probe stimulus are reduced in proportion as the ongoing level of discharge of cells increases during attention to novel stimulation. The initial depth negativity, which corresponds to the initial surface positivity, probably represents summed extracellularly recorded EPSPs. Thus the decrease during attention is a genuine instance of inhibition in that it is a reduced synaptic excitation. The cells in association cortex of cat behave very much like SOKOLOV’S hypothetical novelty cells [16]. They respond a great deal to the first few presentations of a novel stimulus, but habituate rapidly. During this time they respond very little to a long repeated peripheral probe stimulus. In the absence of a novel stimulus, certain of the cells fire fairly regularly to the repeated probe stimulus. Assuming common underlying generators for gross and unit responses, the increased ongoing activity of cells during attention may result in fewer cells being available to respond to the repeated probe stimulus and hence a marked reduction or inhibition of the gross evoked association response. As a control procedure, it is necessary to show that this type of “novelty” effect is not general to both association and primary sensory systems. Figure 16 illustrates a comparable experiment recording evoked gross and unit activity in the depths of the auditory cortex of the normal waking cat in the inattentive (A) and attentive (B) states to earspeaker click. Note that, in contrast to the inhibition of the association response, there is a small increase in the initial large negative component of the evoked response and a small increase in the
230
R. F.
THOMPSON:
1..
A.
t
I&T-I
IIGI.II,
H. BIRCII. I’. M. Gkovrs and K. S. hl,~v~.ns
--_ J
H 50 mle‘ FIG. 16. Effect of attention on averaged earspeaker click evoked gross responses and unit poststimulus histograms in primary auditory cortex (dorsal portion of area AI). A, gross response (1) and unit histogram (2) recorded 1 mm below surface of cortex during control state (animal sitting quietly with eyes open). B, gross response (1) and unit histogram (2) under identical conditions to A except that animal given series of novel visual stimuli. Each tracing average of 256 successive responses.
poststimulus histogram during novel visual stimulation, but HO clear churge in the level of ongoing unit activity under the two conditions. The increase in primary sensory evoked response amplitude described here for cat is consistent with recent data on monkey reported in this volume by PRIBRAM [17]. Returning to the effects of frontal stimulation, Fig. 17 illustrates the changes in the gross response and multiple unit poststimulus histogram evoked in association cortex by a light flash stimulus following a shock train to frontal cortex in the anesthetized preparation. Figure 17A is control responses and Fig. 17B shows reductions following frontal stimulation. Note that here, in contrast to effects of attention on units in waking cat, there is no change in baseline activity. Figure 18 shows the enhancement of the gross response and a corresponding increase in the evoked poststimulus histogram in primary visual cortex to light flash stimulus following frontal stimulation. Again, there is no obvious change in ongoing level of cellular activity. Finally, Fig. 18 illustrates the same finding for response to click in the primary auditory cortex. To summarize, when an animal attends to a novel stimulus, there is a marked and selective increase of cell firing in association cortex. Concomitantly, there is a substantial inhibition or reduction in evoked gross and unit responses to a long repeated probe stimulus. In contrast, in primary sensory areas of the cortex there is little or no change in ongoing cellular activity during novel stimulation but small increases in evoked gross and unit responses. Shock to frontal cortex mimics effects of attention on evoked gross and unit responses in association and primary areas of the cortex but, at least in the anesthetized preparation, does not seem to influence the level of spontaneous activity of cells.
THE ROLE OF SYNAPTIC
INH!HllORY
MECHANlShlS
IN NEUROI’SYCI1DLO(jIC’\L
SYSTLMS
1
-
A
‘v B
PIG. 17. Effect of frontal shock train on gross responses (Al, Bl) and unit poststimulus histograms (A2, B2) in association cortex (area PMSA) of chloralosed cat; light flash stimulus. A, control state; 8, following frontal shock train. Each tracing average of 16 successive responses.
FIG. 18. Effects of prior frontal shock train on gross responses (Al, Bl) and unit poststimulus histograms (A2,82) in primary visual cortex (area VI) to light flash stimulus. A, control state: B, following frontal shock train. Each tracing average of 16 successive responses.
232
R. F. THOMPSON, L. A. B~TTINGEI<, H. BIRCH, P. M.
C~ROVES
and K. S. MAY~KS
FIG. 19. Effects of prior frontal shock train on gross responses (Al, Bl) and unit poststimulus histograms (AZ, B2) in primary auditory cortex (area AI) to click stimulus. A, control state; B, following frontal shock train. Each tracing average of 16 successive responses.
REFERENCES of evoked cortica! association responses on behavioral I. SHAW, J. A. and THOMPSON, R. F. Dependence variables. P.rq’chonom. Sci. 1, 153-l 54, 1964. responses and 2. SHAW, J. A. and TFIOMPSON. R. F. Inverse Ielation between evoked cortical association behavioral orienting to repeated auditory stimuli. P.~~chonom. Sci. 1, 399400, 1964. of attention. In Atfention: ,4 Behaviornl 3. THOMPSON, R. F. and BETTINGBR, I.. A. Neural substrates Anahsis. D. MOS~OFSKY (Editor). Appleton-Century-Crofts, New York, 1969. In press. correlates of evoked activity recorded from association 4. THOMPSON, R. F. and SHAW, J. A. &havioral areas of the cerebral cortex. J. conm. phvsiol. Psvchol. 60, 329-339, 1965. correlates of habituation and other manifestations of plastic 5. HERNAN~EZ-PENN, R. Neurophysidlo$al inhibition. Electroenceph din. Newophysiol. 12, 41-58, 1960. on evoked auditory 6. MARSH, .I. T., WORDEN, F. G. and HICKS, L. Some effects of room acoustics potentials. Science 137, 280-284, 1962. control of specific and nonspecific sensory 7. TIIOMPSON, R. F., DFNNEY, D. and SMITH, 11. Cortical projections to the cerebral cortex. P.syc/zononr Sri. 4, 93-94, 1966. 8. BET.CINGER.L. A.. BIRCH. H.. GROVES. P. M.. MAYER% K. S. and THOMPSON, R. F. Effects of stimulation of frontal cortex on neuronal activity in association and sensory areas of the cortex. Psychonow. Sri. 12, 167-168. responses from association areas in waking 9. GOLDRING. S.. SHEPTAK. P. and KARAHASHI. Y. Averaged cat. Electroenceph. din. Nerrroph)~siol. 23, 241-247. cats. J. Physiol. 147, 226-238, 1959. 10. HUBEL. D. H. Single unit activitv in striate cortex of unrestrained and evoked discharge of single units in I I. EVARTS, E. V. Effects of sleep and waking on spontaneous visual cortex. Fe& Proc. Fe&. Am. Sots. esp. Biol. 19, 828-837, 1960. of auditory, somatic sensory, and II. THOMPSON, R. F., JOHNSON, R. H. and HOOPES J. Organization visual projection to association fields of cerebral cortex in cat. J. Newoph),sio/. 26, 343-364, 1963. of evoked potential waveform by curve of probability of 13. Fox, S. S. and O’BRIEN, J. H. Duplication firing of a single cell. Science 147, 888, 1965. and 14. VERZEANO, M., DILL, R. C., VALLEC~I.I.E. E., GROVES, P. and THOLIAS. J. Evoked responses neuronal activity in the lateral geniculate. E.rperientiu 24, 696-698, 1968. neuronal activity and stimulus 15. DILL, R. C., VALLECALLE. E. and VERZEANO, M. Evoked potentials, intensity in the visual system. Phvsiol. Behav. 3, 1968. E. N. Neuronal modelsand the orienting reflex. In The Cenfrnl Nervous System am/ Behavior. 16. SOKO&. M. A. B. BRAZICIC (Editor), Vol. 111. Macy Foundation, New York, 1960. 196’). Il. PRIBRAM, K. H. The primate frontal cortex. Neurop.~ycho/ogia 7, 259-266,
THE
ROLE
OF SYNAPTIC
INHIBII-ORY
MLCHANISMS
IN NEUROPSYCliOLOGlCAL
SYSTEMS
Resum&On considtre les mecanismes synaptiques possibles qui pourraient prod&-e 1’“inhibition” de la sortie d’un systeme nerveux limit& telle que la reponse d’une assemblee don&e de neurones. On analyse un exemp!e particulier d’inhibition, la reduction d’amplitude des reponses evoquees globales du cortex d’association polysensorielle qui survient durant le comportement d’attention. 11apparait que lorsque I’animal (chat) recoit un nouveau stimulus. le niveau preexistant d’activite des neurones individuels dans le cortex d’association s’accroit de facon marquee. La reduction concommittante d’amplitude de la reponse Cvoquee globale dfie a un stimulus ptripherique rep& tel que click, flash de lumiere, choc sur la patte semble etre proportionnelle au degre d’augmentation de I’activite preexistante des unites. On montre que l’activation Clectrique du cortex frontal dans les preparations anesthtsiees a les memes effets que l’attention chez I’animal eveille sur I’activitd aussi bien globale que cellulaire au niveau du cortex d’association. Zusammenfassung-Katzenexperimente an frei beweglichen Tieren mit Oberflachen und Tiefenableitungen des EEG und von einzelnen Zellen des Gehirns a) aus Assoziationsfeldern (Gyrus suprasylvius und Gyrus anterior lateralis) und b) aus den spezifischen primlren (akustischen, optischen, somatosensiblen) Areae. Wenn ein Tier sich einem ne~en Reiz zuwendet, nimmt die Zelltltigkeit im Assoziationscortex selektiv zu. Gleichzeitig tritt eine deutliche Verminderung der corticalen Reizantworten und der Antworten von einzelnen Zellen auf, wie sie vorher und wlhrend des ganzen Versuches gegeniiber einem eintiinig wiederholten Reiz bestanden, der wlhrend der PrIsentierung des neuen Reizes weiterlauft. In den primlren sensorischen Rindenfeldern dagegen findet sich unter denselben Redingungen keine Anderung in der St&kc der spontanen Zelltltigkeit wlhrend eines neuen Reizes, lediglich eine kleine Zunahme der corticalen Reizantworten und der Einzelzellantworten auf die fat tlaufende eintonige Reizung. Elektrische Reizung det Stirnhirnrinde (bei narkotisierten Tieren) fuhrt ZLI einem Bhnlichen Effekt wie Aufmerksamkeitszuwendung auf corticale und Einzelzellantworten in assoziativen Rindenfeldern und primaren sensorischen Rindenfeldern; sie scheint aber die spontane Zelltltigkeit nicht ZLI beeinflussen. Del- Autor mochte die Wirkung eines neuen Reizes auf die corticalen Antworten im Assoziationscortex auf emen aktiven Hemmungsvorgang zuriickftihren; der Versuch mit der etektrischen Reizung der Stirnhirnrinde, bei der eine allgemeine Zunahme der Zelltltigkeit im assoziativen Cortex nicht auftritt spricht jedenfalls dafiir, da’3 cs sich nicht urn einen Okklusionseffekt handelt.
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