Cortical incremental responses to thalamic stimulation

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C O R T I C A L I N C R E M E N T A L RESPONSES TO T H A L A M I C S T I M U L A T I O N

J. SCIILAG AND J. VII,I.ABI,ANCA* Department of Anatomy am/ Brabt Research ln.stitute, Univer.sity o] Califi~rnia, Lo.~ Angeh,.~, Calif. L.S.A.)

IN I'ROI)UCTION Caudate stimulation can induce a particular type of motor inhibition affecting only complex learned movements and sparing the performance of simple acts~L Identical effects can be produced - - perhaps even more readily' by' certain thalamic stimulations;," L In both cases, behavioral impairment is accompanied by the appearance of 8-12/see st, trace-negative potentials on the frontal cortex. The presence of 8--I 2"see activity in this frontal location seems more than a mere coincidence in that it appears there naturally--i.e., without any electrical stimulus to the brain---when animals withhold responses during extinction procedures a5. There are ways to suppress it, t\~r instance by surgically interrupting thalamo-orbitofrontal connections. Then, a particular syndrome is created, of which hyperactivity and distractability are dominant features e°. We are interested in the mechanism of cortical surface-negative potentials since they appear to be intimately related to an aspect of forebrain inhibition. Best-known among cortical surface-negative potentials are the so-called 'recruiting responses elicited by repetitive stimulation of certain thalamic loci. Dempsey and Mo,'ison'sl', e~ original description led to a conceptualization of the thalamic "nonspecific' system as something special. Repetitive stimulation of 'nonspecific' nuclei induces surface-negative (recruiting) responses having a very long latency and a broad (diffuse) distribution on the cortical surface, whereas repetitive stimulation of other thalamic nuclei (e.g., the sensory relay nuclei) gives rise to cortical positivenegative (augmenting) responses in their respective projection areas. This is the accepted view, supported by firmly established observations. We have been impressed, however, by the fact that both kinds of potentials can be simultaneously evoked at different cortical sites by the same thalamic stimulus. Many investigators, we think, have made this observation. It may have no particular signiticance since a thalamic electrode can be located so as to stimulate several close * U.S. Public tlcalth Service International Postdoctoral Fellow (11:05 TW998) on leave from Czitedra de l-:isiopatologia, Escttela de Medicina, Universidad de. Chile, Santiago (Chile). Brabz Research, 6 (1967) 119 -142

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structures at the same time, thereby achieving this result, if this is the correct interpretation, we then have to admit the presence of systematic bad luck in our thalamic placements for, consistently, augmenting-like and recruiting-like responses appeared simultaneously in practically all of our experiments an. In particular, extensively distributed, typical recruiting responses were always accompanied by initial positive responses in the orbitofrontal region of the cat's cerebral cortex :~:~. This tinding prompted us to consider that, perhaps, cortical surface-negative and initially surfacepositive evoked potentials are not such independent phenomena as previously claimed. The present experiments were designed to test the validity of this hypothesis, and to explore its implications.

METHODS

Experiments were performed on 45 cats. The general procedures for surgical preparation, stimulation, and recording have been previously describeda~. 3:~. Yet a few points need to be restated here because of their importance in evaluating the data. The use of general anesthetics (e.g., barbiturate or chloralose) was avoided since they alter considerably the electrical phenomena under study. The animals were under local anesthesia, and all necessary precautions were taken to prevent their experiencing pain. They were immobilized by Fiaxedil injections. When exposed, the brain was immediately covered with mineral oil. Transcortical recording (between a surface silver ball and the extremity of a 150/z stainless steel wire implanted !.5-2.5 mm under the surface at the same point) was the preferred technique for monitoring cortical potentials. Theoretically, this is the best method for deriving local activity because it minimizes the interference of distant dipoles. However, as systematic exploration of an area would have required piercing the cortex too many times, monofocal recording was most often used. Differences in waveform were occasionally noticeable15; therefore, all observations reported here have been repeated using both recording methods. In the figures presented, 4 CRO traces are superimposed to illustrate the relative stability of the responses. Downward deflections correspond to relative positivity (the polarity of cortical potentials is always stated as that at the surface electrode). Instead of showing all responses to a train of repetitive stimulation, a selection has been made (e.g., the I st and the 6th), allowing a clear display of all details in less space. During many experiments, records of potentials were averaged with a Mnemotron CAT or an Enhancetron. Our main concern with regard to thalamic stimulation was to keep it as localized as possible, though intense enough to induce effects which would minimally fluctuate from time to time. The diameter of the concentric electrodes was 0.63 ram, and there was less than 0.5 mm between the uninsulated metallic poles through which pulses of 0.1-0.5 msec duration and 0.05-0.3 mA were applied. All subcortical positions were verified histologically. The following abbreviations are used for the designation of thalamic nuclei: AM, anterior medialis, AV, anterior ventralis; CL, centralis Brain Research, 6 (1967) 119--142

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lateralis; CM, centrum medianum; GL, lateral geniculate; G M , medial geniculate; LD, lateralis dorsalis; LP, lateralis posterior, M D, medialis dorsalis ; N C M , centralis medialis: Pc, PC, paracentralis: RE, reunicns; Rh, rhomboidalis; SbM, submedius: VA, vcntralis anterior; VL, ventralis lateralis; VM, ventralis medialis: VPL, vcntralis postcrolatcralis; VPM, ventralis posteromedialis. RESULTS

(1) Cortical distribution of responses to repetitive thalamic stimulation Let us start with a simple example: the VL nucleus was stimulated at 10/sec and responses were recorded from various cortical sites as depicted in Fig. 1. Within about 2 msec following the 1st stimulus (upper records in each pair of traces), positivenegative potentials appeared on the anterior sigmoid gyrus and on the rostral third of the posterior sigmoid gyrus (points I, 3 and 4), that is on the projection area o f VL.

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Fig. 1. Distribution of cortical responses to 10/see stimulation of the rostral part of VL. In each pair, upper records are responses to 1st stimulus, lower records are responses to 8th stimulus. 4 traces superimposed; surface rnonofocal recordings; surface-negativity upwards in this and all following figures. Not much could be seen elsewhere. But repetition of the stimuli brought about considerable change, illustrated here by the responses to the 8th shock (lower traces).

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The sigmoid potentials increased in peak to peak amplitude. This is the well-known phenomenon of augmentation, the characteristics of which will be specified later. For the moment, we would like to direct attention to events occurring outside the cortical projection area of VL, in particular to those on the suprasylvian, lateral and orbital gyri. Long latency negative waves developed there. From the beginning of the train, they progressively grew, reached their maximum size around tile 8th stimulus, and then declined. Their latency was stable. They were not preceded by an~, positive deflections. They could be considered as being recruiting responses were it not for the fact that the causal stimulus was applied ill a so-called specific nuclet, s ---the VL. By and large, the elicitation of such purely negative potentials by stimulation of specific nuclei was not an exception. Careful exploration of tile cortical surface was often necessary to find them, but they could practically always be found. In Fig. 2, we see the results of repetitively stimulating the G M at 10/see. The traces represent the responses to the 6th stimulus. Positive-negative potentials with no, or very small, initial positive deflections were found on the ectosylvian and posterior suprasylvian gyri. It seemed interesting to inquire as to whether a similar distribution of cortical responses would exist when stimulating any other thalamic site. Fig. 3 summarizes the explorations completed up to now. All the points indicated on these thalamic maps correspond to placements where a 10/see stimulation provoked both kinds of cortical potentials: positive-negative and purely negative. The positive-negative potentials were located within the cortical areas marked by the corresponding signs.

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Fig. 2. Distribution of cortical responses to 10/sec stimulation of the GM (at place indicated in the insert). Monofocal recordings of the responses to the 6th stimulus. Brain Research, 6 (1967) 119-142

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Fig. 3. I,ocation of thalamic points giving both cortical positive-negative and initial negative resp-~nses on stimulation. Thalamic maps according to Jasper and Ajmone Marsan ~s. Approximate site of toci of p~sitive-negative responses are indicated by corresponding signs on the sketches of the brain. The 2 arrows (in planes A9 and AI0) point to the positions of electrodes in cxpcrimcnt illustrated in Fig. 7. The cortical territory o f the negative potentials varied in location and extensi,~n in a complex manner which will be specified later. Regarding the information summarized in this Figure, we wish to make it clear that whenever cortical projections (on the basis of finding short latency positive-negative responses) were observed, the stimulating and recording sitcs were entered in these maps: but every point of the cortex was not explored in every case of thalamic stimulation. Therefore, the map is probably incomplete: it might have happened that a projection area escaped our attention, considering the likely possibility that stimulating a thalamic paint induces positivenegative potentials in more than one region. This might be expected if the stimulated thalamic field encompassed parts of several nuclei. Fig. 3 shows that the observations described here were verified for a number of thalamic stimulations delivered almost anywhere. Stimulation o f the VL, VPL or G M nuclei resulted in positive-negative responses on the motor, somato-sensory and auditory areas respectively. This is in agreement with the literature, except for the finding of initially negative responses in some immediately adjacent regions. There was an exception though: repetitive G L stimulation never induced purely negative potentials, nor was there any progressive augmentation of the responses in the G L projection area on the lateral gyrus. The amplitude of these responses was either large or small in a seemingly unpredictable sequence. We have no explanation to oiler for this peculiarity. Brain Research, 6 (1967) 119-142

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Fig. 4. Distribution of cortical responses to 10isec stimulation in laterodorsal part of MD. Up is top view of anterior pole, down is view of the precallosal part of the mesial face. Transcortical recordings of the responses to the I st (lower traces in each pair) and 6th stimuli (upper traces). Access to the mesial face was obtained after removal of the anterior pole of the contralateral hemisphere.

(2) Thalamic stimulations characterized by a broad cortical distribution of negative evoked potentials S t i m u l a t i o n of the points indicated by circles (open or filled) a n d plus signs in Fig. 3 produced negative responses so broadly distributed o n the lateral surface of the b r a i n that they could hardly pass u n n o t i c e d even on cursory exploration. These

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responses were the ones that Dempsey and Morison called 'recruiting '1". To find the positive-negative evoked potentials in those cases, we had to record from less accessible parts of the cortex, namely the mesial face of the hemisphere (Fig. 4) or the depth of the suprasylvian sulcus (Fig. 6). Projections on the orbital gyrus (open circles) were grouped in a rather small area at the angle formed by the rhinal fissure and presylvian sulcus. Those on the anterior part of the mesial face of the hemisphere (filled circles) were less well localized in or around Rose and Woolsey's orbitofrontal area ?8 (Fig. 4). They always were below the agranular part (area 6) of the anterior sigmoid gyrus on the mesial face. The cortical location of these maximal positive-negative responses varied from experiment to experiment. Sometimes the first positive components of the responses were very small in comparison with the second positive (augmenting) components (Fig. 4). By analogy with the observations made on the more accessible surface of the brain (described in detail below), we assumed that the recording electrodes were close to the center of a projection area though the latter itself remained out of reach. Negative potentials were observed in front of and behind the cruciate sulcus on the mesial and lateral faces of the hemisphere, and as far as the suprasylvian gyrus (Fig. 4). In a few cases, positive-negative responses were elicited simultaneously on both the orbital gyrus and the mesial face. These regions are very close to each other: on frontal sections through the anterior pole of the brain, they appear separated only by a narrow layer of white matter. Both are reached by fibers which degenerate following a very circumscribed medial thalamic lesion2:L Nevertheless, our mapping revealed at least one aspect of systematization which may be significant: as seen in Fig. 3, open circles in the thalamus (projection on the orbital gyrus) are located lower (under Horsley-Clarke level H • 1) and more medially than tile filled circles (projection on the anterior mesial face). Stimulation of LP and the most lateral wing of the internal medullary lamina produced negative potentials on the medial and posterior parts of the suprasylvian gyrus and on the lateral gyrus (Fig. 5). This disposition has already been observedl6,17,1:~ and is, sometimes, referred to as 'posterior recruiting', in contrast to the 'anterior recruiting' involving mainly the sigmoid gyri (e.g. Fig. 4). The "posterior recruiting waves' often included an initially positive potential, usually small, depending on the exact site of recording. Because of the initial positivities, some investigators have been reluctant to regard the phenomenon as recruitment (hence, the frequent distinction in the literature between 'true recruitment' and this one which nobody, though, ever called 'untrue'). We, too, were puzzled by the initial positive deflections- not because their presence surprised us, since this is in agreement with our other d a t a - - b u t , on the contrary, because they were generally quite small. After carefully exploring the region, we finally realized that the largest surface positive-negative responses to stimulations in the LP region were to be found in the depth of the suprasylvian sulcus (Fig. 6). Thus, the major portion of the projection area in these cases seemed to be on buried cortex. In our experiments, the distinction between the so-called 'anterior' and 'posterior recruiting' was often clear: 'posterior recruiting' could be correlated with the most Brain Research, 6 (1967) 119 142

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Fig. 5. Distribution of cortical responses to 10/see stimulation of VA close to lateral wing of internal medullary lamina (at place indicated in the insert). Same experiment as in Fig. 2. Monofocal recordings of the re.sponses to the 6th stimulus.

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Fig. 6. Deep location within suprasylvian sulcus of augmenting positive-negative responses elicited by 10/sec stimulation of LP. At left, sketch of frontal section of the right hemisphere. Arrows point to sites from which records A and B were obtained. Transcortical recordings between surface and depth. At site B the electrode track has been redrawn as fotmd in the histological sections. Its end marked by electrocoagulation and staining clearly indicated a 'surface' position. "lhe indifferent electrode was close in the white matter at a place from where no significant responses were monofocally detectable.

lateral i n t r a l a m i n a r s t i m u l a t i o n s a n d w i t h s u p r a s y l v i a n p o s i t i v e - n e g a t i v e r e s p o n s e s on o n e h a n d , a n d ' a n t e r i o r r e c r u i t i n g ' w i t h the m o s t m e d i a l i n t r a l a m i n a r s t i m u l a t i o n s a n d w i t h p o s i t i v e - n e g a t i v e r e s p o n s e s on e i t h e r the o r b i t a l gyrus, the a n t e r i o r m e d i a l face, o r b o t h , o n t h e o t h e r h a n d . T h e s e t w o ' r e c r u i t i n g s ' c o u l d be i n d e p e n d e n t l y Brain Research, 6 (1967) 119-142

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generated in the same experiment. Fig. 7 shows the results obtained by applying trains of 10/see stimuli successively at the two points indicated by the arrows in Fig. 3. One stimulation triggered incremental negative responses on the suprasylvian gyrus (Fig. 7A), the other on the anterior sigmoid gyrus (Fig. 7B). But neither induced the respcmscs at both places simultaneously* (the irregular waves recorded on the suprasylvian gyrus in B were not time-locked to the stimuli and, therefore, could not be regarded as individual responses). Stimuli were also applied at the rate of 5/see, alternately through both electrodes, in such a manner that, for the whole system, this actually represented a 10/sec stimulation (Fig. 7C). Under this condition, negative potentials failed to appear thus demonstrating no effective interaction between the stimuli. Were there an 'intralaminar system' functioning as a whole, it would be expected that stimulating one point of it would be equivalent to stimulating any other point. This did not occur. Insofar as incremental negative responses and spindling can be compared, it is interesting that suprasylvian and sigmoid spindles can also appear independently of each other, and in distinguishable behavioral situations aa. In summary, stimulations at thalamic locations indicated by circles and plus signs in Fig. 3 were characterized by an extensive distribution of cortical negative potentials. All the stimulation points were within or relatively close to the internal medullary lamina of the thalamus (CL, Pc, NCM) or in the region of the midline nuclei (Rh, RE).

(3) Wart:form of the cortical potentials triggered by repetitil'e thalamic stimulation Up to now we have considered cortical positive-negative and initial negative evoked potentials without entering into any description of waveforms. We shall see now that the similarities stressed in the 2 previous sections still hold when analyzing the details of waveforms. The differences noticed while stimulating various thalamic structures were mainly quantitative. They concerned: (1) the latency, (2) the amplitude of the components, and (3) the size of the cortical area where each of the components described below could be detected. It is well established that a single thalamic stimulus triggers a positive-negative response somewhere within the limits of its cortical projection area. The lower traces in each of the 5 right pairs in Fig. 8 are typical examples in a case of VL stimulation, recording from the anterior sigmoid gyrus. The minimal latencies were on the order of 2 msec; a similar value was obtained whether recording from the anterior sigmoid, posterior sigmoid, orbital, suprasylvian, ectosylvian or cingulate gyri, or anterior mesial face of the hemisphere, given that the stimuli were applied, of course, ai the appropriate thalamic locations (i.e., as schematized in Fig. 3). Peripheral to the point of largest positive deflections, the initial response could be surface-negative (see the left 2 in Fig. 8). The latency of this negativity was the * "lhtmgh it happened in other cases that medial thalamic stimulation induced negative responses also on the suprasylvian gyrus. This was still an 'antcrior recruiting', however, in that the sigmoid negative responses were larger, more regular, and appeared at a lower threshold of stimulation than the suprasyh'ian ones.

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Fig. 7. lndependenl elicilation of "anterior' a n d 'posterior recruiting responses'. Transcortical recordings from the posterior s u p r a s y l v i a n g y r u s (upper records in each pair) and f r o m the anterior sigmoid g y r u s (lower records). At right, 4 s u p e r i m p o s e d traces of the r e s p o n s e s to the ! I th stimulus, on an extended lirne scale. I0 sec siin~ulatioi3 of lateral w ing of internal m e d u l l a r ? lamina in -%, a n d of N C M in B. In C, alternate 5 so,: > t i m u l a t i o , at both site.-

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big. 8. Distribution of responses to 10,'see stimulation of VI., recorded on the anterior sigmoid gyrus (midline is at right, upper line represents cruciate sulcus). Monofocal recordings of responses to the 1st (lower traccs in each pair) and 2nd stimuli (upper traces).

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FROM CENTER TO PERIPHERY Fig. 9. Type of transformation affecting cortical responses during the process of augmentation. A and C, potential waveforms redrawn from actual rccords obtained following VL stimulation in ~ln experiment similar to the one illustrated in Fig. 8. A, Responses to the first stimulus. C, Responses to the second stimulus. From left to right, types of responses encot, nteted while going away from the focus of largest initial positive deflections. B, Wavcforms obtained in each 3 cases when subtracting records A from rccords C.

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same or slightly shorter than that of the negative component of the positive-negative response. Initial short latency negative responses were often observed in cases of V L VPL or other thalamic stimulations. They were localized but not always in the same topographical relation with the primary focus of positive-negative responses. On 10/sec repetition of the stimuli, the positive-negative waveforms underwent the following changes: (I) the initial positive deflections decreased in 90 °,i of the cases (sometimes it was completely erased); (2) a second positive component appeared and progressively grew with the subsequent stimuli; (3) the second positivc component was followed by a late negative potential. These alterations are illustrated by the upper traces of each pair in Fig. 8, though here the second positive component merges with the first. Other examples, more typical from this point of view, can be seen in Fig. 4 (note the double downward deflections in the records from the mesial face). There is nothing new--we think--in this description of the phenomenon known as 'augmentation'; it is adequate for all cases of thalamic stimulation (except GL) inducing positive-negative responses on the cortex. In the hope of detecting the changes brought about by repeating the thalamic stimuli at 10/see, we subtracted, in many cases, the waveform of the first response of a train from that of the nth rcsponse. An example ofthe results is given in Fig. 9 (row B). Such an operation would be meaningful only if there were reasons for believing that the repetition of stimuli introduced something new in the response and that this 'something new' simply summated with the waveform of the 1st response. Beforehand, we had no justification for making this assumption. However, the results disclosed consistencies which seemed worth considering. Indeed, augmenting responses recorded at various places while~stimulating the same thalamic point differed somewhat from each other (see Figs. 4 and 5). I

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Fig. 10. Cortical extension o f 3 c o m p o n e n t s o f responses to VL stimulation. Schematic ~iews of the dorsal aspect o f the frontal pole (right hemisphere). Maximal amplitudes o f the 3 c o m p o n e n t s (as illustrated in Fig. 9) were measured at 37 places and ranked in classes o f equal, arbitrarily chosen, range. C o n t o u r lines encompass the areas of potentials falling in each class. Darker areas are those where potentials were larger. Left: Territory o f the 1st positive c o m p o n e n t as measured in responses to the Ist VL stimulus (main focus was on posterior lip o f cruciate sulcus). Middle: Territory of the 2nd positive (augmenting) c o m p o n e n t in responses to 2nd stimulus. Right: Territory of the late negative c o m p o n e n t in responses to 2nd stimulus.

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The differences were the following: The second positive component could be larger or smaller than the first, the late negative component varied considerably in size, and the latencies of the three components (e.g., measured at the peak for convenience) were not the same in all places. But, after subtracting the waveforms of the tirst responses from the augmenting responses, these discrepancies wcrc much reduced. The latcn,:ies of the isolated 2nd positive and late negative components were much morc stable, and their amplitudes were fluctuating much less irregularly from point to point. Note that the timing of the 2nd positive (augmenting) component was such that it fell within the period of the negative wave of the 1st response. Its apparent latency and its apparent size would thus depend on the amplitude of the negative wave, if the 2 potentials were superimposed and summated. We do not want to conchtde that it is a simple summation which actually occurred, but our results suggest that there was a topographical organization of potentials at the surface of the cortex, and that each contributing component combined (in some fashion) with the others to determine--according to its size--the shape of responses at each place.

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Fig. I I. T e m p o r a l correspondence between negative c o m p o n e n t s o f s i m u l t a n e o u s l y recorded positive-negative a n d initial negati,,c responses. M o n o f o c a l recordings of responses to the 9th s t i m u l u s of a 10:'scc train. Stimulation of lower part of M D ; in each pair, Iov, cr trace from anterior sigmoid gyrus, upper trace from orbital g,,rus. Stimulus intensity was shifted from 0.07 m A (5 V) to 0.14 m A (10 V), p r o v o k i n g a parallel s h o r t e n i n g of the latencies of the 2 responses.

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Tiffs kind of analysis was carried on under various conditions in which not only the recording sites and places of stimulation, but also the intensity of each stinlulus in a train were independent variables. Three points deserve further mention here in connection with results reported above. Firstly, confirming previous tindings :34, it was observcd that the cortical area on which the 2nd positive (augmenting) component developed was always larger than the area where the Ist positive component appeared, and it included all or most of it (contour maps of Fig. 10). Still larger was the area of the late negative component* (in Fig. 10, and also Figs. 2, 4 and 5). * T h e areas o f late negative waves, very generally, extended preferentially in one direction, for instance pt)steriorly from loci of positive-negative responses on the anterior suprasylvian gyrus.

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Secondly, the latencies of the 2nd positive and late negative components induced by 10/sec stimulation of the thalamic points indicated by circles and plus signs in Fig. 3 were longer than the latencies of the corresponding components induced by 10/sec VL or VPL stimulation. The areas of distribution of the 2nd positive and late negative components on the cortical surface were also much larger in the former than in the latter cases. Thirdly, negative evoked potentials had the same latency as that of the negativc component in the positive-negative responses developing concomitantly. This latency could be modified by changing the intensity ofthalamic stimulation, and, as illustrated in Fig. 11, it was altered in a parallel manner in both responses. The relationship between simultaneously elicited positive-negative and purely negative potentials was thus also established from a temporal, in addition to a topographical, point of view. (4) To what extent is the thalamus necessary in the production oJ cortical incremental responses ?

Stimulations were applied in the subcortical white matter in attempts to produce cortical incremental responses. For instance, with a stimulating electrode placed laterally to the head of the caudate nucleus, potentials analogous to those elicited by VL stimulation were readily obtained. Waveforms and topographical distribution on and around the sigmoid gyri were the same, and the responses changed in the same manner--but less dramatically--on 10/sec repetition of the stimuli. There was clear evidence of augmentation as characterized by the development of a 2nd positive potential. Initial negative evoked potentials, though, could not be found. In these experiments, a lesion was placed behind the stimulating electrode to eliminate the thalamus as completely as possible. Three times, a section rostral to the thalamus was performed with a spatula or by suction. In 2 cases, the entire thalamus (except the GL, GM and posterior part of the ventrobasal complex) and most of the head of the caudate nucleus were sucked away under visual control after removing the contralateral anterior pole of the brain. These operations did not modify the characteristics of the cortical responses to the stimulation of the white matter, in contradistinction to earlier reports2L Stimulation of the white matter under the head of the caudate nucleus, where Nauta and Whitlock z3 detected thalamo-orbitofrontal projections, elicited positivenegative potentials in the orbitofrontal region. The cortical responses were analogous to those produced by medial thalamic stimulation, but, again in this case, purely negative potentials were absent. Isolation of the frontal pole or thalamectomy did not alter the results. Fig. 12 presents the pattern closest to cortical recruitment that could be observed. The potentials were predominantly negative, and their progressive change in size gave a spindle-shape typical of recruiting; yet, initial positive deflections, though very small, were undeniably present.

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10 mse¢ Fig. 12. Type of cortical incremental response elicited by subcortica[ stimulation after destruction of the whole thalamus by suction. 10/see stimulation of the internal capsule ventrolaterally to the head of the caudate nucleus. Monofocal recording from the rostromedial part of the anterior sigmoid gyrus. Lower traces are superimposed 1st and 6th responses on an extended time scale.

DIS('USSION

There are 2 broad categories of responses to 6-15/sec thalamic stimulation: those which begin with one or several positive deflections, and those which develop very late and consist solely or mainly of a negative wave. Dempsey and Morisont', '-'1,'-''' described these phenomena a long time ago. But we shall try to avoid the bias that knowledge of their work, undoubtedly, imposes; our observations will be summarized as follows. When thalamic structures were stimulated at 10/sec and potential deflections were detectable on the cortex, the responses were always of two kinds: positivenegative and initially negative. The two kinds coexisted (except with G L stimulation); they evolved in parallel; they had, in each case, a definite topographical relation (i.e., one which could be reproduced on stimulating the same point in other animals); the negative components were temporally related (in latency and duration). All these were common characteristics and, therefore, suggest a similar mechanism. But differences were noticeable with respect to the exact thalamic site of stimulation: they concerned the location of the projection area, absolute value of the latencies and sizes of the potential deflections, and 'spread' of the responses on the cortical mantle. From the latter viewpoint, it appeared that negative responses were much more broadly distributed in some cases than in others. The area of this distribution was largest when positive-negative responses were found on the orbitofrontal cortex, less extensive when they were found in the suprasylvian region, and smaller yet in all remaining cases (which we shall not r a n k - - n o t necessarily because they did not show any differences but because our information is presently insufficient for deciding on an objective ranking). This way of presenting the facts certainly departs from Dempsey and Morison's Brain Research, 6 (1967) 119--142

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conception. They made a sharp distinction between what they called 'augmenting" and 'recruiting' responses. For them, these were separate entities, contrasted by their dynamic properties and by their anatomical origin. Thus, were introduced the notions of 'specific' and 'nonspecific' thalamic systems, the significance of which we have to discuss, since, in our experiments, stimulation almost anywhere in the thalamus gave results which differed more quantitatively than qualitatively (see also rcf. 25). Responses of augmenting and recruiting types always coexisted. Where then were these specific and nonspecific thalamic systems? By locating the areas of positive-negative responses on the cortex, we came to recognize, of course, a few well-established projections; those of VI. on the pericruciate region, of VPL on the posterior sigmoid gyrus, and of GM on the ectosylvian gyrus. Direct thalamo-cortical connections with the suprasylvian and posterior cingulate gyri have been studied less often. But there is enough anatomical evidenceZ,a4,:~7,~8,~0----we think--to suggest that the afferent pathways come from the LP and LD respectively; our results were consistent with this interpretation (see Fig. 3). More difficult was the determination of the structures from ,~,hich positivenegative responses on the orbitofrontal cortex were elicited. In some cases, we found foci of maximum positive-negative potentials in Rose and Woolsey's twbitofrontal area where the MD projects ~,',~,9,~~,'-'8,~9. But, in other cases, as we have explained, we could not locate accurately the center of the projection area. Anatomical studies suggest several possibilities: we may have been stimulating VA which projects to the foot of the orbitofrontal cortex ~0, RE and SbM which project to, and under, the infralimbic field ',9,11,H,''7, or even AM which projects to the rostral part of the cingulate gyrus 9,14,27,z7,4°. As seen in Fig. 3 (circles and plus signs), many thalamic points of stimulation were situated within or near these nuclei. Although we cannot specie, in every case, which thalamo-cortical connections have been involved, we think that not all orbitofrontal responses had the same origin. Their slightly different cortical distributions probably depended on slightly different thalamic origins. As far as negative cortical potentials are concerned, we have stressed the fact that they could be found in the close vicinity of foci of positive-negative responses. This is very clear in some cases (Fig. 2). In other cases, the concept of vicinity has to be 'stretched' somewhat if it is to be applied. This seems justified however. Broadly distributed negative responses on and around the sigmoid gyri (anterior recruiting) were found in continuity with the positive-negative orbitofrontal responses (Fig. 4). Similarly, the extensive negative responses on the suprasylvian and lateral gyri (posterior recruiting) surrounded a suprasylvian tbcus of positive-negative responses (Fig. 5). We shall recall that the latencies and durations of initial negative responses corresponded to those of the negative components of simultaneously evoked positivenegative responses. Therefore, we suggest that cortical negative potentials represent the peripheral aspect of the whole cortical response whenever and wherever thalamic stimuli were applied, either singly or repetitively. The finding that recruiting responses disappear following ablation of the orbitofrontal cortex 36 (where we have found the loci of positive-negative responses) supports our hypothesis. Up to now we have not mentioned the intralaminar nuclei which are regarded Brain Research, 6 (1967) 119-142

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as tile main part of tile 'nonspecitic' thalamic system, and the source of recruiting responses. In several instances (Fig. 3), the electrodes were placed within or close to the internal medullary lamina, and, no doubt, intralaminar neurons were among those subjected to stimulation. What then was the effect of this stimulation? First, was it to produce positive-negative responses in areas such as the orbitofrontal cortex or the suprasylvian gyrus? We do not know. Anatomical evidence exists for cortical afferences coming from cell bodies located in the lamina :~l. Let us ascribe to their action the generation of positive-negative responses: it would mean that intralaminar neurons did not show any peculiarity of their own that differentiated them from their 'extralaminar' neighbors. Indeed, stimuli applied to the lateral wing of the lamina induce positive-negative responses in regions which arc considered as the AM, LD, LP, or M D projection areas. Similarly, stimuli applied closer to the midline induced the same type of responses within the RE, Rh, MD, or VA projcction areas. Thus, the effects which could be attributed to eorticopetal intralaminar neurons were simply the oncs expected if these neurons belonged to one of the nearest nuclei. Second, were the intralaminar neurons involved in the generation of cortical negative responses? Here again, we do not know. But we have shown that these negative responscs--far from being diffusely distributed--were topographically related to the foci of positive-negative responses. This suggests that, if intralaminar neurons are responsible for inducing the negative responses, their activity must be intimately related to the one which caused positive-negative responses. Certainly, the intralaminar population would not be affected en m a s s e during stimulation (Fig. 7); on the contrary, various fractions of it would have to be associated differentially with one or another closeby 'extralaminar' nucleus. The physical substratc for such functional relations could be the numerous collateral connections between intralaminar and 'extralaminar' cells, which the Scheibels have nicely demonstrated 31. This hypothesis is clearly at variance with the idea of a central, unique 'nonspecific' system. At least 4 possibilities can account for the described topographical relationship of negative and positive-negative potentials: (I)interaction between 'extralaminar' and intralaminar neurons as discussed above; (,2) intranuclear mechanisms in which thalamic interneurons (e.g., see ref. 3) would play a role similar to the one postulated for intralaminar cells; (3) a thalamo-cortical-thalamic loop whereby the activated cells within the cortical projection area would tire back to or close to the thalamic population stimulated~, t:~ ; and (4) cortico-cortical connections from the foci of positivenegative responses toward neighboring cortical regionsS. In the first 3 hypotheses, the origin of negative responses is assumed to be thalamic. The basic postulate is: negative responses occurred close to the loci of positive-negative responses as a result of a n ~ a s yet unspecified--action of thalamic neurons close to the ones which were fired by the electric shock. If such is the case, it is important to inquire how thalamic neurons respond to a local stimulation. A few microelectrode studies are relevant in this respecta".='6,"9; they revealed that thalamic cells could be inhibited following an electric shock. In experiments to be reported elsewhere, ,ae found: (1) that most 'responding' cells were silenced after a delay of Brain Research, 6 (1967) I 19-142

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about 25 msec, (2) that an important proportion of cells was immediately silenced (i.e., without prior activation), and (3) that the proportion of these last cells was a function of the distance from the stimulating electrode whereas (4) it did not seem particularly dependent on the exact place of stimulation. These results are introduced here because it is generally assumed that the direct effect of an electrical stimulus is purely excitatory. Actually, the functional significance of the impressive blocking of spikes observed cannot be ignored, and more attention should be given to the possibility that cortical potentials might arise not solely by intensifying the afferent barrage to a cortical area, but also by suddenly cutting it off. In the 4th hypothesis, the origin of negative responses is assumed to be cortical. By capsular stimulation in completely isolated frontal lobes, we were able to partly replicate the results obtained by thalamic stimulation. Predominantly negative responses could be elicited but initial positive components, though small, were always present (Fig. 12). At the present time, we are unable to evaluate the significance of such quantitative differences which depended on whether thalamo-cortical connections or thalamic nuclei were stimulated. Some unorthodox views oll the mechanism of evoked negative cortical potentials have been presented here. In particular the concept of 'recruiting responses" has been questioned, though most of the observations made by Dempsey and Morison, and many others, remain unchallenged. Nevertheless, we have shown that the concept of a 'recruiting' phenomenon as something radically distinct from an augmenting process may be misleading. Let us call incremental negative responses what they objectively are: incremental negative responses. Inasmuch as such potentials are related to certain inhibitory or disrupting behavioral effects, it may be useful to realize that they have different significances depending on from where they are induced in the thalamus and where they develop on the cortex. SUMMARY

The topographical distribution of cortical responses evoked by 10/sec repetitive stimulation of various thalamic points has been analyzed. In all cases, a focus of surface positive-negative potentials could be identified, even when the stimuli were applied in the midline or intralaminar regions. The transformation of these responses upon repetition of the stimuli characterizing the process of 'augmentation', has been described. Concomitant with this 'augmentation', initial surface-negative potentials developed in cortical areas adjacent to the foci of positive-negative potentials. These responses had all the features typical of so-called 'recruiting responses', especially when they were broadly distributed. The relationship of augmenting and recruitinglike responses was established from several points of view, both topographical and temporal. It is suggested that 'cortical recruitment' is not a distinct entity, and is not solely an attribute of stimulation of a particular thalamic locus.

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A('KNOWLEI)GEMENTS W e a r e m u c h i n d e b t e d t o M r . D. D e a r m o r e f o r his t e c h n i c a l a s s i s t a n c e , a n d to M r s . B. B e d a r d for t h e h i s t o l o g i c a l p r e p a r a t i o n s . T h i s i n v e s t i g a t i o n w a s s u p p o r t e d by G r a n t

N B - 0 4 9 5 5 a n d , in p a r t , by G r a n t

NB-02501 from N.I.H. REI,ERENCES I AKERF, K., Comparative anatom2,, of frontal cortex anti thalamofrontal connections. In J. M. WARRI-.~ A~D K. AKI-:R'r (Eds.), The t)'ontal Granular Cortex and Behavior, McGraw-Ilill, New York, 1964, p. 372. 2 AKIMOrO, H.. NI~GISIII, K., ANt) YAMADA, K.. Studies on thalamo-cortical conncction in cat by means of retrogradc dcgcneration method, Folia p,s.vchiat, nettrol, jap., 10 (1956) 39 82. 3 AXDV.RSEr,;,I"., E c o I-.s, J. C., AND SEARS, T. A., The vcntro-basal complex of the thalamus: types of cells, thcir rcsponses and t heir functional organization, J. Physiol. (Lond.), 174 (1964) 370-399. 4 AHiR, J., Terminal degeneration in the diencephalon after ablation of frontal cortex in thc cat .I. Anat. (Lore/.), 90 (1956) 30-41. 5 BIGNALL. K., IMBFRI', M., ET BUSI:R, P., Connexions cortico-corticales chez le chat apres 61imination des structures profondcs, J. Physiol. (Paris), 56 (1964) 295-296. 6 Bt;CHW..',LD, N. A., WYLRS, E. J., LAUPRI-:CHr, C. W., AND IIEt~SER, G., The caudatc-spindle. IV. A behavioral index of caudate-induccd inhibition, Eleclroenceph. ch'n. Neuroph)'.siol., 13 (1961) 531-537. 7 Bt:sliR, I'L, Rot:(iEUt, A., ANI~,PFRRI-:T, C., Caudate and thalamic influences on conditioned motor rcsptmscs in the cat, Bol. Inst. Estud. todd. biol. (,~h;x.), 22 (1964) 293 .307. CH,~.',;C;, H. T., The repetitive discharges ofcortico-thalamic rcvcrbcrating circuit, J. Neurophysiol., 13 (1950) 235-257. 9 CLARK, W. E. LI-GRos, AND BO(;(iC'N, R. H., On the connections of the medial cell groups of the thalamus, Brain, 56 (1933) 83 .98. 10 CoHEr,,', B., HOUSI-:PIAN, E. M., AND PURPt:RA, D. P., Intratbalamic regulation of actixity in a ccrebello-cortical projection pathway, Exp. Neurol., 6 (1962) 492-506. 11 CowA~, W. M., ANt~ POWELL, T. P. S., The projection of the midline and intralaminar nuclei of the thalamus of the rabbit, J. Neurol. Neurosurg. Psychiat., 18 (1955) 266-279. 12 DJ~r,IPSl:Y, E. W., ANI~ MORISON, R. S., The production of rhythmically recurrent cortical potentials after localized thalamic stimulation, Amer. J. Phv.viol. 135 (1942) 293-300. 13 I)ORMONr, J. I'., l-:r MASSIOr,,',J., I~tude des relations entre les aires sensori-motrices ct le noyau entro-lat6ral du thalamus chcz le chat, J. Physiol. (Paris), 57 (1965) 603604. 14 l)RoC~il.Fl:',.'l:R [:oRTUYN, J., On the contiguration and the connections of the medioventral area and the midlinc cells in the thalamus of the rabbit, l.olia psychiat, m,erl., 53 (I 950) 213-254. 15 I'oUR~,tt:~r, A., JAML L., CAuvl-:r, J., l-:T SC'm-RR~:R, J., Comparaison tic I'EEG recucilli sur le scalp avec l'activite eldmentaire ties dipoles corticaux radiaires, Electroenceph. clin. Neurophysiol., "13 19 (1965) _17-,_9. 16 I-I-XNBERY, J., AJMONI~ MARSA~,, C., AND DIt.WORIH, M., F'athways of non-spccilic thalamocortical projection system, Electroenceph. clin. Neurophysiol., 6 (1954) 103 I 18. 17 HORV..VIH, t:., l:r Bt:SER, P., Factcurs affcctant la r6partition corticale des fuseaux e,,'oqu6s chcz Ic chat, J. Phy.siol. (Pari.Q, 58 (1966) 534. 18 JASPER, H., AND AJMONE MARSAN, C., A Stereotaxic Atlas of the Diencephalon of the Cat, Nat. Res. Council of Canada, Ottawa, 1954. 19 JaSPeR, I1., NAQt:I-.~, R., AND KIN¢I, E. E., Thalamocortical recruiting responses in sensory rccei,,ing areas in the cat, Eleclroenceph. clin. Neuroph)'siol., 7 (1955) 99-114. 20 Koxo~sKt, J., AN~) LAW~CKA, W., Analysis of errors by prefrontal animals on the delayedresponse test. In J. M. \VARRe.~ AND K. AKErT (Eds.), "/7w Frontal Granular Cortex attd Behavim, McGraw-tlill, New York, 1964, p. 271. 21 MOR~S~N, R. S., ANt) DEX,IPSEY, E. W., A study of thalamo-cortical relations, ,4mer. J. Physiol., 135 (1942) 281-292. 22 .'VIt)RISt)N,R. S., AND DEMPSEY, E. W., Mcchanismofthalamocortica augmentationand repetition, .4nwr. J. Physiol., 138 (1943) 297 308.

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23 NAUTA, W. J. H., AND WHrrLocK, D. G., An anatomical analysis of the non-specific thalamic projection system. In J. F. DELAFRESNAYE(Ed.), Brain Mechanisms and Consciousness, Blackwell, Oxford, and Masson, Paris, 1954, p. 81. 24 PERRET,C., ET ROUGEUL,A., Suppression du mouvement volontaire par stimulation du thalamus m~dian chez le chat, J. Physiol. (Paris), 56 (1964) 421. 25 PURPURA,D. P., Discussion. In D. P. PURPURAAND M. D. YAHR(Eds.), 7he Tltalamus, Columbia Univ. Press, New York, 1966, p. 231. 26 PURPURA,D. P., SCARFF,T., AND McMURTRY,J. G., lntracellular study of internuclear inhibition in ventrolateral thalamic neurons, J. Neurophysiol., 28 (1%5) 487-496. 27 RosE, J. E., AND WOOLSEY, C. N., Structure and relations of limbic cortex and anterior thalamic nuclei in rabbit and cat, J. comp. Neurol., 89 (1948) 279 -340. 28 ROSE,J. E., AND WOOLSEY,C. N., The orbitofrontal cortex and its connections ~vith the mediodorsal nucleus in rabbit, sheep and cat, Res. Publ. Ass. herr. merit. Dis., 27 (1948) 210-232. 29 SAKATA,H., ISHIJIMA, T., AND TOYODA, Y., Single unit studies on ventrolateral nucleus of the thalamus in cat: its relation to the cerebellum, motor cortex and basal ganglia, Jap. J. Physiol.. 16 (1966) 42--60. 30 SCHEtBEL, M. E., AND SCHEtBEL,A. B., The organization of the ventral anterior nucleus of the thalamus, a Golgi study, Brain Research, 1 (1966) 250-268. 31 SCHEIBEL,M. E., AND SCHEmEL,A. B., Structural organization of nonspecific thalamic nuclei and their projection toward cortex, Brain Research, 6 (1967) 60-94. 32 SCHLAG,J., Reactions and interactions to stimulation of the motor cortex of thc cat, J. Neurophysiol., 29 (1966) 44-71. 33 SCHLAG,J. D., KUHN, R. L., AND VEL~CO, M., An hypothesis on the mechanism of cortical recruiting responses, Brain Research, 2 (1966) 208--212. 34 SPENCER W. A., AND BROOKHART,J. M., Electrical patterns of augmenting and recruitingwavcs in depths of sensorimotor cortex of the cat, J. Neurophysiol., 24 (1961) 26-49. 35 STERMAN M. B., AND WYRWICKA, W., EEG correlates of sleep: evidence for separate forebrain substrates, Brain Research, 6 (1967) 143-163. 36 VELASCO M., AND LINDSLEY, D. B., Role of orbital cortex in regulation of thalamocortical electrical activity, Science, 149 (1965) 1375-1377. 37 WALKER,A. E., Internal structure and afferent-efferent relations of the thalamus. In D. P. PURPtJRA AND M. D. YAHR(Eds.), The Thalamus, Columbia Univ. Press, New York, 1966, p. 1. 38 WALLER W. H., AND BARRtS,R. W., Relationships of thalamic nuclei to the cerebral cortex in the cat, J. comp. Neurol., 67 (1937) 317-337. 39 WARREN J. M., WARREN,H., AND AKERT, K., Orbitofrontal cortical lesions and learning in cats, J. comp. Neurol., 118 (1962) 17-41. 40 YAKOVLEV,P. 1., LOCKE, S., AND ANGEVtNE,JR., J. B., The limbus of the cerebral hemisphere, limbic nuclei of the thalamus, and the cingulum bundle. In D. P. PURPURAAND M. D. YAHR (Eds.), The Thalamus, Columbia Univ. Press, New York, 1966, p. 77.

DISCUSSION Dr. Buchwald: I w o u l d like very m u c h to hear an a n a t o m i c a l i n t e r p r e t a t i o n o f Drs. Schlag and Villablanca's results f r o m Dr. Scheibel. Dr. Scheibel: In c o n s id e r i n g the d i c h o t o m y between the so-called midline and i n t r a l a m i n a r system and the m o r e laterally located specific and associational system, the a n a t o m i c a l a r r a n g e m e n t is such that there is an a l m o s t pure culture o f medial i n t r a l a m i n a r p r o j e c t i o n s r u n n i n g close to midline, anteriorly, to the o r b i t o f r o n t a l areas m e n t i o n e d in this p a p e r and in Drs. Skinner and Lindsley's paper. On the o t h e r hand, the specific a n d associative nuclei tend to project not only in an a n t e r o m e d i a l d i r ect i o n but increasingly m o r e laterally, superiorly and posteriorly. T h e r e also a p p e a r to be axonal projections f r o m the t h a l a m i c nonspecific system laterally, Brain Research, 6 (1967) 119-142

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superiorly and posteriorly. Therefore, some projections coming from the more medial nonspecific cell populations are intermixed at most levels with the projections coming from the more lateral-lying specific nuclei. This might account for the combination of effects when stimulating the thalamus, and for an increasing dilution of 'nonspecific" effects as more lateral stimulus stations are chosen. In addition, axons from specific and associative nuclei are poorly ramified and have few collaterals. Thus, these projections remain rather restricted spatially and project from point A to point B. Axons from intralaminar nuclei, although they may also eventually reach point B, generate multiple collaterals en route, and activate many fields with secondary projections. This produces the divergence characteristic of this system. Dr. Clemente: Dr. Schlag, if I understand you clearly, you would have to eliminate from the definitions of either recruiting or augmenting the site of stimulation, and only rely on the electrical characteristics of the cortical potentials. If, by caudate stimulation, for instance, cortical responses are induced which are of the types you have described here, is it fair to call such responses recruiting and augmenting? Dr. Schlag: Yes, 1 guess s o - - a s long as you wish to use these terms--because the most significant criterion seems to be the response waveform. Dr. Clemente: You would also tend to eliminate the criterion of latency, would you not? Dr. Schlag: Absolute values of latency may vary somewhat from one case to another. More important, in my opinion, is the existence of a relation between the latencies of positive and negative components recorded at different cortical sites. Dr. Buchwald: All the emphasis is placed on cortical events; what about subcortical recordings? Dr. Schlag: Suppose that you stimulate at a thalamic place from where you can elicit surface-negative potentials, widely distributed on the surface of the brain. Your stimulating electrodes are producing a so-called 'cortical recruitment'. But if you record in the thalamus at 1 or 2 mm from the stimulating electrodes, most often you will pick up short latency bursts of discharges, increasing in number on repetition of the stimuli at 10/see. These bursts precede the cortical negative potentials. Thus, by their timing, they are comparable to typical augmenting responses. You can see that cortical surface-negative responses are related not only with cortical positive-negative (augmenting) responses, but also with similarly augmenting thalamic responses. Dr. Clemente: [ am still not quite clear about what should be called recruiting and what should be called augmenting. Could you list the criteria which could be used to differentiate the two types of phenomena? Brain Research, 6 (1967) 119-142

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Dr. Schlag: 1 am sorry; 1 prefer not to do it because it would imply that we recognize these two phenomena as distinct entities, and we do not. For us, these are just two aspects of the same thing. The nature of the so-called 'recruiting responses', andtheir functional.sigJlificance. is a problem that we have faced now for many years without solving it. I would like to suggest that this may not be a crucial issue because we are less and less convinced of the reality of what we try to explain. Perhaps the question to ask should be phrased somewhat differently. From the early work on cortical incremental responses, a very important observation remains: it is that some surface-negative responses are quite widely distributed on the cortex when stimulating certain definite regions of the thalamus. Now we begin to have some idea of the particular topographical repartition of these responses, of their relation with definite systems of thalamo-cortical projection. and of their probable thalamic origin. On the other hand, Dr. Sterman ~, is reaching the point where he can make a correlation between particular localization of spindles and particular behavioral states (i.e. response withholding and satiation). 1 believe that Dr. Sterman's anterior and posterior spindles correspond to our anterior and posterior negative evoked potentials. If this is so, then it may be possible some day to define the functions of medial thalamic nuclei in behavioral terms. In this respect, I think that the most fruitful questions to ask are: What is the significance of these thalamo-cortical projections to the orbitofrontal and suprasylvian regions? What is their exact origin? Why are surface-negative potentials so widely distributed in these cases? What kind of physiological operations go on when negative potentials develop on the cortex? Dr. Clemente: In the past, recruiting responses have been defined as something recordable over association areas, and augmenting responses over specific receiving areas. Do you think that this is still a valid differentiation? Dr. Schlag: In our experience with cats, initially surface-negative responses are best formed on the anterior sigmoid, suprasylvian gyri and parts of the lateral gyrus. But they can be found almost anywhere. Positive-negative responses develop in territories which are the projection areas specific to the different thalamic nuclei, as defined by the finding of anatomical thalamo-cortical connections. Dr. Clemente: The term 'augmenting response' is used as a noun, not a verb. I want to know where this type of response can be recorded and what the electrical waveform is; in other words, I want the 'augmenting response' to be defined. Dr. Schlag: For the position of cortical sites where augmenting responses can appear, 1 shall refer you to Fig. 3 of our paper. The answer to your question is in the form of a list of cortical areas, each one of them associated with a thalamic location. As for the electrical waveform, I think that the most characteristic feature is the second surface-positive component of the response, which appears and grows on repetition of the stimuli. Brain Research, 6 (1967) 119-142

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Dr. Clemente: This is exactly what I wanted to know. Now can you define recruitment in the same way?

Dr. Schlag: I am afraid not! If we first admit that the main characteristic of recruiting responses is to be surface-negative, then we have to recognize that the distribut ion of such responses depends on where positive-negative responses are found, and we have to admit that there are all possible intermediate wave forms between large initially positive responses and initially negative responses. Therefore, the recruiting response does not appear to be a distinct entity. If, on the other hand, our tirst consideration in defining recruiting responses is their wide distribution, then we are faced with the problem of what to do with responses which are very similar -sometimes identical--in waveform, but remain narrowly localized. Our own conclusion is that the concept of'recruiting response" is confusing. Dr. Scheibel: Is seems to me that we are in a transition period. Formerly wc were dealing with scalar entities; now we are trying to think of these patterns in vectorial terms. Dr. Schlag is indicating that, for any augmenting series, if you search the cortex, you will lind an area where there is another time series with different characteristics resembling'what we formerly called 'recruitment waves'. Dr. Clemente: Dr. Schlag, did you ever find a thalamic site which upon stimulation would not evoke a so-called recruiting response somewhere on the cortex? Dr. Schlag: No, there was no instance in our series of experiments where wc could elicit incremental positive-negative responses without simultaneously eliciting incremental negative responses. Conversely, we never elicited incremental negative responses withot, t finding somewhere incremental positive-negative responses. But. curiously enough, there wcrc thalamic points from which wc could not elicit any type of cortical response. We did not systematically explore the surface of the brain in these cases. But, undoubtedly, it would be interesting to place stimulating electrodes at arbitrarily chosen locations ~ithin the thalamus in order to determine whether or not locations exist from which no response can be provoked, no matter how hard you v¢ould try. Dr. Buchwald: Is there a relation between incremental responses and spindling induced by the same type of stimulation'? Dr. Schlag: Robert Kuhn, in our laboratory, has studied the phcnomcnon of spindle tripping. Hc thinks that tile induced spindle starts with a surface-positive wavc at the sites where the stimulation induces early surface-positive responses and that it starts with a surface-negative wave where repetitive stimulation induced surface-negative responses. This result, if verified, suggests a common factor in the mechanism of early responses and after-activity. You may recall that Spencer and Brookhart distinguished two types of spontancous spindle waves: the positive-negative ones. Braht Research, 6 (I 967) 119-142

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which they called the augmenting type, and the negative ones, which they called recruiting type 4. It is interesting that, whenever there was a mixture, they always found that the augmenting type preceded the recruitment type. And they suggested 'that the events associated with the former caused those responsible for the latter by activation of intracortical or inter-areal connections'. Dr. Scheibel: Eventually, we shall have to have multiple-array laminar analysis in various stations in and around a focus to understand what is happening at some point in time. Then we shall know a little more about so-called augmenting and recruiting waves. Potential theory has generally suggested that when you see a positive deflection on the surface, it indicates a negative source deep. Some time ago, Eidelberg 3 showed by cross-correlation analysis that this is not necessarily so. The various laminae may well be living lives of their own. Dr. Schlag: I am particularly thinking of Calvet's study t,2 in this respect. He has tried to locate vertical dipoles as accurately as possible within the cortex, and simultaneously explore unit activity in various layers. His results indicate that potentials of the same surface-polarity may correspond to quite different kinds of events. In addition, different events may go on simultaneously at different depths, all contributing more or less efficiently to the surface potential! Certainly, this type of approach seems well indicated at the present time. We now begin to understand what happens in the cortex during surface-positive potentials, but there is as yet no consensus of opinion on what happens during surface-negative potentials. Dr. Demetrescu: Augmenting and recruiting responses are differentially affected by brain stem reticular stimulation, ls this not an argument for the usefulness of a distinction between the two phenomena? Dr. Schlag: Can you really say that brain stem reticular stimulation differentially affects the two phenomena? Surface-negative waves are wiped out, whether or not they are preceded by surface-positive deflections. This is an additional argument in favor of the identity of the negative components of so-called recruiting and augmenting responses. The second (augmenting) positive components are reduced in size; the first positive components, on the contrary, are increased. It seems rather that brain stem reticular stimulation differentially affects the different components of the responses but affects in the same way the corresponding components. 1 CALVET, J., I-1"CALVET, M. C., G6n6rateurs corticaux responsables des r6ponses attgmentantes et rccrutantes, J. Physiol. (Paris), 57 (1965) 503-510. 2 CALVET, J., CALVFT, M. C., ~r SC~tERRFR, J., l~tude stratigraphique de l'activit6 EI-G spontanee, Electroenceph. clin. Neurophysiol., 17 (1964) 109-125. 3 EIDELBERG, E., 'Phase reversal' of electrical activity in the cerebral cortex. A discussion. In A. ESCOBAR(Ed.), Feedback Systems Controlling Nervous Activity, Soc. M~x. de Ciencial Fisiol., A. C. Mexico, 1964, pp. 308-312. 4 SPENCER, W. A., AND BROOKHAR'I, J. M., A study of spindle waves in sensorirnotor ct, rtex ot" cat. J. NeurophysioL, 24 (1961) 50-65. 5 STERMAN,M. B., AND WYRWlCKA, W., EEG correlates of sleep: evidence for separate forebrain substrates, Brain Research, 6 (1967) 143-163.

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