Thalamic mechanisms involved in cortical desynchronization and recruiting responses

ELECTROENCEPHALOGRAPHYAND CLINICAL NEUROPHYSIOLOGY

39

THALAMIC MECHANISMS INVOLVED IN CORTICAL DESYNCHRONIZATION AND RECRUITING RESPONSES J. D. SCHLAGAND F. CHAILLET Department of Anatomy, School of Medicine, UnirersiO, of California, Los Angeles 24, Calif. (U.S.A.) and Institute of Expert.mental Therapeutics, University of Liige (Belgium): (Received for publication: May 25, 1962)

INTRODUCTION

A few years ago, much importance was given to some limited regions of the thalamus with widespread cortical projections in explaining the mechanism of the cerebral rhythms. First, it was shown that the spindling activities probably find their origin in these subcortical structures. This hypothesis is derived from Morison and Dempsey's pioneer work (1942), Secondly, as soon as the concept of a "reticular ascending activating system" was proposed by Moruzzi and Magoun in 1949, it was felt that the diffuse thalamo-cortical projections could also play a major role in the production of the EEG arousal patterns, indeed, cortical desynchronization as well as synchronization could be provoked by electrical stimulation el" the medial thalamus~. Mainly for these reasons, the denomination of "thalamic reticular system" was coined by Hunter and Jasper (1949). Most authors considered it as "the cephalic end of the reticular activating or waking system" (Jasper 1958a). Remarkably at that level, only one mechanism needed to be postulated in order to explain the synchronization and desynchronization procesThe first investigations were made at the Institute of Experimental Therapeutics, University of Liege, Belgium, under contract 61(052)-22 with the Air Re,arch and Development Command, USAF. The work was completed in the Department of Anatomy, University of California at Los Angeles, Los Angeles 24, Calif. (U.S.A.) with a grant (B-611) from the U. S. Public Health Service. " The terms dcsynchronization and synchronization will I~e used to designate EEG patterns, without any implication of the underlying mechanisms. Similarly, the expression EEG (or cortical) arousal will refer to the cortical fast rhythms, whatever the corresponding state of consciousness of the animal.

ses, for they were solely determined by the critical frequencies of the electrical triggering. However, there are difficulties in this concept, which have been already pointed out, for instance by Jasper and Ajmone-Marsan (lq52). Particularly, it has always bee,', hard to understand why a good portion of the reticular system, namely the thalamic one, which remains in connection with the telencephalon in acute cerveau isoh; preparations is nevertheless unable to exert its desynchronizing influence on the cerebral cortex (Bremer 1954, 1955). Considering this "important gap in our knowledge" (Bremer, 1954, p. 437) we attempted to analyze the functional relationship between the lower portion of the reticular system and the non-specific thalamic systern and to reinvestigate the mechanisms involved in cortical desynchronization and recruiting phenor,,ena. METItOI)

Sixty-three cats were used in these experi ments. They were operated on under ether anesthesia and the teguments were infiltrated with procaine near the sites of incision and at the pressure points of the Horsley-Clarke head-holder. At the time of recording, the animals were kept motionless by intravenous injection of Flaxedil, while artificial respiration was provided. The various experiments to be described have also been duplicated in six encdphales isol#s (section at the C I level). No general anesthetic could have been used as it would have interfered with the occurrence of normal EEG arousal reactions. Complete miosis, normal heart rate and rectal temperature were taken as criteria of the good state of the preparations during the entire session. In all cases considered here, the EEG records showed a spontaneous alternance Electroenceph. clin. Ncurophysiol., 1963, 15:39~62

40

J. D. SCHLAG AND F. CHAILLET

of periods of fast rhythms and spindle bursts. The cortical activity was recorded with silver ball electrodes in contact with the exposed dura. When the latter had to be removed, the brain was covered with mineral oil at 38°C. In four animals, small holes were drilled in the skull for the introduction of deep electrodes and the EEG was monitored from phonograph needles inserted into the bone. Except as otherwise specified, all surface derivations were monopolar with reference to a large area of the calvarium covered with moistened cotton. Deep electrodes for stimulation or recording were either double 0.4 mm or concentric electrodez with the bare tip of the inside wire protruding by less than 0.5 ram. For some special purposes, other types of electrodes were used, for instance multi-electrodes with up to ten wires. Specifications will be given later in the text when r~,levant to the results concerned. Stainless steel microelectrodes (with the tips reduced by electrolysis to less than 10 microns) served for very localized derivation of the responses. All the deep electrodes were oriented according to stereotaxic coordinates. The recordings were usually made with an 8-channel EEG ink-writer but, for precise control, also with a 6-channel CRO with Allen B. Dumont tubes. The stimuli were delivered in the form of square pulses by Tektronix units through isola. tion transformers. The electrode implantation in the unspecific thalamic nuclei was performed routinely by determination of the points from which the most generalized cortical recruitment could be evoked with the lowest threshold and without any contamination by other types of repetitive responses. All implantations in the medial thalamus were made between the planes F 4- 9 and F at I1, according to Jasper and Ajmone Marsan's atlas (1954). They included the nuclei: centralis lateralis, paracentralis, centrails medialis, reuni~,ts and rhomboidalis. The reticular complex of the thalamus, the centre m~dian and the nucleus anterior ventralis were not explored. The lesions were performed either with a spatula or by electrocoagulation (constant current of 3 mA passing for 15 sec between adjacent pairs of electrodes 1.5 mm apart and with about 0.5 mm of their tips exposed). The histological

controls were made systematically, using either the Mulligan-Le Mosurier technique or the thionine staining. The tips of the steel microelectrades were located by means of the potassium ferrocyanide reaction in 80-micron sections stained with basic fuchsin. RESULTS

1. Alteration of the EEG desynchronization induced by thalamic stimulation following transection of the brain stem In eight cats, a total transection of the brain stem was performed either in front of the cerebellar tentorium, or below the tentorium after removal of the cerebellum. In the first case, the sections were precollicular and passed through the rostral part of the mesencephalon. In the second case, the sections could be called transcollicular, but the interruption of the neuraxis extended down to the level of the nucleus tuber. Thus, these two preparations differed by the fact that the tectal and pretectal regions were or were not left in connection with the telencephalan. Prior to the transection, a pair of stimulating electrodes had been implanted in one of the midline or intralaminar nuclei of the thalamus. The parameters of stimulation had been determined for the production of both stable cortical recruitment and a generalized EEG desynehro. nization. After the section, it was verified that the recruiting responses could still be elicited without any change in its threshold. High frequency stimulation (from 50 to 300/see), on the other hand, no longer induced the enduring EEG arousal previously obtained in the intact preparationt. in about two-thirds of the cases, the cortical desynchronization appeared during, but did not overlast, the stimulation, at the end of which the typical EEG pattern of the eert,eau isolO immediately resumed (Fig. 1). In the other one.third, spontaneous spindles remained unaffected even Our results differed somewhat from the observations made in apparently similar conditions by Brookart et al. {1957) and Arduini (193"/).These authors have indeed reported ~ner~!i~ arousal reactions upon stimui~tion of the diffuse thalamic nuclei in cerreau isold preparations sectioned at the precoilicular level, This discrepancy,wiU be dealt with later in the discussion,

Electroenceph, din. Neurophysiol., 1963115:39-62

41

DESYNCHRONIZATION AND RECRUITMENT

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Fig. I Con)par/son of the EEG responses to it high frequency stimulation o f , midline thalamic nucleus. befi.'e ~md after complete hil,teral transection of the brain stem. A: Control recorded 2 h 30 rain after the end of ether anesthesia: EEG arousal and bilateral recruiting responses obt,ined by stimulation of nucleus centralis medi,lis (NCM, slightly on the right side) at ~(~0/sec and R/see respectively, B: Following the mesencephalic transection (performed after removal of the cerebellum) the characteristic fast rhythms are absent, whereas tripped spindles are induced. Time cal. (I ~c) between the ,~:) pulses (100pV), Negativity upward= ,

during high frequency stimulation (for instance, see Fig. 8, C). Pupillary dilatation, which normally paralleled the development of the EEG arousal reaction, was also absent.

2. Similar effects obtained by partial destruction of the brain stem it seemed interesting to further examine the critical region which had to be destroyed in order to get results similar to those of a total transection. Thus an array of four to six coagulating electrodes, disposed in a frontal plane, was implanted in the brain stem and was advanced downward at successive 1 mm steps. The EEG arousing capacity of a high frequency thalamic stimu-

lation was tested between each series of coagulation, The critical destruction (rin 39 animals) was found to involve the posterior commissure and close regions of the pretectum on both sides (Fig. 2, A, BI and CIL that is to say the area just caudal to the parafascicular complex and habenulo-peduncular tract which remained intact in most cases (Fig. 2, B2). Typical examples of the findings are given in Fig. 3, as well as in our previous notes (Schlag eta/. 1961aand b). The EEG desynchronization upon thalamic stimulation did not disappear when this area, especially on the midline, was spared, In some animals, more extensive lesions were required, encroachE/ectroenceph, c/in. Neuroph.vsiol., 1963, 15: 39-62

Fig. 2 ?, Some histological controls. A: One o f the most restricted lesions by elcctrocoagulation of the posterior commissure, sufficient to prevent the enduring cortical ~ desynchronization by high frequency stimulation o f the medial thalamus. B!: More extensive lesion by electrocoagulation. B2: Section passing at the Ice,el of the habenulo-interpeduncular tract in the same preparation showing the absence ., o f damage in front of the lesion. B3: Track o f the thalamic stimulating electrode in a still more frontal ~.'ction. C: Spatula sections in the experiment illustrated by Ftg. 8. CI: Partial transection of the brain stem. C2 to C4: Successive more rostral levels, showing the ~o extent o f the midline division o f the corpus callosum, massa htt©Ji~cdia and anterior commissure in the same preparation. The tr,cks of two thalamic stimulating electrod~ can he seen in C2.

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DESYNCHRONIZATION AND RECRUITMENT

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Fig. 3 Comparison of the EEG responsesto a hilJh frequency stimulation ~f the thalamus and the mesencephalic reticular formation following a partial sectimt of the brain stem. Cat immobilized by in~jection of Flaxedil. ,4, C, and E: Controls./, and C: EEC arousal reactions respectively by stimulation of the rii~ht nucleus centralis lateralis (CL) and the reticular formation (RF). E: Recruiting responses. The electrocoagulation was performed bilaterally but showed lar~r defects on the left side where the whole pretectal area was destroyed. The other records (B.D,F) were taken 30 rain later, B: The voltage of the high frequency shocks in the thalamus was increased, but the occurrence of spontaneous spindle bursts ¢oldd not be prevented any more. even during the, stimulation itself, D: In contradistinction, the reticular stimulation remained effective, E: The recruiting responses were still well developed after the lesion, Neg~ttivity downward.

Electroenceph. c/in. Neurophysiol., 1963, 1.5:39-62

44

J . D . SCHLAG AND F. CHAILLET

i,g on the superior half of the central gray. For the purpose of control, the converse experiment was made in two cats, by starting with stereotaxically placed lesions in the brain stem tegmentum extending them upward and sparing the pretectal area. Theft both the EEG arousal reactions mediated from the thalar,.,us as well as from the lower part of the brain stem, below the lesion, were abolished simultaneously. But the preparations obtained in such a way were actually equivalent to c e r v e a u x isok;s. It is worthwhile insisting on the difference between the classical destruction of the reticulttr ascending pathway (performed by localized electrocoagulation, or as described in Section I, by complete transection of the neuraxis) and a lesion limited to the dorsal aspect of the brain stem. In the latter case, the EEG patterns were ,~ot altered: the periods of spontaneous cortical desynchronization were as frequent and as sustained as uefore. Furthermore, an EEG arousal could be easily induced either by intravenous injection of d-amphetamine (2+4 mg/kg) and the threshold

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for a cortical desynchronization by electrical stimulation of the mesencephalic reticular formation (see Fig. 3, B, D) or peripheral afferences (for instance, with needles inserted in the fingerpads) did not change. The levels at which the lesions were placed with identical effects were not systematically explored in three dimensions. In this study we were more concert,ed with the physiological problems and we tended to keep the anatomical variable to a minimum in all experiments. Most of the coagulations were made at frontal planes -t-4.5 to fi-6. Since a comparison of spontaneous EEG tracings from period ~o period might be somewhat inaccurate, we looked for a more objective test to appreciate the desynchronizing effects. The procedure used by Moruzzi and Magoun (1949) seemed quite suitable and was adopted for this purpose. These authors have shown that the cortical recruiting responses to low frequency stimulation of one of the intralaminar nuclei were depressed by a simultaneous high frequency

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A: Control 3 h 30 min after ether anesthesia, Stimulationsti8htlylateral to the nucleus rhomboidalis on the right side. Trains of 10/see shocks were applied intermittentlyto produce the recruiting responses. A 300/see stimulation(between the up and down strokes of the signal pen) of the same point was interposed in the series, The subsequent recruiting responses were depressed for about ! rain. B: After electrocoagulation of the posterior commissure (histologicalcontrol presented in Fig, 17), the depression of the+recruiting responses by the highfrequencyshocksdisappeared, Negativity upward.

Eleetroeneeph. din. Neurophysiol., 1963, 13:39-62

DESYNCHRONIZATIONAND RECRUITMENT stimulation of the. homologous contralateral nucleus. Normally this depression lasts for many seconds, depending on the intensity of the activating stimuli. Fig. 4 shows the results obtained by stimulating the same thalamic point successively with low and high frequency shocks. In Fig. 5, the stimulations were almost simultaneous in both nuclei paracentralis. In eight experiments, we found that a coagulation at the level of the

45

synchronized potentials could be, confirmed in the case of similar evoked activity. The lesions performed at the level of the posterior commissure did no,c encroach upon the nearby diffuse thalamic system. Actually, except in one case which was rejected for this reason, no histological control showed such destruction to involve or even to approach the medial diencephalon, (e.g. Fig. 2, B2 and 3). In addition, Proreus R i ght Lateral

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Comparison of the effectson inducedsynchronization,of high frequencystimulationsof the thalamus and reticular formation following partial sec6on of the brain stem. Cat immobilizedby injection of Flaxedil. In each series, upper record from the right proreus gyrus and lower from the right lateral gyrus. A: Control. Stimulations of the nucleus para~ntralis (Pc) at low frequency (10/see indicated by the dots) on the right side of the dienc~phelonand at high frequency(100/seeindicated by the bar) on the left side. Triggered spindling activity depressed by the stimulation of the con. tralaterel nucleus. B: This effect disappears after a lesion involvingthe posterior commissure and the prcteetum. C: Stimulation of the right lateral mesencephalic(R F) reticular formationstill blocking the induced synchronized potentials. Negativity downward. posterior commissure could prevent the desynehronizing effect of thalamic stimulation responsible for the obliteration of the recruiting responses. Thus the results concerning the spontaneous

in all instances, recruiting responses of unaltered amplitude and cortical extension were elicited at the same threshold after the lesion. We prepared three chronic animals with coag-

Electroenceph. clin. NeurophysioL, 1963, 15:39-62

46

J. D. SCHLAG AND F. CHAILLET

ulations of the posterior commissure and tested them from six days to four weeks later. In these three cases, there was a clear EEG desynchronization upon high frequency stimulation of the intralaminar nuclei. However, at the same time, n-,ovements of the head and of the contralateral paws were induced by stimulation, so that EEG reactions which might result from the feedback excitation of proprioceptive afferenccs could not b¢ excluded. That such could be the case was suggested by two other experiments in which the animals were allowed to recover from the barbiturate anesthesia alter the electrocoagulation. They were operated on again two days later under ether narcosis and immobilized by an injection of Flaxedil. Thus, the results could be compared with those of the acute experiments and actually they were the same: there was no EEG arousal by 50 to 300/see stimulation (of up LO6 volts) of the thalami¢ sites from which cortical A

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has been redrawn fcom the originalrecord to reduce the time scale. An EEG arousal reaction was seen '..,, A but not in B. Between ,4 and B: electrocoagulation ~,f the posterior commissure, pretectum and superior half of the central gray. The responsessccn in A practicallydisappear in B.

recruitment could be elicited. However, under these circumstances, the normal threshold for EEG arousal was not known since the control tests had to b¢ made under barbiturate anesthesiaL For this reason, the two-stage p~ocedure was not repeated on more animals. Incidentally, no behavioral changes were noticeable in the five cats with a chronic lesion of the dorsal brain stem. The EEG desynchronization induced by thalamic stimulation is normally accompanied by other signs of general activation. Typical alterations of the dermal potential, heart rate and blood pressure arc shown in Fig. 6, ,4 following 300/s¢c stimulation of nucleus paraccntralis. In three cats, these changes were found to disappear almost completely after a coagulation of the posterior commissure and pretectum (Fig. 6, B). We have already mentioned that the pupillary dilatation was similarly prevented, but this might result from specific action on visual reflex mechanisms (see Discussion).

3. Responses in the reticular farmation to single shocks applied in the midline and intralaminar thalamic nuclei Since the results in Section 2 could b¢ explained by the existence of thalamo-reticular connections, it seemed justified to search for action potentials to the thalami¢ shocks at the level of the posterior comnJissur¢ and preteetum. Hence, microelectrodes were used to explore that region. As the points of stimulation and recording were but a few millimeters apart, the shock artefact was often exceedingly large. To reduce it, recording from close electrodes seemed indicated. Thus an ordinary electrode with a large bare tip was inserted I mm behind the microelectrode and, by monopolar derivation, it was verified that this electrod~ did not detect any response" it was thus safe to use it as "indifferent electrode", Some samples of the responses arc presented in Fig. 7, They were picked up in quite limited regions. Moving the microclcctrodcs 1 or 2 mm vertically often made them disappear. They had a duration of I to 3 msec and a latency of 3 to t We objected to preparing chronic animals without

general anesthesia.

Electroenceph. clin. Neurophy~iol., I ~

15:39-62

DESYNCHRONIZATION AND RECRUITMENT

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5.5 msec. Sometimes, there were two components in the first 7 msec. For purposes o f comparison, responses similarly evoked were sought in the mesencephalic reticular formation. The ones found there usually had a shorter latency of 0.3 to I msec suggesting their antidromic nature. But some reticular responses were also obtained with a delay o f 1.5 to 5 msec.

4. Differentiation of the mechanisms of sy~chrcni:.'ation and desynchronization by stimulation of the medial thalamus

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As a retrothalamic lesion could prevent the cortical arousal by high frequency stimulation of the midline and intralaminar tha!amic nuclei, it should be supposed that the thalamo-corticai pathway involved in the desynchronizieg mechanism differs from that which is responsible for the recruitment. Experiments were designed to settle this question. Enomoto (1959) ha,~ shown that a sagittal section of the massa intermedia and corpus callosum abolishes contralaterally the cortical recruiting responses. He also mentioned that a sa~ittal section of the posterior commissore was ineffective. In two of our cats, a section of the massa intermed!a, anterior commissure and corpus callosum was made with a blunt spatula (histological controls proved the complete section of the massa intermedia, the sparing, in one case, of a small rostral portion of the corpus callosum and, in the other, the sparing of the lower part of th0, anterior commissure, Fig. 2,

C4). The damage to the medial thalamus was qu,te negligible (Fig. 2, C). In these preparations, as in Enomo~o's findings, the recruitment recorded with bipola," electrodes on the contralateral sigmoid gyrus disappeared (Fig. 8, B). Yet a high frequency stimulation at the same thalamic site remained capable of desynchronizing the contralag~:ral hemisphere. An additional frontal transection of the mediodorsal brain stem (Fig. 8, CI) prevented bilaterally the BEG arousal by thalamic stimulation. These two sets of lesions performed on the same preparations in such a way that the recruitment first and the desynchronization later were suppressed, provide a convincing evidence of the duality of these proccsses.

However, this differentiation by experimenF.leetroenceph. clin. NeuropkysioL, 1963, 15:39-62

48

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Eiectwenceph, olin, NeurophysioL, 1963, 15:39-62

49

DEFYNCHRONIZATION AND RECRUITMENT

tal procedures only concerned the conduction pathways from the thalamus to the cortex. With regard to the thalamic origin itself, Starzl et el. (1951) had already noticed that the act.ivating area does not correspond exactly to the diffusely projecting nuclei. It seemed des:'rable to investigate the problem further. For this purpose, multi-el~trodes with a tip separation of 0.5 mm or less were implanted in the thalamus near the midline as shown in Fig. 9, and then trains of shoci~s of the same voltage, frequency and ¢luration were applied between every pair ofelectrod~. Taking into account the changes of polarity, that makes n (n-I) combinations when using n wires. These experiments were made in two stages on three cats. In the first stage, 10/see pulses were used to induce a cortical recruitment which was monitored and found to behave similarly from seven cortical derivations. Hence, only the recordings from the ipsilateral onterior sigmoid gyrus are presented in the typical example of Fig. 10. The 90 frontal recordings were tabulated

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according to the site and polarity of the stimulation in the thalamus: each column corresponds to the cathode, while the ranks refer to the anodes. For instance, the recruiting response found at the intersection of entries - 6 and + 7 was induced with a positive potential at electrode number 7, with reference to electrode number 6 (see Fig. 9). In this particular instance, it can be seen that a cortical recruitment was obtained only when the electrodes !, 6, or 8 (and 3, to a much lesser extent) were made negative. It is also quite clear that the position of the cathode only was really critical. During the second stage of the same experiments, the thalamic shocks were applied at the rate of 300/see. This occasionally induced EEG arousal (also monitored from the ipsilateral frontal area). In Fig. ! !, the results are tabulated in the same manner, as for the recruiting responses. The results are symbolized by black blocks, the height of which indicates the total duration of the desynchronization. The meaning of this code is given by the actual recordings

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Electroenoeph.olin. Neurophysiol.,1963,/5:39--62

J, D. SCHLAG AND F. CHAILLET

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FiB, II $~l~r~ ~l~ri,.cnt and same presentation of the results as in Fig, I0. The stimuli (300/s~, O,S reset, I0 V) were applied at exact!y the same sites and the recordings were also made from ~he same cortical areas, The black blocks represent the EEG arousal reactions, Their height is proportional to the duration of the desynehronization,with the mttximum size metming at least i rain I$ sec of

sustained fast rhythms. The sign 0 stands for no arousal response. Under the table,samples of the EEG re~:ordingillustrate the codificationin ~ . ~ A. B and C (the bars indicatethe duration of the stimuli). ¢orrespondi,8 to the items A (maximum height). B (medium size block) and C (zero or no EEG arousal). The table is not completely filled because it seemed unwise to attempt 90 arousal reactions (not i,cluding duplications for verification) on the same animal in a few hours. Thus. only 37 "combinations" were studied; they were selected to cover the entire field and were tested in a random order. It appears that the longer lasting cortical desynchronizations were obtained

from electrode number ! which was the deepest in the thalamus. Shorter. but still evident E E G arousals were induced from the nearest wires n~lmbers 2. 3 and 4. The polarity of the shocks did not seem to have significance and the results were no longer related, as in the previous situation. only to the position of the cathode. The comparison of the data in Fig. 10 and I I demonstrates that cortical recruitment and desynchronization were not obtained when stim£1ectme~'e~. di.. Newo~hysiol..1953.15:39-62

DESYNCHRONIZATION AND RECRUITMENT

ulating the same points in the medial thalamus, notwithstanding some overlapping between the two fields. We must point out that such a differentiation as shown here was possible only with small, closely spaced electrodes. From the results, it can be assumed that the field of the stimulating currents was quite limited, because the effects were different for electrodes only 0.5 mm apart. In these studies only a limited area of the thalamic recruiting nuclei was investigated. Even in such a restricted field it was often possible to make a clear systematization as to where the cortical responses developed: those obtained by stimulating nucleus ¢entralis lateralis were found on the suprasyivian and lateral gyri, whereas those elicited from the more medial and inferior par,ts of the thalamus predominated on the frontal areas. This is in good agreement with the findings of Jasper et al, (1955). it is worthwhile to point out that the observations in this report did not vary in relation to the selected sites of stimulation. V

6 5 4 2.5

50 7"5 I00 /see Fig. 12 Cortical recruitment, spindle tripping and desynchronization as a function of the parameters of thalamic stimulation. Cat immobilized by injection of Flaxedil, Stimulalion ;. the upper part of nucleus omtralis lateralis. TL:is table refers to a t,'ain duration of 4 sec. with 0.5 mscc pulses. The effects: recruitment, spindling afteractivity, no EEG alteration and des;,nchronization have been symbolized for the convenience of the presentation (the ipsilateral frontal recording was used as the index). Trials with shorter duration of the stimulation shifted the distribution in such a way that the threshold for the arousal responses appeared higher for the two parameters under consideration. I0

25 33

~i

5. Thalamic stimulation and spindle tripping Spindle tripping occurs normally following one single shock or a few repetitive pulses applied at a low rate in the region of the mlOiine or intralaminar nuclei of the thalamus. This form of after-activity is rather infrequent after a brief train of high-frequency shocks, but it may be noticed occasionally, depending on tile position and extent of the stimulated area; sometimes it appears in the short delay preceding the arousal reaction. In the present series of experiments, spindle tripping was a common feature following high frequency stimulation in preparations where the posterior commissure had been cut. Not only EEG arousal, as shown, was no longer elicitable but bursts of synch~'onized acti;'ity were caused by what is usually considered asa desynchronizing stimulation. So this point was investigated in various preparations ana under different conditions, with particular reference to the parameters of thalamic stimulation which would seem capable to induce spindles. From the sites from which both recruitment and desynchronization could be elicited, the former developed easily with frequencies between 6 and 12/see. As the rate of the shocks increased from 12 to 25/see, the amplitude of the responses diminished, but the chance of getting spindli.~g after-activity improved. With further increase of frequency or voltage or total duration of the trains, cortical desynchronization appeared. At some intermediary stages there could be either spindle tripping followed by a desynchronization or else no change in the EEG as if the synchronizing and desynehronizing processes were cancelling each other. A schematic example is given in Fig. 12. The same evolution was seen in two other cases analyzed, although there have been variations in the absolute values of the parameters. In those instances in which cortical arousal could be obtained only when exceptionally high voltages were used, it was possible to study the occurrence of spindling after.activities without interference from desynehronizing processes. Here too spindle tripping was observed as soon as the frequency of the repetitive shocks was too high (i.e. between 12-25/see) for producing recruiting responses. Further increase of frequency orduration of the train or of voltage of the shocks resulted in earlierappearance of thetrippedspindles(Fig. 13), Electroenceph. clin. NcurophysioL, 19(O, 15:39-62

C

F r e q u e n o y .....

Vol

0

10 •

single

shocks

20

£+V, l

/n.

,IAMIM i r

.

,'-qq~"

4 ~/OeO

""

- - - -

20/uo

Fig, 13 Spindling aher-activity .s a hmction of the parameters of stimulation of a midline thalamic nucleus. Cat immobilized by Injection or Flax~iL Double electrode implanted at the level of nucleus centralis medialis, puIMs of 0.5 ms~ duration. R~rdings from the ipsilateml anterior sismoid 8yrus. In this cat, the EEG aroummlreactions, induced by hill1 frequen~ stimulation had a hish threshold and were always delayed by about 10 ~ , A-Frequency: Shocks of 4 V applied during 0.75 sec at frequencies varying from 6/see to 33/soc. B-L~uration: Shocks at 4 V and 15, 20 or 2g/see applied for 0.75, 1,5 or 4 ~ . C-Voltage: Sinsle shocks or repetitive volleys at 20, 25 or 33/see applied during 0.?5, I +5 or 4 soc, with voltaps varying from 2,5 to 6 V. The records must be compared in each series where only one parameter was air©red, it thus aplx~rs that any increase of any one of the parameters increased the probability of an abet-activity and made it occur sooner.

£1ectme~cejg~. olin. Neurol~ysiot,, 1953, IS: 39-62

DESYNCHRONIZATION AND RECRUITMENT

By comparing the results obtained under these two condit;.~ns, it appeared that both spindling after-activity and cortical desynchronization were conditioned by the same changes in the stimulation, provided that they would cause an increment of the electrical charges released. Tripping of spindles had a lower threshold and hence occurred before the EEG arousal when frequency, voltage or duration were progressively enhanced. If a cortical desynchronization could be induced from the selected thalamic spot, then it "took over" and prevented the synchronized activity. Rather unexpectedly, the frequency ef stimulation did not seem to play any critical role in producing the synchronized and desynchronized patterns under study.

6. Cortical spindling elicited by high .frequency stimulation of the midline and intralaminar nuclei of the thalamus In the last section, it was assumed that the cortical spindling resulting from a stimulation

53

of the thalamus, would be prevented if this stimulation induced an EEG arousal reaction at the same time. In other words, if the conditions for cortical synchronization and desynchronization were realized simultaneously, the latter would effectively antagonize the first. In relation to this, it was shown in Sections I and 2 that an outburst of" spindles regularly occurred at the end of" the thalamic high frequency trains as soon as the brain stem was transected or destroyed. The simplest interpretation is to assume that the reticular ascending influence was blocked; the synchronizing process was then released and the spindles could appear: But it is not immediately clear why the spindle tripping would occur only at the end of the repetitive shocks. Indeed, in most cases there still remained a desynchronization during the time of the electrical stimulation in cerveau isol~ preparations as well as in preparations with a lesion of' the posterior commissure and pretectum (see sections I and 2). Thus, whatever the cause of this transient

A - Control

.

NC~,5 V, 300/see

B - Nembutal

C - After

Lesion

L

m

$e¢, ]00 vV

IIIU

Fig. 14 Experimental conditions revealing the synchronizing action of a high frequency stimulation of a midlin¢ thalamic nucleus. Stimulation of nucleus ctntralis medialis (NCM) with 300/see,0.~ m~¢, 5-V pulses, lpsilaterai recordings from the posterior sii~noid ~rus. A: Control. B: After intravenous injection of Nembutal 50 mg (17 ml/kg), slow cortical activity slightly depressedduring the stimulation itself. C, D and E: Following a bilateral electrocoasulation of the posterior commi,ure and pretectat area, long bursts of irregular slow waves triggered by the high frequency shocks. Negativity upward.

F.lectroenceph.clin. Neurophysiol.,1963, 15:39-62

54

J . D . SCHLAG AND F. CHAILLET

phase, we attempted to eliminate it by means of barbiturates. High frequency stimulation of the midline or A - Control

B -

After

Rh. it V , 3 O O / s e c

Lesion IJ

C -

Nembutal I se¢

-

.

_ .

.

.

.

.

.

I I

i

10o ~lV ~_J.dllll:..

......

Illd....

0-

L

..iAtiJiJtJd.i .......

..... |

|

VPL, 2 V , l O O / s e c

.,,,,dill[......

Fig, 15

Similar to Fill. 14, but the conditions for the inductinn ot' slow waves by high-frequency stimul,tion of the thalamus were realized in reverse order. Ipsilateral recording from the anterior (upper trace) and posterior sigmoid 8yri (lower trace). A: Control. Cortical d©synchronization following a 300/see stimulation of nucleus rhomboidalis (Rh). B: After a bilateral electrocoagulation of the posterior commissure and pzetectal regions down to the level of the cerebral aqueduct, this effect disappeared. C: Fol. lowing !he intravenous injection of 60 mg of Nembutal (I 5 mg/kg), the 300/see stimulation of nucleus rhomboidalis regularly triggered the spindlins activity as shown in 4 samples. D: A high frequency stimulatiott of nucleus ventralis posterolateralis (VPL, 300/sec, 2 V) i~rformed in ~.ile same conditions still blocked the spontaneous spindles (4 records). Negativity upward.

intralair.aar thalamic .u¢1¢i, "as w e r ~ ~ _ - y part of the reticular system in a deeply anesthetized cat induces a flattening of the EEG (Dempsey and Morison 1942). This means that the synchroniz.~! activity is s o p p r e s ~ d!lring the stimulation, but no fast rhythms are induced. A slight effect of this kind may be seen in Fig. 14. When, secondarily, an electrocoagulation of the posterior commissure and pretectum was performed, it was observed in four animals that the flattening caused by the stimulation was replaced by the triggering of long lasting, low frequency spindles (Fig. 14, C, D, E). The same experiments were also performed in the reverse order in three other cats. Here again, spindle bursts were induced by a 300/see stimulation (of nucleus rhomboidalis) only when the lesion was made and the barbiturate injected afterwards (Fig. 15). In order to know how specific this effect was, a sensory relay nucleus (nucleus ventralis posterolateralis) was submitted to the same 300/see stimulation at each successive step. The result was quite different (Fig. 15, D): whereas the stimulation of the midline nucleus consistently triggered the spindle bmsts (32 times in 32 trials performed in this instance), a similar activation of the relay nucleus had the opposite effect: it blocked the spontaneously occurring spindles. Finally, in three cats the intravenous injection of the barbiturate was replaced by its topical application on the exposed cerebral cortex at the site of the recording. It was thought that the relevant action of the drug could be limited to the place where the desynchronizing afferences terminate. Typical records are shown in Fig. 16. J,fter section of the posterior commissure, a burst of spindles triggered by the high frequency sti. mulation of a midline thalamic nucleus appeared on the cortical area treated with Nembutal, while the corresponding contralateral point of the cortex did not display any major change in its electrical activity. Following a subsequent intravenous injection of Nembutal the spindles were generated on both fool upon thalamic stimulation. Once more, the 300/see stimulation of the nucleus ventralis posterolateralis immediately disrupted the spontaneous slow wave activity. In conclusion, these experiments have demonstrated that a stimulation of the thalamic £1ectroenceph. din. Neu~ophysiol., 1963, I$: 39-62

DF.SYNCHRON|ZATION AND RECRUITMENT

A

VPL, 3 V, I 0/see - - - - - ~

55

I sec,200 pV

Re,2 V, lO/sec

B

~

VPL,~ V,3OO/se(

, , . , , , , , , , ~ ........ , . , , , , , , . , . , , , , , , , , , , , , . , , , , , , , , . , , , , .

C - Nembutal

1.5

Re,tt, V, IO/sec F - Ne~al~t:al 30 mg IV

G

4V

~V Fig. 16 Effect of a topical application of Nembutal. Stimulating electrodes in the right nucleus ventroposterolateralis (VPL) and in the lateral part of nucleus reunions(Re), also on the rirht side (stimulus marks respectively indicated at the top and at the bottom of each record). ,4: Control showing two trains of a,gmenting responses separated by a burst of recruiting responses. ~: Blocking of the recruiting responses on the frontal area by 300/sec shocks applied to the VPL. C to G: Only the two frontal recordings are presented. After bilateral eloctrocoagulation involving the posterior commissure, prete(:tal field, superior half of the central gray and adjacent region, a small piece of filter paper was placed under the electrodes, the dura being removed. On the right side (upper trace) the paper was soaked in a 1.5% solution of Nembutal (pH .... 8.5; about 0.2 mg of Nembutal). On the left side, the paper was imbibed with only the solvent of this solution. C and D: 300/sec stimulationof nucleusreuniensinducingaburstof spindles on the barbiturized area only. £: Burst of spindles, started by a high-frequency stimulation of nucleus reuniens and stopped by a high.frequency stimulation of the VPL. F: After an intravenous injection of Nembutal (30 rag), bilateral spindling generated by the 300/soc stimulation of nucleus reuniens (less evident on the right side, now strongly depressed by the additive effect of the topical application and the intravenous injection). G: The VPL stimulation still blocked the spontaneous synchronized activity. Negativity upward.

Electroeneeph. clin. Neurophysiol., 1963, 15:39-62

56

J. D. SCHLAG A N D F. CHAILLET

recruiting nuclei, at any frequency, could trigger peripheral signs of the arousal reaction to thaa corticalspindling activity,This activitystarted lamic stimulation disappeared simultaneously with the EEG signs. Secondly, our observations could be ascribed to a greater disposition for synchrony. This explanation is acceptable in the case of cerveau isold preparations, but there was no EEG change DISCUSSION suggesting such a tendency in the animals with a lesion of the posterior commissure and pre1. Validity of the present observations The first point to be discussed concerns the tectal area. In these instances, the threshold for discrepancy between our data and those of cortical desynchronization upon stimulation of Brookhatt el al. (1957) and Arduini (1957). The the mesencephalic reticular formation or of the divergence cannot be minimized since Brookhart peripheral afferences was not increased. Thirdly, it could be argued that injury was et al. (1957) had observed arousal reactions of up to several minutes upon stimulation of the caused to the medial nuclei of the thalamus by non-specific thalamic nuclei in precollicular ani- the lesions placed a few mm caudally. However mals. Since no record was published in the pa- this was not apparent in the histological controls. pers cited above, we cannot compare and discuss On the other hand, the induction of recruiting the data themselves. It is possible that the "arou- responses was in no way impaired. Fourthly, it could be suspected that abnormal sal reactions" reported therein consisted mainly of a flattening of the EEG. Indeed, Arduini conditions were unintentionally created by the (1957) suggested that the high frequency shocks lesions in acute cats. The real nature of such in the thalamus acted by blocking the synchro- conditions may be hard to determine, but the nizing influence exerted on the non-frontal areas difficulty of duplicating our results in chronic of the cortex. The same nuclei of the thalamus animals could be taken as an indication that were stimulated, especially those on the midline. some sort of functional impairment occurred. But the studies of Brookhart eta/. (1957) and This interpretation is not likely because the thaArduini (1957) were performed with a different lamically induced arousal reactions were absent objective (the study of slow cortical potential in Flaxedilized preparations studied two days changes) and the effects of thalamic stimulations after pretectal lesion. Technical difficulties howseemingly were not appreciated with reference ever prevented us to provide more convincing of control tests in the same unsevered prepara- evidence on this point. tions. Thus the significance of the EEG arousal Fifthly. it could be postulated that the lesions reactions could be different, for instance if they were interrupting thalamo-reticular connections were elicited with higher voltages from nearby which would mediate the activation generated structures. by diencephalic stimulation. Actually, following We found that the cortical arousal reaction thalamic stimuli, we found short-latency responby high-frequency stimulation of the unspecific ses at the level where the electrocoagulations and thalamic nuclei was prevented by a transection sections were usually performed. This is not pre. of the brain stem performed caudally (complete sented as a crucial argument because the medial transection in eight cats, coagulation limited to thalamus where the stimulating electrodes were the dorsal part of the midbrain in 39 animals). placed, is a complex structure with intermingling Some possible explanations of this finding will fibers belonging to different systems, But, had be briefly considered: we been unable to find such responses, the presFirst, our observations could be due to a mis- ent hypothesis should have been rejected, Ininterpretation of the EEG records, as fast rhythms stead, it presently seems to be the one which could occur spontaneously at any moment. But deserved more consideration, the depression of cortical recruitment was affected in the same way and at the same time as the 2. The hypothesis o f thalamo.reticular connections spontaneous synchronized potentials. Besides, Kuhlenbeck and Miller (1942) have consideras soon as the desynchronizing action was removed. Thus, they provided an example of high amplitude and low rate electrical activity induced by a high-frequency stimulation.

Electroe,ceph, din, Neuro~ysiol., 1963, 15:39-62

DESYNCHRONIZATION AND RECRUITMENT

57

ed the pretectal region in rabbits as an important link correlating the tectum, some parts of the thalamus and tegumvntal centers. In man, the same authors (I 949) and Kuhlenbeck (1954) notcd thC CXiSt~iiC.~ u f ~I.uuz~uuz~'Ui~l t~t~tu-uz~z~tzHIt;

I Jl~'l l' • 4 Jf /

,j

A

tract, including habenulo-tectai fibers, and a diffuse ventromedial tecto-Dretecto-thalamic tract running rostral as far as the lateral and medial thalamic nuclei. In sagittal sections of small mammalian brains, Le Gros Clark (1932) described a descending pretecto-tegmental tract which could be traced down to the tegmental region of the midbrain immediately dorsal to the substantia nigra, in cat, following a m~diudors,,i lesion of the thalamus, Le Gros Clark and Boggon (1933) found degenerated fibers extending on either side into the pretectal nucleus, the nucleus of the posterior commissure and further ventrally into the dorsal part of the ;egmentum. More useful information, however, has been given by Bucher and Btirgi (1945), who observed a tract which they called V-bundle degenerating after a lesion caudal to the habenulo-peduncular tract and rostral to the dorsoventral fibers of the posterior commissure. This circumscribed tract of fibers is thought to originate in the pretectal, sub- and parafascicular nuclei and to end in the region of the dorsal tegmental nucleu In addition, Btirgi and Bucber (1955) described a habe-

nulo-tegmental tract (Fig. 17) passing dorsal to the area of the nucleus ruber and disappearing in the tegmentum near the midline above the rostral end of the pens. This tract was also recognized by Nauta (1958), who found diffuse

SC iqlSdlm

projections, coming from the habenular region, spreading over the parafascicular complex and more posteriorly, and finally reaching caudal parts of the central gray matter. On the other ........

Fig. 17 Sagittal section of the brain in the experimentdescribed and illustrated by Fig. 4. The large arrow indicatesthe

•. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

..................................

direction of the s~tion, the small one is pointed toward the trace left by the thalamic electrode. Under the picture, two schemas representing the position of the habenulotegmentai tract discussed in the text. They were redrawn, on the same scale as the histological section, from Nauta 0958) and B~rgi and Bucher (1955), respectively. The gathering of these documents does not intend to suggest a particular hypothesis, but only to illustrate some of the main anatomical relations under C.iscussion. (3 Gudden nucleus. Hb = Habenula. IP == Nucleus interpeduncularis. Mm = Mamillary bodies. PC ~ Posterior commissure. SC -----Superior colliculus.

Eiectroenceph. din. NeurophysioL, 1963, 13:39-62

58

J. D. SCHI.AG AND F. CHAILLET

hand, a corticof~g~l pathway passing at the level of the mesoodiencephalic junction and reaching the tegmentum was reported by Hugelin and Bonvallet (1957). They stated that they could phy~,iulo~ically trace these projectiong between the centrum medianum frontally and the posterior commissure dorsally. It is not established, however, whether the fibers project on reticular neurons or directly on motor cells of the brain stem (Bremer 1960). Thus far, it is hard to relate our observations to these data. We do not know which intermediary relays may be implicated in the hypothet-

that the pretectal region has any "reticular" property, because the cytoarchitectonic organization is clearly different from that of the reticular formation (Feremutsch and Simma 1961). But it remains interesting that simi!~r resuhs ;;,~re. obtained in stimulating both structures. Anatomically and physiologically, their relations seem evident. 3. One or two thalamic mechanisms for the control of the electrocorticai rhythms?

One of the main implications of our work is that the thalamo-cortical systems of conduc[nal~illO-[g~Ut;LIIX'tl" t~OlUll~t~UOll:5, tvlttll~Ov~:.t, tion . . . . . . . :k,,, for ""- ~ - ~ . . . . . . ~'"'-":"-"-,there can be more than one path, as the simul- and synchronization are different. This conclutaneous recording of early action potentials and sion was already suggested by the results oblong latency recruiting response would suggest tained following a section or a lesion of the brain (see Fig. 7 and also Schlag and Faidherbe 1961). stem, since under these circumstance~ only one From previous investigations (Nauta 1958; Hu- phenomenon, i.e. the production of arousal by gelin and Bonvallet 1957) it appears likely that high-frequency shock, was lost. The complemenat least a good part of the descending projections tary evidence was provided by showing that the impinging upon the tegmental structures of the interruption of the interhemispheric pathways brain stem follows a course quite different from carrying the recruiting impulses to the opposite the ascending activating pathway. More pre- side, did not impair the contralateral EEG cisely, these descending afferences have an orien- arousal. tation similar to the fasciculus retroflexus (or The assun',ption of two separate mechanisms habenulo-peduncular tract); they run down- of projection leads to the idea of two distinct ward and slightly caudalward. If this information mechanisms of generation or "triggering" at the is relevant, it would explain why we had to per- thalamic level. As their anatomical overlapping form our coagulations within a varying range of was not perfect, it was possible to make the difdepth to block the arousal reactions, for, as the ferentiatio~.~ with multi.lead electrodes, thus concoagulating electrodes intersected these path- firming the previous observations of Starzi et al. ways quite obliquely, small variations in the (1951). Theoretically, the discrimination could frontal plane and in the diameters of the lesions also be achieveu [," !t were possible to block could strongly affect the results. one of the mechanisms while activating the other The pretectal region is concerned mostly with one. We thought that a lesion of the posterior visual reflexes and especially with the pupillary commissure, and pretectal area could be used for light reflex, which was investigated by Magoun this purpose, since it prevented the enduring corand gansou (1935) ~nd Magoun et aL (1936). In tical desynchronir~tion by thalami¢ stimulation, chronic experiments on cats, electrical stimula- However, as shown, a transient desynchronization induced characteristic postural changes of tion remained during the stimulation itself in the eyes and head (Hess et al. 1945). In rats, about two-thirds of the experiments. This short lesions in this area were reported to impair the effect does not have the characteristics of an retention of visual discrimination (Thompson actual EEG arousal reaction. We assumed that and Rich 1961). However, other kinds of effects it was due to a direct excitation of fibers, prowere seen upon stimulation: rise in blood pres- bably the reticular ascending efferences shown sure, increased motor activity and readiness of by Nauta and Kuypers 0958) in the ventral part responses, and increased respiratory activity of the dorsal thalamus. Hence, in addition to the (Hess 1957) which were considered as typical brain stem lesion, we used a barbiturate ~tber of an "ergotropic zone". It cannot be suggested intravenously or in application on the cortex, F_.lectrocn~pb. din. Neurol~ysiol., 1963, 1~: 39-62

DESYNCHRONIZATIONAND RECRUITMENT

in an attempt to block the reticulo-cortical projections at the level of their terminations. With such a procedure, we succeeded in producing cortical spindling activity by high-frequencystimulation of the intraiaminar and midline nuclei of the thalamus. This result does not mean that all the assumptions which lead to the design of the experiments are necessarily foundt, but it showed that the basic hypothesis of two thalamic mechanisms 'as ,iseful. In addition, it demonstrates that the frequency of the EEG patterns is not always dependent on the frequency of the stimulationt. 4. General implications

Considering broadly the current theories of subcortical control of the cortical rhythms, it would not have been easy to predict the results of the experiments reported here. On one hand, much evidence had been provided that an EEG arousal is impossible when the brain is disconnected from the reticular formation of the brain stem. Bremer (1935) first reported the absence of spontaneous fast rhythms in the eortigram of acute cerveau isol~ preparations and later, this effect was shown to be related to the destruction of the central tegmentum (Lindsley et al. 1949, 1950). In such preparations, arousal by peripheral stimulation is lost. This is the case for the visual affcrences which remain intact in the cer. veau isold (Bremer 1935) as well as for the olfactory afl'erences following high midbrain transection (Batsel 1959; Moruzzi 1961). Even the direct stimulation of the cerebral cortex itself was found ineffective (Mollica 1958). Thus, on the ground of such concordant data, it would have been reasonable to expect that the desynchronizing capacity of the medial thalamic nuclei would disappear after precollicular transection. But on the other hand, these same nuclei were regarded as the cephalic end of the reticular waking system (Jasper 1958a) and many investigators have used the thalamic stimulation as an equivalent substitute to that of the mesent Actually,there are now other examples of slow wave activity induced by high-frequency stimulation of various structures: the posterior lobe of the cerebellum (Sawyer et ai. 1961), the reticular formation (Ingvar and Soderberg 1958) and the preoptic region of the hypothalamus (Clemente and Sterman: personal communication).

59

cephalic or bulbar reticular formation in order to get experimental arousals. Such a concept would necessarily imply that a section caudal to the thalamus could not alter the usual effect of the thaiamic stimulation. There are in the literature rare but clear indications that the "thalamic reticular system" and the actual reticular formation are not quite the same thing (Jasper and Ajmone Marsan 1952; Jasper 1958b, 1961; Rossi and Zanchetti 1957). Tissot and Monnier (1959) made a distinction between two kinds of cortical responses to single shocks applied to the diffusely projecting nuciet or the thalamus and they concluded for the existence of separate pathways. However, at that time they had no reason to conceive these channels as having a different anatomical course. Tissot and Monnier pointed t.o the difficulty of reproducing Hess's experiments on the induction of sleep, because two systems with opposite effects are always stimulated at the same time in the thalamus. In man, nevertheless, the disso. ciation of the two mechanisms seems clearer than in cats: the human diffuse thalamic projection system does not appear t~ mediate arousal responses, since ,lung and Riechert (1954)were unable to elicit an EEG arousal pattern by a 30 to 100/see stimulation of the medial and intralaminar thalamic nuclei. This was recently confirmed by Housepian et al. (1961). Jasper (1958b), quoting Rothballer's results (1956, 1957), point. ed out that no part of the thalamic reticular system is adrenaline sensitive, whereas the brain stem areas, caudal to the centrum medlanum can be activated by local adrenaline micro-injection. This pharmacological differentiation fits other physiological data. In connection with this, it should be mentioned that ohlorpromazine increases the threshold for behavioral arousal following thalamic stimulation relatively more than following reticular stimulation (Killam and Killain 1958). The impairment of a non-adrenergic system by an adrenergic blocking agent would be hard to understand .'n the traditional concepts,' but the interpretation becomes simpler by assuming that the thalamic impulses activate first the reticular neurons. Finally, it is worth recalling the contrasts found by Brookhart et aL (1958) and by Arduini (1958) between the enduring potential changes Electroenceph. din. Neurophysiol., 1963, 1.5:39-62

(30

J . D . SCHLAG AND F. CHAILLET

on the cerebral cortex and the arousal reaction

simtdtaneously elicited by a medial thalamic stimulation. Indeed, the D.C. shifts induced by exciting the recruiting nuclei by high-frequency pulses are: (I) much shorter than the desynchronization, (2) rather unaffected by the barbiturates and (3) limited to the frontal areas from which recruiting responses are obtained by stimulating the same point at a low frequency. Hence, by their time span, susceptibility to anesthetics and cortical extent, the D.C. changes are easier to relate to a recruitment process than to a generalizcd EEG ~r,m~el reaction. Our results have shown that the thalamic mechanism ~c~ponsible for cortical synchronization can be activated by high frequency as well as by low-frequency shocks. Thus, it can be su~ ?used that the D.C. changes correspond to the activity of this mechanism rather than to the concomitant but independent excitation of the reticular system. If this hypothesis is correct, it would also explain why the shifts due to a stimulation of the unspecific thalamic nuclei are never so broadly distributed than those induced by reticular stimtdation. This fact could not be easily interpreted on the account that the generalized effects ofretieular stimulation are brought about by widespread diffusion at the level ofthe thalamic nuclei. SUMMARY

The present experiments have been performed on 63 cats, unanesthetized but immobilized with Flaxedil, Some of them wereencephale isold preparations. It was found that a mesencephalic transection prevented the EEG arousal induced by high frequency stimulation of the intralaminar and midline nuclei of the thalamus. The same effect was obtained by a partial interruption at the level of the meso.
described, which differentially blocked the recruiting or arousing responses, showing thus that the pathways involved in these two processes are separate. Furthermore, careful mapping of the medial thalamus revealed that the recruiting and desynchronizing areas, although overlapping, do not coincide entirely. A systematic study of the parameters of stimulation was made with respect to the electrocortical patterns induced. Finally experimental conditions were designed, which allowed a cortical spindling to be induced by a high-frequency stimulation of the unspecific thalamic nuclei. The hypothesis of thalamo-reticular connections is discussed on the ground of .qn~tomical and physiological data. The role of these connections is postulated in the mechanism of the EEG arousal caused by thalamic stimulation. Some general implications of these results are presented

n~SUMt MI~CANISMES THALAMIQUES DANS LA Dt~SYNCHRONISATION CORTlCALE ET LE$ RI~PONSES DE RECRUTHMENT

Les exp6riences d~crites ont ~t6 r~alis~es sur 63 chats, non anesth~si~,s mais immobilis6s par injection de Flax~dil. Cer~ins d'entre eux 6taient des "enc6phales isol6s". Une transection m6senc6phalique complete peut emp6cher I'~veil EEG qui est normalement induit par stimulation A haute fr6quence des noyaux thalamiques intralaminaires et de la ligne m~diane. Le meme effet peut etre a~teint par une interruption partielle du u'onc c6phalique c~r~bral, au niveau de la junction m~so-dieno~phalique, ~pargnant les connexions ascendantes du syst6me r~:ticulaire, L'absen~ de ddsynchronisation duns ce cas est bien d6montr~ par le fair que les r6ponses corticales de recrutement ne sent plus bloqu~s par les vol~s thalamiques/t haute fr~quence, De la r6gion o~ les I~stons m~:senc~phaliques sent offectuC~s, il est possible de d~river des r~ponses b courte latenoe, b la stimulation des noyaux thalamiques responsables du recrutement. Par des sections sagittales et frontales qui sent db~rites, les r~ponses de recrutement et d'6veil EEG peuvent etre diff~:rentiellement supprim~s, Eleetroeneep&din. Ne,trophysioL, 1963,13:39-62

DESYNCHRONIZATION AND RECRUITMENT c¢ qui montre que It.~ voies emprunt&~ vers le

cortex dans ces deux cas sont s6par~tes. De plus, une exploration minutieuse du thalamus m~lian r~v~.le que les zones dont l'excitation provoque soit un recrutement, soit une d6synchronisation ne coincident pas entib.rement, bien qu'elles chevauchent. Les param~:tres de la stimulation thaiamique sont 6tudi6s en fonction des effets EEG induits dans chaque cas. Finalement, des conditions exl~rimentales ant 6t6 raises au point dont la cons~luence remarquable est la production de bouff~s de fuseaux Iorsque les noyaux tl,~alao miques non Sl~Cifiques sons stimulds /t haute fr~luence. L'hypoth6se de connexions thalamo-r~ticulaires est avanc~e et discut~c sur la base des donn6es anatomiques et physiologiques. L'©xistence de telles connexions parait n ~ c ~ a k c pour ox~ pliquer l'~veil ~lectrocortical par stimulation thalamique. Enfin quelques implications de ces r6sultats sont envisag~es. REFERENCES AnDUtNI, A. Lense oscillazioni di potenziale della corteccia cerebrale per stimolazione dei sistemi a proiezione diffusa. Atti del Conveltno di Parma, 19~7, 83=101. AnDUml, A. Enduring potential changes evoked in the cerebral cortex by stimulation of brain stem reticular formation and thalamus, in J,~eea, H, ct al. (Editors), Retieular formation of the brain. Little, Brown and Co., Boston, Toronto, 19S8, 333-3~1. B~rset., H. L. EEG pettem~ ofwaking in the chronic iso. laird cerebrum of the do~. Report.~80, U. $. Army Med. ical Research and Development Command, 1959, 41 p. Br.eMSa, F. Cerveau "isoW' et physiologie du sommeil. C. R. $o¢. Biol. (Paris), 1935, 118: 123~=1241. BIt|MI~, F. General di~ussion. In De|oAl~e~SAVe, J. F. (EG~tor), Brain mechanism~ and consciousness. Blackwell, Oxford and Mauon, Paris, 1954, 479-513. BlteMea, F..Qnelques aspects physiologiqnes du probl~me des relations r~proques de l'~w,orce c~r~brale et des stn~ctures sous corticales. Acts neural, belg., 1955, $3: 947-965. Bttmen, F. Les r~lations nerveu~es de I'aetivit~ cortitale. Schwel~. Arch. Neurol. Neurochlr. Psychiat., 19{'0, 86: 34-48. Bnoo,maa~, J. M,, AaDum~, A., M~NCt~, M. and Moauzzl, G. Risve81io elettrocn~efalosrafico da stimolazione talamica. Boll. $oc. ltal. Biol. sper., 1~7, 33: 1631-1632. BacoKXAaT, J. M., AaDUmt, A., MANa~, M. and Monuzzt, G. Thalamo-cortical relations as revealed by induced slow potential chan[es. J. Newophysioi., 1 9 ~ 21: 499-525.

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