Alterations in corticospinal neuron activity associated with thalamocortical recruiting responses

ALTERATIONS IN CORTICOSPINAL NEURON ACTIVITY ASSOCIATED WITH THALAMOCORTICAL RECRUITING RESPONSES 1 DOMINICK P. PURPURA, M . D . "~ AND EDGAR M. HOUSEPIAN, M.D. a Paul Moore Neurosurgical Research Laboratory, Department of Neurological Surgery, College of Physicians and Surgeons, Columbia University, New York (U.S.A.) (Received for publication: October 11, 1960)

spinal neuron activity associated with the latter might be due to involvement of mixed specific Although interhemispheric and specific thalaand non-specific projections. A similar intermocortical afferents to sensorimotor (pericrucipretation was proposed by Brookhart and Zanate) cortex engage neuronal organizations synaptichetti (1956) to account for the results of Arduini cally linked to corticospinal neurons (Adrian and and Whitlock (1953) who observed both short Moruzzi 1939; Amassian e t al. 1955; Branch and (10-12 m s e c ) a n d long-latency (20 40 msec) Martin 1958; Brookhart and Zanchetti 1956; Li pyramidal tract discharges during recruiting 1959; Purpura and Girado 1959; Patton and responses evoked by intralaminar thalamic Amassian 1960), few data are available concernstimulation. Some resolution of this controversy ing the extent to which these organizations are appears to have been effected during collaboraalso influenced by thalamocortical activities gentive studies (Brookhart e t al. 1958) which erated by stimulation of different components of emphasize the absence of relayed pyramidal tract the thalamic reticular system (TRS) (Dempsey discharges during long-latency recruiting waves. and Morison 1942 a; Jasper 1949; Morison and Specific and non-specific thalamocortical Dempsey 1942). projections appear to engage cortical neurons in Previous studies concerned with this problem different ways (Chang 1952; Clare and Bishop have led to dissimilar views on the relationship 1956; Li e t al. 1956a. b; Purpura 1958, 1959; between thalamically evoked non-specific Smith and Purpura 1960), but subsequent activities in motor cortex and corticospinal dispersion of activities initiated by these two neuron responsiveness. In the study reported by varieties of inputs results in facilitatory and Brookhart and Zanchetti (1956), alterations in inhibitory interactions at different loci in cortical corticospinal responsiveness were observed in organizations available to both types of afferents relation to short-latency (8 15 msec) cortical (Brookhart e t al. 1957; Jasper and Ajmonerecruiting responses evoked by stimulation of Marsan 1952, Jung 1958, Li 1956). Since such antero-lateral components of the thalamic interactions are prominent in sensorimotor reticular system (TRS), but not in relation to cortex, the question arises as to whether the long-latency ( > 15 msec) responses initiated by powerful effects of non-specific volleys on the mid-line thalamic stimulation. Uncertainty as to excitability and discharge characteristics of unthe composition of antero-lateral pathways identifiable neurons in sensorimotor cortex (Li involved in short-latency recruiting responses e t al. 1956b) are reflected in similar changes in prompted the suggestion that changes in corticocorticospinal neuron activity. The present study analyzes the relationship 1 This work was supported in part by a research grant (B 1312 C 3) from the National institute of Neuro- between different varieties of thalamically evoked logical Diseases and Blindness, USPHS, United Cerebral recruiting responses in pericruciate cortex and Palsy Research and Educational Foundation, R-133-60, corticospinal neuron activity in order to reand the Paul Moore Neurosurgical Research Gift. evaluate the role of TRS in the regulation of " Sister Elizabeth Kenny Foundation Scholar. motor cortical function and to further charac3 Parkinson's Disease Foundation Fellow. 365 INTRODUCTION

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terize the cortical synaptic events associated with recruiting waves (Purpura 1959). METHODS

Experiments were performed on 39 adult cats initially anesthetized with ether to permit introduction of tracheal and saphenous vein cannulas, routine craniectomy and enlargement of the foramen magnum. In 5 animals mid-line cerebellar ablation was performed for placement of microelectrodes in the lower brain stem. The upper cervical cord was also exposed in 4 animals. At the completion of all operative procedures, including severance of upper cervical roots in animals with cervical laminectomy, all exposed skin margins and pressure points were infiltrated with 2 per cent procaine. The ether was then discontinued and the animals were paralyzed with succinylcholine chloride and artificially ventilated. The exposed cortex was covered with warm liquid paraffin or periodically rinsed with warm Ringer's solution. Thalamic stimulation was carried out with 0.75 mm diameter concentrically-bipolar electrodes with tips separated less than 0.5 mm. These were held in three-dimensional manipulators and oriented for stimulation of different thalamic nuclei in accordance with modified stereotaxic methods. Stimuli were 0.1 0 5 msec square wave pulses delivered through radio frequency stimulus isolation units. Stimulus strength and frequency were adjusted in each experiment in order to evoke cortical responses with characteristics to be described below. Prior to insertion of thalamic stimulating electrodes, the ipsilateral medullary pyramidal tract was identified by motor cortex stimulation (Patton and Amassian 1954; Purpura and Grundfest 1956). In three preparations, both medullary pyramids and the lateral corticospinal tract in the contralateral upper cervical cord were similarly identified. Cortically evoked responses were recorded bipolarly or monopolarly from the pial surface with chlorided-silver ball electrodes. The reference electrode during monopolar recording consisted of a clip on the posterior neck muscles or scalp edge. Recruiting or augmenting responses from anterior sigmoid gyrus were recorded from a locus about 1.0 mm rostral to

the mid-point of the cruciate sulcus. Corticifugal activity in the medullary pyramids or lateral corticospinal tract was generally recorded monopolarly with a 100/z Teflon-coated silver wire. Unitary discharges in the cervical cord were recorded with either electro-polished steel needles insulated to the tips (10-25 #) or saline filled micropipettes. In a few preparations, the characteristics of relayed tract discharges elicited by thalamic stimulation were examined with pairs of 100 # Teflon-coated wires cemented together (0.3 mm vertical tip separation). After passage through RC-coupled differential amplifiers responses led from cortex and corticospinal pathways were simultaneously displayed on a dual channel oscilloscope. Details as to additional stimulation and recording techniques and the preparation of ~o-amino acid drugs are to be found in subsequent sections and in previous reports (Purpura and Grundfest 1956; Purpura et al. 1959). At the conclusion of the experimental period, the animals were re-anesthetized with pentobarbital sodium (30 mg/kg) and perfused with 10 per cent formalin in saline. Thalamic placements were checked grossly and in Nissl and Mahon preparations. RESULTS

Long-latency recruiting responses and corticospinal tract discharges Various medial thalamic nuclei were stimulated in 26 animals. Long-latency (~> 20 msec) surface-negative recruiting responses were evoked from anterior sigmoid gyrus on the initial penetration into either nucleus centrum medianum (CM) or nucleus reuniens (RE) in 18 animals. In the remainder, multiple thalamic penetrations were made with one or two pairs of stimulating electrodes. Stimulating electrodes were progressively lowered until regions were encountered in which stimulation (6 10/sec)produced slow oscillations in background electrocortical activity. In such instances, further advancement of the stimulating electrodes generally yielded excellent recruitment and maximum relayed corticospinal tract activity. In the present study, thalamic stimuli were adjusted throughout the course of an experiment involving medial thalamic stimulation such that the first stimulus of a repetitive 6-10/sec train

RECRUITING RESPONSES AND CORTICOSPINAL NEURON ACTIVITY

evoked a barely detectable surface response from anterior sigmoid gyrus. Since the relative amplitudes of the first and maximal (5th or 6th) response in a recruiting sequence varied in different experiments and at different times during the same experiment, no attempt was made to define the relationship between relayed corticospinal tract discharges and thalamic stimulus thresholds. It was noted, however, that weak stimuli evoking no alterations in background spontaneous electrocortical activity with the first stimulus produced minimal recruitment and no relayed pyramidal tract discharges. In 4 of the 26 animals in the series, no relayed tract pyramidal activity was detectable even after very strong medial thalamic stimuli capable of evoking prominent surface responses with the first stimulus of a repetitive train. In these preparations, however, pyramidal tract discharges were observed in association with specific

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thalamocortical evoked activities in pericruciate cortex. Typical examples of the alterations in medullary pyramidal tract activity associated with long-latency recruiting responses in anterior sigmoid gyrus are shown in Fig. 1 and 2. In the

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Upper channel, long-latency (20-30 msec) recruiting responses in anterior sigmoid gyrus, a n d lower channel, associated relayed corticospinal tract discharges. Stimulation in nucleus c e n t r u m m e d i a n u m at 7/sec for 6 sec d u r a t i o n ; time of s t i m u l a t i o n m a r k e d by dots. Corticifugal discharges recorded in ipsilateral m e d u l l a r y p y r a m i d at level o f obex. Cortical surface activity recorded m o n o polarly (negativity upwards) in this a n d s u b s e q u e n t illustrations. Note recruitment o f relayed tract discharges along w.ith progressive d e v e l o p m e n t o f surface evoked activity, stabilization o f the latter with c o n t i n u e d stimulation and tendency for relayed discharges to exhibit alternation. Cals: 100 c/sec; 0.1 mV.

Fig. 2 S i m u l t a n e o u s recording o f long-latency recruiting responses in anterior sigmoid gyrus and corticospinal tract activity during 7/sec s t i m u l a t i o n o f lateral margin o f nucleus reuniens for 5 sec. Note decrease or absence o f tract activity prior to a n d after relayed volley, especially d u r i n g initial 2-3 sec of stimulation. F u r t h e r explanation in text. Cals: 100 c/sec; 0.1 mV.

experiment illustrated in Fig. l, prolonged (6 sec) repetitive stimulation (7/sec) of CM elicited little initial surface activity and maximal responses by the 5 t h - 6 t h stimulus. Minimal initial positivity was detectable in the 4 t h - 10th responses, thereafter only surface-negative components of 25-30 msec latency. (The figure illustrales a feature of recruiting responses characteristically observed in the unanesthetized-paralyzed preparation, viz., absence of "waxing and waning"). The development of surface-negativity paralleled the build-up of long-latency (25-30 msec) temporally-dispersed pyramidal tract volleys which attained maximum amplitude at the peak of cortical recruiting negativity. Continued stimulation resulted in stabilization of surface evoked activity at a lower amplitude and a

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tendency for relayed volleys to exhibit m i n o r changes in latency a n d magnitude. Brief phases of late-developing " a l t e r n a t i o n " in relayed tract volleys were n o t u n c o m m o n with prolonged repetitive stimulation.

tract activity. The 20 msec-latency surfacenegative recruiting responses shown in Fig. 2 were associated with bursts of long-latency tract discharges which attained m a x i m u m intensity by the 4 t h - 5 t h stimulus. Thereafter, the initial

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Fig. 3 A. Upper channel, superposed stimulus-triggered sweeps o f long-latency recruiting

responses in anterior sigmoid gyrus and relayed corticospinal tract volley recorded in ipsilateral medullary pyramidal tract (lower channel). Stimulation in CM at 7/sec. l, initial phases of recruitment; 2, early stabilization; 3 and 4, late phases during continued stimulation. Cals: 100 c/sec; 0.1 mV. B. - E. Same conditions as in A. In B, pairs of stimuli delivered every 4 sec in order to obtain build-up of triggered spindles. In C and D, short trains of stimuli are employed and in E nearly 2 sec of continuous stimulation are shown. Time of stimulation indicated by dots. Note complex relationship between triggered spindles in B and associated corticospinal tract activity. "Abortive" bursts follow last stimulus of trains in C and D. Delayed recruitment of relayed tract activity shown in E. During stabilization of surface response relayed discharges exhibit variations in amplitude. F u r t h e r details o f the alterations in tract activity observed d u r i n g 7/sec medial thalamic stimulation were recorded in p r e p a r a t i o n s showing a high degree o f s p o n t a n e o u s corticospinal

surface-negativity increased in d u r a t i o n and a n o t h e r surface-negative c o m p o n e n t appeared o n its falling phase. This was especially p r o m i n e n t t h r o u g h o u t the 6 t h - 16th stimulus in the

R E C R U I T I N G RESPONSES A N D C O R T I C O S P I N A L N E U R O N A C T I V I T Y

repetitive 7/sec train. The appearance of this second component was associated with a delayed burst of tract activity which summed with the earlier. Reduction in background spontaneous activity during the 20-25 msec period prior to the burst of summated multi-unit discharges and after the latter is clearly shown during the first 3 sec of the applied stimulus (Fig. 2). Later at a stage when tract discharges exhibited some "alternation" in magnitude, tract activity was detectable during the 40 msec period preceding each stimulus (Fig. 2, lines 5-7). Though modified in character during prolonged medial thalamic stimulation, relayed corticifugal discharges followed each cortical recruiting wave (Fig. I and 2). This finding is of importance with respect to the question of whether such discharges are related to synaptic events associated with recruitment or are initiated by processes set into operation by the first few thalamic stimuli and registered in cortex as 8-12/sec spindle bursts (Dempsey and Morison 1942a; Jasper and Droogleever-Fortuyn 1947), phenomena known to be associated with relayed corticifugal discharges (Whitlock et al. 1953; Brookhart and Zanchetti 1956). To explore this problem further, attempts were made to trigger spindle bursts in the intact locally anesthetizedparalyzed cat with single or multiple medial thalamic stimuli. In instances when this was successful, single or paired medial thalamic stimuli delivered every 2-4 sec produced progressive build-up of 10-12/sec spindles (Fig. 3B). When well developed, triggered spindle bursts were complexly related to corticifugal discharges. The latter were of relatively low amplitude compared with the 30 msec-latency relayed tract discharges associated with recruiting responses evoked by 7/sec stimulation of CM (Fig. 3A, E). Distribution of relayed corticifugal activiO, in lower brain stem and spinal cord Brookhart and Zanchetti (1956) occasionally observed minor disturbances in the pyramidal recording during recruitment elicited by medial thalamic stimulation. These were attributed to activity in the medullary reticular formation possibly mediated by extrapyramidal pathways descending from the diencephalon. While it

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would appear sufficient to note that in the present experiments the position of the wire recording electrodes in the medullary pyramidal tract was determined by selecting sites at which maximal 0.3-0.5 msec direct (D) responses were evoked by motor cortex stimulation (Patton and Amassian 1954), it was considered necessary to establish that activity recorded in the ventral medulla during non-specific thalamic stimulation originated in corticospinal fibers. In one approach to this problem a wire recording electrode was inserted into the ipsilateral medullary pyramid and another in the contralateral lateral column of the upper cervical cord (Fig. 4, 5). Recruiting responses in anterior sigmoid gyrus evoked by 7/sec stimulation of CM were associated with relayed discharges in the ipsilateral medullary pyramidal tracl and contralateral column (Fig. 4, l 4, 7). Prior to a stimulus sequence the medullary electrode was raised 1 mm from its position at a locus in the tract giving maximum direct responses to pericruciate cortex stimulation. The magnitude of the responses recorded with the wire electrode elevated 1 mm above the "center" of the medullary pyramidal tract was significantly reduced (Fig. 4, 8). Later in the experiment, in a further attempt to prove the cortical origin of relayed tract discharges, recruiting responses in anterior suprasylvian gyrus served as a control of thalamocortical excitability before (Fig. 4, 9) and after (Fig. 4, 10) suction-ablation of pericruciate cortex (Fig. 4 B). Relayed activity in the contralateral lateral cervical cord was abolished by the cortical lesion which did not, however, significantly alter thalamocortical excitability', as indicated by the character of recruiting responses in anterior suprasylvian gyrus. Although the foregoing results indicated that activity recorded in the ventral medulla during long-latency recruiting responses evoked by medial thalamic stimulation originated in corticospinal fibers, it is not to be inferred from this that the observations of Brookhart and Zanchetti (1956) pertaining to evoked reticular formation activity were not confirmed. Indeed, in addition to relayed discharges in corticospinal fibers, repetitive medial thalamic stimulation produced a wide variety of alterations in the discharge patterns of elements in the pontomedullary

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reticular f o r m a t i o n a n d i n t e r n e u r o n s at the base of the posterior h o r n (Fig. 5, 5-16). Such alterations, r a n g i n g from excitation of " s i l e n t "

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and were temporally related to cortical surface recruiting responses. It is a p p a r e n t from this that corticifugal discharges initiated by medial thala-

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/VV JV' Fig. 4 A. Stimulating site in medial thalamus (CM) marked by arrow at tip of tract. Repetitive stimulation (7/sec) evoked 20 msec latency recruiting responses in anterior sigmoid gyrus and relayed discharges in contralateral lateral column of upper cervical spinal cord (l -4). 1, Early phase of recruitment; 2 and 3, early and late stabilization phases; 4, phase of reduced relayed volley and further stabilization of surface-evoked activity; 5, direct (D) and indirect (I) responses recorded in ipsilateral medullary pyramidal tract (upper channel) and contralateral upper cervical cord (lower channel) following motor cortex stimulation; 6, spontaneous activity from medullary and cervical corticospinal tract as in 5, but at slower sweep; 7, dispersed relayed volleys during early stabilization of recruiting responses; 8, same as in 7, but after 1 mm upward movement of electrode in medullary pyramidal tract; 9, stabilization phase of recruiting responses in ipsilateral anterior suprasylvian gyrus and relayed corticospinal tract volleys recorded in contralateral cervical cord; 10, abolition of relayed tract volley, but persistence of recruiting responses in anterior suprasylvian gyrus after suction-ablation of ipsilateral pericruciate cortex (as shown in B). Cals: 100 c/sec for all but 5 shown in lower right; that for 5, 1000 c/sec. elements to inhibition or driving of spontaneously active neurons, were e n c o u n t e r e d in the lower brain stem and upper cervical spinal cord

mic s t i m u l a t i o n are mediated by fibers passing in the medullary p y r a m i d to i n t e r n e u r o n s in the contralateral spinal cord a n d by c o r t i c o b u l b a r

RECRUITING RESPONSES AND CORTICOSP1NAL NEURON ACTIVITY

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AJ~',ZVXzV\ Fig. 5 Microphotograph shows stimulating site in MD. 1. Upper channel, right, and lower channel, left ventral medullary pyramidal tract recordings following left motor cortex stimulation; 2. same as in 1, right motor cortex stimulation Cals: below 2, 1000 c/sec; 3. Stabilization phase of recruiting response in ipsilateral anterior sigmoid gyrus and relayed volleysin ipsilateral pyramidal tract (8/sec stimulation); 4. stabilization of recruiting responses in contralateral anterior sigmoid gyrus and relayed volley in contralateral tract. Cals: below 4, 100 c/sec; 0.1 inV. 5-8. Microelectrode recordings from base of posterior horn, contralateral upper cervical cord. 5, control; 6, during 8/sec MD stimulation; 7, spontaneous discharges of units after activation by thalamic stimulation; 8, grouping of discharges during thalamic stimulation; 9, spontaneous activity in ipsilateral anterior sigmoid gyrus and contralateral cervical cord; 10, same as in 9 during early stabilization of recruiting responses. Cals: for 5 - 10, below 8; 100 c/sec; 0.1 mV. 1 l. 0.5/sec stimulation of MD. Recordings same as in 9. 12-16. Various stages of recruitment of cortical surface activity and cervical cord unit discharges during 8/sec MD stimulation. Note progressive shortening of cord unit discharge latency during recruiting negativity (12 14), then delay (15), and finally cessation of unit activity (16) during stabilization of surface recruiting response.

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were observed in the contralateral pyramidal tract (Fig. 5, 1~/). Some evidence bearing on the complexity of the relationship between recruiting responses and relayed tract activity was obtained in six preparations in which aliphatic ~o-amino carboxylic acids were employed to eliminate or enhance surfacenegative components of recruiting responses I

projections to elements in the brain stem reticular formation.

Cortical-synaptic events associated with longlatency thalamically evoked corticifugal discharges Stimulation of central regions of mid-line thalamic nuclei (CM, RE) evoked recruiting responses bilaterally in anterior sigmoid gyrus

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Fig. 6 A. Recruiting responses in left anterior sigmoid gyrus and relayed discharges in ventral medullary corticospinal tract evoked by 7/sec stimulation of ]eft lateral margin of n. reuniens. B. Left (upper channel) and right (lower channel) anterior sigmoid gyrus recruiting responses during same stimulation as in A. C. Left (upper channel) and right (lower channel) medullary pyramidal tract discharges associatedwith surface responsesas in B. Time of stimuli noted by dots above upper c h a n n e l records. Cals: 0.1 inV.

which were associated with discharges in both medullary pyramidal tracts. Stimulation of the lateral margins of these mid-line nuclei yielded recruiting responses from contralateral motor cortex that were frequently of lower amplitude and longer latency than ipsilateral responses (Enomoto 1959). The lower amplitude responses were associated with only minor fluctuations in the contralateral medullary pyramidal tract activity (Fig. 6). Although such findings suggested that the size of the relayed corticospinal tract volley was dependent on the magnitude of evoked cortical surface-negativity, other data indicated that synaptic events other than those reflected in the evoked surface responses played a major role in the production of relayed corticospinal tract discharges. Thus stimulation of medial thalamic nuclei (e.g., portions of n. medialis dorsalis (MD); Ajmone-Marsan 1954) produced prominent bilateral recruiting responses maximal in the anterior sigmoid gyri, but only minor discharges

1 T h e pharmacological actions of aliphatic oJ-amino acids on different varieties of evoked cortical responses have been described in detail elsewhere ( P u r p u r a 1960; P u r p u r a e t al. 1959). Suffice it to say that the action o f G A B A is representative o f the g r o u p of short chain ,--amino acids with 5 or less c a r b o n a t o m s in the aliphatic chain, whereas that o f c-amino caproic acid (C6) is representative of the actions of long chain a m i n o acids with m o r e t h a n 6 carbons in the aliphatic chain. Surfacenegative c o m p o n e n t s o f evoked responses in neocortex are eliminated by G A B A and e n h a n c e d by C6. Elimination o f surface-negativity by G A B A generally reveals a surfacepositivity which varies in m a g n i t u d e in different evoked responses. T h e u n m a s k e d surface-positivity h a s been interpreted as a n axodendritic hyperpolarizing p.s.p. w h e n revealed in superficial cortical responses evoked by weak surface stimulation, or a c o m p o s i t e of depolarizing sub-surface a n d surface hyperpolarizing p.s.p.'s in different p r o p o r t i o n s w h e n revealed in responses o f greater complexity (Purpura, G i r a d o and G r u n d f e s t 1959, 1960). E n h a n c e m e n t of surface-negativity or e l i m i n a t i o n of surface-positivityin s o m e responses by C~ has been attributed to blockade o f hyperpolarizing axodendritic p.s.p.'s. This action is frequently a c c o m p a n i e d by the d e v e l o p m e n t o f paroxysmal discharges ( P u r p u r a e t at. 1959).

RECRUITING RESPONSES AND CORTICOSPINAL NEURON ACTIVITY

The effects of ~,-aminobutyric acid (GABA) and a representative convulsant long-chain w-amino acid (C6) are shown in Fig. 7 in records taken from different experiments. The 20 mseclatency surface-negative recruiting responses in anterior sigmoid gyrus (Fig. 7 A 1, 2) were A

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wvw Fig. 7 Effect of topically applied G A B A , (A), and E-aminocaproic acid (C6), (B), o n recruiting responses in anterior sigmoid gyrus a n d relayed ipsilateral m e d u l l a r y pyramidal tract discharges. T w o different preparations. 1 a n d 2, early a n d late phases respectively o f recruitment prior to application o f G A B A in A a n d C6 in B. 3 a n d 4, same as in 1 and 2, but 5 m i n after c o n t i n u e d application o f the ~o-amino-acids. 5 and 6, in A, recovery o f surfacenegativity after cortex had been rinsed repeatedly with w a r m Ringer's solution. B, (5 a n d 6), persisting c o n v u l s a n t action o f C6 and continued e n h a n c e m e n t o f surfacenegativity. F u r t h e r e x p l a n a t i o n in text. Cals: 100 c/sec; 0.1 inV.

rapidly eliminated after topical application of GABA (1 o/) and were replaced by long-latency recruiting surface-positive responses similar to those described previously (Goldring et al. 1958: lwama and Jasper 1957: Purpura 1958). Despite wide and continued application of GABA to all exposed rostral cortex, relayed tract volleys were relatively unaltered in latency and magnitude, in one experiment involving the use of 5 per cent GABA solutions, a significant reduction in relayed volleys was observed. However, in view of the failure to obtain adequate recovery of cortical surface and tract responses after removal of GABA, no conclusions could be drawn concerning the action of high GABA concentrations. In contrast to the effects of GABA on long-

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latency recruiting responses, C6 facilitated the development of recruitment and markedly augmented the surface-negativity (Fig. 7 B). Although this resulted in a more rapid build-up of relayed tract volleys (Fig. 7 B 3) their magnitude did not exceed those associated with responses prior to application of C6 (Fig. 7 B 2). Of significance also was the finding that paroxysmal discharges initiated by C6 did not interfere with recruitment of relayed tract activity during repetitive thalamic stimulation (Fig. 7 B5). Additional information on the cortical synaptic events associated with long-latency recruiting responses in motor cortex was obtained by considerable modification of the procedures utilized by Brookhart and Zanchetti (1956) to test for alterations in corticospinal neuron responsiveness. 1 In the experiments illustrated in Fig. 8 and 9, corticospinal neuron responsiveness was tested prior to and after long-latency relayed volleys by varying the interval between pairs of 7/sec cortical and thalamic stimuli. The following procedure was routinely adopted: Control D and I tract responses (Patton and Amassian 1954; Purpura and Grundfest 1956) were evoked by weak 7/sec motor cortex stimulation. When these responses stabilized, various thalamic nuclei were stimulated at 7/sec for 1-3 sec. Cortical stimulation (7/sec) continued throughout the period of thalamic conditioning and for 2-3 sec thereafter. This sequence was repeated every 1-2 min over a 15-45 min period providing that the cortical stimulation did not initiate seizure activity. If seizure developed, at least 15-30 min were allowed for recovery before testing was resumed. In 15 preparations marked depression of D and particularly I responses was observed in 8 out of 21 experiments in which medial nuclei were stimulated (Fig. 8 and 9 B). In 4 preparations, only minimal changes were noted in I responses. Stimulation of anterolateral components of the TRS giving rise to T h e technique employed by B r o o k h a r t and Zanchetti (1956) consisted in testing for alterations in the m a g n i t u d e of direct (D) and indirect (I) or synaptically relayed responses in the medullary pyramidal tract evoked by weak s t i m u l a t i o n of anterior sigmoid gyrus at various intervals after the last of a train o f 6 or 7 stimuli (8/sec) to medial t h a l a m i c nuclei.

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Fig. 8 Depression of corticospinal neuron responsiveness prior to and after relayed tract volleys associated with recruiting waves in motor cortex, l and 2, build-up and stabilization phases respectively of recruiting responses evoked by 7/sec stimulation in CM. 3, D and I responses in corticospinal tract evoked by weak 7/sec motor cortex stimulation. 4, repetitive thalamic stimulus precedes repetitive motor cortex stimulus by 5-6 msec. Depression of D and 1 responses shown in greater detail in faster sweep records (5-12). In this series, left column records are unconditioned D and I responses evoked by 7/sec motor cortex stimulation. In right hand column, CM stimulation precedes (6, 8) or follows (10, 12) motor cortex stimulation. Note complete inhibition of I and marked depression of D responses. Inhibition of D waves, though prominent prior to the tbalamic stimulus, is reinforced 8-10 msec after the latter (8). Further details in text. Cals: on left for l-4, 100 c/sec; 0.1 mV. Right for 5-12, 1000 c/sec; 0.1 mV. short-latency (8-15 msec) relayed tract volleys always depressed and occasionally abolished I waves, a n d to a lesser degree, depressed D waves (Fig. 9 A). In favorable experiments involving medial thalamic s t i m u l a t i o n tested D a n d I waves were m a r k e d l y depressed when elicited d u r i n g the period after a thalamic stimulus a n d preceding the development of the relayed tract volley (Fig. 8, 6, 8). M a x i m a l depression occurred prior to the a p p e a r a n c e of the long-latency relayed volley (8). After the relayed volley, depression of D a n d I waves was detectable in the period prior to a subsequent thalamic stimulus (Fig. 8, 10, 12). It is of considerable significance tha! the periods of D and I wave depression coincided with the periods d u r i n g which s p o n t a n e o u s tract activity was reduced d u r i n g 7/sec medial thalamic stimulation (cf Fig. 2). The phasic alteration in corticospinal n e u r o n

activity observed d u r i n g stimulation of medial thalamic nuclei was f o u n d to be d e p e n d e n t on

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RECRUITING RESPONSES AND CORTICOSPINAL NEURON ACTIVITY

activity in cortical synaptic organizations capable of responding to low-frequency (6-10/see) thalamic volleys. At higher stimulus frequencies, D and I wave depression was eliminated and a tendency for facilitation of I c o m p o n e n t s was observed (Fig. 9 C). Observations on the depression of tested direct and indirect corticospinal discharges during long-latency recruiting responses were extended to include an analysis of the effects of T R S stimulation on short-latency relayed tract 1

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Fig. 10 I. N o n - a u g m e n t i n g specific responses in anterior sigmoid

gyrus evoked by 7/sec stimulation of specific thalamocortical projections with laterally placed electrodes. 2. Similar surface responses evoked by 7/sec stimulation of postero-medial specific projection pathways with more medially situated electrodes. 3. Paired 7/sec stimulation, 35 msec stimulus intervals. Short-latency (4 msec) relayed discharges minimally depressed. 4-6. Progressive elevation of more medial electrodes initiates long-latency recruiting responses. Note longlatency relayed tract volley associated with these responses and inhibition of short-latency discharges and specific evoked responses evoked by continued lateral thalamic stimulation (6). 7, 8. More medial stimulating electrodes lowered again into specific projection pathways. 9-12. Single sweep records of similar sequence during continued 12/sec stimulation through medial and lateral electrodes. 9, Lateral stimulation alone; 10, paired stimulation at 12/sec; stimulus interval 30 msec. Medial electrodes in non-specific system. 11 and 12, Medial electrodes lowered into specific projections then progressively re-elevated (13-16). Further explanation in text. Cals: 100 c/sec.

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discharges evoked by stimulation of specific thalamocortical projections. In these experiments two pairs of concentrically-bipolar stimulating electrodes were initially placed in specific t h a l a m o c o r tical projections to pericruciate cortex. The more "medially" placed electrodes were so situated as to permit engagement of non-specific nuclei when they were elevated 1-2 ram. With both pairs of electrodes in specific projections, repetitive stimulation (7/sec) through either pair (Fig. 10, 1, 2) evoked short-latency specific responses from pericruciate cortex that were associated with 3--4 msec latency short-duration relayed corticospinal tract volleys. Stimulation at both sites at 7/sec with 35 msec pulse intervals evoked surface responses with slightly reduced negativity and relayed tract volleys whose magnitude was decreased by 30 per cent (Fig. 10, 3). Despite this reduction, cortical synaptic organizations involved in short-latency activation of corticospinal neurons responded for relatively long periods. Following stabilization of both responses, the " m e d i a l " electrodes were elevated progressively until non-specific pathways were stimulated and long-latency relayed tract discharges were evoked. Short-latency tract discharges associated with stimulation of lateral specific projections were blocked and the surface evoked responses reduced (Fig. 10, 6). Lowering the more " m e d i a l " electrodes brought about return of specific activity and associated shortlatency tract discharges (Fig. 10, 7, 8). Repetition of this experiment with 12/sec stimulation at both sites and with a 30 msec interval between paired pulses is shown in Fig. 10 (9-16). The latter illustrates the blockade of short-latency specific evoked relayed tract discharges induced by interposed non-specific stimulation (10) and the immediate return of such discharges following small displacements of the more " m e d i a l " electrodes (11).

Patterns of relayed corticospinal tract activity evoked b), stimulation of various thalamic nuclei and their projections The present study provided an opportunity for examining the electrographic characteristics and distribution of a wide variety of responses evoked by thalamic stimulation. Some of the relationships between surface evoked responses

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and patterns of relayed tract activity examined in 8 experiments are summarized in Fig. 11. Repetitive (7/sec) stimulation of specific thalamocortical projections to pericruciate cortex evoked short (1 msec latency) initially surface-positive responses associated with 2-4 msec-latency shortduration synchronous tract discharges (Fig. l 1 A) (Brookhart and Zanchetti 1956; Purpura 1958). An example of augmenting responses (Dempsey and Morison 1942 b) in anterior sigmoid gyrus evoked by repetitive stimulation in ventralis lateralis (VL) and the powerful short-latency relayed corticospinal tract volley accompanying them is shown in Fig. 11 B. The surface responses in B are identical with those recorded by Hanbery and Jasper (1953, c f Fig. 12 B) during repetitive VL stimulation. Comparison of responses in A and B with those evoked by stimulation of antero-lateral components of the TRS ( D - F ) reveals that although the latter responses may frequently exhibit short-latency surface-positivity in anterior sigmoid gyrus (D1, A

B

C

Fig. I 1 Patterns o f relayed corticospinal tract discharges (lower channel t h r o u g h o u t ) associated with different varieties o f responses evoked in m o t o r cortex by 7/sec t h a l a m i c stimulation. Examples f r o m eight different preparations. A. Stimulation o f specific thalamocortical projections. B. Stimulation in VL. C. 1, s t i m u l a t i o n o f m i x e d pathways, inferior lateral m a r g i n o f V A ; 2, stimulating electrodes elevated 1.5 m m into superior part of VA. D, E, and F. 1, anterior sigmoid gyrus; 2, anterior suprasylvian gyrus. Stimulation in antero-lateral c o m p o n e n t s of thalamic reticular system. G a n d H. Medial thalamic stimulation. C a l s : 100 c/sec.

E1 and F1) they are invariably associated with prominent surface-negative recruiting responses in anterior suprasylvian gyrus (D2, E2 and F2) as well as relayed tract discharges of 8-[5 msec latency. Short-latency responses evoked by stimulation of antero-lateral components of the TRS (n. ventralis anterior, VA; n. reticularis, Ret) may reveal an initial prominent surfacepositivity, but the latter never has temporal characteristics similar to responses evoked by specific system stimulation. That relatively shortlatency recruiting responses lacking initial positivity can be evoked in anterior sigmoid gyrus by stimulation in VA is well known (Hanbery and Jasper 1953; Verzeano ct al. 1953). It is of interest, however, that responses exhibiting rapid recruitment (Hanbery and Jasper 1953: Hanbery et al. 1954) were associated with relayed tract discharges of longer latency than those which appeared to be mixtures of augmenting and short-latency recruiting responses (Fig. l l CI and C2). Suffice it to say that during penetration of the stimulating electrodes through thalamic regions 2-3 mm from the mid-line it was not uncommon to evoke four varieties of surface responses from anterior sigmoid gyrus that were associated with four patterns of relayed-tract activity. Responses similar to those shown in Fig. 11 C2 were generally evoked by stimulation of the most dorsal parts of the antero-lateral thalamus. Approximately 2 mm deeper, surfacepositivity became more prominent as in Fig. I I C1; still deeper augmenting sequences (B) and finally non-augmenting specific sequences (A) were elicited. Long-latency (,_> 20 msec) relayed tract discharges similar to those evoked by medial thalamic stimulation (Fig. 3, Fig. II G, H) were not observed during antero-lateral thalamic stimulation. DISCUSSION

The foregoing results support the conclusion of Arduini and Whitlock (1953) that recruiting responses evoked in motor cortex by repetitive stimulation of non-specific thalamic nuclei are associated with relayed corticospinal tract discharges. They also bear on several aspects of thalamocortical relations that require additional comment.

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RECRUITING RESPONSES AND CORTICOSPINAL NEURON ACTIVITY

Distribution o f non-specific afferents in motor cortex

In view of the scanty histological data on the origin, course and termination of non-specific thalamocortical afferents (Akimoto et al. 1956; Hanbery et al. 1954; Hanbery and Jasper 1953; Nauta and Whitlock 1954; Rose and Woolsey 1949), considerable emphasis has been placed on electrophysiological and pharmacological analyses of the intracortical synaptic distribution of these pathways. Such studies indicate that in sensorimotor cortex, non-specific and specific afferents terminate in fundamentally different ways, and that activation of superficial cortical elements by synaptic organizations linked to nonspecific afferents is associated with a variety of subsurface synaptic events ( c f Purpura, 1959). Support for this is provided by the lack of relationship between the magnitude of lecruiting surface-negativity and the intensity of relayed corticospinal tract discharges found in the present experiments. These results suggest that non-specific afferents terminate at all levels in ipsilateral motor cortex in relation to excitatory and inhibitory interneurons, some of which synapse at various loci on the soma-dendritic surface of corticospinal neurons. Thus, failure of topically applied ~o-amino acids to alter relayed tract discharges at a time when surface-negative recruiting responses are eliminated or enhanced (Fig. 7) may be viewed as a reflection of the extent to which non-specific afferents engage elements in motor cortex other than those involved in the generation of p.s.p.'s in apical dendrites of corticospinal neurons. Persistence of short-latency relayed corticospinal tract discharges associated with augmenting responses has also been observed after GABA-induced elimination of augmenting negativity (Purpura et al. 1959) and after similar changes produced by moderate cooling of the cortical surface (Brookhart et al. 1958). Although these data point to the operation of independent synaptic events in superficial and deep cortical organizations during augmenting as well as recruiting responses, the persistence of relayed discharges after GABAblockade of surface-negativity in both varieties of responses suggests that similar intracortica[ relay pathways to corticospinal neurons in the cortical depths may be activated at different

sites by specific and non-specific afferents. Mid-line thalamic stimulation evokes bilateral recruiting responses and relayed tract discharges with similar characteristics, whereas stimulation of some non-specific pathways ordinarily fails to elicit contralateral tract discharges despite the fact that such stimulation may evoke prominent long-latency recruiting responses from contralateral motor cortex. These findings suggest that surface recruiting responses and relayed discharges are triggered by separate synaptic events and that non-specific thalamocortical afferents to sub-surface organizations involved in corticospinal neuron activation are distributed primarily to the ipsilateral pericruciate cortex. Classification motor cortex

o f thalamocortical

activities

in

The long-latency (20-40 msec) recruiting negativity in surface evoked responses in sensorimotor cortex is frequently associated with shorter-latency negative components in the cortical depths (Li et al. 1956b; Purpura and Housepian, unpublished observations). Recruiting negativity evoked by repetitive stimulation in VA or Ret. may be preceded by prominent 8-10 msec surface-positivity (Brookhart and Zanchetti 1956). Whether short-latency recruiting responses have prominent initial surface-positivity in motor cortex (Fig. 11 D-F) or are devoid of this component (Fig. 11 G, H), such responses are accompanied by relayed tract discharges. In the case of short-latency recruiting responses with prominent initial surface-positivity, relayed volleys are triggered during the middle and late phases of this component and recruit with the subsequent negativity. When surface-positivity is absent, relayed tract volleys are initiated during the recruiting negativity. Thus short-latency and long-latency recruiting responses have characteristics which distinguish them in surface recordings and in the effects on interposed relay elements to corticospinal neurons which accompany them. The distinctive characteristics of evoked thalamocortical activities in motor cortex are emphasized by comparison of the effects on corticospinal neurons observed in association with short and long-latency recruiting responses and those accompanying augmenting and non-augmenting (specific) responses. The present results reveal

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differences in latency, magnitude and temporal characteristics of relayed discharges in association with these four varieties of thalamocortical activities, rather than the presence or absence of tract activity as reported by Brookhart and Zanchetti (1956). It should be recalled that although the latter workers described relayed tract discharges during short-latency recruiting responses, their failure to observe relayed discharges during longer latency recruiting responses devoid of initial surface-positivity, led to the suggestion that short-latency recruiting responses might be compounded of specific and non-specific activities. The extraordinary complexity of antero-lateral thalamic projection pathways and the difficulties involved in interpreting the effects of their stimulation have been repeatedly noted in many of the reports cited above. Notwithstanding these difficulties, the results of the present study permit some distinction to be made between specific and short-latency non-specific responses evoked in motor cortex by the different patterns of associated relayed tract activity.

Organization of intracortical relays between nonspecific thalamic afferents and corticospinalneurons Single shock stimulation anywhere in the non-specific thalamic system fails to evoke detectable relayed corticospinal tract activity, whereas single stimuli to specific projections to motor cortex often produce a small but significant relayed volley. Repetitive stimulation of non-specific nuclei (6-12/see)induces typical recruitment and with this, recruiting relayed discharges. Thus, despite the independence of synaptic events involved in the production of long-latency surface-negativity and long-latency relayed tract discharges, both events are initiated by mechanisms set into operation by stimulation of non-specific pathways. Although it has been shown that cortical surface recruiting responses may be elicited following massive destruction of specific thalamic relay nuclei (Hanbery and Jasper 1953) the question arises whether the activation of intracortical relay pathways to corticospinal neurons observed during TRS stimulation might be due to involvement of intrathalamic pathways between non-specific and specific nuclei (Nauta and Whitlock 1954). If such were the case, it

might be expected that synaptic activation of specific thalamocortical pathways by non-specific afferents would be signaled by surface responses with prominent initial positivity and closely related tract discharges. Such has not been found in the present experiments when stimulating a variety of intralaminar nuclei. Indeed, the fact that specific evoked responses and their shortlatency relayed tract discharge are depressed by suitably timed simultaneous stimulation of specific and non-specific pathways at 6-12/sec strongly argues in favor of a cortical locus for the inhibitory interaction and for mediation of nonspecific effects on corticospinal neurons over pathways independent of specific projections (~J~ Jasper and Ajmone-Marsan 1952). The inhibition of corticospinal neurons observed prior to and after long and shortlatency relayed tract volleys coincides with the period during which spontaneous tract activity is reduced or abolished during recruiting sequences. Of particular importance is the finding that the inhibition following a long-latency relayed volley initiated by 7-10/sec TRS stimulation is reinforced during the period prior to a subsequent volley and in some instances is converted to facilitation during 25-50/sec stimulation. These findings indicate that at frequencies optimal for recruitment of corticospinal discharges each stimulus of a 6-12/sec train re-inforces a sequence of inhibitory-excitatory-inhibitory drives on corticospinal neurons. Higher TRS stimulus frequencies (25-50/sec) which block recruitment and initiate electrocortical activation (Moruzzi and Magoun 1949)abolish the inhibitory phases and may increase corticospinal neuron excitability. The different effects on corticospinal neurons observed during TRS stimulation at different frequencies suggest that as in the case of transcallosal activation of corticospinal neurons (Purpura and Girado 1959) different organizations in the intracortical relay pathways to corticospinal neurons appear to be operated by different input frequencies over non-specific projections.

TRS modulation of corticifi, gal activity The pattern of corticifugal discharges associated with long-latency recruiting responses resembles in many respects that seen in con-

RECRUITING RESPONSES AND CORTICOSPINAL NEURON ACTIVITY

junction with some spontaneous spindle waves in motor cortex (Whitlock et al. 1953). The complex relationship between spindle waves and relayed tract activity found in the present study suggests that spindle waves, like recruiting responses, are compounded of surface and subsurface synaptic events. The latter, related to activity in intracortical organizations involved in excitation and inhibition ofcorticospinal neurons, may not be reflected in overt surface responses (Purpura 1959). The independent nature of surface and sub-surface synaptic activities could account for the observations of Whitlock et al. (1953) that pyramidal tract discharges during spindle waves sometimes cease without any appreciable decrease in the amplitude of the spindle waves recorded from the cortical surface. These findings and those reported above emphasize the extra-ordinary complexity of the synaptic events involved in the production of different varieties of spindle waves (Spencer and Brookhart 1961) recruiting responses and their related corticifngal discharges. Corticifugal activity initiated by TRS stimulation affects a wide variety of interneuronal organizations in the lower brain stem and spinal cord. These results would appear to extend the range of action of the diffusely projecting system of the thalamus to the modulation of synaptic activities influenced by corticifugal inputs (Jasper 1949). Finally, it should be noted that the nonspecific thalamo-corticospinal relay pathways described here may be set into operation by impulses converging on non-specific nuclei from widespread sources (Albe-Fessard and Massoin 1959). Such pathways may also be involved in the long-latency ( > 25 msec) activation of corticospinal neurons asseciated with stimulation of ipsilateral and contralateral somatic sensory receptors (Brooks 1960; Patton 1960). SUMMARY

l. The relation between different varieties of repetitively evoked thalamocortical responses in motor cortex and corticospinal neuron activity has been studied in locally anesthetized-paralyzed cats. 2. Long-latency ( > 20 msec) recruiting responses evoked by medial thalamic stimulation are associate dwith long-latency ( > 20 msec)

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relayed corticospinal tract discharges which recruit pari passu with surface-negativity. Shortlatency (8-15 msec) l ecruiting responses evoked by stimulation of antero-lateral components of the thalamic reticular system (TRS) are associated with recruiting tract discharges that ate initiated during the prior surface-positivity that characterizes many of these responses. 3. Relayed tract discharges triggered during short or long-latency recruiting responses are distinguishable from those associated with augmenting and non-augmenting specific thalamocortical activities in terms of latency, magnitude and duration. 4. Direct and indirect corticospinal tract responses evoked by 7-10/sec weak motor cortex stimulation and short-latency (2-4 msec) relayed discharges evoked during specific thalamocortical responses are inhibited prior to and after relayed tract volleys associated with short and long-latency recruiting responses. 5. Relayed activity in corticobulbar and corticospinal pathways associated with recruiting responses in motor cortex is distributed to a wide variety of elements in brain stem reticular organizations and spinal cord. 6. Evidence is presented indicating that subsurface synaptic events responsible for the alterations in corticospinal neuron activity during different varieties of recruiting responses are independent of those involved in the production of recruiting surface-negativity. REFERENCES

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JUNG, R. Coordination of specific and non-specific afferent impulses at single neurons of the visual cortex. In: H . H . JASPER, L . D . PROCTOR, R.S. KNIGHTON, W. C. NOSnAV and R. T. COSTELLO(Editors), Reticular.[ormation of" the br.qin. Little, Brown, Boston, 1958, pp. 423 434. LI, C.-L. The facilitatory effect of stimulation of an unspecific thalamic nucleus on cortical sensory neuronal responses. J. Physiol. (Lond.), 1956, 131: 115-124. LI, C.-L. Some properties of pyramidal neurones in motor cortex with particular reference to sensory stimulation. J. Neurophysiol., 1959, 22: 385-394. L1, C.-L., CULLEN, C .and JASPER, H. H. Laminar microelectrode studies of specific somato-sensory cortical potentials. J. Neurophysiol., 1956a, 19:I11-130. LI, C.-L., CULLEN, C. and JASPER, H. H. l_.aminar microelectrode analysis of cortical unspecific recruiting responses and spontaneous rhythms. J. Neurophysiol., 1956b, 19: 131-143. MORISON, R. S. and DEMPSEY, E. W. A study of thalamocortical relations. Amer. J. Physiol., 1942, 135: 281-292. MORUZZI, G. and MAGOUN, H. W. Brain stern reticular formation and activation of the EEG. Electroenceph. clin. Neurophysiol., 1949, •:455-473. NAUTA, W. J. H. and WnITLOCK, D. G. An anatomical analysis of the non-specific thalamic projection system. In: E. D. ADRIAN, F. BREMER, H. H. JASPER and J. F. DELAr'RESNAYE(Editors), Brain mechanisms and consciousness. C. C. T h o m a s , Springfield, 1954, pp. 81-116. PATTON, H. D. Pyramidal corticifugal discharges elicited by ipsilateral cutaneous stimulation. ?i,d, Proc., 1960, 19: 287. PATTON, H. D. and AMASSIAN, V. E. Single and multiple unit analysis of the cortical stage of pyramidal tract activation. J. Neuroph)siol., 1954, 17:345 363. PATTOn, H. D. and AMASSlAN,V. E. The pyramidal tract: its excitation and functions. In: J FIELD, H . W . MAGOUN and V. E. HALL (Editors), Handbook o f physiology. American Physiological Society, 1960, II, pp. 837-861. PURPURA, D. P. Organization of excitatory and inhibitory synoptic electrogenesis in neocortex. In: H. H. JASPER, L. D. PROCTOR, R. S. KNIGHTON, W. C. NOSHAY and R. T. COSTELLO (Editors), Reticular .[ormation o f the brain. Little, Brown, Boston, 1958, pp. 435-457. PURPURA, D. P. Nature of electrocortical potentials and synaptic organizations in cerebral and cerebellar cortex. In: C. C. PFEIFFER and J. R. SMYTHIES (Editors), International review o[' neurobiology. Academic Press, New York, 1959, pp. 47 163. PURPURA, D. P. Pharmacological actions of ,~-amino acid drugs on different cortical synoptic organizations. In: E. ROBERTS (Editor), Inhibition it; the nervous system and F-aminobutyric acid. Pergamon, New York, 1960, pp. 495-.514. PURPURA, D. P. and GmAOO, M. Synaptic mechanisms involved in transcallosal activation of corticospinal neurons. Arch. ital. Biol., 1959, 97: I I 1-139. PURPURA, D. P,, GIRADO, M, and GRUNDFEST, H. Synap-

RECRUITING RESPONSES AND CORT1COSPINAL NEURON ACTIVITY tic components of cerebellar electrocortical activity evoked by various afferent pathways. J. gen. Physiol., 1959, 42:1037 1066. PURPURA, D. P., GIRADO, M. and GRUNDFEST,H. Compooer, ts of evoked potentials in cerebral cortex. Electroenceph. clin. NeurophysioL, 1960, 1 2 : 9 5 ll0. PURPURA, D. P., GIRADO, M., SMITH, T. G. Jr., CALLAN, D . A . and GRUNDFEST,H. Structure-activity determinants of pharmacological effects of amino acids and related c o m p o u n d s on central synapses. J. Neurochem., 1959, 3: 238-268. PURPURA, D. P. and GRUNDFEST, H. Nature of dendritic potentials and synaptic mechanisms in cerebral cortex of cat. J. Neurophysiol., 1956, 19:573 595. ROSE, J. E. and WOOLSEY, C. N. Organization of the mammalian thalamus and its relationship to the

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Reference: PURPURA,D. P. and HOUSEPIAN,E. M. Alterations in corticospinal neuron activity associated with thalamocortical recruiting responses. Electroenceph. clin. NeurophysioL, 1961, 13:365 381.