J. Phy8i0l. (1975), 247, pp. 745-757 With 5 text-ftgure8
745
Printed in Great Britain
CORTICOFUGAL EFFECTS SENSORIMOTOR FROM AREA I AND SOMATOSENSORY AREA II ON NEURONES OF THE PONTINE NUCLEI IN THE CAT
BY D. RUEGG AND M. WIESENDANGER From the Department of Physiology, University of Western Ontario, London, Ontario, Canada N6A 3K7 (Received 28 August 1974) SUMMARY
1. The objective of the present experiments was to study the cortical influence from sensorimotor area I (SM I) and from somatosensory area II (S II) on single neurones of the pontine nuclei (PN) in cats under N20thiamylal anaesthesia. 2. Extracellular single unit recordings revealed a considerable convergence from S II and SM I. Out of ninety-one PN neurones (identified as ponto-cerebellar neurones by antidromic stimulation of the contralateral brachium pontis), fifty-seven neurones were influenced by stimulation of at least one cortical site. Slightly less than half of these neurones (twentyfive) had a convergent input from SM I and S II; twenty-three PN neurones were excited by SM I only and nine PN neurones by S II only. The proportion of PN neurones excited via collaterals of cortico-spinal neurones was small and restricted to those neurones which had an input from SM I. 3. Sixty per cent of the ponto-cerebellar neurones were reliably activated by natural stimulation such as tapping or passive manipulations of limbs of various joints. The vast majority (thirty-three out of thirtysix PN neurones) which had receptive fields were also influenced by electrical stimulation of one or both cortical areas. The long latency and low probability of discharge to peripheral nerve stimulation suggest a complex, probably transcortical, pathway from the periphery to the PN. 4. The distribution of latencies to both cortical and brachium pontis stimulation indicates that the PN are a relay for fast and slow cerebrocerebellar connexions. 5. The convergence from cortical areas on PN indicates that the neurones influenced from somatic areas SM I and S II transmit integrated patterns of activity to the cerebellum.
746
D. RUEGG AND M. WIESENDANGER INTRODUCTION
The pontine nuclei (PN) are the most important of the various relays of cerebro-cerebellar pathways (Allen & Tsukahara, 1974; Tsukahara, Korn & Stone, 1968). Corticofugal neurones from somatosensory area II (S II) which may contribute to a cortico-pontocerebellar pathway have recently been characterized electrophysiologically (Atkinson, Seguin & Wiesendanger, 1974). S II neurones with descending axons were classified into three categories: (1) cortico-bulbar neurones, invaded antidromically by stimulation of the cerebral peduncles; (2) neurones antidromically invaded by stimuli applied to the dorsal column nuclei; (3) cortico-spinal neurones invaded antidromically from cervical segments. The output neurones from S II projecting to bulbar structures were more numerous than cortico-spinal neurones. Both types had generally larger receptive fields (sometimes covering more than one limb) than intrinsic S II neurones. On anatomical grounds, 'descending' output neurones of S II may synapse on PN neurones, either directly or via collaterals of pyramidal tract fibres. Thus, cortical lesions restricted to the anterior ectosylvian gyrus resulted in three longitudinal columns of degeneration in the pontine grey (P. Brodal, 1968a). A similar arrangement of longitudinal or transverse projection fields were subsequently discovered in degeneration studies involving various cortical areas of the cat (P. Brodal, 1968b, 1971 a, b, 1972a, b). The aim of the present study was (1) to verify the assumption made in a previous report on S II neurones (Atkinson et al. 1974) that the neurones of that area contribute an important input to the PN; (2) to determine whether or not single PN neurones receive a convergent input from S II and sensori-motor cortex I (SM I); (3) to investigate whether or not PN neurones, influenced by somatic cortical areas, retain some of the receptive field characteristics of S II neurones which then would be transmitted to the cerebellum. These questions seemed to be relevant to the more general problem about the two roles ascribed to the cerebellum: the 'long-range planning of movements' and the feed-back control of movements (Allen & Tsukahara, 1974). Preliminary results were communicated at the meeting of the Canadian Federation of Biological Societies (Ruegg & Wiesendanger, 1974). METHODS
Successful experiments performed in seven cats. Anaethesia was first induced by ketamine (4 mg/kg I.M.). Repeated small doses (2 mg/kg) of the ultrashort acting barbiturate sodium thiamylal were given intravenously during surgery. were
CORTICAL EFFECTS ON PONTINE NEURONES
747
During recordings anaesthesia was maintained by inhalation of N20 and 02 (50% each) and additional small doses of sodium thiamylal injected when necessary (the animals were not curarized). The pericruciate and anterior ectosylvian gyri of one hemisphere were exposed with the dura left intact. Laminectomy at cervical 1-2 was performed and the cerebellar hemisphere, ipsilateral to the exposed cerebral cortex, was removed to facilitate dorsoventral penetration of a micro-electrode into the PN. Four pairs of stimulating electrodes (fine steel needles varnished except at the tips) were inserted manually through the dura, about 2 mm, into the cortical white matter. Two pairs were located in SM I and two pairs in S II as illustrated in Fig. 1. A further pair of stimulating electrodes was placed stereotaxically into the fibres of the brachium pontis, contralateral to the PN, for identification of pontocerebellar neurones. The following criteria for antidromic invasion were used: (1) invariable, short-latency response to single stimuli; (2) capability of the neurone to follow frequencies of stimulation (short trains) of 500 Hz or more; (3) collision of orthodromic and antidromic spikes (Darian-Smith, Phillips & Ryan, 1963).
SI' b
91
~~~~~~~~~~~~DLF
10 mm Fig. 1. Experimental arrangement of stimulating electrodes (SM Ia, b; S IIa, b; brachium pontis = BP; dorsolateral funiculus = DLF) and microelectrode (ME).
Peripheral nerves were stimulated by electrodes (two needles insulated except at the tips) placed transcutaneously near the brachial plexus, contralateral to the exposed cortex. Finally, in two animals, a pair of stimulating electrodes (short insect pins, insulated except at the tips) were inserted into the dorsolateral funiculus at the cervical level, contralateral to the exposed cortex, in order to ascertain whether or not PN neurones were activated via collaterals of cortico-spinal fibres. The cortex was stimulated by single pulses (0.02-0-1 msec) or trains of pulses, usually of less than 1 mA intensity (rarely intensities up to 1P5 mA were used). Single unit activity from the pontine grey were usually recorded by means of glass capillaries filled with 4 M-NaCl. Metal micro-electrodes were used occasionally for marking the recording sites (electrolytic lesions with currents of 10 ,tA for 30 sec). In order to avoid the tentorium, all tracks were made at an angle of 300 to the vertical Horsley/Clarke plane, i.e. nearly parallel to the tentorium; the micro-electrodes reached the ventral surface of the pons at about A 1.0 mm (Fig. 1). Receptive fields were investigated
748
D. RUEGG AND M. WIESENDANGER
manually using blunt probes and passive manipulation of limbs at the various joints. If no responses were detected by these gentle stimuli the effect of nociceptive stimuli (pin prick, squeezing of skin folds) were also tested. The animals were killed with an overdose of pentobarbitone sodium. The brain stem and cerebellum were then removed and fixed in buffered formalin for histology. Electrolytic lesions, made with the stimulating electrodes in the brachium pontis at the end of the experiments, were easily recognized in the Nissl-stained sections. Most of the micro-electrode tracks were also identified histologically by leaving glass capillaries in situ at the end of a track. The depth of recording was estimated from microdrive readings with a further allowance for 10 % shrinkage. In four experiments, small electrolytic lesions were made at two micrometer positions for use as reference points. RESULT8
Identification of PN neuroses. Single stimuli, applied to the brachium pontis, were used to search for single cells in the general region of the PN as determined stereotaxically. Short latency responses were established as antidromic or orthodromic according to the criteria described in the methods. The collision technique was used when a presumed PN cell discharged regularly to stimulation of the brachium pontis. Collision of evoked unit discharges with spontaneous discharges were observed on a storage oscilloscope. Minimal intervals of less than 2 msec for driving PN cells by two or more pulses applied to the brachium pontis was used as a positive criterion of antidromic invasion for cells which did not respond to each stimulus cycle. Only those cells with clear antidromic responses were included in the results. In this way ninety-one neurones were identified as ponto-cerebellar neurones. As illustrated in Fig. 2, most latencies were in the range of 0 5-3 msec with a peak near 1 msec. With a conduction distance of about 20 mm this corresponds to a conduction velocity of 13-20 m/sec. It is noteworthy that a considerable proportion of pontocerebellar fibres conduct at rates as low as about 6 m/sec. Responses of PN neuroses to cortical stimulation. Identified pontocerebellar neurones were then tested for responses to stimulation of the various cortical points. Out of ninety-one PN neurones, thirty-four units (37 %) did not respond to any of the cortical train stimuli. The fifty-seven responsive neurones were classified as follows. (1) S II-driven neuroses. Nine PN neurones (10 %) were found which exclusively reacted to one or both S II stimuli. The example illustrated in Fig. 3A had a receptive field on the contralateral face and the effective stimulus was strong tapping in this region. (2) SM I-type units. Twenty-three PN neurones (25 %) were excited by stimulation at one or both stimulus sites of SM I, but not by S II stimulation (Fig. 3B). (3) Convergence neuroses. Twentyfive PN neurones (27 %) were readily excited by both S II and SM I
749 CORTICAL EFFECTS ON PONTINE NEURONES stimulation. Often the threshold for one of the stimulus sites was slightly lower than for the others. The particular unit of Fig. 3C had receptive field characteristics suggesting the involvement of proprioceptive receptors: excitation was induced by passive rotation of the shoulder as indicated by arrow (b); rotation in the opposite direction (a) inhibited the ongoing activity of the cell, but activated a nearby neurone simultaneously recorded with the same micro-electrode. The location of these two units was found to be in the lateral division of the PN. 30
20
n
10
5 msec
Fig. 2. Distribution of antidromic latencies of ninety-one PN neurones. Stimulation of contralateral brachium pontis.
The latencies to cortical stimulation of SM I and S II varied over a wide range. The distribution, shown in Fig. 4, strongly suggests that both fast and slow-conducting fibres were involved even if one takes into account a slow rise time of cortically induced e.p.s.p.s of PN neurones (Allen, Korn, Oshima & Toyama, 1970). Statistical analysis by means of Spearman's rank correlation test revealed no significant relation (r = 0.07) between the latencies of the responses to brachium pontis and cortical stimulation. Plotting of all recording sites of PN neurones in a transverse plane of the pons (up to 4 mm from the mid line) revealed no preferential distribution for cells activated by SM I, S II, or both. A further question to
D. IREGG AND M. WIESENDANGER be answered was whether or not PN neurones activated by cortical stimulation (especially those reacting to SM I) received their input via collaterals of cortico-spinal fibres. Such an organization was assumed to exist by Blomfield & Marr (1970) in their theoretical paper on motor cortexcerebellum operation. A direct spinal afferent input to the PN appears to be minimal (Kerr, 1966); it has been found to be restricted to a very 7.50
A
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~~~~ B
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10 msec
Cb 5 msec
SMI
10 Msec
and_ C~~~~~~~L.l
No receptive No ~~~~field
*1 S 11
a
i_-i 500 msec. Fig. 3. A, example of a S II-driven unit. Cb = stimulation of brachium pontis. Single and repetitive stimulation of S II. No response was elicited by SM I stimulation. This unit had a restricted receptive field. B, example of an SM I-driven unit with no response to S II stimulation. This particular neurone displayed no receptive field. C, convergence neurone excited antidromically by brachium pontis (Cb) stimulation and orthodromically by SM I and S II stimulation. An electrolytic lesion was made through a metal micro-electrode at the recording site. Consistent activation of the cell by passive rotation of forelimb in the shoulder (b) and suppression of activity by rotation in opposite direction (a). This stimulus activated a smaller unit nearby.
small but consistent area in the most caudal and dorsolateral portion of the PN (D. Riiegg & M. Wiesendanger, unpublished observations). Short latency, trans-synaptic responses recorded in more rostral and medial parts of the PN evoked by stimulation of the dorsolateral funiculus are therefore most probably mediated via collaterals of cortico-spinal fibres. In two cats, twenty-five PN neurones were tested and only seven cells
751 CORTICAL EFFECTS ON PONTINE NEURONES reacted to the spinal stimulus with latencies varying between 1 and 5 msec. These cells were all activated by SM I and four of these also by S II stimulation. These results indicate that only a relatively small proportion of PN neurones may be contacted by collaterals of cortico-spinal fibres and that the majority of PN neurones (all S II-driven neurones of the present experiments) are activated by direct cortico-pontine fibres. S 1 stim
n=29.
M~~~nnin
n
10
I^
I
SM Istim
n=49
Nerve stim
n=13
l r1 ri 20l n f [iX n 30 msec
Fig. 4. Latency distribution of identified PN neurones activated by ipsilateral S II and/or SM I stimulation and by contralateral nerve stimulation.
Differentiation between responses of PN neurones and neurones qf the nucleuB reticulari8 teymenti ponti8 (NRTP). This nucleus is situated dorsally to the PN proper and receives an input from various cortical areas; it projects also to the cerebellum which in turn feeds back to the NRTP (A. Brodal & P. Brodal, 1971). Some difficulty was encountered in the attempt to differentiate responses of the PN and of the NRTP. The depth reading provided the main criterion for differentiation, since neurones from both nuclei were driven antidromically by cerebellar stimuli. Larger spikes were recorded in the most dorsal parts of the pontine grey matter which indicated to us that we were recording from the larger cells of the NRTP. Out of 15 presumed responses from the NRTP five neurones reacted to SM I stimulation only and three showed convergence from SM I and S II (Fig. 5A), whereas none was activated exclusively from S II. The remaining seven neurones did not respond to any of the cortical stimuli.
D. RUEGG AND M. WIESENDANGEJR Receptive field characteristics. Examples of receptive fields have been shown in Fig. 3; the effective stimuli were not uniform and often rather complex. Fifty-four PN neurones (60 %) did not react at all in a reproducible way to the various cutaneous and kinaesthetic as well as noxious stimuli. A common feature was an unspecific increase in spontaneous activity with nociceptive stimuli. In eleven neurones, such as the one shown in Fig. 3A, the receptive fields were relatively restricted. Six neurones were selectively activated by passive movements of the limbs 752752
A4
Sit~~~~~~~~~1
B
SMI
10
Msec
.1-11
11 Nerves
2.5 msec
511
"
I- T
1-M
_.
-
a---
-I
Coiitrol
Fig. 5. A, neurone recorded in the dorsal portion of the pontine grey, presumably within the N. reticularis tegmenti pontis. Short latency activation by both SM I and S II stimulation. B, convergence neurone activated orthodromically by S II and SM I. This unit was activated by passive manipulation in several joints of contralateral forelimb. Electrical stimulation of brachial plexus above twitch threshold (nerves) also activated this cell with low probability and at long latency (five superimposed sweeps). Beside (right) are five control sweeps without stimulation.
joints. There was no apparent difference in receptive field characteristics between 'SM I-type units' and 'S II-type units'. In order to gain some information on the number of synapses involved in the transmission from the periphery to the PN, the effect of electrical stimulation of forelimb nerves was also tested in those cells responding to natural stimulation in the forelimb region. As indicated in the latency histogram of Fig. 4, the latencies were rather long and scattered over a range of 8-33 msec. Characteristically, the probability of discharges, even to strong stimuli which elicited vigorous twitches, was low (Fig. 5B). at one or more
CORTICAL EFFECTS ON PONTINE NEURONES
753 These results are compatible with the notion of a circuitous, presumably
transcortical pathway. Correlation between responsiveness of PN neuroses to cortical stimulation and receptive fields. Table 1 lists all the PN neurones according to their responsiveness to cortical stimulation. The table also indicates the number of PN cells with receptive fields in each category. It is noteworthy that those cells which were not responsive to any of the cortical stimuli rarely had receptive fields. On the other hand, the largest proportion of receptive fields was found in PN neurones with convergence from S II and SM I. TABiL 1. Responsiveness of PN neurones to cortical stimulation. Figures in parentheses show PN neurones with receptive fields
N
SM I only 23 (8)
S II only 9 (8)
Both 25 (17)
None 33 (3)
DISCUSSION
1. Functional relationship between SM I and SII cortical areas and the pontine nuclei Previous results of degeneration studies in monkeys obtained with the Marchi method already revealed that the terminal areas of corticopontine fibres form well-defined, lengthened, rostrocaudally oriented zones with little, if any, overlapping (Nyby & Jansen, 1951). More recent studies with refined degeneration techniques disclosed a very precise point-to-point cortico-pontine projection from cortical areas SM I and S II (P. Brodal, 1968a, b). The present experiments confirmed that both SM I and S II indeed exerted a pronounced influence on PN neurones but failed to disclose any spatial separation of pontine cell columns excited by electrical stimulation of the two cortical areas. Similarly, Sasaki, Kawaguchi, Shimono & Prelevid (1970) were unable to differentiate separate foci within the PN activated by stimulation of subdivisions of the pericruciate cortex. One could argue that, in these latter experiments, electrical stimulation of nearby cortical areas would not provide enough discrimination to reveal the pattern of projection described in anatomical studies. In the present experiments, however, two widely separated cortical areas were stimulated with selective intracortical electrodes at intensities low enough to preclude spread of current from one area to the other. The discrepancy between anatomical and electrophysiological observations may be due to three factors: (1) the presence of pontine interneurones which would relay activity from one column to the other; (2) recurrent collaterals from PN neurones to other PN neurones of
D. RUEGG AND M. WIESENDANGER neighbouring columns; (3) overlapping dendritic fields. The Golgi pictures of PN neurones by Cajal (1909, figs. 437 and 438) indeed indicate that all three factors may account for the observed convergence seen in our electrophysiological studies: there are a large number of recurrent collaterals which may spread over more than one 'projection column'. Similarly, dendritic fields of neighbouring columns may intensively overlap. Furthermore, Cajal described small cells with short axons which may represent local interneurones ('type cellulaire villeux ou moussu 'a cylindreaxe court'). Despite the convergence seen in electrophysiological studies the possibility remains that, for each PN cell assembly, one particular input is predominant. Indeed it was found that most PN neurones with convergence had a lower threshold to stimulation of one of the cortical areas. 754
2. Slow cortico-cerebellar pathway It is well known that electrical stimulation of cerebro-cortical areas elicits early and late cerebellar responses (Jansen, 1957), which were considered to be transmitted via climbing fibres (Provini, Redman & Strata, 1968). It appears that long latency cerebellar responses are not exclusively relayed through the inferior olive but also through the pontine relay (Allen, Korn & Oshima, 1969; Allen et al. 1970; Sasaki et al. 1970). In the present experiments, the conduction velocity of ponto-cerebellar neurones was in the same slow range as reported by Allen et at. (1969), but the values were lower than those given by Sasaki et al. (1970). It may be that, in the latter study, many recordings were made from the nucleus reticularis tegmenti pontis, which has larger cells and hence probably faster conduction velocities than the cells of the PN proper. The demonstration of a slow cortico-cerebellar pathway relayed in the PN does not necessarily imply that the PN are a source of climbing fibres since some of the long latency cerebellar responses to cerebral cortical stimulation were found to be mediated via mossy fibres (Kitai, Oshima, Provinci & Tsukahara, 1969). On the other hand, climbing fibre responses elicited by pontine stimulation were discovered by Sasaki, Kawaguchi, Shinomo & Yoneda (1969). Additional experimental results which do or do not support the concept that the inferior olive is the sole origin of climbing fibres has recently been reviewed (Armstrong, 1974). This controversial problem remains to be fully elucidated, particularly in view of most recent results based on degeneration experiments in monkeys reported by Rivera-Dominguez, Mettler & Noback (1974). These authors claim that the inferior olive is only a minor source of climbing fibres. Long latency climbing fibre responses are recorded chiefly contralaterally to cerebro-cortical stimulation (Provini et al. 1968; Miles & Wiesendanger,
755 CORTICAL EFFECTS ON PONTINE NEURONES 1975a, b). This relationship is difficult to explain by a direct cortico-olivocerebellar path since the projection to the olive is predominantly crossed and the olivo-cerebellar fibres re-cross on their way to Purkinje cells (Armstrong, 1974). The relationship is, however, compatible with a cortico-ponto-cerebellar pathway. 3. Functional implications
The degree of convergence found in the present electrophysiological experiments suggest that a considerable integration takes place at the level of the PN. It thus appears that the cerebellar nuclei and the cerebellar cortex are 'interested' in processed information, spatial, visual and other, in addition to details as transmitted from the receptors to the cerebellum via more direct pathways. One may furthermore visualize that this processing is a gradual one, increasing from relay to relay as has been demonstrated for example for the somatosensory pathway to the cerebral cortex (Werner, Whitsel & Petrucelli, 1972). In a previous study on S II neurones (Atkinson et al. 1974) it was shown that output neurones of S II with axons descending to the brain-stem or to the spinal cord typically had larger receptive fields than intrinsic neurones of S II. It was therefore assumed that the output neurones receive a convergent input from the classical 'lemniscal-type' neurones of S II. A progressive convergence at the pontine level would then explain the further increase in complexity of 'receptive fields' of the pontine target neurones (for instance responsiveness to passive movements at more than one joint). Such input of processed information from cortical areas would be expected in view of the hypothesis that the PN may relay an 'internal substitute of the external world' to the cerebellum (Allen & Tsukahara, 1974). Considering that the PN receive information not only from primary cortical areas but also from association areas, one might conjecture that some PN cell assemblies relay to the cerebellum much more complex stimulus features than could be disclosed by our simple procedures for testing receptive fields. PN neurones which did not respond to electrical stimulation of the somatic motor and sensory areas were probably neurones with a predominant input from other primary cortical areas and association areas. Allen & Tsukahara (1974) discussed the hypothesis that the medial cerebellum may be chiefly concerned with ongoing corrections of movements by means of feed-back signals whereas the lateral cerebellum would be concerned with the 'programming' and initiation of movements. It would be interesting to know whether or not those PN neurones which transmit relatively 'crude' data (i.e. cells with an input from primary areas) project medially and those with associational input project laterally to the cerebellum.
756
D. RIEGG AND M. WIESENDANGER
We wish to thank Drs J. J. S6guin and J. Hore for helpful comments and criticism. Our thanks are also due to D. H. Atkinson, M.R.C. summer student, who participated in the initial experiments of this study. The technical assistance provided by Mrs P. Dhanarajan is much appreciated. Generous financial support was received by grants from the Medical Research Council of Canada (Numbers MA-4992 and ME-5092) and from the Multiple Sclerosis Society of Canada to M.W.
REFERENCES ALLEN, G. I., KORN, H. & OsHrmA, T. (1969). Monosynaptic pyramidal activation of pontine nuclei cells projecting to the cerebellum. Brain Re8. 15, 272-275. ALLEN, G. I., KORN, H., OsCnA, T. & TOYAmA, K. (1970). Time course of pyramidal activation of pontine nuclei cells in the cat. Brain Res. 19, 291-294. ALLEN, G. I. & TsuKAHAaA, N. (1974). Cerebro-cerebellar communication systems. Physiol. Rev. 54, 957-1006. ARMSTRONG, D. M. (1974). Functional significance of connections of the inferior olive. Phy8iol. Rev. 54, 358-417. ATKINSON, D. H., SAGUIN, J. J. & WIESENDA.NGER, M. (1 974). Organization of corticofugal neurones in somatosensory area II of the cat. J. Phygiol. 236, 663-679. BLOMFIELD, S. & MAPR, D. (1970). How the cerebellum may be used. Nature, Lond. 227, 1224-1228. BRODAL, A. & BRODAL, P. (1971). The organization of the nucleus reticularis tegmenti pontis in the cat in the light of experimental anatomical studies of its cerebral cortical afferents. Expl Brain Res. 13, 90-110. BRODAL, P. (1968a). The corticopontine projection in the cat. Demonstration of a somatotopically organized projection from the second somatosensory cortex. Arch8 ital Biol. 106, 310-332. BRODAL, P. (1968b). The corticopontine projection in the cat. I. Demonstration of a somatotopically organized projection from the primary sensorimotor cortex. Expl Brain Res. 5, 210-234. BRODAL, P. (1971a). The corticopontine projection in the cat. I. The projection from the proreate gyrus. J. comp. Neurol. 142, 127-140. BRODAL, P. (1971b). The corticopontine projection in the cat. II. The projection from the orbital gyrus. J. comp. Neurol. 142, 141-152. BRODAL, P. (1972a). The corticopontine projection from the visual cortex in the cat. I. The total projection and the projection from area 17. Brain Res. 39, 297-317. BRODAL, P. (1972b). The corticopontine projection from the visual cortex in the cat. II. The projection from areas 18 and 19. Brain Re8. 39, 319-335. CAJAL, RAM6N Y S. (1909). Hi8tologie du Sy8tMme Nerveux de l'Homme et des Vert8brts, vol. 2. Paris: Maloine. DARIAN-SmITH, I., Pmiiirs, G. & RYN, R. D. (1963). Functional organization in the trigeminal main sensory and rostral spinal nuclei of the cat. J. Physiol. 168, 129-146. JANSEN, J. (1957). Afferent impulses to the cerebellar hemisphere from the cerebral cortex and certain subcortical nuclei. Acta phyaiol. scand. 41, suppl. 143, 1-99. KERR, F. W. L. (1966). On the question of ascending fibers in the pyramidal tract: with observations on spinotrigeninal and spinopontine fibers. Expl Neurol. 14, 77-85. KITAI, S. T., OsHmnA, T., PRovnu, N. & TSUNAHARA, N. (1969). Cerebro-cerebellar connections mediated by fast and slow conducting pyramidal tract fibers of the cat. Brain Re8. 15, 267-271.
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MILES, T. S. & WIESENDANGER, M. (1975a). Organization of climbing fibre projections to the cerebellar cortex from trigeminal cutaneous afferents and from the face area of the sensorimotor cortex in the cat. J. Phy8iol. 245, 409-424. MILES, T. S. & WIESENDANGER, M. (1975b). Climbing fibre inputs to cerebellar Purkinje cells from trigeminal cutaneous afferents and the S I face area of the cerebral cortex in the cat. J. Phy8iol. 245, 425-445. NYBY, 0. & JANSEN, J. (1951). An experimental investigation of the corticopontine projection in Macaca mulatta. Skr. nor8ke Viden8k-Akad. (I. Mat.-naturv. KZ), no. 3, 1-47. PRoviri- L., REDMAN, S. & STRATA, P. (1968). Mossy and climbing fibre organization on the anterior lobe of the cerebellum activated by forelimb and hindlimb areas of sensorimotor cortex. Expl Brain Re8. 6, 216-233. RIVERA-DOMINGUEZ, M., METTLER, F. A. & NOBACK, C. R. (1974). Origin of cerebellar climbing fibers in the rhesus monkey. J. comp. Neurol. 155, 331-342. RUEGG, D. & WIESENDANGER, M. (1974). Effects of cortical stimulation on the pontine nuclei in cats. Proc. Can. Fed. Biol. Soc., 17th Ann. Meeting, p. 97. SASAKI, K., KAWAGUCHI, T., SHIMONO, T. & YONEDA, Y. (1969). Responses evoked in the cerebellar cortex by the pontine stimulation. Jap. J. Physiol. 19, 95-109. SASAKI, K., KAWAGUCHI, T., SHIMONO, T. & PRELEVI6. (1970). Electro-physiological studies of the pontine nuclei. Brain Res. 20, 425-438. TsUxA ARA, N., KORN, H. & STONE, J. (1968). Pontine relay from cerebral cortex to cerebellar cortex and nucleus interpositus. Brain Re8. 10, 448-453. WERNER, G., WHITSEL, B. L. & PETRUCELLI, L. M. (1972). Data structure and algorhithms in the primate somatosensory cortex. In Brain and Human Behaviour, ed. KARCZMAR, A. & EccLEs, J. C. Berlin, Heidelberg, New York: Springer.
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Printed in Great Britain
CORTICOFUGAL EFFECTS SENSORIMOTOR FROM AREA I AND SOMATOSENSORY AREA II ON NEURONES OF THE PONTINE NUCLEI IN THE CAT
BY D. RUEGG AND M. WIESENDANGER From the Department of Physiology, University of Western Ontario, London, Ontario, Canada N6A 3K7 (Received 28 August 1974) SUMMARY
1. The objective of the present experiments was to study the cortical influence from sensorimotor area I (SM I) and from somatosensory area II (S II) on single neurones of the pontine nuclei (PN) in cats under N20thiamylal anaesthesia. 2. Extracellular single unit recordings revealed a considerable convergence from S II and SM I. Out of ninety-one PN neurones (identified as ponto-cerebellar neurones by antidromic stimulation of the contralateral brachium pontis), fifty-seven neurones were influenced by stimulation of at least one cortical site. Slightly less than half of these neurones (twentyfive) had a convergent input from SM I and S II; twenty-three PN neurones were excited by SM I only and nine PN neurones by S II only. The proportion of PN neurones excited via collaterals of cortico-spinal neurones was small and restricted to those neurones which had an input from SM I. 3. Sixty per cent of the ponto-cerebellar neurones were reliably activated by natural stimulation such as tapping or passive manipulations of limbs of various joints. The vast majority (thirty-three out of thirtysix PN neurones) which had receptive fields were also influenced by electrical stimulation of one or both cortical areas. The long latency and low probability of discharge to peripheral nerve stimulation suggest a complex, probably transcortical, pathway from the periphery to the PN. 4. The distribution of latencies to both cortical and brachium pontis stimulation indicates that the PN are a relay for fast and slow cerebrocerebellar connexions. 5. The convergence from cortical areas on PN indicates that the neurones influenced from somatic areas SM I and S II transmit integrated patterns of activity to the cerebellum.
746
D. RUEGG AND M. WIESENDANGER INTRODUCTION
The pontine nuclei (PN) are the most important of the various relays of cerebro-cerebellar pathways (Allen & Tsukahara, 1974; Tsukahara, Korn & Stone, 1968). Corticofugal neurones from somatosensory area II (S II) which may contribute to a cortico-pontocerebellar pathway have recently been characterized electrophysiologically (Atkinson, Seguin & Wiesendanger, 1974). S II neurones with descending axons were classified into three categories: (1) cortico-bulbar neurones, invaded antidromically by stimulation of the cerebral peduncles; (2) neurones antidromically invaded by stimuli applied to the dorsal column nuclei; (3) cortico-spinal neurones invaded antidromically from cervical segments. The output neurones from S II projecting to bulbar structures were more numerous than cortico-spinal neurones. Both types had generally larger receptive fields (sometimes covering more than one limb) than intrinsic S II neurones. On anatomical grounds, 'descending' output neurones of S II may synapse on PN neurones, either directly or via collaterals of pyramidal tract fibres. Thus, cortical lesions restricted to the anterior ectosylvian gyrus resulted in three longitudinal columns of degeneration in the pontine grey (P. Brodal, 1968a). A similar arrangement of longitudinal or transverse projection fields were subsequently discovered in degeneration studies involving various cortical areas of the cat (P. Brodal, 1968b, 1971 a, b, 1972a, b). The aim of the present study was (1) to verify the assumption made in a previous report on S II neurones (Atkinson et al. 1974) that the neurones of that area contribute an important input to the PN; (2) to determine whether or not single PN neurones receive a convergent input from S II and sensori-motor cortex I (SM I); (3) to investigate whether or not PN neurones, influenced by somatic cortical areas, retain some of the receptive field characteristics of S II neurones which then would be transmitted to the cerebellum. These questions seemed to be relevant to the more general problem about the two roles ascribed to the cerebellum: the 'long-range planning of movements' and the feed-back control of movements (Allen & Tsukahara, 1974). Preliminary results were communicated at the meeting of the Canadian Federation of Biological Societies (Ruegg & Wiesendanger, 1974). METHODS
Successful experiments performed in seven cats. Anaethesia was first induced by ketamine (4 mg/kg I.M.). Repeated small doses (2 mg/kg) of the ultrashort acting barbiturate sodium thiamylal were given intravenously during surgery. were
CORTICAL EFFECTS ON PONTINE NEURONES
747
During recordings anaesthesia was maintained by inhalation of N20 and 02 (50% each) and additional small doses of sodium thiamylal injected when necessary (the animals were not curarized). The pericruciate and anterior ectosylvian gyri of one hemisphere were exposed with the dura left intact. Laminectomy at cervical 1-2 was performed and the cerebellar hemisphere, ipsilateral to the exposed cerebral cortex, was removed to facilitate dorsoventral penetration of a micro-electrode into the PN. Four pairs of stimulating electrodes (fine steel needles varnished except at the tips) were inserted manually through the dura, about 2 mm, into the cortical white matter. Two pairs were located in SM I and two pairs in S II as illustrated in Fig. 1. A further pair of stimulating electrodes was placed stereotaxically into the fibres of the brachium pontis, contralateral to the PN, for identification of pontocerebellar neurones. The following criteria for antidromic invasion were used: (1) invariable, short-latency response to single stimuli; (2) capability of the neurone to follow frequencies of stimulation (short trains) of 500 Hz or more; (3) collision of orthodromic and antidromic spikes (Darian-Smith, Phillips & Ryan, 1963).
SI' b
91
~~~~~~~~~~~~DLF
10 mm Fig. 1. Experimental arrangement of stimulating electrodes (SM Ia, b; S IIa, b; brachium pontis = BP; dorsolateral funiculus = DLF) and microelectrode (ME).
Peripheral nerves were stimulated by electrodes (two needles insulated except at the tips) placed transcutaneously near the brachial plexus, contralateral to the exposed cortex. Finally, in two animals, a pair of stimulating electrodes (short insect pins, insulated except at the tips) were inserted into the dorsolateral funiculus at the cervical level, contralateral to the exposed cortex, in order to ascertain whether or not PN neurones were activated via collaterals of cortico-spinal fibres. The cortex was stimulated by single pulses (0.02-0-1 msec) or trains of pulses, usually of less than 1 mA intensity (rarely intensities up to 1P5 mA were used). Single unit activity from the pontine grey were usually recorded by means of glass capillaries filled with 4 M-NaCl. Metal micro-electrodes were used occasionally for marking the recording sites (electrolytic lesions with currents of 10 ,tA for 30 sec). In order to avoid the tentorium, all tracks were made at an angle of 300 to the vertical Horsley/Clarke plane, i.e. nearly parallel to the tentorium; the micro-electrodes reached the ventral surface of the pons at about A 1.0 mm (Fig. 1). Receptive fields were investigated
748
D. RUEGG AND M. WIESENDANGER
manually using blunt probes and passive manipulation of limbs at the various joints. If no responses were detected by these gentle stimuli the effect of nociceptive stimuli (pin prick, squeezing of skin folds) were also tested. The animals were killed with an overdose of pentobarbitone sodium. The brain stem and cerebellum were then removed and fixed in buffered formalin for histology. Electrolytic lesions, made with the stimulating electrodes in the brachium pontis at the end of the experiments, were easily recognized in the Nissl-stained sections. Most of the micro-electrode tracks were also identified histologically by leaving glass capillaries in situ at the end of a track. The depth of recording was estimated from microdrive readings with a further allowance for 10 % shrinkage. In four experiments, small electrolytic lesions were made at two micrometer positions for use as reference points. RESULT8
Identification of PN neuroses. Single stimuli, applied to the brachium pontis, were used to search for single cells in the general region of the PN as determined stereotaxically. Short latency responses were established as antidromic or orthodromic according to the criteria described in the methods. The collision technique was used when a presumed PN cell discharged regularly to stimulation of the brachium pontis. Collision of evoked unit discharges with spontaneous discharges were observed on a storage oscilloscope. Minimal intervals of less than 2 msec for driving PN cells by two or more pulses applied to the brachium pontis was used as a positive criterion of antidromic invasion for cells which did not respond to each stimulus cycle. Only those cells with clear antidromic responses were included in the results. In this way ninety-one neurones were identified as ponto-cerebellar neurones. As illustrated in Fig. 2, most latencies were in the range of 0 5-3 msec with a peak near 1 msec. With a conduction distance of about 20 mm this corresponds to a conduction velocity of 13-20 m/sec. It is noteworthy that a considerable proportion of pontocerebellar fibres conduct at rates as low as about 6 m/sec. Responses of PN neuroses to cortical stimulation. Identified pontocerebellar neurones were then tested for responses to stimulation of the various cortical points. Out of ninety-one PN neurones, thirty-four units (37 %) did not respond to any of the cortical train stimuli. The fifty-seven responsive neurones were classified as follows. (1) S II-driven neuroses. Nine PN neurones (10 %) were found which exclusively reacted to one or both S II stimuli. The example illustrated in Fig. 3A had a receptive field on the contralateral face and the effective stimulus was strong tapping in this region. (2) SM I-type units. Twenty-three PN neurones (25 %) were excited by stimulation at one or both stimulus sites of SM I, but not by S II stimulation (Fig. 3B). (3) Convergence neuroses. Twentyfive PN neurones (27 %) were readily excited by both S II and SM I
749 CORTICAL EFFECTS ON PONTINE NEURONES stimulation. Often the threshold for one of the stimulus sites was slightly lower than for the others. The particular unit of Fig. 3C had receptive field characteristics suggesting the involvement of proprioceptive receptors: excitation was induced by passive rotation of the shoulder as indicated by arrow (b); rotation in the opposite direction (a) inhibited the ongoing activity of the cell, but activated a nearby neurone simultaneously recorded with the same micro-electrode. The location of these two units was found to be in the lateral division of the PN. 30
20
n
10
5 msec
Fig. 2. Distribution of antidromic latencies of ninety-one PN neurones. Stimulation of contralateral brachium pontis.
The latencies to cortical stimulation of SM I and S II varied over a wide range. The distribution, shown in Fig. 4, strongly suggests that both fast and slow-conducting fibres were involved even if one takes into account a slow rise time of cortically induced e.p.s.p.s of PN neurones (Allen, Korn, Oshima & Toyama, 1970). Statistical analysis by means of Spearman's rank correlation test revealed no significant relation (r = 0.07) between the latencies of the responses to brachium pontis and cortical stimulation. Plotting of all recording sites of PN neurones in a transverse plane of the pons (up to 4 mm from the mid line) revealed no preferential distribution for cells activated by SM I, S II, or both. A further question to
D. IREGG AND M. WIESENDANGER be answered was whether or not PN neurones activated by cortical stimulation (especially those reacting to SM I) received their input via collaterals of cortico-spinal fibres. Such an organization was assumed to exist by Blomfield & Marr (1970) in their theoretical paper on motor cortexcerebellum operation. A direct spinal afferent input to the PN appears to be minimal (Kerr, 1966); it has been found to be restricted to a very 7.50
A
Cb
]1MV
-j 5 msec
-.
I-.
Sll i-
J
~~~~ B
Tapping
Msec
~~~
Cb 5 msec
SMI
10 msec
Cb 5 msec
SMI
10 Msec
and_ C~~~~~~~L.l
No receptive No ~~~~field
*1 S 11
a
i_-i 500 msec. Fig. 3. A, example of a S II-driven unit. Cb = stimulation of brachium pontis. Single and repetitive stimulation of S II. No response was elicited by SM I stimulation. This unit had a restricted receptive field. B, example of an SM I-driven unit with no response to S II stimulation. This particular neurone displayed no receptive field. C, convergence neurone excited antidromically by brachium pontis (Cb) stimulation and orthodromically by SM I and S II stimulation. An electrolytic lesion was made through a metal micro-electrode at the recording site. Consistent activation of the cell by passive rotation of forelimb in the shoulder (b) and suppression of activity by rotation in opposite direction (a). This stimulus activated a smaller unit nearby.
small but consistent area in the most caudal and dorsolateral portion of the PN (D. Riiegg & M. Wiesendanger, unpublished observations). Short latency, trans-synaptic responses recorded in more rostral and medial parts of the PN evoked by stimulation of the dorsolateral funiculus are therefore most probably mediated via collaterals of cortico-spinal fibres. In two cats, twenty-five PN neurones were tested and only seven cells
751 CORTICAL EFFECTS ON PONTINE NEURONES reacted to the spinal stimulus with latencies varying between 1 and 5 msec. These cells were all activated by SM I and four of these also by S II stimulation. These results indicate that only a relatively small proportion of PN neurones may be contacted by collaterals of cortico-spinal fibres and that the majority of PN neurones (all S II-driven neurones of the present experiments) are activated by direct cortico-pontine fibres. S 1 stim
n=29.
M~~~nnin
n
10
I^
I
SM Istim
n=49
Nerve stim
n=13
l r1 ri 20l n f [iX n 30 msec
Fig. 4. Latency distribution of identified PN neurones activated by ipsilateral S II and/or SM I stimulation and by contralateral nerve stimulation.
Differentiation between responses of PN neurones and neurones qf the nucleuB reticulari8 teymenti ponti8 (NRTP). This nucleus is situated dorsally to the PN proper and receives an input from various cortical areas; it projects also to the cerebellum which in turn feeds back to the NRTP (A. Brodal & P. Brodal, 1971). Some difficulty was encountered in the attempt to differentiate responses of the PN and of the NRTP. The depth reading provided the main criterion for differentiation, since neurones from both nuclei were driven antidromically by cerebellar stimuli. Larger spikes were recorded in the most dorsal parts of the pontine grey matter which indicated to us that we were recording from the larger cells of the NRTP. Out of 15 presumed responses from the NRTP five neurones reacted to SM I stimulation only and three showed convergence from SM I and S II (Fig. 5A), whereas none was activated exclusively from S II. The remaining seven neurones did not respond to any of the cortical stimuli.
D. RUEGG AND M. WIESENDANGEJR Receptive field characteristics. Examples of receptive fields have been shown in Fig. 3; the effective stimuli were not uniform and often rather complex. Fifty-four PN neurones (60 %) did not react at all in a reproducible way to the various cutaneous and kinaesthetic as well as noxious stimuli. A common feature was an unspecific increase in spontaneous activity with nociceptive stimuli. In eleven neurones, such as the one shown in Fig. 3A, the receptive fields were relatively restricted. Six neurones were selectively activated by passive movements of the limbs 752752
A4
Sit~~~~~~~~~1
B
SMI
10
Msec
.1-11
11 Nerves
2.5 msec
511
"
I- T
1-M
_.
-
a---
-I
Coiitrol
Fig. 5. A, neurone recorded in the dorsal portion of the pontine grey, presumably within the N. reticularis tegmenti pontis. Short latency activation by both SM I and S II stimulation. B, convergence neurone activated orthodromically by S II and SM I. This unit was activated by passive manipulation in several joints of contralateral forelimb. Electrical stimulation of brachial plexus above twitch threshold (nerves) also activated this cell with low probability and at long latency (five superimposed sweeps). Beside (right) are five control sweeps without stimulation.
joints. There was no apparent difference in receptive field characteristics between 'SM I-type units' and 'S II-type units'. In order to gain some information on the number of synapses involved in the transmission from the periphery to the PN, the effect of electrical stimulation of forelimb nerves was also tested in those cells responding to natural stimulation in the forelimb region. As indicated in the latency histogram of Fig. 4, the latencies were rather long and scattered over a range of 8-33 msec. Characteristically, the probability of discharges, even to strong stimuli which elicited vigorous twitches, was low (Fig. 5B). at one or more
CORTICAL EFFECTS ON PONTINE NEURONES
753 These results are compatible with the notion of a circuitous, presumably
transcortical pathway. Correlation between responsiveness of PN neuroses to cortical stimulation and receptive fields. Table 1 lists all the PN neurones according to their responsiveness to cortical stimulation. The table also indicates the number of PN cells with receptive fields in each category. It is noteworthy that those cells which were not responsive to any of the cortical stimuli rarely had receptive fields. On the other hand, the largest proportion of receptive fields was found in PN neurones with convergence from S II and SM I. TABiL 1. Responsiveness of PN neurones to cortical stimulation. Figures in parentheses show PN neurones with receptive fields
N
SM I only 23 (8)
S II only 9 (8)
Both 25 (17)
None 33 (3)
DISCUSSION
1. Functional relationship between SM I and SII cortical areas and the pontine nuclei Previous results of degeneration studies in monkeys obtained with the Marchi method already revealed that the terminal areas of corticopontine fibres form well-defined, lengthened, rostrocaudally oriented zones with little, if any, overlapping (Nyby & Jansen, 1951). More recent studies with refined degeneration techniques disclosed a very precise point-to-point cortico-pontine projection from cortical areas SM I and S II (P. Brodal, 1968a, b). The present experiments confirmed that both SM I and S II indeed exerted a pronounced influence on PN neurones but failed to disclose any spatial separation of pontine cell columns excited by electrical stimulation of the two cortical areas. Similarly, Sasaki, Kawaguchi, Shimono & Prelevid (1970) were unable to differentiate separate foci within the PN activated by stimulation of subdivisions of the pericruciate cortex. One could argue that, in these latter experiments, electrical stimulation of nearby cortical areas would not provide enough discrimination to reveal the pattern of projection described in anatomical studies. In the present experiments, however, two widely separated cortical areas were stimulated with selective intracortical electrodes at intensities low enough to preclude spread of current from one area to the other. The discrepancy between anatomical and electrophysiological observations may be due to three factors: (1) the presence of pontine interneurones which would relay activity from one column to the other; (2) recurrent collaterals from PN neurones to other PN neurones of
D. RUEGG AND M. WIESENDANGER neighbouring columns; (3) overlapping dendritic fields. The Golgi pictures of PN neurones by Cajal (1909, figs. 437 and 438) indeed indicate that all three factors may account for the observed convergence seen in our electrophysiological studies: there are a large number of recurrent collaterals which may spread over more than one 'projection column'. Similarly, dendritic fields of neighbouring columns may intensively overlap. Furthermore, Cajal described small cells with short axons which may represent local interneurones ('type cellulaire villeux ou moussu 'a cylindreaxe court'). Despite the convergence seen in electrophysiological studies the possibility remains that, for each PN cell assembly, one particular input is predominant. Indeed it was found that most PN neurones with convergence had a lower threshold to stimulation of one of the cortical areas. 754
2. Slow cortico-cerebellar pathway It is well known that electrical stimulation of cerebro-cortical areas elicits early and late cerebellar responses (Jansen, 1957), which were considered to be transmitted via climbing fibres (Provini, Redman & Strata, 1968). It appears that long latency cerebellar responses are not exclusively relayed through the inferior olive but also through the pontine relay (Allen, Korn & Oshima, 1969; Allen et al. 1970; Sasaki et al. 1970). In the present experiments, the conduction velocity of ponto-cerebellar neurones was in the same slow range as reported by Allen et at. (1969), but the values were lower than those given by Sasaki et al. (1970). It may be that, in the latter study, many recordings were made from the nucleus reticularis tegmenti pontis, which has larger cells and hence probably faster conduction velocities than the cells of the PN proper. The demonstration of a slow cortico-cerebellar pathway relayed in the PN does not necessarily imply that the PN are a source of climbing fibres since some of the long latency cerebellar responses to cerebral cortical stimulation were found to be mediated via mossy fibres (Kitai, Oshima, Provinci & Tsukahara, 1969). On the other hand, climbing fibre responses elicited by pontine stimulation were discovered by Sasaki, Kawaguchi, Shinomo & Yoneda (1969). Additional experimental results which do or do not support the concept that the inferior olive is the sole origin of climbing fibres has recently been reviewed (Armstrong, 1974). This controversial problem remains to be fully elucidated, particularly in view of most recent results based on degeneration experiments in monkeys reported by Rivera-Dominguez, Mettler & Noback (1974). These authors claim that the inferior olive is only a minor source of climbing fibres. Long latency climbing fibre responses are recorded chiefly contralaterally to cerebro-cortical stimulation (Provini et al. 1968; Miles & Wiesendanger,
755 CORTICAL EFFECTS ON PONTINE NEURONES 1975a, b). This relationship is difficult to explain by a direct cortico-olivocerebellar path since the projection to the olive is predominantly crossed and the olivo-cerebellar fibres re-cross on their way to Purkinje cells (Armstrong, 1974). The relationship is, however, compatible with a cortico-ponto-cerebellar pathway. 3. Functional implications
The degree of convergence found in the present electrophysiological experiments suggest that a considerable integration takes place at the level of the PN. It thus appears that the cerebellar nuclei and the cerebellar cortex are 'interested' in processed information, spatial, visual and other, in addition to details as transmitted from the receptors to the cerebellum via more direct pathways. One may furthermore visualize that this processing is a gradual one, increasing from relay to relay as has been demonstrated for example for the somatosensory pathway to the cerebral cortex (Werner, Whitsel & Petrucelli, 1972). In a previous study on S II neurones (Atkinson et al. 1974) it was shown that output neurones of S II with axons descending to the brain-stem or to the spinal cord typically had larger receptive fields than intrinsic neurones of S II. It was therefore assumed that the output neurones receive a convergent input from the classical 'lemniscal-type' neurones of S II. A progressive convergence at the pontine level would then explain the further increase in complexity of 'receptive fields' of the pontine target neurones (for instance responsiveness to passive movements at more than one joint). Such input of processed information from cortical areas would be expected in view of the hypothesis that the PN may relay an 'internal substitute of the external world' to the cerebellum (Allen & Tsukahara, 1974). Considering that the PN receive information not only from primary cortical areas but also from association areas, one might conjecture that some PN cell assemblies relay to the cerebellum much more complex stimulus features than could be disclosed by our simple procedures for testing receptive fields. PN neurones which did not respond to electrical stimulation of the somatic motor and sensory areas were probably neurones with a predominant input from other primary cortical areas and association areas. Allen & Tsukahara (1974) discussed the hypothesis that the medial cerebellum may be chiefly concerned with ongoing corrections of movements by means of feed-back signals whereas the lateral cerebellum would be concerned with the 'programming' and initiation of movements. It would be interesting to know whether or not those PN neurones which transmit relatively 'crude' data (i.e. cells with an input from primary areas) project medially and those with associational input project laterally to the cerebellum.
756
D. RIEGG AND M. WIESENDANGER
We wish to thank Drs J. J. S6guin and J. Hore for helpful comments and criticism. Our thanks are also due to D. H. Atkinson, M.R.C. summer student, who participated in the initial experiments of this study. The technical assistance provided by Mrs P. Dhanarajan is much appreciated. Generous financial support was received by grants from the Medical Research Council of Canada (Numbers MA-4992 and ME-5092) and from the Multiple Sclerosis Society of Canada to M.W.
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