The role of cerebral cortex in evoked somatosensory activity in cat cerebellum

EXPERIMENTAL

NEUROLOGY

The

14,

13-32

Role of Cerebral Somatosensory Cat

THELMA Department

(1966)

T. KENNEDY, of Physiology

School

Cortex Activity

in Evoked in

Cerebellum

ROBERT J. GRIMM,

AND ARNOLD

and Biophysics, The University of Medicine, Seattle, Washington Received

July

of

L.

TOWER

Washington

16, 1965

Gross responses were recorded at various cerebellar loci following forepaw electrical stimulation. In chloralose-anesthetized cats responses are large over posterior culmen and adjacent simplex, somewhat reduced in paramedian lobules bilaterally, and considerably smaller in posterior vermis and cerebellar hemispheres. Although variable, responses are usually positive-negative and appear to contain components indicated by notches or slope changes in the main wave. Following decerebration, responses in culmen and simplex are greatly reduced and simplified; responses elsewhere are abolished. Similar results follow administration of barbiturates, KU-induced depression of cerebral cortex, ablation of somatosensory cortex, lesions of dorsal column, medial lemniscus or nucleus ventralis posterolateralis. In addition to “direct afferent pathways” from forepaw to cerebellum, activity travels via the dorsal column-medial lemniscal system to somatosensory cortex and thence to cerebellum and provides a “cortical loop pathway” which acts to enhance the spinocerebellar responses, resulting in increase of response amplitude and duration as well as enlargement of the responsive area. The major route from cortex to cerebellum appears to be via the corticopontocerebellar pathway, and the wide distribution of the forepaw response beyond forelimb area in culmen is presumably due to the wider distribution of this pathway. Introduction

While investigating the influence of pyramidal tract activity on the cerebellum and brain-stem nuclei of chloralose-anesthetizedcats, Towe and Kennedy (unpublished observations) found that transecting the medial lemniscusat a midolivary level markedly alters the cerebellar responseto skin stimulation. Decerebration similarly causesa striking and permanent 1 Aided by Grants Z-B5082 and B-396 from the National Institute Diseases and Blindness. Dr. Grimm’s present address is: Laboratory ogy, Good Samaritan Hospital, Portland, Oregon.

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reduction in the cutaneously evoked cerebellar response. The size and configuration of these changes, however, are not uniform. Responses on posterior culmen (lobule V of Larsell: 22, 23) and lobulus simples (VI) in the intact animal under chloralose range from 0.5 to 1.0 mv; responses in more posterior vermis (VIIA,B and VIIIA,B), paramedian lobes (HVIIB and HVIIIA), and the cerebellar hemispheres (HVIIA) are considerably smaller. Following decerebration the responses in culmen and simplex are merely reduced while those elsewhere are abolished. ln contrast, responses in cats anesthetized with barbiturates range from 75 to 400 uv (26,27,31), and no marked changes are noted after decerebration. Darian-Smith and Phillips (7) demonstrated that trigemino-cerebellar projection neurons having cell bodies in the region of the lateral reticular nucleus can be fired by stimulating the thalamic arcuate nucleus. They thus found a link between the lemniscal system and the trigeminocerebellar pathway. The possibility of a cortical loop was not pursued, but can be raised since the response latencies were 5 to 10 msec. The present study establishes the existence of the cortical loop pathway from skin to cerebellum, describes the pathway involved and shows its relative contribution to the cutaneously-evoked cerebellar response. Methods

Fifty-five cats were anesthetized with alpha-chloralose (40-60 mg /kg, ip), paralyzed with decamethonium bromide (approximately 2 mg/kg, iv) and artificially respirated. Cerebellum was exposed by removing occipital bone up to the tentorium, the opening being extended laterally as required, and the anterior cerebral hemisphere of one or both sides was exposed for stimulating and recording. Care was taken to minimize bleeding and to maintain normal body temperature, and warmed mineral oil was used on exposed surfaces to minimize drying. Additional exposures, made in some animals, included dorsal cervical cord, larger areas of cerebral cortex, and ventral aspect of brain stem. Brain-stem and thalamic electrodes were placed with the aid of a stereotaxic frame. During some of the experiments, the animals were decerebrated by first ligating the carotid arteries and then, while manually compressing the vertebral arteries, making a midcollicular transection and removing all rostra1 structures. The general condition of the animals, including heart rate, was noted before and following decerebration, and responses were followed for several hours for comparison with the predecerebrate records. In each of eight animals, the cerebral peduncles were transected bilaterally in a one-stage aseptic operation three to five weeks before the acute

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experiment. The lateral surface of each hemisphere was exposed, the head was tilted 70-80” laterally, and the temporal lobe elevated to expose the cerebral peduncle. After resection of the pia, the peduncle was transected with a dull, oblongate knife. This procedure was then repeated on the opposite side. The forepaw footpads were stimulated, via bipolar steel-needle electrodes, with O.l-msec pulses induced through a radio-frequency isolation transformer. The amplitude was variable, usually several times threshold. Occasionally forearm nerves were exposed and stimulated directly, via hooked silver-wire electrodes, with 0.05msec pulses. Cortical stimulation was effected through bipolar silver-ball electrodes with 2-mm tip-separation using 0.05-0.1 msec pulses of lo-25 v amplitude. The cortical stimuli were delivered to the points on somatosensory areas I and II yielding the largest primary responses to contralateral forepaw stimulation. Gross electrical recordings of responses in cerebral and cerebellar cortex were obtained with monopolar, silver-ball electrodes; the indifferent lead was clipped to the edge of the skin incision. Responses were recorded simultaneously at several loci with four Tektronix type 122 preamplifiers and four type 360 oscilloscopes. The over-all time constant on each channel was 200 msec. The responses were registered photographically for later analysis. Bipolar recording was rarely employed; the complexity of cerebellar fissuration precluded precise localization. In some experiments a computer of average transients was employed obtaining an average response of 40 to 60 sweeps for each situation. This technique was used sparingly as the variability in timing was often great enough to obscure small, but significant details. Results

Following stimulation of the forepaw footpad, prominent responses appeared in contralateral pericruciate cortical tissue and bilaterally in posterior culmen and anterior simplex; lesser responses were widely distributed. Figure 1 illustrates the cortical (CP) and the cerebellar (CbP) primary response? recorded at these maximum foci following skin stimulae Components of the cerebellar response have been variously designated, although agreement concerning their origin has not been reached. The assignment by Morin et al. (26) of x for the small, early positive component and y for the subsequent large positive-negative potential is satisfactory. However, additional components appear in y under chloralose, and until these can be sorted out it seems reasonable to refer to the complex as the cerebellar primary response or CbP. The long latency response originally noted by Curtis (6) and often seen following CbP will be called the late wave.

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tion. Although they are variable among different animals (Fig. 2) and in the same animal over time, some prototype waveforms can be distinguished for different sites. Recording simultaneously from a ‘Sxed” electrode and from three exploring electrodes gave a reference ‘Lcontrol” for variability over time. The large responses seen in lobulus simplex (VI) were similar to those in posterior culmen (V) (Fig. 3), the major waveform being a large positive and a smaller, more variable negative complex. The positive phase appeared lo-16 msec after forepaw stimulation, peaked at 22-25 msec (occa-

FIG. 1. Stimulation of right forepaw (RFP) ; primary response recorded from left cerebral cortex (CP), somatosensory area I (%I), and cerebellum (CbP), midline simplex. Positive is downward in this and following illustrations. Calibrations: right, 200 pv for cerebellum; left, 300 pv for cerebral cortex; time: IOmsec.

sionally later) and had a duration of 20-30 msec. It was characteristically interrupted by notches or spikes on both limbs. The peak-to-peak amplitude sometimes was 1.0-1.5 mv, but more often was 0.5-0.8 mv. The early, small x wave had a latency of 5-8 msec and peaked at lo-12 msec. Rarely, an even earlier positive deflection with a latency of 4-5 msec could be identified; this corresponds to the earliest deflection reported by Grundfest and Campbell (14) and Mountcastle, Covian and Harrison (28) to hind-limb nerve stimulation. After a latency of 80-120 msec, a diphasic wave of variable amplitude-the late wave-often appeared. In the paramedian lobule, responses were often quite large (Fig. 3) and of slightly longer latency than in culmen. The z wave was not often seen; the CbP sometimes was preceded by a small negative deflection. The

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ipsilateral responses In more posterior responses were less particularly in crus

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were generally larger than the contralateral responses. vermis (posterior folia of VI, VIIA, VIIB and VIII) consistent and smaller in amplitude. Laterally, and I, the CbP was more often negative or negative-

FIG. 2. Responses recorded at culmen from different experiments illustrating variability of responses obtained. Left, responses to ipsilateral forepaw stimulation; right, responses to contralateral forepaw stimulation. Corresponding curves in the two columns are recorded from the same culmen “point,” same experiment, same series, changing only the forepaw stimulated. Calibration: 200 pv (note different gains) ; time, 10 msec.

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positive. Sometimes negative II or, more rarely, on lower prominent, it was widely hemispheres. Responses could also be were remarkably similar to shorter latencies. As shown

GRIMM,

AND

TOWE

primary responses appeared laterally in crus vermal points. When late wave activity was distributed over the vermis and cerebellar evoked by direct cerebral stimulation; they the cutaneously-evoked CbP except for their in Fig. 3, the responses to stimmation just

FIG. 3. Map of evoked cerebellar responses following stimulation of: IC, ipsilateral cerebral cortex; CF, contralateral forepaw; IF, ipsi!ateral forepaw; CC, contralateral cerebral cortex. Letters at left refer to recording loci on map. Calibrations: 500 WV; upper bar applies to rows A, B, C; lower bar applies to rows D, E, F, G; time: 10

msec.

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posterior to the lateral tip of cruciate fissure were largest in culmen (V) and simplex (VI), smaller over posterior vermis, large over paramedian lobule (HVIIB) and often inverted laterally. These cerebrally-evoked responseswere usually of the short latency or the combined short- and long-latency variety described by Jansen (18). The cerebrally-evoked responseswere generally larger in amplitude than those produced by forepaw stimulation. Effect of Barbiturates on CbP. Small dosesof pentobarbital markedly reduced or abolished the CbP over its chloralose control level. When 18

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mg’kg of pentobarbital (one-half normal surgical dose) was given 9 hours after the first administration of chloralose, the CbP to forepaw stimulation disappeared from the simplex and paramedian monitoring points, although the CP remained. In a separate experiment a single injection of pentobarbital (6 mg/kg) reduced the forepaw-evoked CbP from 400 to 80 pv in posterior culmen (V) ; only the x wave and the earliest portion of the CbP remained. Interestingly, in this preparation, the simultaneously recorded corticofugal discharge in the medullary pyramid decreased to 30% of its control amplitude while the medial lemniscus response remained unchanged. Pentobarbital administered to another animal in 2-mg/kg increments reduced the forepaw-evoked CbP, as recorded from simplex and crus I, in a stepwise manner: first to two-thirds of the control amplitude, then to one-third, one-fourth, etc., and eventually to zero when a full surgical dose had been given. During this series, the CP showed only minor changes; it was 1.0 mv in amplitude following the third dose of barbiturate and 0.8 mv when the full surgical dose had been given. The changes in CbP following administration of 0.2 ml/kg Dial-urethane (one-third normal surgical dose) were also mapped. Midvermal responses to forepaw stimulation were reduced to 30-5070 of control amplitude; responses from lateral points on simplex showed a greater reduction on the side contralateral to the forepaw stimulated. Cerebellar hemispheric responses were also decreased. All waveforms-notched and spiked initially -were simplified into smoother deflections. The early portions of the CbP were attenuated and the later parts abolished, making the total wave duration shorter; occasionally the latency increased. In the same preparation, the CbP following direct cerebral stimulation were much less altered by Dial-urethane. The largest reduction seen was to 70% of the control amplitude, while the waveforms were somewhat simpler and of slightly shorter duration. Efiect of Decerebration on CbP. To compare directly the CbP from intact preparations with those obtained from decerebrate preparations, midcollicular decerebration was performed on five animals after chloralosecontrol responses had been obtained. Following decerebration, only negligible responses could be produced by forepaw stimulation when recording from crus I and II (HVIIA) , folium and tuber vermis (VIIA,B) (Fig. 4). Occasionally a small, early response remains in the ipsilateral paramedian lobule, consisting of x and a small part of CbP. Records from culmen and simplex are more complex. As shown in Fig. 4, the culmen CbP is much reduced, although x remains. A greater attenuation occurs in simplex.

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Evidently the upper brain stem or cerebrum, or both, are essential for production of the large CbP seen in both vermal and hemispheral regions. Culmen responses are least affected by decerebration.

FIG. 4. Evoked cerebellar responses to stimulating ipsilateral forepaw (left column of each pair) and contralateral forepaw (right column of each pair) preceding (upper traces) and 70 min following (lower traces) decerebration. A, culmen; B, simplex; C, upper folium vermis; D, tuber vermis; E, paramedian; F, mid-crus I; G, lateral tip of cerebellar hemisphere; H, crus II. Calibration: 500 pv; time, 10 msec.

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In the experiment shown in Fig. 5, the response in left culmen to left forepaw stimulation contains no clear X, but a complex CbP with three distinguishable peaks. Immediately following decerebration (Fig. 5B) only

FIG. 5. Left forepaw (LFP) stimulation; recording left culmen. A, control response; B, 5 min following midcollicular decerebration; C, 3045 min following decerebration; D, one hour following decerebration; E, 2 hours following decerebration. Calibration: 200 pv; time, 10 msec.

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the first peak of CbP, much reduced, seems clearly present. With time (Fig. 5 C, D, E) the third peak also returns; the middle component remains absent. Although in many instances the first peak of CbP was not separately defined or was often only suggested as a change in slope, this early peak of CbP remained attenuated, following decerebration. The second peak, the major element of CbP, was most often affected by decerebration. The unusual aspect of the experiment illustrated in Fig. 5 is the clearly defined and relatively undiminished third peak. Further, the x wave is not obvious in the control record but is readily distinguished after decerebration. Cerebral Contribution to CbP Following Cutaneous Stimulation. To assess the role of frontal cerebral cortex in production of CbP, a variety of maneuvers were performed, including ablation of one or both frontal cortices, removal of frontal poles including white matter, application of ice or ethyl chloride to exposed cerebral cortex or institution of spreading depression by application of KC1 to frontal regions. In some animals the surgical maneuvers were confined to pericruciate cortex and in others from ansate sulcus rostrally and laterally to include both somatosensory areas I and II. The results varied according to the amount of interruption of cerebral cortex and the configuration of the control CbP. Spreading depression, induced with KCl, resulted in almost complete loss of CbP but had no effect on the x wave. The CbP returned in 30 min and fully recovered in 80 min-paralleling the time-course of recovery of the cerebral primary response. Figure 6A illustrates the dramatic reduction in CbP to left forepaw stimulation 5 minutes after KC1 application to right frontal cortex. Figure 6C shows that CbP to right forepaw stimulation is unaffected; occasionally, however, such responses are slightly enhanced. If the spreading depression involves both hemispheres and obliterates both cerebral primary responses, the CbP to both forepaws disappears. Visual and auditory CbP were also examined following bilateral spreading depression of the cerebral cortex, and results were obtained similar to and confirming the work of Munson and Snider (29). The visual CbP appeared to be more greatly affected than the auditory CbP. Application of ethyl chloride or ice to frontal cerebrum similarly reduced CbP at simplex and culmen. In cases where control responses showed separate components, the second and third peaks of the CbP were obliterated, while the x and the first peak of the CbP remained. Brain-stem recordings showed a drastic reduction in the corticofugal reflex discharge

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with no change in the lemniscal response.Full recovery occurred in about 30 min. Figure 7 shows the marked reduction in CbP to stimulation of forepaw following ablation of frontal cortex; inclusion of white matter in the ablation caused a more severe reduction. This is true for vermal and paramedian recording sites; the cerebellar hemispheres were not sampled. Bilateral ablation of primary auditory cortex caused a mild reduction in the click-evoked CbP, asreported alsoby Munson and Snider (29). Spinal Aterent Pathways Essential for CbP. The dependence of the

FIG. 6. (Left). Effect of KU-induced spreading depression: A, LFP stimulation recording midline simplex preceding and 5 min following application of KCI to right SSI; B, LFP stimulation, recording on right SSI preceding and 5 minutes following application of KC1 to right SSI; C, RFP stimulation, recording midline simplex preceding and 5 min following application of KC1 to right SSI. Calibrations: 200 pv for cerebellum; 400 pv for cerebral cortex; time: 10 msec. FIG. 7. (Right). RFP stimulation, recording midline simplex. A, control response; B, 15 minutes following ablation of left SSI (to ansate sulcus posteriorly and coronal sulcus laterally) ; C, 50 min following left SSI ablation and 30 minutes following left SSII ablation. Control LFP-to-midline simplex (not shown) remained unchanged following ablation. Calibration: 200 pv; time, 10 msec.

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forepaw-evoked CbP upon the integrity of certain cerebral regions is clear-but what of the routes involved? Complete hemisection of the cord at Cl abolishedboth the x and CbP. Stimulating the forepaw after transection of the ipsilateral dorsal funiculus greatly reduced or abolished the CbP over all cerebellar regions except culmen (V) and simplex (VI). The amplitude of the responsein culmen was not markedly changed, and the responsein simplex was decreasedup to 50% ; the responsesat both sites were much more variable than during the control periods. However, stimulation of a dorsal column strand in isolation from the remainder of the cord produced almost normal CbP throughout the cerebellum; they appeared with a 3-5 msec shorter latency and were not preceded by an x wave. In all casesstimulation on the unoperated side yielded normal CbP. Stimulation of any forearm nerve produced CbP markedly similar to that produced by stimulation of footpad skin. However, after dorsal column transection, CbP in culmen and simplex were apparently less attenuated following nerve stimulation than following skin stimulation-as though certain fibers in the mixed nerve input travel outside the dorsal funiculi, yet relay through higher centers. When a dorsal column transection was made following decerebration no changescould be observed in CbP. Histological verification showedthat the dorsal funiculi transections were never complete-the criterion for completenessduring the experimental procedure being elimination or drastic reduction of the cerebral primary evoked response. Thus, the remaining responsivenessof culmen and simplex, although most likely due to the activity in other spinal routes, could be ascribed to incomplete dorsal funicular transections. Several attempts to transect the lateral portions of the spinal cord, leaving only the dorsal funiculus intact, likewise fell short of compete success. However, the x wave, when present in the control response,was eliminated and a small change in configuration of the early portion of the CbP was noted. The latency and amplitude of CbP remained unchanged, and late wavespresent before the transections also remained, apparently unchanged. Brain-Stem ABerent Pathways for CbP. Lesions produced from the ventral surface of the bulb which encroach on the medial lemniscus sufficiently to distort the cerebral primary evoked responselikewise distort the CbP. In two animals, when NVPL of the thalamus was electrolytically destroyed unilaterally, CbP was greatly reduced or obliterated to stimulation of the forepaw contralateral to the lesion. The CbP to stimulation of the forepaw ipsilateral to the lesion was unaffected. Further, a CbP produced by stimulating either cerebral cortex was unaltered in the animal

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in which the lesion was confined to NVPL. In the second cat, the lesion encroached on internal capsule, thereby reducing the cerebrally-evoked CbP. In both animals, cutaneously evoked CbP were abolished in the hemispheres but only reduced in the vermal regions sampled. In the few instances where it was possible to make some comparisons of the cerebellar responses on lateral points of simplex and culmen to stimulation of the forepaw contralateral to the lesion, the responses recorded on the contralateral vermis curiously were more affected than on the ipsilateral vermis. Direct stimulation over the surface of cuneate nucleus produced a complex response consisting of several early, spikelike variations followed by a large and later wave. The early “spikes,” two or three in number, appeared in less than 3 msec, faithfully followed iterative stimulation at least to the 60/set frequency tested and remained after the cortical loop pathway had been broken by medial lemniscus transection at the pontotrapezoidal level. The later wave, on the other hand, was similar in configuration to CbP produced by forepaw and dorsal column stimulation but appeared 5 msec earlier. This wave was abolished or much reduced by transection of the cortical loop pathway. Stimulation along the ventral surface of the brain stem with sufficient strength to activate medial lemniscus fibers yielded CbP throughout the cerebellum. Small, relatively short latency responses appeared with weak stimuli; larger and later components developed as stimulus intensity was increased. In four experiments where simultaneous records were taken from pericruciate cerebral and vermal cerebellar cortices, the early responses (2-5 msec latency) were present in cerebellum when the brainstem stimulus produced only the a and b waves (19) in the cerebrum. Increasing the stimulus strength sufficiently to add the d wave (19) to the cerebral response brought in the large CbP (peak near 20 msec). At intermediate intensities, in two experiments, a smaller “CbP” at 9-11 msec appeared. When the brain stem was sectioned above the stimulus site deep enough to divide the medial lemniscus, only the early responses (latency less than 3.5 msec) could be produced. Cerebellar primary responses similar to those produced by forepaw stimulation could be produced by stimulating the dorsal columns, dorsal column nuclei, medial lemniscus (both rostra1 and caudal levels) and NVPL of the thalamus. By the time the latter position was reached, the CbP peaked 10 msec earlier than to forepaw stimulation. The largest responses following stimulation of somatosensory areas I and II occurred

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in simplex (VI) and culmen (V). The latency to peak varied from 7 to 12 msec, and a second component, signaled by a notch on CbP, occasionally occurred at 16-20 msec. In the paramedian lobule, this second response often exceeded the first in amplitude. Hemispheral (HVIIA) CbP to cerebral stimulation were often Ynverted,” especially in lateral folia of crus I. Cerebral Efferent Pathways. Attempts to transect one cerebral peduncle, retaining the other as control, met with varying success.Histological studies showed one transection complete, two 8590% complete and the remainder poor. Since, from these animals, it appeared that one intact peduncle could transmit impulses from either forepaw to the cerebellum, bilateral transections were attempted (in chronic experiments, to permit recovery from this rather traumatic procedure). Histological studies in eight animals showed four with complete peduncle section on one side, two with partial sections unilaterally, one with partial bilateral sections and only one with both peduncles completely sectioned. In the animals with complete unilateral pedunculotomies,CbP to stimulation of forepaw contralateral to the lesion was consistently, but only slightly, reduced. The responseto stimulation of ipsilateral cerebral cortex was more severely affected in all cases.Both amplitude and latency of CbP to cerebral stimulation changed, the increase in latency apparently resulting from the lossof an early component of the CbP. In crus I and crus II, the only responsesof any reasonablesize were recorded on the side of the peduncular lesion following stimulation of ipsilateral forepaw or contralateral cortex. In the animal with complete bilateral pedunculotomy, no CbP could be produced anywhere in cerebellar hemispheresby cutaneous stimulation, and only minimal responsesfollowed cerebral stimulation. At vermal and paramedian recording sites, small responsesappeared to cutaneous stimulation and somewhat larger responsesappeared to cerebral stimulation. Lobulus simplex was affected least-the CbP following forepaw stimulation was 0.5 mv in amplitude. Concerning other possible pathways, only the role of the pyramidal tract below pons was investigated. When one pyramidal tract was transected at the level of trapezoid body, the CbP to cerebral stimulation showeda small but clear reduction in amplitude. When the CbP displayed two components,the secondof the two was affected. Following stimulation of forepaw contralateral to the lesion, only minimal changeswere observed.

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Discussion

In intact cats anesthetized with chloralose and immobilized with decamethonium bromide, a brief electric shock to the skin evokes a large response, the CbP, over a wide area of the cerebellum. This CbP is strikingly altered when the cerebrum is transiently depressed or after removal of the anterior cerebrum or transection of the corticofugal fibers. In the “primary” forelimb areas of the cerebellum, such as culmen, CbP is reduced in amplitude; in “off focus” areas such as tuber vermis or the hemispheres, CbP usually is eliminated altogether. Thus, the cerebral cortex plays a powerful role in production of the main cerebellar gross voltage change following cutaneous stimulation. In those folia supplied directly by forelimb afferents, the CbP results from combined direct and cortical loop action; in cerebellar areas sparsely supplied by direct fibers, the CbP depends upon the integrity of the cerebral cortex. The cerebral cortex, after a brief delay, extends the effects of a cutaneous volley throughout the cerebellum. The earliest cerebellar response to forepaw stimulation sometimes consists of a small positive deflection (4.0-msec latency) followed immediately by a small x wave. This corresponds with the beginning of activity in the underlying cuneate nucleus and a forelimb afferent volley in inferior peduncle (15)-corticofugal activity does not begin for another 5 msec. Towe, Patton and Kennedy (33) have found pericruciate corticofugal activity in pyramidal tract cells to cascade to two maxima, one at about 15-msec and the other at 21-msec latency. If corticopontine cells behave similarly, we would expect the cerebellar response to peak 2-4 msec later, an expectation in good accord with our observations. The major component of CbP peaks at 22-25 msec latency l-4 msec after the more widely distributed second maximum in corticofugal discharge (33). The cerebellar response to forepaw stimulation in the decerebrate cat is usually of small amplitude (3, 9, 10, 26) and is little affected by the administration of a barbiturate. In the intact chloralose-anesthetized cat, which shows large amplitude CbP, administration of small amounts of barbiturate markedly reduces the cerebellar response. Berry et al. (1) showed a similar effect on photically-evoked CbP, and Snider and Stowell (31) and Koella (20) remarked on the sensitivity of both optic and auditory CbP to barbiturate drugs. In view of the powerful role of the cerebrum in production of a large CbP, the marked reduction or elimination of the reflex corticofugal discharge following small amounts of bar-

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biturate (30) may be sufficient to account for this apparent sensitivity of cerebellum. Since no work has been done on intact, unanesthetized animals, the relative roles of barbiturates in depressing or chloralose in enhancing the electrical activity cannot be evaluated. Among the afferent routes from forelimb to cerebellum, perhaps the main one occupies a lateral position in the dorsal columns, relays in external cuneate nucleus and projects to cerebellum via restiform body (12, 15, 16, 24), although the findings of Combs (5) detract from this suggestion. It is perhaps this pathway which yields the x wave-a pathway which may explain the inconsistent behavior from animal to animal of the x wave when a dorsal column strand was produced. Apparently few fibers from the forelimb use either spinocerebellar tracts (13, 16), but another route clearly is available through the lateral reticular nucleus and could underlie the early remaining component of the CbP after interruption of the cortical loop pathway. Combs (5) considered the lateral reticular nucleus responsible for the localized cerebellar responses. Darian-Smith and Phillips (7) found that some cutaneous afferents from the face reached the lateral reticular nucleus over the trigeminal nerve and many of the cells projected to cerebellum. Bohm (2)) recording within or in the vicinity of the nucleus found responses to stimulation of low-threshold cutaneous afferents. While he did not define the spinal pathway, he ruled out dorsal columns and located the route in the anterolateral cord. Other possible afferent routes include the spino-olivary path (4, 5, 17, 27). The cortical loop pathway from the forelimb evidently utilizes the cuneate nucleus and nucleus ventralis posterolateralis in thalamus. However, a few fibers originating in cuneate nucleus may eschew this route and go directly to the cerebellum-analogous to those found in gracile nucleus by Gordon and Seed (11). The forepaw electrical stimulus activates fibers normally driven by skin receptors. Nerve stimulation activates mixed afferents, proprioceptive as well as exteroceptive, and yet yields CbP indistinguishable from those produced by skin stimulation. However, following transection of the dorsal columns, the skin-evoked CbP is markedly altered, while the nerve-evoked CbP is not nearly so depressed. It is therefore quite probable that proprioceptive fibers contribute proportionately more to nondorsal column routes. Further, it is clearly evident that the major part of CbP to cutaneous stimulation depends upon the integrity of the dorsal columns, other lateral and anterolateral spinal pathways playing minor roles insofar as amplitude of the potential is concerned.

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The regions of cerebral cortex involved in production of CbP have not been precisely defined. It is clear, however, that both somatosensory areas I and II are strongly involved. Bilateral ablation of these two areas yields a condition resembling the decerebrate picture; lesions elsewhere in the cerebrum have little or no effect. Although corticopontine projections arise from the whole convexity of the cerebrum, with the possible exception of middle ectosylvian and occipital parts of lateral gyri (ZS), there is a heavy supply from somatosensory cortex. These fibers traverse the middle of the cerebral peduncle, relay in the pons and project largely to the ansoparamedian lobes (HVIIA) of the opposite cerebellar hemisphere. Pontocerebellar fibers also terminate bilaterally in the vermis. Jansen and Brodal (17) stressed a cortico-olivocerebellar pathway that distributes throughout the intermediate zone but supplies the vermis only minimally. Kuypers (2 1) found corticobulbar fibers ending in the contralateral lateral reticular nucleus, and Jansen and Brodal (17) described connections from the paramedian reticular nucleus and perihypoglossal nucleus to the anterior lobe, uvule (IX) and pyramis (VIIIA,B) and some to lobulus simplex (VI), but none to the ansoparamedian lobes (HVIIA) Thus, the anatomical findings offer several potential cortico-cerebellar routes. The work of Deura (8) in light barbiturate cats and Jansen (18) in chloralose cats suggests that the cerebellar inflow from cerebral cortex comes largely by way of the middle cerebellar peduncle. In the present study, section of the pyramidal tract below the trapezoid level led to equivocal results. It seems likely then that the major route of the cerebrallyevoked CbP is the corticopontocerebellar pathway via the middle cerebellar peduncle; other routes, while apparently present, play only minor roles. From the forelimb, direct afferents and the cortical loop pathway converge in culmen, simplex and paramedian lobules, combining in an undefined way to generate the large chloralose CbP. More posterior regions of vermis and crus I and II give a forelimb cutaneous response that is dependent upon the cortical loop pathway. Thus, when the cortical loop pathway is depressed or interrupted, the area of the cerebellum responsive to cutaneous stimulation shrinks to that of the direct inflow. Ipsilateral responses are relatively stronger, contralateral simplex responses may disappear and posterior vermal and hemispheral responses disappear altogether. The cerebrally-evoked CbP in this study activated from somatocensory areas I and II were largely of the short latency type, which, according to Jansen ( 18) are transmitted over the corticopontocerebellar pathway to

CEREBELLAR

SOMATOSENSORY

ACTIVITY

31

terminate throughout the cerebellum as mossy fibers in the granule cell layer. The projections of the direct afferent pathways terminating as mossy fibers reach the granule cell layer of the same folia, especially in posterior culmen (V) and simplex (VI). In such regions these systems of fibers may converge onto the same population of granule cells or perhaps onto different sets of granule cells within the same folia. Results from interaction studies, not reported in this paper, although not decisive, are consistent with the latter possibility. The report by Szentagothai and Rajkovits (32) of laminar arrangement of certain afferent projections to the granule cell layer of the cerebellum provides an intriguing possibility for the solution of this problem. References 1.

2.

3.

4. 5. 6. 7.

8. 9. 10.

11.

12. 13.

C. M., J. S. HAFT, P. J, HARMAN, and C. A. HOVDE. 1959. Significance of pharmacologic state in recording optic potentials from cat cerebellum. Neurology 9: 846-852. BOHM, E. 1953. An electrophysiologic study of the ascending spinal anterolateral fiber system connected to coarse cutaneous afferents. Acta Physiol. Stand. Suppl. 106, 29: 106-137. BREMER, F., and V. BONNET. 1953. Action de la strychnine sur les responses sensorielles et sur les potentiels ClCctriques spontanes de l’ecorce cerebelleuse. L’activitC convulsive du cervelet. Folia Psychiut. Neevl. 56: 438-446. COMBS, C. M. 1954. Electroanatomical study of cerebellar localization. J. Neurophysiol. 17: 123-143. COMBS, C. M. 1956. Bulbar regions related to localized cerebellar impulses. J. Neurophysiol. 19: 285-300. CURTIS, H. J. 1940. Cerebellar action potentia!s in response to stimulation of cerebral cortex. Proc. Sot. Exptl. Biol. Med. 44: 664-668. D~RIAN-SMITH, I., and G. PHILLIPS. 1964. Secondary neurones within a trigemino-cerebellar projection to the anterior lobe of the cerebellum in the cat. J. Physiol. London 170: 53-68. DEURA, S. 1961. Long latency cerebellar responses in cerebellar pedunculi and cortex. Neurology 11: 940-949. DOW, R. S. 1939. Cerebellar action potentials in response to stimulation of various afferent connections. J. Neurophysiol. 2: 543-555. FARNARDZHYAN, V. V. 1962. Interaction of afferent systems of the cerebellum. Fiziol. Zh. SSSR. 48: 823. [Cited in Federation Proc. Trans. Suppl., 1963, !Z2: 983-986.1 GORDON, G., and W. A. SEED. 1961. An investigation of nucleus gracilis of the cat by antidromic stimulation. J. Physiol. London 155: 589-601. GRPNT, G. 1962. Projection of the external cuneate nucleus onto the cerebellum of the cat. Exptl. Neural. 5: 179-195. GRANT, G. 1962. Spinal course and somatotopically localized termination of the spinocerebellar tracts. Acta Physiol. Stand. Suppl. 193, 55: l-45.

BERRY,

32 14.

KENNEDY, GRUNDFEST,

of impulses

GRIMM,

1942. H., and B. CAMPBELL. in the dorsal spino-cerebellar

AND

TOWE

Origin, tract

conduction and termination of cats. J. NeuroPhysiol. 5:

275.294.

15. 16.

17. 18.

1963. Functional organization B., 0. OSCARSSON, and I. ROSEN. of the cuneocerebellar tract in the cat. Acta Physiol. Scand. 58: 216-235. HOLMQVIST, B., 0. OSCARSSON, and N. UDDENBERG. 1963. Organization of ascending spinal tracts activated from forelimb afferents in the cat. Acta Physiol. Scand. 58: 68-76. “Aspects of Cerebellar Anatomy.” Tanum, JANSEN, J,, and A. BRODAL. 1954. Oslo. JANSEN, J., JR. 1957. Afferent impulses to the cerebellar hemispheres from the cerebral cortex and certain subcortical nuclei. Acta Stand. Physiol. SupPl. 143,

HOLMQVIST,

41:

19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

29. 30.

31. 32. 33.

l-99.

1962. Identification of a fast lemniscoKENNEDY, T. T., and A. L. TOWE. cortical system in the cat. J. Physiol. London 160: 535-547. KOELLA, W. P. 1959. Some functional properties of optically evoked potentials in cerebellar cortex of cat. /. Neurophysiol. 22: 61-77. KUYPERS, H. G. J, M. 1958. An anatomical analysis of cortico-bulbar connexions to the pons and lower brain stem in the cat. J. Amt. 92: 198-218. LARSELL, 0. 1953. The cerebellum of the cat and monkey. J. Camp. Neural. 99: 135-199. LARSELL, 0. 1958. Lobules of the mammaIian and human cerebellum. Amt. Record 130: 329-330. LIU, C.-N. 1956. Afferent nerves to Clarke’s and the lateral cuneate nuclei in the cat. A.M.A. Arch. Neural. Psychiat. 75: 67-77. MECHELSE, K. 1957. The pedunculus cerebri of the cat. Psychiat. Neural. 133: 257-275. MORIN, F., J. V. CATALANO, and G. L.~MARCIIE. 1957. Waveform of cerebellar evoked potentials. Am. J. Physiol. 188: 263.273. MORIN, F., and B. HADDAD. 1953. Afferent projections to the cerebellum and the spinal pathways involved. Am. J. Physiol. 173: 497-510. MOUNTCASTLE, V. B., M. R. COVIAN, and C. R. HARRISON. 1952. The central representation of some forms of deep sensibility. Res. P&l Assoc. Res. Nervom Mental Disease 30: 339-370. MUNSON, J. B., and R. S. SNIDER. 1965. Cerebral modulation of auditory and visual input to the cerebellum. Federation Proc. 24: 206. PATTON, H. D., and V. E. AMASSIAN. 1960. The pyramidal tract: its excitation and functions, pp. 837-861. In: “Handbook of Physiology, Sect, I, Neurophysiology.” vol. 2. Am. Physiol. Sot., Washington, D. C. SNEER, R. S., and A. STOWELL. 1944. Receiving areas of the tactile, auditory and visual system in the cerebellum, J. NeurophysioZ, 7: 331-3.57. SZENTAGOTHAI, J., and K. RAJKOVITS. 1959. tfber den Ursprung der Kletterfasern des Kleinhirns. Z. Anat. Entze,ickk~ngsgesckichte 121: 130-141. TOWE, A. L., H. D. PATTON, and T. T. KENNEDY. 1963, Properties of the pyramidal system in the cat. Exptl. Neural. 8: 220-238.