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Multiple somatic projections to frontal lobe of the squirrel monkey
EXPERIMENTAL
NEUROLOGY
Multiple
27, 438-453
Somatic of the
(1970)
Projections to Frontal Squirrel Monkey
P. SINGER AND K. E. BIGNALL Departmertt University
of Physiology, of
Rochester, Received
School of Medicine Rochester, New January
Lobe
1 and Dentistry, York 14620
21, 1970
Precentral evoked electrical responses in the frontal lobe to subcutaneous electrical stimulation were studied in the chloralose-anesthetized squirrel monkey and were found to consist of essentially three components: a very short-latency, somatotopically organized response in pericentral cortex, interpreted as “primary somatic” on the basis of cytoarchitectonic studies on this area; a longer-latency, somewhat less somatotopically organized wave extending rostrally into Brodmann areas 4, 6, and, perhaps, 8, considered to be due to intracortical conduction from pericentral areas l-3 since it was abolished by destruction of the latter region; and a widespread heterotopic component independent of pericentral cortex and medial thalamus having some relation to lateral thalamus. Analyses of these components and comparisons with similar data from the macaque were made in an attempt to distill from some sharply disparate data a composite picture of multiple inputs converging on frontal association cortex, perhaps reflecting in some ways the possible sequence of evolution of the neocortex involving differentiation of primary areas out of primitive association cortex, with retention of strong intercortical connections between the two as this occurs and as the association areas grow. Introduction
Since Woolsey and his colleagues (34) first demonstrated somatic projections to the simian frontal lobe a number of studies have been directed at deciding whether these inputs are relayed through postcentral somatic cortex or by projections from specific or nonspecific thalamus (16, 22, 23, 30, 34), whether they are proprioceptive or cutaneous in origin (2, 5, 6, 18, 21, 23, 27, 35), and even whether or not such “nonprimary” (12) responsesare artifactual (8, 9, 20). In the macaquethe consensusseemsto be that with natural stimuli responsesin precentral gyrus (motor cortex) are proprioceptive rather than cutaneous in origin (2, 21, 27, 34)) yet in the squirrel monkey natural cutaneous stimuli elicit somatotopically organized responsesfar anterior to the central dimple (6). With regard to the question 1 This research was supported by Grant NB 05713 from the National Neurological Diseases and Blindness. 438
Institute
of
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of dependence on postcentral cortex there have been dissenting opinions, with some finding dependence (5, 16, 30) and others not (18, 22, 23). The problem is compounded by the discovery by Albe-Fessard and co-workers in the classical (4) of two types of responses in frontal lobe : “somatotopic” sense and “nonsomatotopic” in that the same cortical point exhibits relatively equal responsiveness to stimulation of all four legs. Since, in connection with other studies (S, 9), we also recognized in the squirrel monkey the dual system described by Albe-Fessard et al. C'4), we decided that some additional information concerning these difficult problems (of origin, pathways and dependenceon somatic cortex) could be obtained by comparing somatotopic and nonsomatotopic inputs to frontal lobe of this species.The squirrel monkey was selected becausefor this particular problem it offers the advantage of having a tortes which is semilissencephalic, with the central sulcus being only a dimple rather than a deep sulcus, so questions of response distribution can be referred less to “post-vs pre-Rolandic” configuration and more preferably to cytoarchitectonic boundaries (i.e., since the dimple is small the boundary between sensory koniocortex and motor agranular cortex is for the most part on the dorsal surface (31) rather than buried in the depths of the sulcus as in the casein the macaque), The cytoarchitectural boundaries between frontal sensory koniocortex, motor agranular cortex, and premotor granular cortex are all thus exposed on a smooth surface for easy electrophysiological investigation. Methods
Data were obtained from 25 adult squirrel monkeys (Saimiri scizwetu). The animals were anesthetized with 50 mg/kg a-chloralose dissolved in propylene glycol and given intravenously after initial induction with chloroform. The animals were then paralyzed with Flaxidil or Syncurine, then ventilated artificially with room air through a tracheal cannula. Detailed methods have been presented elsewhere (S-10). Briefly, they consisted of : fixation of the animal in a stereotaxic apparatus, bilateral craniotomy, protection of the exposed cortex with a pool of mineral oil, and then presentation of somatic stimuli through needle electrodes inserted in the skin of the distal fore- and hind limbs and recording of the cortical evoked potentials elicited by these stimuli. The recording was monopolar, between the active electrode and a reference electrode on bone. The reference electrode was tested periodically for electrical neutrality. Cortical stimuli were presented via silver ball electrodes on the pial surface of the cerebral cortex. Display and recording of electrical responses,as well as histological verification of lesions (see Results and Interpretations) were by standard techniques (8, 9). All experiments were acute in the sense that all data were obtained from animals under anesthesiaon the same day they were anesthetized.
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Results
Peripheral and Cortical Stiwzulation. Brief subcutaneous electrical stimulation (single shocks : 0.1 msec, l-4 v) of the limbs elicited responses in pericentral and precentral cortex having the configurations and distributions illustrated in the left column of diagrams in Fig. 1. The responses were sur-
FLA,
3-9msec LATENCY 9-15 msecLATENCY u
OVERLAP k 50
msdc
SOMATIC
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441
face positive-negative as shown and were two general types : (a) shortlatency (3-9 msec), short-duration potentials (dark hatching) elicited by contralateral stimulation only, and organized somatotopically as illustrated by the differences of distribution of CHL and CFL inputs [with the exception of the small medially situated foreleg MS II (11) area shown in the CFL diagram of Fig. I] ; and (b) longer latency (9-15 msec) responses distributed in general between the central and arcuate dimples (light hatching) and elicitable by stimulation of all four limbs. This region between the central and arcuate dimples coincides with a polysensory area in frontal lobe previously described and named the “postarcuate polysensory area” (S), so this term or its abbreviation PPA will thus be used herein to refer to this area regardless of whether the reference is to the short- or long-latency responses within it, to distinguish it from what will be called SM I after Woolsey (33) ; i.e.. the pericentral Brodmann areas 1, 2, and, perhaps, 3 as recently outlined for the squirrel monkey by Sanidez (31). In addition, note that all evoked responses shown in Fig. 1 are only representative presentations typifying results of detailed mapping experiments in lo-15 similar preparations. As can be seen from Fig. 1 (e.g., lower crosshatched region of CFL diagram) there were areas of overlap in frontal lobe where both the shortlatency contralateral responses and the longer-latency heterotopic potentials appeared at the same recording electrode, resulting in “double-humped” waves. These two components can be differentiated experimentally, as will be shown below. Although the term heterotopic is applied to the long-latency responses or second hump of the double-humped responses, Fig. 1 illustrates a consistent finding that even for these there was some somatotopic organization (i.e., the responses to hind-leg stimulation in general were of higher amplitude medially than laterally). The notable exception to this was the region shown FIG. 1. Summary maps (hatched areas) of distributions of pericentral and frontal cortical responses to peripheral (left) somatic and to cortical (right) stimulation as indicated, with sample responses on each illustrating the types of potentials observed. The sample responses are all from the same animal but typify results of detailed maps from IO-15 animals. Abbreviations: CHL, CFL, IHL, IFL indicate subcutaneous stimulation (1 msec, 1-4~) of contralateral hind leg, contralateral foreleg, ipsilateral hind leg, ipsilateral foreleg, respectively. HLA, FLA, refer to stimulation (0.1 msec 1-5~) of contralateral hind leg and foreleg cortical areas of the same side, and CFLA indicates stimulation of the foreleg cortical area of the opposite side. The circled areas in the left column indicate areas of “pure heterotopy” (see text). In this and subsequent figures downward deflection of the trace denotes surface positivity, and in all figures oscillographic traces have been retouched when necessary for optimal clarity. Traces are superimposed responses from renetitive stimuli (1 pulse each 6 set) in all figures.
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within the dashed lines in the left column in Fig. 1, wherein essentially the same amplitude were seen to stimulation of all four legs. This area is probably the homologue of the “pure convergence” area described previously by Albe-Fessard et al. (4) in the macaque and other monkeys. The necessary tests that the PPA responses were not volume conduction or chloralose artifacts have been described elsewhere by us on identical preparations (8, 9) and indeed were themselves simply confirmation of previous controls of this nature by others (1, 14), so will not be recounted. No attempt was made to determine whether the PPA responses represented stimulation of the skin as opposed to underlying muscle, but it was observed that light touch of the hair of the skin elicited PPA responses similar in waveform to the long-latency heterotopic ones produced by subcutaneous electrical stimulation. On the right in Fig. 1 are presented maps of distribution, with representative responses from which the maps were derived, of PPA responses to electrical stimulation (arrows) of ipsilateral and contralateral pericentral SM I cortex, for a comparison with peripherally evoked responses in reference to the possibility suggested by some studies on the macaque (5, 16, 30) that the latter may be relayed through SM I. The distributions are as shown similar td those of the short-latency peripherally evoked potentials, and agree well with identical experiments performed by Eidelberg and Jenkins (16) for the same purpose in the macaque. (This rather restricted distribution of cortically elicited responses was true only with stimuli slightly above threshold for PPA responses, since with increasing voltages in the same preparation the separate response areas diagrammed in Fig. 1 expanded and eventually merged.) The latency of these responses increased by (2-3 msec) between the central dimple and their most anterior extent, indicating neuronal conduction anteriorly rather than electrotonic spread. The striking similarity between the location of the frontal PPA projection fields to contralateral leg stimulation (Fig. 1 left) and those of responses to primary sensory cortical stimulation (right) led to the following investigation of the possibility, noted above, that the peripherally elicited PPA responses may be relayed through SM I. Ablation of P¢ral Cortex. To test the proposition presented above, pericentral somatic cortex (SM I) was removed unilaterally in ten animals and the immediate (l- to 6-hr) effect of this ablation on PPA responses evaluated. The results, illustrated in Fig. 2 (A, B) were that the procedure abolished the short-latency PPA responses to contralateral peripheral stimulation in all animals, whereas the long-latency potentials persisted (in six of the ten animals thus tested). In the remaining four animals the spontaneous cortical activity was reduced also, indicating general cerebral depression. Subsequent removal of the homologous contralateral pericentral cortex
SOMATIC
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PROJECTIONS
CLHL
FIG. 2. Effects of removal by suction of pericentral cortex (stippling) on postarcuate polysensory area (PPA) responses to stimulation of contralateral and ipsilateral foreleg (CLFL, ILFL) and contralateral hind leg (CLHL) stimulation (single pulse, 0.1 msec, 4.5~. A : responses at pts 1 and 2 in PPA prior to ablation. B : disappearance of PPA short-latency response (pt 2) but not the long-latency ones after removal of cortex of the same side. C: failure to abolish the long-latency responses by subsequent removal of contralateral pericentral cortex. Calibration marks in Figs. 2-5 : 40 msec ; 800 gv.
sometimes
depressed but did not abolish the long-latency responses (Fig.
ZC). Since these data suggest dependency of the short-latency PPA responses on SM I, the question then arises as to whether they are mediated by corticocortical fibers or by a corticosubcortical loop. The following experiments were directed at this question. A third possibility, that such responses reflect direct input through the thalamus, will be considered later. Transection of Corticocortical Fibers. In seven monkeys pericentral cortex was left intact and a cut was made between it and frontal lobe, transecting (as verified histologically later) the white matter between the two cortical areas. The cuts, made 2-3 mm anterior to the central dimple (at the anterior border of area 3, after Sanidez, averaged 4-5 mm deep and extended from the midline laterally 12-14 mm. As illustrated in Fig. 3, the cut immediately abolished (or at least reduced by a factor of 10) the short-latency responsesanterior to it. The primary potentials posterior to the cut persisted as shown, as did the long-latency heterotopic frontal responsesand responses to contralateral cortical stimulation. Thus, both the L‘relay” cortex behind the cut and the projection area anterior to it could be assumedviable, so the short-latency PPA responsescan be attributed to transmission along the subcortical white matter, since they were abolished by the cut, whereas the various control responsesall persisted. Furthermore, the system relaying these peripherally evoked responses
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STIM.CFL CUT A-B STIM.CFL 1 2
FIG. 3. Abolition of short-latency but not long-latency PPA responses to contralateral foreleg stimulation (STIM. CFL) by a cut (CUT A-B) through cortex and white matter between pericentral and PPA regions. Control responses (in pt 2 to leg stimulation and pts 3 and 4 to contralateral cortical stimulation-STIM. C) are essentially unaffected.
from pericentral to PPA cortex appears to be the sameas that responsible for the responsesin frontal lobe to pericentral cortical stimulation (as maps in Fig. 1 suggest), since both kinds of responseswere essentially abolished by the same cut (Fig. 4). (As shown, controls for viability of cortex in Fig. 4 were the sameas those for the experiments illustrated in Fig. 3.) In Fig. 4 there was obviously some general depression of responsiveness but this was not sufficient to account for the virtual disappearanceof the short-latency centrally or peripherally evoked responses. Both Figs. 3 and 4 illustrate a consistent observation that with elimination of the short-latency PPA responses to cortical stimulation, longlatency responsesat the same point appeared, as if “unmasked” by these procedures. This was probably not the result of simple lengthening of the latency of the activity seen prior to the cut since (as Fig. 4 shows) the latency of inputs from other sources (contralateral cortex in this instance) were not changed. When this unmasking effect was examined in more detail it was found that with elimination of the short-latency responsesto contralateral peripheral stimulation, the area of distribution of the long-latency PPA responsesto such stimulation approximated that of the similar responsesto ipsilateral stimulation (i.e., the distribution of the lower left two diagrams in Fig. 1). There is thus a definite suggestion of a h&rotopic projection system essentially the same in distribution for both sides of the body, overlayed in pericentral areas by somatotopically organized projections from the contralateral body, and in PPA by cortical projections from SM I. This interpretation will be elaborated upon below (Discussion) in connection with Fig. 6.
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STIM.5
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ST1M.b
STIM. 5
FIG. 4. Simultaneous abolition of short-latency PPA responses (at pts 1, 2) to stimulation of contralaterat foreleg (STIM. CFL) and an ipsilateral foreleg cortical point (STIM. 4) by a cut (CUT A-B) through white matter between SM I and PPA. STIM. 5 and record pts 3 and 4 are controls that the cortex on both sides of the cut have retained viability. Note emergence of long-latency response at pt 2 after the cut.
Section of the Corplrs Callosli?lz. Section of the corpus callosum had no effect on either the short-latency or longer-latency PPA responses to stimulation of either the ipsilateral or contralateral leg. This does not agree with findings on the macaque by Eidelberg and Jenkins (16) but is consistent with previous reports that in the cat ipsilateral cortical somatic responses are not dependent on contralateral cortex ( 1,3). The discrepancy between the present findings on a primate and those of Eidelberg and Jenkins might be related to differences in methods (i.e., acute V.Xchronic). Removal of the Cerebellum. Since the cerebellum projects via the dentatothalamic system to cortical area 4 which is part of the frontal PPA cortex described herein, complete cerebellectomy was performed in two animals to test the possibility that the peripherally elicited responses seen were relayed through this system. In confirmation of Malis et a& (23) this had no effect on any of the PPA responses, so this system is deemed nonessential for such evoked activity. Lesions of Thalawus OY Corona Radiata. The persistence of the heterotopic PPA responses after bilateral removal of SM I indicates relay of this activity through a more direct thalamocortical projection system, rather than an indirect route through pericentral cortex. Since it had already been
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found from previous studies that such responses (at least the contralaterally elicited ones) persisted after removal of medial nonspecific thalamus in squirrel monkey (9) as well as in the cat (7), attention was directed at attempting to determine which group of the lateral thalamus might be important in this projection system, and where within the corona radiata the essential pathway lies. To this end, electrolytic lesions were placed at stereotaxic (17) coordinates anterior 4-6 in ventralis posterolateralis and medialis (VPL and VPM) , the somatic relay nuclei. Damage also involved lateralis posterior (LP) and ventralis lateralis (VL) . This was done in eight animals, after prior removal by suction of contralateral thalamus by methods described previously (S, 9), to preclude possible input from the other hemisphere. In two other animals the thalamus medial to VPM was removed by suction by access through the contralateral side, and in addition in two animals all thalamus anterior to the lateral geniculate body was removed by this same approach. This latter procedure abolished all cortical somatic responses, leaving photically and acoustically evoked activity remaining as controls. As previously reported (8, 9) the medially pIaced lesions had only transient (1-3 hr) effects on the peripherally evoked responses. The general effect of the more restricted electrolytic lesions (in VPL and VPM) was that they depressed SM I responses more profoundly (Fig. 5) and for longer durations then the long-latency PPA potentials. (Short-latency PPA responses were not examined in sufficient detail to aliow comment.) It thus appears that although lateral but not medial thalamus is essential for the long-latency PPA responses at least,
FIG. 5. Comparison of the effect of massive electrolytic destruction of n. ventralis posteralateralis and medialis (VPL, VPM) and lateralis posterior (LP) on peripherally elicited responses in SM 1 (pt 1) and those in PPA (pt 2) to peripheral stimulation (STIM. CHL in this instance), and also to cortical stimulation STIM. pt 3). Other abbreviations: CM; n. centrum medianurn, MD ; n. medialis dorsalis. Left column: responses before lesion. Right column: diminished response in SM I but not in PPA (pt 2) by the lesion as indicated, with increase of response to cortical stimulation.
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these potentials are not necessarily completely dependent upon VPL-VP% VL or LP, at least at the levels lesioned. The heterotopic responses do, however, appear to be of thalamic rather than striatal or archipalial origin since small lesions confined to the corona radiata at anterior 7-10 abolished them, leaving only the corticocortical responses (as controls for viability ) . Figure 5 also shows an unexpected result concerning the behavior of these control (corticocortical) responses after the lateral thalamic lesions. In all animals tested the cortical responses (PPA) response to ipsilateral S MI stimulation) increased in amplitude immediately after the lesion (trace 2, Fig. 5), at the same time that peripherally elicited activity was either depressed or unaffected. Being so immediate and differential, this effect suggests release of a tonic inhibition of the corticocortical or thalamocorticocortical system normally exerted by the lateral thalamus. Similar effects of large thalamic lesions were reported previously (10) in the cat ( 14). Discussion
A summary of our data and interpretations is shown in Fig. 6, a highly stylized diagram of the types of responses recorded and the possible pathways mediating them (combined with a small map of Brodmann area 1, 2, and 3 after Sanidez, the significance of which will be pointed out below j . As indicated, the earliest response (component 1) seen was that to contralateral leg stimulation, in the appropriate pericentral cortical area and presumably relayed through the ventrobasal complex. Surrounding this, and projecting especially anteriorly, is a broader area of somewhat longer latency responses (component -?) retaining some somatotopy by virtue of the orientation of the corticocortical projections presumed, on the basis of this study and some others (5, 16, 30) to mediate them. There is ample anatomical (25, 26, 29) and physiological 124) evidence for such post- to precentral projections ; indeed, they can be demonstrated physiologically in the absence of most of the possible subcortical relay systems (8). Finally, in addition to and partially encompassing the regions exhibiting components 1 and ,7 there is a larger distribution of even longer latency responses (component 3) with very little or no somatotopy. This latter wave is often present along with component 1 and 2 as shown and when not demonstrable at these points in the intact cortex can be unmasked by abolishing the earlier components (Figs. 3 and 4). The pathway for heterotopic responses is unclear, but since our data (Fig. 5) and previous findings (see below) suggest a greater dependency on the lateral specific and associative nuclei (VPL, VPM, VL, LP) than on medial nonspecific thalamus, the combined specific-associative complex is represented in Fig. 6 (outer projection cone) as being primarily (although not necessarily exclusively ) responsible for mediation of component 3.
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3-1HAlAMOCORTICAL
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[SLOW)
2-CORTICOCORTICAL~
1
FIG. 6. Summary diagram of the kinds of responses observed in this study (upper right) and our interpretation of the probable origin of each. The region ABCD in the large diagram is an expansion of the similarly notated region in the wholebrain drawing at lower right (stippled). In the latter the numbers 1, 2, 3 refer to the corresponding Brodmann areas after Sanidez (31), whereas at the top the same number system refers to points on the cortex within the projection areas indicated. These are: I-THALAMOCORTICAL (SPECIFIC), with the dashed line through the peak of the response, originating in VPL-VPM (inner projection cone) and projecting to pericentral cortex (arm area in this case), Z-CORTICOCORTICAL, representing
intracortical
transmission
mostly
anteriorly
to
precentral
cortex,
and
3-THALAMOCORTICAL (SLOW) re p resenting inputs from a complex of lateral thalamic nuclei ; perhaps including and surrounding VPL-VPM (outer cone with strall arrows at lower left from the inner specific cone). SOMATIC AFFERENTS refers to inputs generated by subcutaneous electrical stimulation only (similarity to natural cutaneous stimulation being implied but not assumed). Each of these three components of this system, derived strictly from our data from chloralose-anesthetized squirrel monkeys using electrical subcutaneous stimulation will now be examined in turn, with particular reference to relevance of findings of others. With regard to component 1, this is the classical primary somatic response which is generally agreed to be relayed through the ventrobasal complex, as indicated in Fig. 6 (inner cone). However, the presence of this response in precentral cortex as shown is not in accord with findings that in the macaque deeply anesthetized with barbiturates, precentral cor-
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tex is insensitive to any type of cutaneous stimulation (2, 21,27, 35). This is not in itself a serious discrepancy, since in contrast to the barbituratedrugged preparation, the chloralose-anesthetized ( 1, 4 j , and unanesthetized ( 15) macaque have broad areas in the frontal lobe which are responsive to electrical stimulation of the skin. Indeed many investigators, most recently Eidelberg and Jenkins (16), have attributed the findings of those using barbiturates to constriction by this drug of the normally wide responsive areas including the precentral gyrus to a small postcentral focus. This is not, however, an entirely satisfactory explanation since even in unanesthetized macaques neurons in precentral gyrus are not sensitive to natural cutaneous stimuli (21, 27). At any rate, in the squirrel monkey the problem of sensitivity of precentral cortex to natural cutaneous stimulation may not be of any particular importance since such responsiveness has been well demonstrated in this species (6). As the drawing from Sanidez (31) in Fig. 6 implies, the species difference may be due primarily to the fact that the immediate precentral cortex in the squirrel monkey is area 3. i.e., primary somatic cortex according to Sanidez, whereas in the macaque it is area 4 (motor) because of the deep central convolution wherein areas l-3 end in the sulcus (1). Thus, our consideration of primary somatic (cutaneous) cortex as extending rostra1 to the central dimple in the squirrel monkey is in keeping with cytoarchitectural expectations (31) and physiological findings using natural stimuli (6) and because of these species differences in morphology is not in conflict with contrasting microelectrode data (2, 27) from the macaque showing essentially no cutaneous input to precentral gyrus. The second type of response in Fig. 6 (component ‘3) is considered different from the first primarily in that it extends, with progressively increasing latency, beyond axea 3 and into motor tortes (32). i.e., areas 4 and 6 (31) and was abolished in our esperiments by removal of areas 1-3. It retains some somatotopy and thus resembles the somatic responses in precentral gyrus of the macaque (16, 22, 23, 30, 34), although in that species relay of activity from post to precentral gyrus is still controversial in that disappearance of precentral responses to peripheral stimuli has been reported by some (5, 16, 30) but denied by others (18, 22, 23j. Also, there is considerable evidence that somatic responses in motor cortex of the macaque ( 1) as well as the cat (12) are relayed through the thalamic region including VL and VP. For this reason component Z is placed in Fig. 6 under the sphere of influence of the outer cone of projections from the VL, VP, and vicinity, even though we visualize it as being projected at least partially from pericentral cortex. The widespread heterotopic component 3 of Fig. 6 seems essentially independent of pericentral cortex and is thus probably analogous to similar
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responses in the motor area of cat (3, 13) and is almost certainly the equivalent of the “convergent” somatic responses described by Albe-Fessard et a~. (4). Similar long-latency components can be detected in the records of Eidelberg and Jenkins (16) from unanesthetized macaques. But unlike the chloralose-anesthetized cat and squirrel monkey, lesions of postcentral cortex abolished the late as well as earlier precentral responses (i.e., abolished all precentral responses) in their experiments. Their lesions were chronic, however, and owing to the possibility of retrograde degeneration in the thalamus and subsequent undetermined amount of impairment of lateral thalamic function in this situation, their results are not directly comparable with the effect of acute ablations, in which distant morphological degenerative effects are not immediately apparent, if indeed they occur at all. In the cat, some contrasting findings by different investigators (1, 3, 7), have engendered some debate (14) as to whether the long-latency heterotopic responses in the motor area of this species are or are not relayed through the center median-parafascicularis complex, but now there seems to be agreement (4, 9) that this complex is not a likely relay for similar frontal cortical responses in the monkey. The pathways, therefore, still have not been worked out, but there are indications from lesions studies in the cat (12) that they involve VL. Ventralis lateralis and perhaps VP have been implicated in the macaque ( 1) , and our data also suggest that these are participating (but not necessarily essential) nuclei in the squirrel monkey. The general plan indicated by Fig. 6 of the widespread projections system, within which is a more specific or specialized system with a connection to the broader and less differentiated area, is consistent with current concepts of the evolution of the neocortex, and the relationships between association and specific cortical area and related thalamic systems. According to these ideas (15, 19), p rimary sensory areas differentiate, for special and highly specific function, out of what is generally called association cortex in man, leaving the association areas for the originally primitive hut now (in man) extremely complex function of establishing these associational or interrelating connections between the various sensory modalities. Figure 6 reflects these hypothesized differentiations in that it shows the presence of the specialized “inner core” of the specific systems within a more undifferentiated outer cone or larger cortical area which includes for all practical purposes the frontal association cortex. And, of course, there is abundant evidence that this association or nonprimary region in the squirrel monkey (8, 9) as well as in other species ( 1, 14) receives multiple sensory inputs which could provide the basis for intermodality integration and association. The mechanisms whereby this might occur remain
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unclear. Some clues are being obtained in our laboratory by studies of the influence of nonspecific thalamus on sensory-evoked activity of single units in the polysensory areas, A preliminary report on this has appeared (28). In general, it was found that this influence is far more profound, plastic, selective, and longer lasting than on units on primary sensory areas. Perhaps the plasticity of cortical function is in part the consequence of such specific-nonspecific interactions in nonprimary areas, and as a result the tremendous differential growth of nonprimary or association areas in primates may stem from a distinct adaptive advantage (to borrow from computer design terminology) of (a) expanding as much as possible the general purpose capability (association systems), while (b) at the same time refining the special purpose components (specific systems) essential for performing very specialized tasks such as manipulation of the digits or face, and (c) maximizing communication between these other two general- and special-purpose functions by developing intracortical and intrathalamic connection systems. References 1. ALBE-FESSARD, D. 1967. Organization of somatic central projections, pp. lOl167. 11, “Contributions to Sensory Physiology,” vol. 2. W. Neff [ed.] Academic Press, New York. 2. ALBE-FESSARD, D., and J. LIEBESKIND. 1966. Origine des messages somato-sensitifs activant les cellules du cortex moteur chex le singe. Exp. Brain Rcs. 1 : 127-146. 3. ALBE-FESSARD, I)., and A. ROUGEL. 19.58. ActivitCs d’origine somesthesique &oquPes sur le cortex non-spCcifique du chat anesthCsie au chloralose: rble du centre mkdian du thalamus. Electroeucephalogr. Clirz. Newrojhysiol. 10 : 131-152. 4. ALBE-FESSARD, D., C. ROCHA-MIRANDA, and E. OSWALD+CRUZ. 1959. ActivitCs d’origine SomesthCsique evoqutes au niveau du cortex non-sp&ifique et du centre median du thalamus chez le singe anestht% au chloralose. Elcctroemcphalogr. Clin. Ncurophysiol. 11 : 777-787. 5. BARD, P. 1938. “Studies on the cortical representation of somatic sensibility.” Harvq Let. pp. 99, 143-169. 6. BENJAMIN, R. M., and W. I. WELKER. 1957. Somatic receiving areas of cerebral cortex of squirrel monkey (Saimiri sciureus) J. Nczwophgsiol. 20 : 286-299. 7. BIGNALL, K. E. 1967. Effects of subcortical ablations on polysensory cortical responses and interactions in the cat. ,%p. Nezhvol. 18 : 5667. 8. BIGNALL, K. E., and hf. IRIBERT. 1969. Polysensory and corticocortical projections to frontal lobe of squirrel and rhesus monkeys. Electroemephaloyr. Clitl. Neuvopkysiol. 26 : 206-215. 9. BIGNALL, K. E., and P. SINGER. 1967. Auditory, somatic and visual input to association and motor cortex of squirrel monkey. Esp. Nertvol. 18: 300-312. 10. BIGNALL, K. E., M. IBIBERT, and P. BUSER. 1966. Optic projection to non-visual cortex of the cat. .I. h’cwoplzysiol. 29 : 396409.
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1965. Projection of dorsal roots and A. J., and C. A. LORENZINI. nerves to cortical sensory motor regions of squirrel monkey. J. Nellyo28 : 1195-1205. 12. BCSER, P. 1966. Subcortical controls of pyramidal activity, PP. 323-W. 1~ “The D. P. Purpura and M. D. Yahr [eds.]. Columbia University Press, Thalamus.” New York. 13. BUSER, P., and P. ASCHER, 1960. Mise en jeu &flex du systcme pyramidal chez le Chat. Arch. Ital. Biol. 98 : 123-164. 14. BUSER, P., and K. E. BICNALL. 1967. Nonprimary sensory projectians on the cat neocortex. I&. Xc;!. Ncwobiol. 10 : 11 I-165. 11.
BLOMQUIST,
sensory physiol.
15.
DIAMOND,
I. T.,
and
W.
C. HALL,
1969.
Evolution
of
neocortex.
Scierlce
164:
251-262. 16.
EIDELBERG,
in
the
E., and I. JENKINS. 1966. Organization of somatic sensory mechanisms Electroencephalogr. Clin. Neurophysiol. 21: macaque cerebral cortex.
452460. 18.
EMMERS,
Squirrel
R., and Monkey
K. AKERT. 1963. (Saimiri sciureus)
“A Stereotaxic .” University
Atlas of of Wisconsin
the Brain of the Press, Madison.
1s. GARDNER, E. D., and F. MORIN. 1953. Spinal pathways for projections of cutaneous and muscular afferents to the sensory and motor cortex of the monkey. :lmcr. J. Phgsiol. 174 : 149-154. 19. KARAMYAN, A. I. 1968. On the evolution of integrative activity of the central nervous system in the phylogeny of vertebrates. Progr. Brain Rex. 22: 427-447. 20. KELLY, D. L., S. GOLDRING, and J. L. O’LEARY. 1965. Averaged evoked potentials from the exposed cortex of man. Arch. Neural. 13 : 1-9. 21. KKUGER, L. 1956. Characteristics of the somatic afferent projection to the precentral cortex in the monkey. Alrcer. J. Physiol. 188 : 475-482. 22. KRUGER, L., and K. H. PRIBRAM. 1954. The ‘evoked response’ in the precentral gyrus of monkey. Fed. Proc. 13: 82. 23. MALIS, L. I., K. H. PRIBRAM, and L. KRCTGER. 1953. Action potentials in “motor” cortex evoked by peripheral nerve stimulation. J. Neurophysiol. 18: 161-167. 24. McCu~r.oca, W. 1944. The functional organization of the cerebral cortex. Physiol. Rev. 24: 39@407. 25. METTLER, F. A. 1935. Corticofugal fiber connections of the cortex of Macaca mulatta. The parietal region. J. Conzp. NertvoE. 62 : 263-291. 26. MILCH, E. C. 1932. Sensory cortical area. An experimental anatomic investigation. A. M. A. Arch. Neural. Psychiat. 28 : 871-882. 27. MOUNTCASTLE, V. B., and T. P. S. POWELL. 1959. Central nervous mechanisms subserving position. Bull. Johns Hopkins Has. 106: l7&2oO. 28. NELSON, C. N., and K. E. BIGNALL, 1969. Influence of nonspecific thalamic stimulation on polysensory cortical cells. Fed. Proc. 28 : 455. 29.
PANDYA,
D.
in the rhesus 30.
31.
and monkey.
N.,
H.
G.
BY&
J.
M.
KUYPERS.
1969.
Cortico-cortical
connections
RES. 13 : 13-36.
T. C., M. D. PAmoN, and M. B. AMASSIAN. 1959. Topographical and functional determinants of cortical localization patterns. Res. p&l. Res. hrerv. Menf. Dis. 30 : 403-429. SANIDEZ, F. 1968. The architecture of the cortical tasts nerve areas in squirrel monkey (Saimiri sciuereus) and their relationships to insular, sensorimotor and prefrontal regions. Iivais Res. 8 : 97-124.
RucH,
SOMATIC
32.
33.
34.
35.
PROJECTIONS
453
W. I., R. M. BENJAAIIN, and R. C. MILES. 1957. Motor effects of stimulation of cerebral cortex of squirrel monkey ( Saimiri sciureus). J. Neurophysiol. 20 : 347-364. WOOLSEY, C. N. 1958. Organization of somatic sensory and motor areas of the cerebral cortex. In “Biological and Biochemical Basis of Behavior.” H. F. Harlow and C. N. Woolsey [eds.]. University of Wisconsin Press, Madison. WOOLSEY, C. N., H. T. CIIAKG, and P. BARD. 1947. Distribution of cortical potentials evoked by stimulation of dorsal roots in Macaca mulatta. Fed. Proc. 6: 230. WOOLSEY, C. N., W. H. MARSHALL, and P. BARD. 1942. Representation of cutaneous tactile sensibility in the cerebral cortex of the monkey as indicated by evoked potentials. Bull. Johns Hopkins Hosp. 70: 399-441.
WELKER,
NEUROLOGY
Multiple
27, 438-453
Somatic of the
(1970)
Projections to Frontal Squirrel Monkey
P. SINGER AND K. E. BIGNALL Departmertt University
of Physiology, of
Rochester, Received
School of Medicine Rochester, New January
Lobe
1 and Dentistry, York 14620
21, 1970
Precentral evoked electrical responses in the frontal lobe to subcutaneous electrical stimulation were studied in the chloralose-anesthetized squirrel monkey and were found to consist of essentially three components: a very short-latency, somatotopically organized response in pericentral cortex, interpreted as “primary somatic” on the basis of cytoarchitectonic studies on this area; a longer-latency, somewhat less somatotopically organized wave extending rostrally into Brodmann areas 4, 6, and, perhaps, 8, considered to be due to intracortical conduction from pericentral areas l-3 since it was abolished by destruction of the latter region; and a widespread heterotopic component independent of pericentral cortex and medial thalamus having some relation to lateral thalamus. Analyses of these components and comparisons with similar data from the macaque were made in an attempt to distill from some sharply disparate data a composite picture of multiple inputs converging on frontal association cortex, perhaps reflecting in some ways the possible sequence of evolution of the neocortex involving differentiation of primary areas out of primitive association cortex, with retention of strong intercortical connections between the two as this occurs and as the association areas grow. Introduction
Since Woolsey and his colleagues (34) first demonstrated somatic projections to the simian frontal lobe a number of studies have been directed at deciding whether these inputs are relayed through postcentral somatic cortex or by projections from specific or nonspecific thalamus (16, 22, 23, 30, 34), whether they are proprioceptive or cutaneous in origin (2, 5, 6, 18, 21, 23, 27, 35), and even whether or not such “nonprimary” (12) responsesare artifactual (8, 9, 20). In the macaquethe consensusseemsto be that with natural stimuli responsesin precentral gyrus (motor cortex) are proprioceptive rather than cutaneous in origin (2, 21, 27, 34)) yet in the squirrel monkey natural cutaneous stimuli elicit somatotopically organized responsesfar anterior to the central dimple (6). With regard to the question 1 This research was supported by Grant NB 05713 from the National Neurological Diseases and Blindness. 438
Institute
of
SOMATIC
PROJECTIONS
439
of dependence on postcentral cortex there have been dissenting opinions, with some finding dependence (5, 16, 30) and others not (18, 22, 23). The problem is compounded by the discovery by Albe-Fessard and co-workers in the classical (4) of two types of responses in frontal lobe : “somatotopic” sense and “nonsomatotopic” in that the same cortical point exhibits relatively equal responsiveness to stimulation of all four legs. Since, in connection with other studies (S, 9), we also recognized in the squirrel monkey the dual system described by Albe-Fessard et al. C'4), we decided that some additional information concerning these difficult problems (of origin, pathways and dependenceon somatic cortex) could be obtained by comparing somatotopic and nonsomatotopic inputs to frontal lobe of this species.The squirrel monkey was selected becausefor this particular problem it offers the advantage of having a tortes which is semilissencephalic, with the central sulcus being only a dimple rather than a deep sulcus, so questions of response distribution can be referred less to “post-vs pre-Rolandic” configuration and more preferably to cytoarchitectonic boundaries (i.e., since the dimple is small the boundary between sensory koniocortex and motor agranular cortex is for the most part on the dorsal surface (31) rather than buried in the depths of the sulcus as in the casein the macaque), The cytoarchitectural boundaries between frontal sensory koniocortex, motor agranular cortex, and premotor granular cortex are all thus exposed on a smooth surface for easy electrophysiological investigation. Methods
Data were obtained from 25 adult squirrel monkeys (Saimiri scizwetu). The animals were anesthetized with 50 mg/kg a-chloralose dissolved in propylene glycol and given intravenously after initial induction with chloroform. The animals were then paralyzed with Flaxidil or Syncurine, then ventilated artificially with room air through a tracheal cannula. Detailed methods have been presented elsewhere (S-10). Briefly, they consisted of : fixation of the animal in a stereotaxic apparatus, bilateral craniotomy, protection of the exposed cortex with a pool of mineral oil, and then presentation of somatic stimuli through needle electrodes inserted in the skin of the distal fore- and hind limbs and recording of the cortical evoked potentials elicited by these stimuli. The recording was monopolar, between the active electrode and a reference electrode on bone. The reference electrode was tested periodically for electrical neutrality. Cortical stimuli were presented via silver ball electrodes on the pial surface of the cerebral cortex. Display and recording of electrical responses,as well as histological verification of lesions (see Results and Interpretations) were by standard techniques (8, 9). All experiments were acute in the sense that all data were obtained from animals under anesthesiaon the same day they were anesthetized.
440
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Results
Peripheral and Cortical Stiwzulation. Brief subcutaneous electrical stimulation (single shocks : 0.1 msec, l-4 v) of the limbs elicited responses in pericentral and precentral cortex having the configurations and distributions illustrated in the left column of diagrams in Fig. 1. The responses were sur-
FLA,
3-9msec LATENCY 9-15 msecLATENCY u
OVERLAP k 50
msdc
SOMATIC
PROJECTIONS
441
face positive-negative as shown and were two general types : (a) shortlatency (3-9 msec), short-duration potentials (dark hatching) elicited by contralateral stimulation only, and organized somatotopically as illustrated by the differences of distribution of CHL and CFL inputs [with the exception of the small medially situated foreleg MS II (11) area shown in the CFL diagram of Fig. I] ; and (b) longer latency (9-15 msec) responses distributed in general between the central and arcuate dimples (light hatching) and elicitable by stimulation of all four limbs. This region between the central and arcuate dimples coincides with a polysensory area in frontal lobe previously described and named the “postarcuate polysensory area” (S), so this term or its abbreviation PPA will thus be used herein to refer to this area regardless of whether the reference is to the short- or long-latency responses within it, to distinguish it from what will be called SM I after Woolsey (33) ; i.e.. the pericentral Brodmann areas 1, 2, and, perhaps, 3 as recently outlined for the squirrel monkey by Sanidez (31). In addition, note that all evoked responses shown in Fig. 1 are only representative presentations typifying results of detailed mapping experiments in lo-15 similar preparations. As can be seen from Fig. 1 (e.g., lower crosshatched region of CFL diagram) there were areas of overlap in frontal lobe where both the shortlatency contralateral responses and the longer-latency heterotopic potentials appeared at the same recording electrode, resulting in “double-humped” waves. These two components can be differentiated experimentally, as will be shown below. Although the term heterotopic is applied to the long-latency responses or second hump of the double-humped responses, Fig. 1 illustrates a consistent finding that even for these there was some somatotopic organization (i.e., the responses to hind-leg stimulation in general were of higher amplitude medially than laterally). The notable exception to this was the region shown FIG. 1. Summary maps (hatched areas) of distributions of pericentral and frontal cortical responses to peripheral (left) somatic and to cortical (right) stimulation as indicated, with sample responses on each illustrating the types of potentials observed. The sample responses are all from the same animal but typify results of detailed maps from IO-15 animals. Abbreviations: CHL, CFL, IHL, IFL indicate subcutaneous stimulation (1 msec, 1-4~) of contralateral hind leg, contralateral foreleg, ipsilateral hind leg, ipsilateral foreleg, respectively. HLA, FLA, refer to stimulation (0.1 msec 1-5~) of contralateral hind leg and foreleg cortical areas of the same side, and CFLA indicates stimulation of the foreleg cortical area of the opposite side. The circled areas in the left column indicate areas of “pure heterotopy” (see text). In this and subsequent figures downward deflection of the trace denotes surface positivity, and in all figures oscillographic traces have been retouched when necessary for optimal clarity. Traces are superimposed responses from renetitive stimuli (1 pulse each 6 set) in all figures.
442
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within the dashed lines in the left column in Fig. 1, wherein essentially the same amplitude were seen to stimulation of all four legs. This area is probably the homologue of the “pure convergence” area described previously by Albe-Fessard et al. (4) in the macaque and other monkeys. The necessary tests that the PPA responses were not volume conduction or chloralose artifacts have been described elsewhere by us on identical preparations (8, 9) and indeed were themselves simply confirmation of previous controls of this nature by others (1, 14), so will not be recounted. No attempt was made to determine whether the PPA responses represented stimulation of the skin as opposed to underlying muscle, but it was observed that light touch of the hair of the skin elicited PPA responses similar in waveform to the long-latency heterotopic ones produced by subcutaneous electrical stimulation. On the right in Fig. 1 are presented maps of distribution, with representative responses from which the maps were derived, of PPA responses to electrical stimulation (arrows) of ipsilateral and contralateral pericentral SM I cortex, for a comparison with peripherally evoked responses in reference to the possibility suggested by some studies on the macaque (5, 16, 30) that the latter may be relayed through SM I. The distributions are as shown similar td those of the short-latency peripherally evoked potentials, and agree well with identical experiments performed by Eidelberg and Jenkins (16) for the same purpose in the macaque. (This rather restricted distribution of cortically elicited responses was true only with stimuli slightly above threshold for PPA responses, since with increasing voltages in the same preparation the separate response areas diagrammed in Fig. 1 expanded and eventually merged.) The latency of these responses increased by (2-3 msec) between the central dimple and their most anterior extent, indicating neuronal conduction anteriorly rather than electrotonic spread. The striking similarity between the location of the frontal PPA projection fields to contralateral leg stimulation (Fig. 1 left) and those of responses to primary sensory cortical stimulation (right) led to the following investigation of the possibility, noted above, that the peripherally elicited PPA responses may be relayed through SM I. Ablation of P¢ral Cortex. To test the proposition presented above, pericentral somatic cortex (SM I) was removed unilaterally in ten animals and the immediate (l- to 6-hr) effect of this ablation on PPA responses evaluated. The results, illustrated in Fig. 2 (A, B) were that the procedure abolished the short-latency PPA responses to contralateral peripheral stimulation in all animals, whereas the long-latency potentials persisted (in six of the ten animals thus tested). In the remaining four animals the spontaneous cortical activity was reduced also, indicating general cerebral depression. Subsequent removal of the homologous contralateral pericentral cortex
SOMATIC
143
PROJECTIONS
CLHL
FIG. 2. Effects of removal by suction of pericentral cortex (stippling) on postarcuate polysensory area (PPA) responses to stimulation of contralateral and ipsilateral foreleg (CLFL, ILFL) and contralateral hind leg (CLHL) stimulation (single pulse, 0.1 msec, 4.5~. A : responses at pts 1 and 2 in PPA prior to ablation. B : disappearance of PPA short-latency response (pt 2) but not the long-latency ones after removal of cortex of the same side. C: failure to abolish the long-latency responses by subsequent removal of contralateral pericentral cortex. Calibration marks in Figs. 2-5 : 40 msec ; 800 gv.
sometimes
depressed but did not abolish the long-latency responses (Fig.
ZC). Since these data suggest dependency of the short-latency PPA responses on SM I, the question then arises as to whether they are mediated by corticocortical fibers or by a corticosubcortical loop. The following experiments were directed at this question. A third possibility, that such responses reflect direct input through the thalamus, will be considered later. Transection of Corticocortical Fibers. In seven monkeys pericentral cortex was left intact and a cut was made between it and frontal lobe, transecting (as verified histologically later) the white matter between the two cortical areas. The cuts, made 2-3 mm anterior to the central dimple (at the anterior border of area 3, after Sanidez, averaged 4-5 mm deep and extended from the midline laterally 12-14 mm. As illustrated in Fig. 3, the cut immediately abolished (or at least reduced by a factor of 10) the short-latency responsesanterior to it. The primary potentials posterior to the cut persisted as shown, as did the long-latency heterotopic frontal responsesand responses to contralateral cortical stimulation. Thus, both the L‘relay” cortex behind the cut and the projection area anterior to it could be assumedviable, so the short-latency PPA responsescan be attributed to transmission along the subcortical white matter, since they were abolished by the cut, whereas the various control responsesall persisted. Furthermore, the system relaying these peripherally evoked responses
343
SINGER
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BIGNALL
STIM.CFL CUT A-B STIM.CFL 1 2
FIG. 3. Abolition of short-latency but not long-latency PPA responses to contralateral foreleg stimulation (STIM. CFL) by a cut (CUT A-B) through cortex and white matter between pericentral and PPA regions. Control responses (in pt 2 to leg stimulation and pts 3 and 4 to contralateral cortical stimulation-STIM. C) are essentially unaffected.
from pericentral to PPA cortex appears to be the sameas that responsible for the responsesin frontal lobe to pericentral cortical stimulation (as maps in Fig. 1 suggest), since both kinds of responseswere essentially abolished by the same cut (Fig. 4). (As shown, controls for viability of cortex in Fig. 4 were the sameas those for the experiments illustrated in Fig. 3.) In Fig. 4 there was obviously some general depression of responsiveness but this was not sufficient to account for the virtual disappearanceof the short-latency centrally or peripherally evoked responses. Both Figs. 3 and 4 illustrate a consistent observation that with elimination of the short-latency PPA responses to cortical stimulation, longlatency responsesat the same point appeared, as if “unmasked” by these procedures. This was probably not the result of simple lengthening of the latency of the activity seen prior to the cut since (as Fig. 4 shows) the latency of inputs from other sources (contralateral cortex in this instance) were not changed. When this unmasking effect was examined in more detail it was found that with elimination of the short-latency responsesto contralateral peripheral stimulation, the area of distribution of the long-latency PPA responsesto such stimulation approximated that of the similar responsesto ipsilateral stimulation (i.e., the distribution of the lower left two diagrams in Fig. 1). There is thus a definite suggestion of a h&rotopic projection system essentially the same in distribution for both sides of the body, overlayed in pericentral areas by somatotopically organized projections from the contralateral body, and in PPA by cortical projections from SM I. This interpretation will be elaborated upon below (Discussion) in connection with Fig. 6.
SOMATIC
STIM. 4
STIM.5
445
PROJECTIONS
CUTA-B STINCFL
ST1M.b
STIM. 5
FIG. 4. Simultaneous abolition of short-latency PPA responses (at pts 1, 2) to stimulation of contralaterat foreleg (STIM. CFL) and an ipsilateral foreleg cortical point (STIM. 4) by a cut (CUT A-B) through white matter between SM I and PPA. STIM. 5 and record pts 3 and 4 are controls that the cortex on both sides of the cut have retained viability. Note emergence of long-latency response at pt 2 after the cut.
Section of the Corplrs Callosli?lz. Section of the corpus callosum had no effect on either the short-latency or longer-latency PPA responses to stimulation of either the ipsilateral or contralateral leg. This does not agree with findings on the macaque by Eidelberg and Jenkins (16) but is consistent with previous reports that in the cat ipsilateral cortical somatic responses are not dependent on contralateral cortex ( 1,3). The discrepancy between the present findings on a primate and those of Eidelberg and Jenkins might be related to differences in methods (i.e., acute V.Xchronic). Removal of the Cerebellum. Since the cerebellum projects via the dentatothalamic system to cortical area 4 which is part of the frontal PPA cortex described herein, complete cerebellectomy was performed in two animals to test the possibility that the peripherally elicited responses seen were relayed through this system. In confirmation of Malis et a& (23) this had no effect on any of the PPA responses, so this system is deemed nonessential for such evoked activity. Lesions of Thalawus OY Corona Radiata. The persistence of the heterotopic PPA responses after bilateral removal of SM I indicates relay of this activity through a more direct thalamocortical projection system, rather than an indirect route through pericentral cortex. Since it had already been
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found from previous studies that such responses (at least the contralaterally elicited ones) persisted after removal of medial nonspecific thalamus in squirrel monkey (9) as well as in the cat (7), attention was directed at attempting to determine which group of the lateral thalamus might be important in this projection system, and where within the corona radiata the essential pathway lies. To this end, electrolytic lesions were placed at stereotaxic (17) coordinates anterior 4-6 in ventralis posterolateralis and medialis (VPL and VPM) , the somatic relay nuclei. Damage also involved lateralis posterior (LP) and ventralis lateralis (VL) . This was done in eight animals, after prior removal by suction of contralateral thalamus by methods described previously (S, 9), to preclude possible input from the other hemisphere. In two other animals the thalamus medial to VPM was removed by suction by access through the contralateral side, and in addition in two animals all thalamus anterior to the lateral geniculate body was removed by this same approach. This latter procedure abolished all cortical somatic responses, leaving photically and acoustically evoked activity remaining as controls. As previously reported (8, 9) the medially pIaced lesions had only transient (1-3 hr) effects on the peripherally evoked responses. The general effect of the more restricted electrolytic lesions (in VPL and VPM) was that they depressed SM I responses more profoundly (Fig. 5) and for longer durations then the long-latency PPA potentials. (Short-latency PPA responses were not examined in sufficient detail to aliow comment.) It thus appears that although lateral but not medial thalamus is essential for the long-latency PPA responses at least,
FIG. 5. Comparison of the effect of massive electrolytic destruction of n. ventralis posteralateralis and medialis (VPL, VPM) and lateralis posterior (LP) on peripherally elicited responses in SM 1 (pt 1) and those in PPA (pt 2) to peripheral stimulation (STIM. CHL in this instance), and also to cortical stimulation STIM. pt 3). Other abbreviations: CM; n. centrum medianurn, MD ; n. medialis dorsalis. Left column: responses before lesion. Right column: diminished response in SM I but not in PPA (pt 2) by the lesion as indicated, with increase of response to cortical stimulation.
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447
these potentials are not necessarily completely dependent upon VPL-VP% VL or LP, at least at the levels lesioned. The heterotopic responses do, however, appear to be of thalamic rather than striatal or archipalial origin since small lesions confined to the corona radiata at anterior 7-10 abolished them, leaving only the corticocortical responses (as controls for viability ) . Figure 5 also shows an unexpected result concerning the behavior of these control (corticocortical) responses after the lateral thalamic lesions. In all animals tested the cortical responses (PPA) response to ipsilateral S MI stimulation) increased in amplitude immediately after the lesion (trace 2, Fig. 5), at the same time that peripherally elicited activity was either depressed or unaffected. Being so immediate and differential, this effect suggests release of a tonic inhibition of the corticocortical or thalamocorticocortical system normally exerted by the lateral thalamus. Similar effects of large thalamic lesions were reported previously (10) in the cat ( 14). Discussion
A summary of our data and interpretations is shown in Fig. 6, a highly stylized diagram of the types of responses recorded and the possible pathways mediating them (combined with a small map of Brodmann area 1, 2, and 3 after Sanidez, the significance of which will be pointed out below j . As indicated, the earliest response (component 1) seen was that to contralateral leg stimulation, in the appropriate pericentral cortical area and presumably relayed through the ventrobasal complex. Surrounding this, and projecting especially anteriorly, is a broader area of somewhat longer latency responses (component -?) retaining some somatotopy by virtue of the orientation of the corticocortical projections presumed, on the basis of this study and some others (5, 16, 30) to mediate them. There is ample anatomical (25, 26, 29) and physiological 124) evidence for such post- to precentral projections ; indeed, they can be demonstrated physiologically in the absence of most of the possible subcortical relay systems (8). Finally, in addition to and partially encompassing the regions exhibiting components 1 and ,7 there is a larger distribution of even longer latency responses (component 3) with very little or no somatotopy. This latter wave is often present along with component 1 and 2 as shown and when not demonstrable at these points in the intact cortex can be unmasked by abolishing the earlier components (Figs. 3 and 4). The pathway for heterotopic responses is unclear, but since our data (Fig. 5) and previous findings (see below) suggest a greater dependency on the lateral specific and associative nuclei (VPL, VPM, VL, LP) than on medial nonspecific thalamus, the combined specific-associative complex is represented in Fig. 6 (outer projection cone) as being primarily (although not necessarily exclusively ) responsible for mediation of component 3.
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3-1HAlAMOCORTICAL
BIGNALL
[SLOW)
2-CORTICOCORTICAL~
1
FIG. 6. Summary diagram of the kinds of responses observed in this study (upper right) and our interpretation of the probable origin of each. The region ABCD in the large diagram is an expansion of the similarly notated region in the wholebrain drawing at lower right (stippled). In the latter the numbers 1, 2, 3 refer to the corresponding Brodmann areas after Sanidez (31), whereas at the top the same number system refers to points on the cortex within the projection areas indicated. These are: I-THALAMOCORTICAL (SPECIFIC), with the dashed line through the peak of the response, originating in VPL-VPM (inner projection cone) and projecting to pericentral cortex (arm area in this case), Z-CORTICOCORTICAL, representing
intracortical
transmission
mostly
anteriorly
to
precentral
cortex,
and
3-THALAMOCORTICAL (SLOW) re p resenting inputs from a complex of lateral thalamic nuclei ; perhaps including and surrounding VPL-VPM (outer cone with strall arrows at lower left from the inner specific cone). SOMATIC AFFERENTS refers to inputs generated by subcutaneous electrical stimulation only (similarity to natural cutaneous stimulation being implied but not assumed). Each of these three components of this system, derived strictly from our data from chloralose-anesthetized squirrel monkeys using electrical subcutaneous stimulation will now be examined in turn, with particular reference to relevance of findings of others. With regard to component 1, this is the classical primary somatic response which is generally agreed to be relayed through the ventrobasal complex, as indicated in Fig. 6 (inner cone). However, the presence of this response in precentral cortex as shown is not in accord with findings that in the macaque deeply anesthetized with barbiturates, precentral cor-
SOM.4TIC
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tex is insensitive to any type of cutaneous stimulation (2, 21,27, 35). This is not in itself a serious discrepancy, since in contrast to the barbituratedrugged preparation, the chloralose-anesthetized ( 1, 4 j , and unanesthetized ( 15) macaque have broad areas in the frontal lobe which are responsive to electrical stimulation of the skin. Indeed many investigators, most recently Eidelberg and Jenkins (16), have attributed the findings of those using barbiturates to constriction by this drug of the normally wide responsive areas including the precentral gyrus to a small postcentral focus. This is not, however, an entirely satisfactory explanation since even in unanesthetized macaques neurons in precentral gyrus are not sensitive to natural cutaneous stimuli (21, 27). At any rate, in the squirrel monkey the problem of sensitivity of precentral cortex to natural cutaneous stimulation may not be of any particular importance since such responsiveness has been well demonstrated in this species (6). As the drawing from Sanidez (31) in Fig. 6 implies, the species difference may be due primarily to the fact that the immediate precentral cortex in the squirrel monkey is area 3. i.e., primary somatic cortex according to Sanidez, whereas in the macaque it is area 4 (motor) because of the deep central convolution wherein areas l-3 end in the sulcus (1). Thus, our consideration of primary somatic (cutaneous) cortex as extending rostra1 to the central dimple in the squirrel monkey is in keeping with cytoarchitectural expectations (31) and physiological findings using natural stimuli (6) and because of these species differences in morphology is not in conflict with contrasting microelectrode data (2, 27) from the macaque showing essentially no cutaneous input to precentral gyrus. The second type of response in Fig. 6 (component ‘3) is considered different from the first primarily in that it extends, with progressively increasing latency, beyond axea 3 and into motor tortes (32). i.e., areas 4 and 6 (31) and was abolished in our esperiments by removal of areas 1-3. It retains some somatotopy and thus resembles the somatic responses in precentral gyrus of the macaque (16, 22, 23, 30, 34), although in that species relay of activity from post to precentral gyrus is still controversial in that disappearance of precentral responses to peripheral stimuli has been reported by some (5, 16, 30) but denied by others (18, 22, 23j. Also, there is considerable evidence that somatic responses in motor cortex of the macaque ( 1) as well as the cat (12) are relayed through the thalamic region including VL and VP. For this reason component Z is placed in Fig. 6 under the sphere of influence of the outer cone of projections from the VL, VP, and vicinity, even though we visualize it as being projected at least partially from pericentral cortex. The widespread heterotopic component 3 of Fig. 6 seems essentially independent of pericentral cortex and is thus probably analogous to similar
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responses in the motor area of cat (3, 13) and is almost certainly the equivalent of the “convergent” somatic responses described by Albe-Fessard et a~. (4). Similar long-latency components can be detected in the records of Eidelberg and Jenkins (16) from unanesthetized macaques. But unlike the chloralose-anesthetized cat and squirrel monkey, lesions of postcentral cortex abolished the late as well as earlier precentral responses (i.e., abolished all precentral responses) in their experiments. Their lesions were chronic, however, and owing to the possibility of retrograde degeneration in the thalamus and subsequent undetermined amount of impairment of lateral thalamic function in this situation, their results are not directly comparable with the effect of acute ablations, in which distant morphological degenerative effects are not immediately apparent, if indeed they occur at all. In the cat, some contrasting findings by different investigators (1, 3, 7), have engendered some debate (14) as to whether the long-latency heterotopic responses in the motor area of this species are or are not relayed through the center median-parafascicularis complex, but now there seems to be agreement (4, 9) that this complex is not a likely relay for similar frontal cortical responses in the monkey. The pathways, therefore, still have not been worked out, but there are indications from lesions studies in the cat (12) that they involve VL. Ventralis lateralis and perhaps VP have been implicated in the macaque ( 1) , and our data also suggest that these are participating (but not necessarily essential) nuclei in the squirrel monkey. The general plan indicated by Fig. 6 of the widespread projections system, within which is a more specific or specialized system with a connection to the broader and less differentiated area, is consistent with current concepts of the evolution of the neocortex, and the relationships between association and specific cortical area and related thalamic systems. According to these ideas (15, 19), p rimary sensory areas differentiate, for special and highly specific function, out of what is generally called association cortex in man, leaving the association areas for the originally primitive hut now (in man) extremely complex function of establishing these associational or interrelating connections between the various sensory modalities. Figure 6 reflects these hypothesized differentiations in that it shows the presence of the specialized “inner core” of the specific systems within a more undifferentiated outer cone or larger cortical area which includes for all practical purposes the frontal association cortex. And, of course, there is abundant evidence that this association or nonprimary region in the squirrel monkey (8, 9) as well as in other species ( 1, 14) receives multiple sensory inputs which could provide the basis for intermodality integration and association. The mechanisms whereby this might occur remain
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unclear. Some clues are being obtained in our laboratory by studies of the influence of nonspecific thalamus on sensory-evoked activity of single units in the polysensory areas, A preliminary report on this has appeared (28). In general, it was found that this influence is far more profound, plastic, selective, and longer lasting than on units on primary sensory areas. Perhaps the plasticity of cortical function is in part the consequence of such specific-nonspecific interactions in nonprimary areas, and as a result the tremendous differential growth of nonprimary or association areas in primates may stem from a distinct adaptive advantage (to borrow from computer design terminology) of (a) expanding as much as possible the general purpose capability (association systems), while (b) at the same time refining the special purpose components (specific systems) essential for performing very specialized tasks such as manipulation of the digits or face, and (c) maximizing communication between these other two general- and special-purpose functions by developing intracortical and intrathalamic connection systems. References 1. ALBE-FESSARD, D. 1967. Organization of somatic central projections, pp. lOl167. 11, “Contributions to Sensory Physiology,” vol. 2. W. Neff [ed.] Academic Press, New York. 2. ALBE-FESSARD, D., and J. LIEBESKIND. 1966. Origine des messages somato-sensitifs activant les cellules du cortex moteur chex le singe. Exp. Brain Rcs. 1 : 127-146. 3. ALBE-FESSARD, I)., and A. ROUGEL. 19.58. ActivitCs d’origine somesthesique &oquPes sur le cortex non-spCcifique du chat anesthCsie au chloralose: rble du centre mkdian du thalamus. Electroeucephalogr. Clirz. Newrojhysiol. 10 : 131-152. 4. ALBE-FESSARD, D., C. ROCHA-MIRANDA, and E. OSWALD+CRUZ. 1959. ActivitCs d’origine SomesthCsique evoqutes au niveau du cortex non-sp&ifique et du centre median du thalamus chez le singe anestht% au chloralose. Elcctroemcphalogr. Clin. Ncurophysiol. 11 : 777-787. 5. BARD, P. 1938. “Studies on the cortical representation of somatic sensibility.” Harvq Let. pp. 99, 143-169. 6. BENJAMIN, R. M., and W. I. WELKER. 1957. Somatic receiving areas of cerebral cortex of squirrel monkey (Saimiri sciureus) J. Nczwophgsiol. 20 : 286-299. 7. BIGNALL, K. E. 1967. Effects of subcortical ablations on polysensory cortical responses and interactions in the cat. ,%p. Nezhvol. 18 : 5667. 8. BIGNALL, K. E., and hf. IRIBERT. 1969. Polysensory and corticocortical projections to frontal lobe of squirrel and rhesus monkeys. Electroemephaloyr. Clitl. Neuvopkysiol. 26 : 206-215. 9. BIGNALL, K. E., and P. SINGER. 1967. Auditory, somatic and visual input to association and motor cortex of squirrel monkey. Esp. Nertvol. 18: 300-312. 10. BIGNALL, K. E., M. IBIBERT, and P. BUSER. 1966. Optic projection to non-visual cortex of the cat. .I. h’cwoplzysiol. 29 : 396409.
452
SINGER
AND
BIGNALL
1965. Projection of dorsal roots and A. J., and C. A. LORENZINI. nerves to cortical sensory motor regions of squirrel monkey. J. Nellyo28 : 1195-1205. 12. BCSER, P. 1966. Subcortical controls of pyramidal activity, PP. 323-W. 1~ “The D. P. Purpura and M. D. Yahr [eds.]. Columbia University Press, Thalamus.” New York. 13. BUSER, P., and P. ASCHER, 1960. Mise en jeu &flex du systcme pyramidal chez le Chat. Arch. Ital. Biol. 98 : 123-164. 14. BUSER, P., and K. E. BICNALL. 1967. Nonprimary sensory projectians on the cat neocortex. I&. Xc;!. Ncwobiol. 10 : 11 I-165. 11.
BLOMQUIST,
sensory physiol.
15.
DIAMOND,
I. T.,
and
W.
C. HALL,
1969.
Evolution
of
neocortex.
Scierlce
164:
251-262. 16.
EIDELBERG,
in
the
E., and I. JENKINS. 1966. Organization of somatic sensory mechanisms Electroencephalogr. Clin. Neurophysiol. 21: macaque cerebral cortex.
452460. 18.
EMMERS,
Squirrel
R., and Monkey
K. AKERT. 1963. (Saimiri sciureus)
“A Stereotaxic .” University
Atlas of of Wisconsin
the Brain of the Press, Madison.
1s. GARDNER, E. D., and F. MORIN. 1953. Spinal pathways for projections of cutaneous and muscular afferents to the sensory and motor cortex of the monkey. :lmcr. J. Phgsiol. 174 : 149-154. 19. KARAMYAN, A. I. 1968. On the evolution of integrative activity of the central nervous system in the phylogeny of vertebrates. Progr. Brain Rex. 22: 427-447. 20. KELLY, D. L., S. GOLDRING, and J. L. O’LEARY. 1965. Averaged evoked potentials from the exposed cortex of man. Arch. Neural. 13 : 1-9. 21. KKUGER, L. 1956. Characteristics of the somatic afferent projection to the precentral cortex in the monkey. Alrcer. J. Physiol. 188 : 475-482. 22. KRUGER, L., and K. H. PRIBRAM. 1954. The ‘evoked response’ in the precentral gyrus of monkey. Fed. Proc. 13: 82. 23. MALIS, L. I., K. H. PRIBRAM, and L. KRCTGER. 1953. Action potentials in “motor” cortex evoked by peripheral nerve stimulation. J. Neurophysiol. 18: 161-167. 24. McCu~r.oca, W. 1944. The functional organization of the cerebral cortex. Physiol. Rev. 24: 39@407. 25. METTLER, F. A. 1935. Corticofugal fiber connections of the cortex of Macaca mulatta. The parietal region. J. Conzp. NertvoE. 62 : 263-291. 26. MILCH, E. C. 1932. Sensory cortical area. An experimental anatomic investigation. A. M. A. Arch. Neural. Psychiat. 28 : 871-882. 27. MOUNTCASTLE, V. B., and T. P. S. POWELL. 1959. Central nervous mechanisms subserving position. Bull. Johns Hopkins Has. 106: l7&2oO. 28. NELSON, C. N., and K. E. BIGNALL, 1969. Influence of nonspecific thalamic stimulation on polysensory cortical cells. Fed. Proc. 28 : 455. 29.
PANDYA,
D.
in the rhesus 30.
31.
and monkey.
N.,
H.
G.
BY&
J.
M.
KUYPERS.
1969.
Cortico-cortical
connections
RES. 13 : 13-36.
T. C., M. D. PAmoN, and M. B. AMASSIAN. 1959. Topographical and functional determinants of cortical localization patterns. Res. p&l. Res. hrerv. Menf. Dis. 30 : 403-429. SANIDEZ, F. 1968. The architecture of the cortical tasts nerve areas in squirrel monkey (Saimiri sciuereus) and their relationships to insular, sensorimotor and prefrontal regions. Iivais Res. 8 : 97-124.
RucH,
SOMATIC
32.
33.
34.
35.
PROJECTIONS
453
W. I., R. M. BENJAAIIN, and R. C. MILES. 1957. Motor effects of stimulation of cerebral cortex of squirrel monkey ( Saimiri sciureus). J. Neurophysiol. 20 : 347-364. WOOLSEY, C. N. 1958. Organization of somatic sensory and motor areas of the cerebral cortex. In “Biological and Biochemical Basis of Behavior.” H. F. Harlow and C. N. Woolsey [eds.]. University of Wisconsin Press, Madison. WOOLSEY, C. N., H. T. CIIAKG, and P. BARD. 1947. Distribution of cortical potentials evoked by stimulation of dorsal roots in Macaca mulatta. Fed. Proc. 6: 230. WOOLSEY, C. N., W. H. MARSHALL, and P. BARD. 1942. Representation of cutaneous tactile sensibility in the cerebral cortex of the monkey as indicated by evoked potentials. Bull. Johns Hopkins Hosp. 70: 399-441.
WELKER,