Thalamic and brainstem contributions to large-scale plasticity of primate somatosensory cortex.

After long-term denervation of an upper limb in macaque monkeys, the representation of the face in somatosensory cortex expands over many millimeters into the silenced representation of the hand. Various brainstem and cortical mechanisms have been proposed to explain this phenomenon. Reorganization in the thalamus has been largely ignored. In monkeys with deafferented upper limbs for 12 to 20 years, it was found that the brainstem cuneate and the thalamic ventral posterior nuclei had undergone severe transneuronal atrophy, and physiological mapping in the thalamus revealed that the face and trunk representations were adjoined while the normally small representation of the lower face had expanded comparable to the expansion in cortex. Reorganization of brainstem and thalamic nuclei associated with slow transneuronal atrophy is likely to be a progressive process. When coupled with divergence of ascending connections, it is likely to make a substantial contribution to representational changes in cortex.

Physiological evidence for serial processing in somatosensory cortex.

Removal of the representation of a specific body part in the postcentral cortex of the macaque resulted in the somatic deactivation of the corresponding body part in the second somatosensory area. In contrast, removal of the entire second somatosensory area had no grossly detectable effect on the somatic responsivity of neurons in the postcentral cortex. This direct electrophysiological evidence for serial cortical processing in somesthesia is similar to that found earlier for vision and, taken together with recent anatomical evidence, suggests that there is a common cortical plan for the processing of sensory information in the various sensory modalities.

Massive cortical reorganization after sensory deafferentation in adult macaques.

After limited sensory deafferentations in adult primates, somatosensory cortical maps reorganize over a distance of 1 to 2 millimeters mediolaterally, that is, in the dimension along which different body parts are represented. This amount of reorganization was considered to be an upper limit imposed by the size of the projection zones of individual thalamocortical axons, which typically also extend a mediolateral distance of 1 to 2 millimeters. However, after extensive long-term deafferentations in adult primates, changes in cortical maps were found to be an order of magnitude greater than those previously described. These results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.

Cortically induced thalamic plasticity in the primate somatosensory system.

The influence of cortical feedback on receptive field organization in the thalamus was assessed in the primate somatosensory system. Chronic and acute suppression of neuronal activity in primary somatosensory cortex resulted in a striking enlargement of receptive fields in the ventroposterior thalamus. This finding demonstrates a dramatic 'top-down' influence of cortex on receptive field size in the somatosensory thalamus. In addition, this result has important implications for studies of adult neuronal plasticity because it indicates that changes in 'higher-order' areas of the brain can trigger extensive changes in the receptive field characteristics of neurons located earlier in the processing pathway.

Progressive transneuronal changes in the brainstem and thalamus after long-term dorsal rhizotomies in adult macaque monkeys.

This study deals with a potential brainstem and thalamic substrate for the extensive reorganization of somatosensory cortical maps that occurs after chronic, large-scale loss of peripheral input. Transneuronal atrophy occurred in neurons of the dorsal column (DCN) and ventral posterior lateral thalamic (VPL) nuclei in monkeys subjected to cervical and upper thoracic dorsal rhizotomies for 13-21 years and that had shown extensive representational plasticity in somatosensory cortex and thalamus in other experiments. Volumes of DCN and VPL, number and sizes of neurons, and neuronal packing density were measured by unbiased stereological techniques. When compared with the opposite, unaffected, side, the ipsilateral cuneate nucleus (CN), external cuneate nucleus (ECN), and contralateral VPL showed reductions in volume: 44-51% in CN, 37-48% in ECN, and 32-38% in VPL. In the affected nuclei, neurons were progressively shrunken with increasing survival time, and their packing density increased, but there was relatively little loss of neurons (10-16%). There was evidence for loss of axons of atrophic CN cells in the medial lemniscus and in the thalamus, with accompanying severe disorganization of the parts of the ventral posterior nuclei representing the normally innervated face and the deafferented upper limb. Secondary transneuronal atrophy in VPL, associated with retraction of axons of CN neurons undergoing primary transneuronal atrophy, is likely to be associated with similar withdrawal of axons from the cerebral cortex and should be a powerful influence on reorganization of somatotopic maps in the somatosensory cortex.

Connections of area 2 of somatosensory cortex with the anterior pulvinar and subdivisions of the ventroposterior complex in macaque monkeys.

The principal goal of the present study was to determine the thalamic connections of area 2 of postcentral somatosensory cortex of monkeys. The placement of injections of anatomical tracers (horseradish peroxidase, wheat germ agglutinin, or 3H-proline) was guided by extensive microelectrode maps of cortex in the region of the injection site. These maps identified the body parts represented in the cortex included in the injection site, and provided information about the physiological boundaries of area 2, which was related later to the cortical architecture. Most injections were placed in the representation of the hand in area 2, which was highly responsive to cutaneous stimuli and could be mapped in detail. Injections were also placed in other parts of area 2, area 1, or area 5, and some injections involved more than one area. As other investigators have determined, regions of retrograde and anterograde thalamic label overlapped, demonstrating that connections with cortex are reciprocal. Injections completely confined to area 2 consistently produced label in two locations: the anterior pulvinar (Pa) and a dorsal capping zone of the ventroposterior complex that we term the ventroposterior superior nucleus (VPS). Single restricted injection sites resulted in one region of label in VPS, and multiple foci of label in Pa. In some cases where the injection was confined to the representation of the hand in area 2, label was also found more ventrally in the ventroposterior complex in ventroposterior nucleus proper (VP). Thus, area 2 receives input from Pa, VPS, and, at least in some locations and individuals, VP. Injections of tracers into area 1 confirmed previous findings that area 1 is densely interconnected with VP. In addition, there appear to be sparse connections with VPS. There was no evidence of connections with Pa. Evidence from injection sites that extended from area 2 into areas 5 and 7, and from injection sites in area 5, indicates that the lateral posterior nucleus (LP) projects to rostral areas 5 and 7. The results support the conclusion that area 2 is a functionally distinct subdivision of somatosensory cortex, and indicate that area 2 has thalamic connections that are characteristic of both "sensory" (VP and VPS) and "association" (Pa) cortical fields.

Corticocortical connections of area 2 of somatosensory cortex in macaque monkeys: a correlative anatomical and electrophysiological study.

The cortical connections of electrophysiologically identified locations in the body representations in somatosensory cortex of macaque monkeys were investigated after injections of horseradish peroxidase, wheat germ agglutinin (WGA) conjugated with horseradish peroxidase, tritiated WGA, or tritiated proline. After extensive microelectrode mapping of portions of the body representations in areas 3b, 1, 2, and 5 and careful determinations of electrophysiological borders between areas, restricted injections of tracers were placed, usually into the representation of the hand in area 2. Other injections were placed in the foot representation in area 2 or in area 1, in the wrist representation in area 1, and in the forearm and wrist representation in area 5. Connection patterns were related to the physiological mapping results and to cortical cytoarchitecture. Injections confined to a lateral portion of area 2 representing the glabrous digits of the hand revealed reciprocal connections with the digit representations in areas 1 and 3b. Projections to area 2 were largely from layer III neurons in both of these fields, and return projections terminated largely in supragranular layers. Other inputs were from layer III cells in one or more separate locations in area 5 and in one or more closely spaced foci in the expected location of S-II in the lateral sulcus. These connections were also reciprocal with terminations apparent in layers IV and III. A few neurons in area 4 were labeled in some of these cases. Results were similar after an injection in the foot representation in area 2 with the differences that infragranular neurons, in addition to supragranular neurons, formed a substantial part of the projection to area 2, terminations as well as projections were noted from area 4, interconnections were found more rostrally in area 6, and a dense focus of label was apparent in the dorsal bank of cingulate sulcus in the apparent location of the supplementary motor area. Injections in the foot representation in area 1 revealed dense layer IV terminations in the foot representation in area 2, as well as connections with area 3b, the S-II region, and areas 5 and 7. The injection in the wrist representation in area 1 resulted in dense terminations in the portion of area 5 responsive to the distal forearm and hand, sparser connections with a lateral location in part of area 2 related to the hand, and interconnections with 3b and S-II.(ABSTRACT TRUNCATED AT 400 WORDS)

Patterns of thalamocortical degeneration after ablation of somatosensory cortex in monkeys.

We examined the pattern of cytochrome oxidase (CO), Nissl staining, and gamma-amino butyric acid (GABA) immunoreactivity in the ventroposterior lateral nucleus (VPL) of the thalamus in monkeys that received no, total, or subtotal, ablation of the hand representations in postcentral somatosensory cortex. In unoperated animals, the region of VPL representing the hand was characterized by relatively dense and homogeneous CO staining throughout the rostral-caudal extent of VPL. Counts of neurons in the VPL hand representation from adjacent thalamic sections processed for Nissl and GABA immunostaining indicated that there were approximately 261.4 neurons/mm2 of which 78.4/mm2 stained positive for GABA. GABA(+) puncta-like terminals were readily apparent throughout the VPL. By contrast, animals that received total removals of the postcentral hand representations showed a dramatic reduction in CO staining in the VPL, which was confined to the expected location of the thalamic hand representation. Counts of neurons in the affected region from adjacent sections that underwent Nissl staining and GABA immunostaining also revealed a dramatic reduction of Nissl-stained neurons, with a smaller reduction in the number of neurons staining positive for GABA. Specifically, large to medium-sized (> 180 microns 2) GABA(-) neurons were virtually eliminated in the affected portion of the VPL, and the numbers of GABA(+) neurons were significantly reduced. The remaining population of GABA(+) neurons was typically shrunken, and no GABA(+) puncta-like terminals were observed in the affected region. The results obtained after subtotal ablation of the postcentral hand representations (only one postcentral area spared, 3b or 3a) differed from those obtained when total removals were made. Instead of virtually complete degeneration of medium-sized to large neurons throughout the hand representation in VPL, as was the case with total removals, after partial removals, we found alternating regions in the VPL hand representation that appeared qualitatively normal, or dramatically degenerated. Thalamic sections stained with CO revealed light, moderate, and darkly stained patches of label within the hand representation in VP, depending on the type of cortical ablation. The most dramatic reduction of Nissl-stained neurons coincided precisely with the lightest staining CO patches. Interestingly, the only statistically significant reduction in the number of GABA(+) neurons occurred in the light CO patches. In the thalamic regions coincident with the dark and moderately stained CO patches, the number of medium-sized and large neurons decreased, but the number of GABA(+) neurons was comparable to normal. Optical density measurements of the dark patches also indicated a statistically significant difference from normal CO staining in this region.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in glutamate immunoreactivity in the somatic sensory cortex of adult monkeys induced by nerve cuts.

Antibodies to glutamate (Glu) were used to study the effects of reduced afferent input on excitatory neurons in the somatic sensory cortex of adult monkeys. In each monkey, immunocytochemical staining was compared to thionin and cytochrome oxidase (CO) staining in adjacent sections. In the cervical spinal cord, dorsal column nuclei, ventroposterior thalamus, and primary somatic sensory cortex (SI), Glu immunoreactivity (Glu-ir) was analogous to that described in normal animals; regions with reduced or absent Glu-ir were never observed and no appreciable differences were noted between the experimental and normal side. There were also no differences in CO or thionin-stained sections from the affected hemisphere. In the insuloparietal operculum, sections in the hemisphere contralateral to the nerve cut showed that most cortical fields had a normal pattern of Glu-ir (pattern a), some exhibited a reduction of Glu-ir (pattern b), and that in the central portion of the upper bank of the central sulcus, which corresponds to the general location of the hand representation of the second somatic sensory cortex (SII), Glu-ir had virtually disappeared (pattern c). Adjacent sections processed for CO or stained with thionin showed that in the regions corresponding to those characterized by pattern c, CO was slightly decreased and that glial cells had increased in number. In the regions of SII characterized by pattern c, small intensely stained glial cells displayed Glu-ir. These findings indicate that Glu-ir is regulated by afferent activity and suggest that changes in Glu levels in neurons as well as in glial cells may trigger the biochemical processes underlying the functional and structural changes occurring during a slow phase of reorganizational plasticity in the cerebral cortex of adult monkeys.

The somatotopic organization of area 2 in macaque monkeys.

Area 2 is a traditional architectonic subdivision of anterior parietal cortex in macaque monkeys, but its overall somatotopic organization and responsiveness to different types of somatic stimuli are poorly understood, and there are uncertainties concerning its rostral and caudal extent. The goals of the present study were to define the rostral and caudal borders of area 2 better, and to describe its overall organization and responsiveness. Somatic receptive fields were defined for hundreds of closely spaced microelectrode recording sites in postcentral parietal cortex of individual macaque monkeys anesthetized with ketamine. Electrophysiological and architectonic evidence suggested that a 3-4 mm-wide strip of cortex along the caudal border of area 1 includes all or most of area 2. The most lateral explored portion of area 2 adjoined the representation of the face in area 1. Much of this sector of area 2 was activated by cutaneous stimulation of the face, especially the chin, but more caudal parts of the head also were represented there. Medially, an adjacent sector of area 2 represented the hand. Rostrally, in the cortex within 1.5 mm from the area 1 border, the glabrous surfaces of digits 5 through 1 were represented in a mediolateral cortical sequence, and from tip to base in a rostrocaudal sequence, mirroring the organization in the adjacent portion of area 1. More caudally at this mediolateral level of area 2, digit tips and other phalanges were represented for a second time. The pads of the palm and the dorsal surfaces of the hand were represented laterally and medially within the portion of area 2 devoted to the hand. More medially, the wrist, forearm, and arm were represented in a lateromedial cortical sequence in area 2, roughly matching the mediolateral organization within the bordering area 1. However, immediately caudal to the representation of the occiput, neck, and shoulder in area 1, a rostrocaudal strip of cortex extending across area 2 represented the arm and forearm for a second time in area 2. This cutaneously activated strip of cortex extended into area 5, where the proximal portion of the hand was represented. More medially, next to the trunk representation in area 1, area 2 was devoted to the trunk and limbs. Next to the representations of the ankle, leg, and thigh in area 1, area 2 was activated from similar locations on the hindlimb.(ABSTRACT TRUNCATED AT 400 WORDS)

The relationship of corpus callosum connections to electrical stimulation maps of motor, supplementary motor, and the frontal eye fields in owl monkeys.

Microstimulation and anatomical techniques were combined to reveal the organization and interhemispheric connections of motor cortex in owl monkeys. Movements of body parts were elicited with low levels of electrical stimulation delivered with microelectrodes over a large region of precentral cortex. Movements were produced from three physiologically defined cortical regions. The largest region, the primary motor field, M-I, occupied a 4-6-mm strip of cortex immediately rostral to area 3a. M-I represented body movements from tail to mouth in a grossly somatotopic mediolateral cortical sequence. Specific movements were usually represented at more than one location, and often at as many as six or seven separate locations within M-I. Although movements related to adjoining joints typically were elicited from adjacent cortical sites, movements of nonadjacent joints also were produced by stimulation of adjacent sites. Thus, both sites producing wrist movements and sites producing shoulder movements were found next to sites producing digit movements. Movements of digits of the forepaw were evoked at several locations including a location rostral to or within cortex representing the face. Overall, the somatotopic organization did not completely correspond to previous concepts of M-I in that it was neither a single topographic representation, nor two serial or mirror symmetric representations, nor a "nesting about joints" representation. Instead, M-I is more adequately described as a mosaic of regions, each representing movements of a restricted part of the body, with multiple representations of movements that tend to be somatotopically related. A second pattern of representation of body movements, the supplementary motor area (SMA), adjoined the rostromedial border of M-I. SMA represented the body from tail to face in a caudorostral cortical sequence, with the most rostral portion related to eye movements. Movements elicited by near-threshold levels of current were often restricted to a single muscle or joint, as in M-I, and the same movement was sometimes multiply represented. Typically, more intense stimulating currents were required for evoking movements in SMA than in M-I. A third motor region, the frontal eye field (FEF), bordered the representation of eyelids and face in M-I. Eye movements elicited from this cortex consisted of rapid horizontal and downward deviation of gaze into the contralateral visual hemifield.

The relation of corpus callosum connections to architectonic fields and body surface maps in sensorimotor cortex of new and old world monkeys.

Corpus callosum connections of parietal and motor cortex were studied in New World owl monkeys (Aotus trivirgatus) and Old World macaque monkeys (Macaca fascicularis) after multiple injections of 3H-proline and horseradish peroxidase, HRP, into one cerebral hemisphere, and extensive microelectrode mapping of architectonic Areas 3b, 1, and 2 of the other hemisphere. Results were obtained both from parasagittal brain sections cut orthogonal to the brain surface and from sections from flattened brains cut parallel to the brain surface. Cortical fields varied in density of callosal connections, and the density of connections varied according to body part within sensory representations. Thus, Area 3b had few, Area 1 had more, and Area 2 had relatively dense callosal connections. Within each of these fields, connections were much less dense for the representations of the glabrous hand and foot and much more dense for the representations of the face and trunk. For the representation of the hand, retrogradely labeled cells were extremely sparse in Area 3b, moderately sparse in Area 1, and moderate in Area 2. There were less dense callosal connections in the hand representations of Areas 3b, 1, and 2 in macaque as compared to owl monkeys. Label in posterior parietal cortex was uneven with zones of extremely dense connections. A large region of very dense callosal connections was noted in motor cortex just medial to the probable location of the hand representation. In all regions, callosally projecting cells appeared to be more broadly distributed than callosal terminations. In no region was the discontinuous arrangement of callosal connections obviously organized into an extensive pattern of mediolateral or rostrocaudal bands or strips.

Co-registration of cortical magnetic stimulation and functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are noninvasive techniques recently used to investigate cortical motor physiology. However, these modalities measure different phenomena, and in studies of human motor control they have given inconsistent results. We have developed a reproducible technique which co-registers TMS and fMRI, using a frameless method. In four normal subjects, the TMS map and fMRI activation were present on the primary motor cortex contralateral to the target hand, with some extension into primary sensory cortex. fMRI activation alone was also present in the medial motor cortex bilaterally and in the sensorimotor cortex ipsilateral to the target hand. This technique allows a more comprehensive evaluation of the physiologic events involved in motor control.

Primary motor cortex receives input from area 3a in macaques.

Intracortical microstimulation was used to define topographic sectors and the rostral border of primary motor cortex in adult macaques (Macaca mulatta). In the same animals, injections of fluorescent tracers were made within defined regions of primary motor cortex. Retrogradely labeled neurons were topographically distributed in area 3a, with most neurons located in layer III, and fewer neurons situated in layers V and IV. These findings suggest that muscle afferent information, thought to be important in a closed-loop mode of function, may reach primary motor cortex directly from cortical area 3a.

A sequential representation of the occiput, arm, forearm and hand across the rostrocaudal dimension of areas 1, 2 and 5 in macaque monkeys.

Receptive fields were determined for recording sites in cortical areas 1, 2 and 5 in macaque monkeys. While a mixture of cutaneous and deep receptors were represented in most regions of area 2, a specific mediolateral level of area 2 was highly responsive to cutaneous input. Anteroposterior rows of recording sites across areas 1, 2 and 5 at this mediolateral location revealed a continuous sequence of cutaneous receptive fields proceeding from the occiput and face in area 1 to the forearm and hand in area 5.

Lesion-induced plasticity in the second somatosensory cortex of adult macaques.

We have reported that elimination of the representation of any body part in the primary (i.e., postcentral) somatosensory cortex of the adult macaque selectively eliminates the representation of that same body part in the second somatosensory area SII. We now report that, although removal of the entire postcentral hand representation does indeed leave the SII hand representation unresponsive to somatic stimulation initially, 6-8 weeks later this cortex is no longer silent. Instead, most or all of the region that had been vacated by the hand representation is now found to be occupied by an expanded foot representation. This massive somatotopic reorganization, involving more than half the areal extent of SII, exceeds that previously observed in the postcentral cortex after peripheral nerve damage and may reflect a greater capacity for reorganizational changes in higher order than in primary sensory cortical areas.

Serial and parallel processing of tactual information in somatosensory cortex of rhesus monkeys.

1. Selective ablations of the hand representations in postcentral cortical areas 3a, 3b, 1, and 2 were made in different combinations to determine each area's contribution to the responsivity and modality properties of neurons in the hand representation in SII. 2. Ablations that left intact only the postcentral areas that process predominantly cutaneous inputs (i.e., areas 3b and 1) yielded SII recording sites responsive to cutaneous stimulation and none driven exclusively by high-intensity or "deep" stimulation. Conversely, ablations that left intact only the postcentral areas that process predominantly deep receptor inputs (i.e., areas 3a and 2) yielded mostly SII recording sites that responded exclusively to deep stimulation. 3. Ablations that left intact only area 3a or only area 2 yielded substantial and roughly equal reductions in the number of deep receptive fields in SII. By contrast, ablations that left intact only area 3b or only area 1 yielded unequal reductions in the number of cutaneous receptive fields in SII: a small reduction when area 3b alone was intact but a somewhat larger one when only area 1 was intact. 4. Finally, when the hand representation in area 3b was ablated, leaving areas 3a, 1, and 2 fully intact, there was again a substantial reduction in the encounter rate of cutaneous receptive fields. 5. The partial ablations often led to unresponsive sites in the SII hand representation. In SII representations other than of the hand no such unresponsive sites were found and there were no substantial changes in the ratio of cutaneous to deep receptive fields, indicating that the foregoing results were not due to long-lasting postsurgical depression or effects of anesthesia. 6. The findings indicate that modality-specific information is relayed from postcentral cortical areas to SII along parallel channels, with cutaneous inputs transmitted via areas 3b and 1, and deep inputs via areas 3a and 2. Further, area 3b provides the major source of cutaneous input to SII, directly and perhaps also via area 1. 7. The results are in line with accumulating anatomic and electrophysiologic evidence pointing to an evolutionary shift in the organization of the somatosensory system from the general mammalian plan, in which tactile information is processed in parallel in SI and SII, to a new organization in higher primates in which the processing of tactile information proceeds serially from SI to SII. The presumed functional advantages of this evolutionary shift are unknown.