Masahiko Inase

Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area

The subthalamic nucleus (STN) is a key structure for somatic motor control via the basal ganglia. In the present study, we demonstrate that the STN of the macaque monkey has dual sets of body part representations. Each of the two separate portions of the STN is characterized with somatotopically arranged direct cortical inputs that are derived from the primary motor cortex (MI) and the supplementary motor area (SMA). The first set of body part representations is transformed from the MI to the lateral STN, whereas the second set is transformed from the SMA to the medial STN. Intracortical microstimulation mapping was carried out to guide paired injections of anterograde tracers into somatotopically corresponding regions of the MI and the SMA. We found that direct inputs from the MI were allocated mostly within the lateral half of the STN, whereas those from the SMA were distributed predominantly within its medial half. Of particular interest was that the arrangement of somatotopical representations from the SMA to the medial STN was reversed against the ordering of those from the MI to the lateral STN; the orofacial, forelimb, and hindlimb parts were represented from medial to lateral within the medial STN, whereas these body parts were represented, in the inverse order, mediolaterally within the lateral STN. Moreover, inputs from homotopical MI and SMA regions were found to converge only partially into the STN. The present findings could account for somatotopically specific involuntary movements manifested in hemiballism that is caused by destruction of the STN.

Corticostriatal projections from the somatic motor areas of the frontal cortex in the macaque monkey: segregation versus overlap of input zones from the primary motor cortex, the supplementary motor area, and the premotor cortex.

Abstract It is an important issue to address the mode of information processing in the somatic motor circuit linking the frontal cortex and the basal ganglia. In the present study, we investigated the extent to which corticostriatal input zones from the primary motor cortex (MI), the supplementary motor area (SMA), and the premotor cortex (PM) of the macaque monkey might overlap in the putamen. Intracortical microstimulation was performed to map the MI, SMA, and dorsal (PMd) and ventral (PMv) divisions of the PM. Then, two different anterograde tracers were injected separately into somatotopically corresponding regions of two given areas of the MI, SMA, PMd, and PMv. With respect to the PMd and PMv, tracer injections were centered on their forelimb representations. Corticostriatal input zones from hindlimb, forelimb, and orofacial representations of the MI and SMA were, in this order, arranged from dorsal to ventral within the putamen. Dense input zones from the MI were located predominantly in the lateral aspect of the putamen, whereas those from the SMA were in the medial aspect of the putamen. On the other hand, corticostriatal inputs from forelimb representations of the PMd and PMv were distributed mainly in the dorsomedial sector of the putamen. Thus, the corticostriatal input zones from the MI and SMA were considerably segregated though partly overlapped in the mediolateral central aspect of the putamen, while the corticostriatal input zone from the PM largely overlapped that from the SMA, but not from the MI.

Corticostriatal and corticosubthalamic input zones from the presupplementary motor area in the macaque monkey: comparison with the input zones from the supplementary motor area

The presupplementary motor area (pre-SMA) is a cortical motor-related area which lies in the medial wall of the frontal lobe, immediately anterior to the supplementary motor area (SMA). This area has been considered to participate in the control of complex forelimb movements in a way different from the SMA. In an attempt to analyze the patterns of projections from the pre-SMA to the basal ganglia, we examined the distributions of pre-SMA inputs in the striatum and the subthalamic nucleus and compared them with the SMA input distributions. To detect morphologically the terminal fields from the pre-SMA and the forelimb region of the SMA, anterograde tracers were injected into such areas that had been identified electrophysiologically in the macaque monkey. Corticostriatal inputs from the pre-SMA were distributed mainly in the striatal cell bridges connecting the rostral aspects of the caudate nucleus and the putamen, as well as in their neighboring striatal portions. These input zones were located, with no substantial overlap, rostral to corticostriatal input zones from the SMA forelimb region. Corticosubthalamic input zones from the pre-SMA were almost localized in the medial aspect of the nucleus, where corticosubthalamic inputs from the SMA forelimb region were also distributed predominantly. However, the major terminal fields from the pre-SMA were centered ventrally to those from the SMA. The present results indicate that the corticostriatal and corticosubthalamic input zones from the pre-SMA appear to be segregated from the SMA-derived input zones. This implies the possibility of parallel processing of motor information from the pre-SMA and SMA in the cortico-basal ganglia circuit.

Corticosubthalamic input zones from forelimb representations of the dorsal and ventral divisions of the premotor cortex in the macaque monkey : comparison with the input zones from the primary motor cortex and the supplementary motor area

Employing double anterograde axonal tracing in combination with intracortical microstimulation, we examined the distribution patterns of corticosubthalamic inputs from forelimb representations of the dorsal (PMd) and ventral (PMv) divisions of the premotor cortex in the macaque monkey. The inputs from the PMd and PMv were distributed mainly in the medial aspect of the subthalamic nucleus (STN), in which their distribution areas overlapped each other. By the same experimental approach, we further compared corticosubthalamic input zones from the PMd/PMv with those from the primary motor cortex (MI) and the supplementary motor area (SMA). The input zones from the PMd/PMv and SMA largely overlapped in the medial aspect of the STN, whereas the input zones from the PMd/PMv and MI were virtually segregated mediolaterally in the STN.

Excitotoxic lesions of the pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the monkey.

Dopaminergic nigrostriatal neurons, degeneration of which causes Parkinsons disease, are known to receive excitatory input almost exclusively from the pedunculopontine tegmental nucleus (PPN). We report here that excitotoxic lesions of the PPN produce abnormal motor signs relevant to hemiparkinsonism in the macaque monkey. Under the guidance of extracellular unit recordings, the electrophysiologically identified PPN was injected unilaterally with kainic acid. These PPN-lesioned monkeys exhibited mild to moderate levels of flexed posture and hypokinesia in the upper and lower limbs contralateral to the lesion. In most of the monkeys, such pathophysiological events were gradually improved and became stationary in 1-2 weeks. The hemiparkinsonian symptoms observed after PPN destruction might be ascribed to a decrease in nigrostriatal neuron activity due to excitatory input ablation.

Comparison of cerebellothalamic and pallidothalamic projections in the monkey (Macaca fuscata): A double anterograde labeling study

To address the question of segregated projections from the internal segment of the globus pallidus (GPi) and the cerebellar nuclei (Cb) to the thalamus in the monkey, we employed a double anterograde labeling strategy combining the anterograde transport of horseradish peroxidase conjugated to wheat germ agglutinin (WGA‐HRP) with biotinylated dextran amine (BDA) transport. The tissue was processed sequentially for WGA‐HRP, and then BDA immunohistochemistry using two different chromogens. Since the two labels were easily distinguishable on the same histological section, the interrelationship between the cerebellar and pallidal projection systems could be directly evaluated. We found that both the cerebellothalamic and pallidothalamic label consisted of dense plexuses of labeled fibers and swellings in a patch‐like configuration. The patches or foci of labeling were distributed either as dense single label or as interdigitating patches of double label. We found dense single label in the central portion of the ventral anterior nucleus pars principalis (VApc) and the ventral lateral nucleus pars oralis (VLo) following the GPi injections or in the central portion of the ventral posterior lateral nucleus pars oralis (VPLo) and nucleus X (X) following the cerebellar nuclei injections. Complementary interdigitating patches of WGA‐HRP and BDA labeling were found primarily in transitional border regions between thalamic nuclei. On occasion, we found overlap of both labels. We observed a gradient pattern in the density of the pallidothalamic and cerebellothalamic projections. The pallidothalamic territory included VApc, VLo, and the ventral lateral nucleus pars caudalis (VLc), with the density of these projections decreasing along an anterior to posterior gradient in the thalamus. Occasional patches of pallidal label were found in VPLo and nucleus X. Conversely, the density of cerebellothalamic projections increased along the same gradient, with the cerebellothalamic territory extending anteriorly beyond the cell‐sparse zones of VPLo, X, and VLc to include VLo and VApc also. These data suggest that although the cerebellar and pallidal projections primarily occupy separate thalamic territories, individual thalamic nuclei receive differentially weighted inputs from these sources.

Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey

The cingulate motor areas reside within regions lining the cingulate sulcus and are divided into rostral and caudal parts. Recent studies suggest that the rostral and caudal cingulate motor areas participate in distinct aspects of motor function: the former plays a role in higher‐order cognitive control of movements, whereas the latter is more directly involved in their execution. Here, we investigated the organization of cingulate motor areas inputs to the basal ganglia in the macaque monkey. Identified forelimb representations of the rostral and caudal cingulate motor areas were injected with different anterograde tracers and the distribution patterns of labelled terminals were analysed in the striatum and the subthalamic nucleus. Corticostriatal inputs from the rostral and caudal cingulate motor areas were located within the rostral striatum, with the highest density in the striatal cell bridges and the ventrolateral portions of the putamen, respectively. There was no substantial overlap between these input zones. Similarly, a certain segregation of input zones from the rostral and caudal cingulate motor areas occurred along the mediolateral axis of the subthalamic nucleus. It has also been revealed that corticostriatal and corticosubthalamic input zones from the rostral cingulate motor area considerably overlapped those from the presupplementary motor area, while the input zones from the caudal cingulate motor area displayed a large overlap with those from the primary motor cortex. The present results indicate that a parallel design underlies motor information processing in the cortico‐basal ganglia loop derived from the rostral and caudal cingulate motor areas.

Thalamocortical and intracortical connections of monkey cingulate motor areas

Although there has been an increasing interest in motor functions of the cingulate motor areas, data concerning their input organization are still limited. To address this issue, the patterns of thalamic and cortical inputs to the rostral (CMAr), dorsal (CMAd), and ventral (CMAv) cingulate motor areas were investigated in the macaque monkey. Tracer injections were made into identified forelimb representations of these areas, and the distributions of retrogradely labeled neurons were analyzed in the thalamus and the frontal cortex. The cells of origin of thalamocortical projections to the CMAr were located mainly in the parvicellular division of the ventroanterior nucleus and the oral division of the ventrolateral nucleus (VLo). On the other hand, the thalamocortical neurons to the CMAd/CMAv were distributed predominantly in the VLo and the oral division of the ventroposterolateral nucleus‐the caudal division of the ventrolateral nucleus. Additionally, many neurons in the intralaminar nuclear group were seen to project to the cingulate motor areas. Except for their well‐developed interconnections, the corticocortical projections to the CMAr and CMAd/CMAv were also distinctively preferential. Major inputs to the CMAr arose from the presupplementary motor area and the dorsal premotor cortex, whereas inputs to the CMAd/CMAv originated not only from these areas but also from the supplementary motor area and the primary motor cortex. The present results indicate that the CMAr and the caudal cingulate motor area (involving both the CMAd and the CMAv) are characterized by distinct patterns of thalamocortical and intracortical connections, reflecting their functional differences. J. Comp. Neurol. 462:121–138, 2003.

Organization of somatic motor inputs from the frontal lobe to the pedunculopontine tegmental nucleus in the macaque monkey

To reveal the somatotopy of the pedunculopontine tegmental nucleus that functions as a brainstem motor center, we examined the distribution patterns of corticotegmental inputs from the somatic motor areas of the frontal lobe in the macaque monkey. Based on the somatotopical map prepared by intracortical microstimulation, injections of the anterograde tracers, biotinylated dextran amine and wheat germ agglutinin-conjugated horseradish peroxidase, were made into the following motor-related areas: the primary motor cortex, the supplementary and presupplementary motor areas, the dorsal and ventral divisions of the premotor cortex, and the frontal eye field. Data obtained from the present experiments were as follows: (i) Corticotegmental inputs from orofacial, forelimb, and hindlimb representations of the primary motor cortex tended to be arranged orderly from medial to lateral in the pedunculopontine tegmental nucleus. However, the distribution areas of these inputs considerably overlapped; (ii) The major input zones from distal representations of the forelimb and hindlimb regions of the primary motor cortex were located medial to those from their proximal representations, although there was a substantial overlap between the distribution areas of distal versus proximal limb inputs; (iii) The main terminal zones from the forelimb regions of the primary motor cortex, the supplementary and presupplementary motor areas, and the dorsal and ventral divisions of the premotor cortex appeared to overlap largely in the mediolaterally middle aspect of the pedunculopontine tegmental nucleus; and (iv) Corticotegmental input from the frontal eye field was scattered over the pedunculopontine tegmental nucleus.Thus, the present results indicate that the pedunculopontine tegmental nucleus is likely to receive partly separate but essentially convergent cortical inputs not only from multiple motor-related areas representing the same body part, but also from multiple regions representing diverse body parts. This suggests that somatotopical representations are intermingled rather than segregated in the pedunculopontine tegmental nucleus.

Overlapping corticostriatal projections from the supplementary motor area and the primary motor cortex in the macaque monkey: An anterograde double labeling study

The purpose of the present study was to determine if the cortical efferents from homologous body regions of the supplementary motor area (SMA) and the primary motor cortex (MI) project to separate or to overlapping regions in the striatum. In order to investigate the dual corticostriatal projections, we employed an anterograde double labeling paradigm in which two tracers could be simultaneously detected in the same histological section. Prior to the injections, the forelimb representation in the two cortical motor areas was identified by using intracortical microstimulation in four Japanese monkeys (Macaca fuscata). Multiple injections of biotinylated dextran amine (BDA) were made into the forelimb regions of MI and wheat germ agglutinin conjugated horseradish peroxidase (WGA‐HRP) was injected into the arm region of the SMA. In additional animals, the tracers were reversed such that BDA was injected into the SMA and WGA‐HRP was injected into the MI. The tissue was processed sequentially using different chromogens in order to visualize both tracers in a single section. We analyzed the distribution of the ipsilateral anterograde label. The striatal labeling from each cortical area basically consisted of a wide band of patchy dense labeling interrupted by lighter labeling. The SMA striatal projections were located mainly within the putamen, distributing from the level of the anterior commissure to the most posterior extent of the putamen. At an intermediate level, the label spread obliquely from the ventrolateral edge of the putamen dorsomedially as far as the lateral edge of the caudate nucleus. The label from the MI was observed in comparable portions of the putamen, although the SMA projections were shifted more anterior and dorsomedial to the MI projections and the heaviest projections from the SMA and the MI were separately located. On the basis of the double anterograde labeling technique, we found considerable overlap mainly in the central portion of the putamen from the SMA and MI forelimb representation. These results suggest that the homologous body regions of the SMA and MI send widespread, and substantially overlapping projections, to portions of the striatum.