https://www.cell.com/trends/neurosciences/pdf/0166-2236(90)90107-L.pdf

Functional architecture of basal ganglia circuits: neural substrates of parallel processing

The central theme of the "segregated circuits" hypothesis is that structural convergence and functional integration occurs within, rather than between, each of the identified circuits Admittedly, the anatomical evidence upon which this scheme is based remains incomplete The hypothesis continues to be predicated largely on comparisons of anterograde and retrograde labeling studies carried out in different sets of animals Only in the case of the "motor" circuit has evidence for the continuity of the loop been demonstrated directly in individual subjects; for the other circuits, such continuity is inferred from comparisons of data on different components of each circuit obtained in separate experiments Because of the marked compression of pathways leading from cortex through basal ganglia to thalamus, comparisons of projection topography across experimental subjects may be hazardous Definitive tests of the hypothesis of maintained segregation await additional double- and multiple-label tract-tracing experiments wherein the continuity of one circuit, or the segregation of adjacent circuits, can be examined directly in individual subjects It is worthy of note, however, that the few studies to date that have employed this methodology have generated results consistent with the segregated circuits hypothesis Moreover, single cell recordings in behaving animals have shown striking preservation of functional specificity at the level of individual neurons throughout the "motor" and "oculomotor" circuits It is difficult to imagine how such functional specificity could be maintained in the absence of strict topographic specificity within the sequential projections that comprise these two circuits This is not to say, however, that we expect the internal structure of functional channels (eg, the "arm" channel within the "motor" circuit) to have cable-like, point-to-point topography When the grain of analysis is sufficiently fine, anatomical studies have shown repeatedly that the terminal fields of internuclear projections (eg, to striatum, pallidum, nigra, thalamus, etc) often appear patchy and highly divergent, suggesting that neighboring groups of projection cells tend to influence interdigitating clusters of postsynaptic neurons While more intricate and complex than simple point-to-point topography, however, this type arrangement should also be capable of maintaining functional specificity As discussed briefly above, it is not yet clear to what extent the inputs to the "motor" circuit from the different precentral motor fields (eg, MC, SMA, APA) are integrated in their passage through the circuit It now appears that at the level of the putamen such inputs remain segregated(ABSTRACT TRUNCATED AT 400 WORDS)

Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions.

The basal ganglia: focused selection and inhibition of competing motor programs.

The activity of single cells in the motor cortex was recorded while monkeys made arm movements in eight directions (at 45 degrees intervals) in a two-dimensional apparatus. These movements started from the same point and were of the same amplitude. The activity of 606 cells related to proximal arm movements was examined in the task; 323 of the 606 cells were active in that task and were studied in detail. The frequency of discharge of 241 of the 323 cells (74.6%) varied in an orderly fashion with the direction of movement. Discharge was most intense with movements in a preferred direction and was reduced gradually when movements were made in directions farther and farther away from the preferred one. This resulted in a bell-shaped directional tuning curve. These relations were observed for cell discharge during the reaction time, the movement time, and the period that preceded the earliest changes in the electromyographic activity (approximately 80 msec before movement onset). In about 75% of the 241 directionally tuned cells, the frequency of discharge, D, was a sinusoidal function of the direction of movement, theta: D = b0 + b1 sin theta + b2cos theta, or, in terms of the preferred direction, theta 0: D = b0 + c1cos (theta - theta0), where b0, b1, b2, and c1 are regression coefficients. Preferred directions differed for different cells so that the tuning curves partially overlapped. The orderly variation of cell discharge with the direction of movement and the fact that cells related to only one of the eight directions of movement tested were rarely observed indicate that movements in a particular direction are not subserved by motor cortical cells uniquely related to that movement. It is suggested, instead, that a movement trajectory in a desired direction might be generated by the cooperation of cells with overlapping tuning curves. The nature of this hypothetical population code for movement direction remains to be elucidated.

https://www.jneurosci.org/content/jneuro/2/11/1527.full.pdf

On the relations between the direction of two-dimensional arm movements and cell discharge in primate motor cortex

Basal ganglia and cerebellar loops: motor and cognitive circuits.

The goal of the present neuroanatomical study in macaque monkeys was twofold: (1) to clarify whether the hand representation of the primary motor cortex (M1) has a transcallosal projection to M1 of the opposite hemisphere; (2) to compare the topography and density of transcallosal connections for the hand representations of M1 and the supplementary motor area (SMA). The hand areas of M1 and the SMA were identified by intracortical microstimulation and then injected either with retrograde tracer substances in order to label the neurons of origin in the contralateral motor cortical areas (four monkeys) or, with an anterograde tracer, to establish the regional distribution and density of terminal fields in the opposite motor cortical areas (two monkeys). The main results were: (1) The hand representation of M1 exhibited a modest homotopic callosal projection, as judged by the small number of labeled neurons within the region corresponding to the contralateral injection. A modest heterotopic callosal projection originated from the opposite supplementary, premotor, and cingulate motor areas. (2) In contrast, the SMA hand representation showed a dense callosal projection to the opposite SMA. The SMA was found to receive also dense heterotopic callosal projections from the contralateral rostral and caudal cingulate motor areas, moderate projections from the lateral premotor cortex, and sparse projections from M1. (3) After injection of an anterograde tracer (biotinylated dextran amine) in the hand representation of M1, only a few small patches of axonal label were found in the corresponding region of M1, as well as in the lateral premotor cortex; virtually no label was found in the SMA or in cingulate motor areas. Injections of the same anterograde tracer in the hand representation of the SMA, however, resulted in dense and widely distributed axonal terminal fields in the opposite SMA, premotor cortex, and cingulate motor areas, while labeled terminals were clearly less dense in M1. It is concluded that the hand representations of the SMA and M1 strongly differ with respect to the strength and distribution of callosal connectivity with the former having more powerful and widespread callosal connections with a number of motor fields of the opposite cortex than the latter. These anatomical results support the proposition of the SMA being a bilaterally organized system, possibly contributing to bimanual coordination.

Transcallosal connections of the distal forelimb representations of the primary and supplementary motor cortical areas in macaque monkeys

The interrelationship of medial area 6 (supplementary motor area) with the thalamus was investigated by means of anterograde and retrograde tracing methods. Nine monkeys were prepared for autoradiography or histochemistry with the marker HRP conjugated to the lectin wheat germ agglutinin. Three of the monkeys received injections into the precentral cortex for comparison. Previous observations were confirmed that the thalamic relays to the motor areas are organized as crescent-shaped lamellae which transgress cytoarchitectonic boundaries. The thalamic VA-VL complex receiving fibres from areas 4 and medial area 6 also sends fibres to these same areas. The thalamic relay to medial area 6 comprised the following subdivisions: VLo, VLc, area X of Olszewski, VLm and, to a smaller extent VA. Labeling (mostly anterograde only) was also prominent in some thalamic compartments outside the 'motor' thalamus: R, CL, CM-Pf, MD, LP, PULo. It was noted that rostral and caudal injections into the medial area 6 resulted in different thalamic labeling: The rostral portion was found to be related mainly with VApc, area X and VLc, the central portion with VLo, and the caudal portion with VLc/VLo. This structural inhomogeneity may reflect also a functional rostro-caudal differentiation of the medial area 6. The thalamic territory projecting to the precentral cortex is separate from the above relay and includes principally VPLo. The present anatomical labeling study is in agreement with the conclusion of Schell and Strick (1984) that the SMA, especially its central portion, is an important target of basal ganglia outflow via the thalamic relay VLo. In addition consistent labeling was also found in thalamic subdivisions (area X, VLc) which had been found to receive cerebellar fibres.

https://link.springer.com/content/pdf/10.1007/BF00237670.pdf

The thalamic connections with medial area 6 (supplementary motor cortex) in the monkey (macaca fascicularis)

The goal of the present study was to clarify whether the primary motor cortex (M1) and the supplementary motor cortex (SMA) both receive, via the motor thalamus, input from cerebellar and basal ganglia output nuclei. This is the first investigation that explores the problem by direct comparison, in the same animal, of thalamic zones that 1) project to M1 and SMA and 2) receive cerebellar-nuclear (CN) and pallidal (GP) afferents. These four zones were mapped in two monkeys by means of two retrograde tracers for M1 and SMA injections and of two anterograde tracers for CN and GP injections. All injections were performed under electrophysiological control (microstimulation and multiunit recordings). Injections in cortical areas were restricted to the hand/arm representation; in the SMA, the tracer deposit was within the "SMA-proper" (or "area F3") and did not include its rostral extension ("pre-SMA" or "area F6"). It was found that zones of all four types formed a number of highly complex patches of labeling that were usually not confined to one cytoarchitectonically defined thalamic nucleus. The overlap of clusters of labeled terminals and perikarya was evaluated morphometrically (area measurements) on a number of coronal sections along the anteroposterior extent of the motor thalamus. In line with previous studies, the thalamic territories innervated by CN and GP afferents rarely overlapped. However, zones projecting to M1 and/or to SMA included thalamic regions receiving CN as well as GP projections, providing the first evidence of such overlap from individual animals. The present observations support the previous conclusion from this laboratory (based on transsynaptic labeling) that the SMA receives, apart from its strong pallidal transthalamic input, a CN transthalamic input. These present findings that both M1 and SMA are recipients of transthalamic inputs from GP and CN thus support the concept that a mixed subcortical input consisting of weighted contributions from cerebellum, basal ganglia, substantia nigra, and spinothalamic tract is directed to each functional component of the sensorimotor cortex.

Cerebellothalamocortical and pallidothalamocortical projections to the primary and supplementary motor cortical areas: A multiple tracing study in macaque monkeys

The supplementary motor area of threeMacaca fascicularis was mapped using intracortical microstimulation (ICMS). Both forelimb and hindlimb movements were evoked using currents of 30 μA or less. However, thresholds for evoking movements were higher than those in the primary motor cortex. Proximal motor effects predominated, but distal joint movements were also elicited. Forelimb points were clustered in mesial cortex of area 6, anterior to the precentral hindlimb and tail region. Distal joint effects were located deep in the cortex, intermingled with proximal effects. Hindlimb responses which were less spatially localized, were found both ventral to the forelimb area, in the dorsal bank of the cingulate sulcus, and in mesial cortex, well anterior to area 4. No movements of facial muscles were elicited. Injections of HRP were made into the spinal cord at the cervical level in two animals and the lumbar level in the third one. An area of labelled cells was seen in mesial area 6 which corresponded closely to the region from which ICMS effects were elicited. No movements were evoked from the anterior portions of the fundal region of the cingulate sulcus which were also labelled.

Microstimulation of the supplementary motor area (SMA) in the awake monkey

In order to investigate the possibility of direct corticomotoneuronal (CM) connections in the rat, an anterograde-retrograde double-labeling method was developed. Phaseolus vulgaris-leucoagglutinin (PHA-L) anterograde tracing of corticospinal axons was combined with retrograde labeling of spinal motoneurons either by a conjugate of choleragen subunit B with horseradish peroxidase (CB-HRP) or by wheat germ agglutinin (WGA). The location of PHA-L injection unilaterally in the forelimb area of sensorimotor cortex and the CB-HRP or WGA injections in corresponding contralateral wrist or digit extensors or flexors were determined and matched on the basis of movement responses elicited by intracortical microstimulation. Light microscopic observation showed, in addition to the main contralateral dorsal corticospinal tract (CST), the presence of four other CST minor components in the contralateral lateral, ipsilateral ventral, and ipsilateral dorsal funiculi of the cervical spinal white matter and at the base of contralateral dorsal horn of the gray matter, respectively. PHA-L-labeled CST axonal arbors were observed from Rexed's lamina I through lamina X of contralateral spinal gray matter, most extensively in laminae VI and VII; some CST axons reached the zone of motoneuronal somata in lamina IX and a few of them also entered the lateral and occasionally the ventral funiculi, ramifying in the white matter. Between the zones of PHA-L-labeled CST axonal arbors on the one hand and CB-HRP/WGA labeled spinal motoneuronal somata with their extensive dendritic trees on the other, there was a large overlap, covering partly both the gray and the white matter. PHA-L-labeled axonal boutons (en passant or terminaux) were seen to contact the dendrites or even the somata of motoneurons in the gray matter, according to light-microscopic criteria for identification of synaptic contacts. Axodendritic CM contacts were occasionally observed in the lateral funiculus of the white matter as well. In general, only a single contact was observed between an individual PHA-L-labeled CST axon and a given retrogradely labeled motoneuron. In contrast to the common notion that direct CM connections are a specialty of primates, the present morphological data support the presence of direct CM connections also in some other mammals, such as the rat.

Mario Wiesendanger

Papers

Transcallosal connections of the distal forelimb representations of the primary and supplementary motor cortical areas in macaque monkeys

The thalamic connections with medial area 6 (supplementary motor cortex) in the monkey (macaca fascicularis)

Cerebellothalamocortical and pallidothalamocortical projections to the primary and supplementary motor cortical areas: A multiple tracing study in macaque monkeys

Microstimulation of the supplementary motor area (SMA) in the awake monkey

Corticomotoneuronal connections in the rat: Evidence from double‐labeling of motoneurons and corticospinal axon arborizations