Neural substrate for the engagement of the ventral visual stream in motor control in the macaque monkey.

The present study aimed to describe the cortical connectivity of a sector located in the ventral bank of the superior temporal sulcus in the macaque (intermediate area TEa and TEm [TEa/m]), which appears to represent the major source of output of the ventral visual stream outside the temporal lobe. The retrograde tracer wheat germ agglutinin was injected in the intermediate TEa/m in four macaque monkeys. The results showed that 58-78% of labeled cells were located within ventral visual stream areas other than the TE complex. Outside the ventral visual stream, there were connections with the memory-related medial temporal area 36 and the parahippocampal cortex, orbitofrontal areas involved in encoding subjective values of stimuli for action selection, and eye- or hand-movement related parietal (LIP, AIP, and SII), prefrontal (12r, 45A, and 45B) areas, and a hand-related dysgranular insula field. Altogether these data provide a solid substrate for the engagement of the ventral visual stream in large scale cortical networks for skeletomotor or oculomotor control. Accordingly, the role of the ventral visual stream could go beyond pure perceptual processes and could be also finalized to the neural mechanisms underlying the control of voluntary motor behavior.

Crossed Corticostriatal Projections in the Macaque Brain.

In nonhuman primates, major input to the striatum originates from ipsilateral cortex and thalamus. The striatum is a target also of crossed corticostriatal (CSt) projections from the contralateral hemisphere, which have been so far somewhat neglected. In the present study, based on neural tracer injections in different parts of the striatum in macaques of either sex, we analyzed and compared qualitatively and quantitatively the distribution of labeled CSt cells in the two hemispheres. The results showed that crossed CSt projections to the caudate and the putamen can be relatively robust (up to 30% of total labeled cells). The origin of the direct and the crossed CSt projections was not symmetrical as the crossed ones originated almost exclusively from motor, prefrontal, and cingulate areas and not from parietal and temporal areas. Furthermore, there were several cases in which the contribution of contralateral areas tended to equal that of the ipsilateral ones. The present study is the first detailed description of this anatomic pathway of the macaque brain and provides the substrate for bilateral distribution of motor, motivational, and cognitive signals for reinforcement learning and selection of actions or action sequences, and for learning compensatory motor strategies after cortical stroke.SIGNIFICANCE STATEMENT In nonhuman primates the striatum is a target of projections originating from the contralateral hemisphere (crossed CSt projections), which have been so far poorly investigated. The present study analyzed qualitatively and quantitatively in the macaque brain the origin of the crossed CSt projections compared with those originating from the ipsilateral hemisphere. The results showed that crossed CSt projections originate mostly from frontal and rostral cingulate areas and in some cases their contribution tended to equal that from ipsilateral areas. These projections could provide the substrate for bilateral distribution of motor, motivational, and cognitive signals for reinforcement learning and action selection, and for learning compensatory motor strategies after cortical stroke.

Laminar Origin of Corticostriatal Projections to the Motor Putamen in the Macaque Brain.

In the macaque brain, projections from distant, interconnected cortical areas converge in specific zones of the striatum. For example, specific zones of the motor putamen are targets of projections from frontal motor, inferior parietal, and ventrolateral prefrontal hand-related areas and thus are integral part of the so-called "lateral grasping network." In the present study, we analyzed the laminar distribution of corticostriatal neurons projecting to different parts of the motor putamen. Retrograde neural tracers were injected in different parts of the putamen in 3 Macaca mulatta (one male) and the laminar distribution of the labeled corticostriatal neurons was analyzed quantitatively. In frontal motor areas and frontal operculum, where most labeled cells were located, almost everywhere the proportion of corticostriatal labeled neurons in layers III and/or VI was comparable or even stronger than in layer V. Furthermore, within these regions, the laminar distribution pattern of corticostriatal labeled neurons largely varied independently from their density and from the projecting area/sector, but likely according to the target striatal zone. Accordingly, the present data show that cortical areas may project in different ways to different striatal zones, which can be targets of specific combinations of signals originating from the various cortical layers of the areas of a given network. These observations extend current models of corticostriatal interactions, suggesting more complex modes of information processing in the basal ganglia for different motor and nonmotor functions and opening new questions on the architecture of the corticostriatal circuitry.SIGNIFICANCE STATEMENT Projections from the ipsilateral cerebral cortex are the major source of input to the striatum. Previous studies have provided evidence for distinct zones of the putamen specified by converging projections from specific sets of interconnected cortical areas. The present study shows that the distribution of corticostriatal neurons in the various layers of the primary motor and premotor areas varies depending on the target striatal zone. Accordingly, different striatal zones collect specific combinations of signals from the various cortical layers of their input areas, possibly differing in terms of coding, timing, and direction of information flow (e.g., feed-forward, or feed-back).

Rostro-caudal Connectional Heterogeneity of the Dorsal Part of the Macaque Prefrontal Area 46.

Based on neural tracer injections we found evidence for 3 connectionally distinct sectors of the dorsal part of the macaque prefrontal area 46 (46d), located at different rostro-caudal levels. Specifically, a rostral sector displayed an almost exclusive and extensive intraprefrontal connectivity and extraprefrontal connections limited to superior temporal areas and the caudal cingulate area 31. Conversely, both a middle and a caudal sector were characterized by robust, topographically organized connections with parietal and frontal sensorimotor areas. Both these sectors shared connections with caudal and medial superior parietal areas (V6A and PGm) where visuospatial information is combined with gaze- and arm-related signals for visuomotor control of arm reaching and/or eye movements. However, the caudal sector was preferentially connected to parietal and frontal oculomotor areas, whereas the middle one was preferentially connected to skeletomotor, mostly arm-related, parietal and premotor areas. The present study provides evidence for a rostro-caudal organization of area 46d similar to that described for the ventrolateral prefrontal cortex, in which more caudal areas are relatively more directly involved in controlling different aspects of motor behavior and more rostral areas are most likely involved in higher order, possibly more abstract, cognitive functions.

Anterior Intraparietal Area: A Hub in the Observed Manipulative Action Network.

Current knowledge regarding the processing of observed manipulative actions (OMAs) (e.g., grasping, dragging, or dropping) is limited to grasping and underlying neural circuitry remains controversial. Here, we addressed these issues by combining chronic neuronal recordings along the anteroposterior extent of monkeys' anterior intraparietal (AIP) area with tracer injections into the recorded sites. We found robust neural selectivity for 7 distinct OMAs, particularly in the posterior part of AIP (pAIP), where it was associated with motor coding of grip type and own-hand visual feedback. This cluster of functional properties appears to be specifically grounded in stronger direct connections of pAIP with the temporal regions of the ventral visual stream and the prefrontal cortex, as connections with skeletomotor related areas and regions of the dorsal visual stream exhibited opposite or no rostrocaudal gradients. Temporal and prefrontal areas may provide visual and contextual information relevant for manipulative action processing. These results revise existing models of the action observation network, suggesting that pAIP constitutes a parietal hub for routing information about OMA identity to the other nodes of the network.

Corticostriate Projections from Areas of the "Lateral Grasping Network": Evidence for Multiple Hand-Related Input Channels.

Corticostriatal projections from the primate cortical motor areas partially overlap in different zones of a large postcommissural putaminal sector designated as "motor" putamen. These zones are at the origin of parallel basal ganglia-thalamocortical subloops involved in modulating the cortical motor output. However, it is still largely unknown how parietal and prefrontal areas, connected to premotor areas, and involved in controlling higher order aspects of motor control, project to the basal ganglia. Based on tracer injections at the cortical level, we analyzed the corticostriatal projections of the macaque hand-related ventrolateral prefrontal, ventral premotor, and inferior parietal areas forming a network for controlling purposeful hand actions (lateral grasping network). The results provided evidence for partial overlap or interweaving of these projections in correspondence of 2 putaminal zones, distinct from the motor putamen, one located just rostral to the anterior commissure, the other in the caudal and ventral part. Thus, the present data provide evidence for partial overlap or interweaving in specific striatal zones (input channels) of projections from multiple, even remote, areas taking part in a large-scale functionally specialized cortical network. Furthermore, they suggest the presence of multiple hand-related input channels, possibly differentially involved in controlling goal-directed hand actions.

Projections from caudal ventrolateral prefrontal areas to brainstem preoculomotor structures and to Basal Ganglia and cerebellar oculomotor loops in the macaque.

The caudal part of the macaque ventrolateral prefrontal (VLPF) cortex hosts several distinct areas or fields--45B, 45A, 8r, caudal 46vc, and caudal 12r--connected to the frontal eye field (area 8/FEF). To assess whether these areas/fields also display subcortical projections possibly mediating a role in controlling oculomotor behavior, we examined their descending projections, based on anterograde tracer injections in each area/field, and compared them with those of area 8/FEF. All the studied areas/fields displayed projections to brainstem preoculomotor structures, precerebellar centers, and striatal sectors that are also targets of projections originating from area 8/FEF. Specifically, these projections involved: (1) the intermediate and superficial layers of the superior colliculus; (2) the mesencephalic and pontine reticular formation; (3) the dorsomedial and lateral pontine nuclei and the reticularis tegmenti pontis; and (4) the body of the caudate nucleus. Furthermore, area 45B projected also to the regions around the trochlear nucleus and to the raphe interpositus. The present data provide evidence for a role of the caudal VLPF areas/fields in controlling oculomotor behavior not only through their connections to area 8/FEF, but also in parallel through a direct access to preoculomotor brainstem structures and to the cerebellar and basal ganglia oculomotor loops.

Projections to the superior colliculus from inferior parietal, ventral premotor, and ventrolateral prefrontal areas involved in controlling goal-directed hand actions in the macaque.

We found that the macaque inferior parietal (PFG and anterior intraparietal [AIP]), ventral premotor (F5p and F5a), and ventrolateral prefrontal (rostral 46vc and intermediate 12r) areas forming a network involved in controlling purposeful hand actions ("lateral grasping network") are a source of corticotectal projections. Based on injections of anterograde tracers at the cortical level, the results showed that all these areas displayed relatively dense projections to the intermediate and deep gray layers of the ipsilateral superior colliculus (SC) and to the ventrally adjacent mesencephalic reticular formation. In the SC, the labeling tended to be richer in the lateral part along almost the entire rostro-caudal extent, that is, in regions controlling microsaccades and downward gaze shifts and hosting arm-related neurons and neurons modulated by the contact of the hand with the target. These projections could represent a descending motor pathway for controlling proximo-distal arm synergies. Furthermore, they could broadcast to the SC information related to hand action goals and object affordances extraction and selection. This information could be used in the SC for controlling orienting behavior (gaze and reaching movements) to the targets of object-oriented actions and for the eye-hand coordination necessary for appropriate hand-object interactions.

Connectional heterogeneity of the ventral part of the macaque area 46.

We found that the ventral part of the prefrontal area 46 (46v) is connectionally heterogeneous. Specifically, the rostral part (46vr) displayed an almost exclusive and extensive intraprefrontal connectivity and extraprefrontal connections limited to area 24 and inferotemporal areas. In contrast, the caudal part (46vc) mostly displayed intraprefrontal connectivity with ventrolateral areas and robust connectivity with frontal and parietal sensorimotor areas. Based on a topographic organization of these connections, 3 fields were identified in area 46vc. A caudal field (caudal 46vc) was preferentially connected to oculomotor prearcuate (8/FEF, 45B, and 8r) and inferior parietal areas. The other 2, located more rostrally, in the bank of the principal sulcus (rostral 46vc/bank) and on the ventrolateral convexity cortex (rostral 46vc/convexity), respectively, were connected with hand/mouth-related (F5a, 44) ventral premotor areas, area SII, and the insula. However, rostral 46vc/convexity was also connected to the hand-related area AIP, whereas rostral 46vc/bank to hand/arm-related areas PFG and PG, to PGop, and to areas 11 and 24. The present data suggest a differential role in executive functions of areas 46vr and 46vc and a differential involvement of different parts of area 46vc in higher level integration for oculomotor behavior and goal-directed arm, hand, and mouth actions.

Disentangling the identity of the zona incerta: a review of the known connections and latest implications.

The zona incerta (ZI) is a subthalamic region composed by loosely packed neurochemically mixed neurons, juxtaposed to the main ascending and descending bundles. The extreme neurochemical diversity that characterizes this area, together with the diffuseness of its connections with the entire neuraxis and its hard-to-reach positioning in the brain caused the ZI to keep its halo of mystery for over a century. However, in the last decades, a rich albeit fragmentary body of knowledge regarding both the incertal anatomical connections and functional implications has been built mostly based on rodent studies and its lack of cohesion makes difficult to depict an integrated, exhaustive picture regarding the ZI and its roles. This review aims to provide a unified resource that summarizes the current knowledge regarding the anatomical profile of interactions of the ZI in rodents and non-human primates and the functional significance of its connections, highlighting the aspects still unbeknown to research.

Involvement of the claustrum in the cortico-basal ganglia circuitry: connectional study in the non-human primate.

The claustrum is an ancient telencephalic subcortical structure displaying extensive, reciprocal connections with much of the cortex and receiving projections from thalamus, amygdala, and hippocampus. This structure has a general role in modulating cortical excitability and is considered to be engaged in different cognitive and motor functions, such as sensory integration and perceptual binding, salience-guided attention, top-down executive functions, as well as in the control of brain states, such as sleep and its interhemispheric integration. The present study is the first to describe in detail a projection from the claustrum to the striatum in the macaque brain. Based on tracer injections in different striatal regions and in different cortical areas, we observed a rough topography of the claustral connectivity, thanks to which a claustral zone projects to both a specific striatal territory and to cortical areas involved in a network projecting to the same striatal territory. The present data add new elements of complexity of the basal ganglia information processing mode in motor and non-motor functions and provide evidence for an influence of the claustrum on both cortical functional domains and cortico-basal ganglia circuits.

Gradients of thalamic connectivity in the macaque lateral prefrontal cortex.

In the primate brain, the lateral prefrontal cortex (LPF) is a large, heterogeneous region critically involved in the cognitive control of behavior, consisting of several connectionally and functionally distinct areas. Studies in macaques provided evidence for distinctive patterns of cortical connectivity between architectonic areas located at different dorsoventral levels and for rostrocaudal gradients of parietal and frontal connections in the three main architectonic LPF areas: 46d, 46v, and 12r. In the present study, based on tracer injections placed at different dorsoventral and rostrocaudal cortical levels, we have examined the thalamic projections to the LPF to examine to what extent fine-grained connectional gradients of cortical connectivity are reflected in the topography of thalamo-LPF projections. The results showed mapping onto the nucleus medialis dorsalis (MD), by far the major source of thalamic input to the LPF, of rostral-to-caudal LPF zones, in which MD zones projecting to more caudal LPF sectors are located more rostral than those projecting to intermediate LPF sectors. Furthermore, the MD zones projecting to the rostral LPF sectors tended to be much more extensive in the rostrocaudal direction. One rostrolateral MD sector appeared to be a common source of projections to caudal prefrontal areas involved in the oculomotor frontal domain, a more caudal and ventral MD sector to a large extent of the ventral LPF, and middle and dorsal MD sectors to most of the dorsal LPF. Additional topographically organized projections to LPF areas originated from the nucleus pulvinaris medialis and projections from the nucleus anterior medialis selectively targeted more rostral sectors of LPF. Thus, the present data suggest that the topography of the MD-LPF projections does not adhere to simple topological rules, but is mainly organized according to functional criteria.

Anatomical evidence for the involvement of the macaque ventrolateral prefrontal area 12r in controlling goal-directed actions.

The macaque ventrolateral prefrontal (VLPF) area 12r is thought to be involved in higher-order nonspatial information processing. We found that this area is connectionally heterogeneous, and the intermediate part is fully integrated in a cortical network involved in selecting and controlling object-oriented hand and mouth actions. Specifically, intermediate area 12r displayed dense connections with the caudal half of area 46v and orbitofrontal areas and relatively strong extraprefrontal connections involving the following: (1) the hand- and mouth-related ventral premotor area F5 and the anterior intraparietal (AIP) area, jointly involved in visuomotor transformations for grasping; (2) the SII sector that is connected to AIP and F5; (3) a sector of the inferotemporal area TEa/m, primarily corresponding to the sector densely connected to AIP; and (4) the insular and opercular frontal sectors, which are connected to AIP and F5. This connectivity pattern differed markedly from those of the caudal and rostral parts of area 12r. Caudal area 12r displayed dense connections with the caudal part of the VLPF, including oculomotor areas 8/FEF and 45B, relatively weak orbitofrontal connections and extraprefrontal connections limited to the inferotemporal cortex. Rostral area 12r displayed connections mostly with rostral prefrontal and orbitofrontal areas and relatively weaker connections with the fundus and the upper bank of the superior temporal sulcus. The present data suggest that the intermediate part of area 12r is involved in nonspatial information processing related to object properties and identity, for selecting and controlling goal-directed hand and mouth actions.

Action observation circuits in the macaque monkey cortex.

In both monkeys and humans, the observation of actions performed by others activates cortical motor areas. An unresolved question concerns the pathways through which motor areas receive visual information describing motor acts. Using functional magnetic resonance imaging (fMRI), we mapped the macaque brain regions activated during the observation of grasping actions, focusing on the superior temporal sulcus region (STS) and the posterior parietal lobe. Monkeys viewed either videos with only the grasping hand visible or videos with the whole actor visible. Observation of both types of grasping videos activated elongated regions in the depths of both lower and upper banks of STS, as well as parietal areas PFG and anterior intraparietal (AIP). The correlation of fMRI data with connectional data showed that visual action information, encoded in the STS, is forwarded to ventral premotor cortex (F5) along two distinct functional routes. One route connects the upper bank of the STS with area PFG, which projects, in turn, to the premotor area F5c. The other connects the anterior part of the lower bank of the STS with premotor areas F5a/p via AIP. Whereas the first functional route emphasizes the agent and may relay visual information to the parieto-frontal mirror circuit involved in understanding the agent's intentions, the second route emphasizes the object of the action and may aid in understanding motor acts with respect to their immediate goal.

Cortical connections to area TE in monkey: hybrid modular and distributed organization.

To investigate the fine anatomical organization of cortical inputs to visual association area TE, 2-3 small injections of retrograde tracers were made in macaque monkeys. Injections were made as a terminal procedure, after optical imaging and electrophysiological recording, and targeted to patches physiologically identified as object-selective. Retrogradely labeled neurons occurred in several unimodal visual areas, the superior temporal sulcus, intraparietal sulcus (IPS), and prefrontal cortex (PFC), consistent with previous studies. Despite the small injection size (<0.5 mm wide), the projection foci in visual areas, but not in IPS or PFC, were spatially widespread (4-6 mm in extent), and predominantly consisted of neurons labeled by only one of the injections. This can be seen as a quasi-modular organization. In addition, within each projection focus, there were scattered neurons projecting to one of the other injections, together with some double-labeled (DL) neurons, in a more distributed pattern. Finally, projection foci included smaller "hotspots," consisting of intermixed neurons, single-labeled by the different injections, and DL neurons. DL neurons are likely the result of axons having extended, spatially separated terminal arbors, as demonstrated by anterograde experiments. These results suggest a complex, hybrid connectivity architecture, with both modular and distributed components.

Cortical connections of the macaque caudal ventrolateral prefrontal areas 45A and 45B.

We have found that the 2 architectonic subdivisions of the prefrontal area 45, 45A and 45B, display connectivity patterns that clearly distinguish them from one another and from their neighboring architectonic areas. Area 45A is primarily connected to the frontal areas 45B, 12l, caudal 12r, 12o, 10, rostrodorsal 46, 9/8B, 44, 8/FEF (frontal eye field), and the SEF (supplementary eye field), temporal area IPa, and unique among all the studied areas, to the superior temporal polysensory (STP) area and auditory parabelt areas. Area 45B displayed much stronger frontal connections with the oculomotor areas 8/FEF, 8r, and the SEF than those of area 45A, primary connections with areas 12l, caudal 12r, 12o, and 8B, and unlike area 45A, with areas ventrorostral 46, rostral 12r, 12m, and 13m. Temporal connections were all virtually confined to areas IPa, intermediate TEa/m, and TE. Additional labeling was found in lateral intraparietal area. Our data suggest that 45A and 45B are 2 distinct areas, possibly playing a differential role in nonspatial information processing: area 45A corresponds to the prefrontal sector for which a role in communication behavior and homology with the human area 45 was proposed, whereas area 45B is a distinct prearcuate area, possibly affiliated to the oculomotor frontal system.

Comparative anatomy of the macaque and the human frontal oculomotor domain.

In non-human primates, at the junction of the prefrontal with the premotor cortex, there is a sector designated as frontal eye field (FEF), involved in controlling oculomotor behavior and spatial attention. Evidence for at least two FEFs in humans is at the basis of the still open issue of the possible homologies between the macaque and the human frontal oculomotor system. In this review article we address this issue suggesting a new view solidly grounded on evidence from the last decade showing that, in macaques, the FEF is at the core of an oculomotor domain in which several distinct areas, including areas 45A and 45B, provide the substrate for parallel processing of different aspects of oculomotor behavior. Based on comparative considerations, we will propose a correspondence between some of the macaque and the human oculomotor fields, thus suggesting sharing of neural substrate for oculomotor control, gaze processing, and orienting attention in space. Accordingly, this article could contribute to settle some aspects of the so-called "enigma" of the human FEF anatomy.

The Complex Hodological Architecture of the Macaque Dorsal Intraparietal Areas as Emerging from Neural Tracers and DW-MRI Tractography.

In macaque monkeys, dorsal intraparietal areas are involved in several daily visuomotor actions. However, their border and sources of cortical afferents remain loosely defined. Combining retrograde histologic tracing and MRI diffusion-based tractography, we found a complex hodology of the dorsal bank of the intraparietal sulcus (db-IPS), which can be subdivided into a rostral intraparietal area PEip, projecting to the spinal cord, and a caudal medial intraparietal area MIP lacking such projections. Both include an anterior and a posterior sector, emerging from their ipsilateral, gradient-like connectivity profiles. As tractography estimations, we used the cross-sectional area of the white matter bundles connecting each area with other parietal and frontal regions, after selecting regions of interest (ROIs) corresponding to the injection sites of neural tracers. For most connections, we found a significant correlation between the proportions of cells projecting to all sectors of PEip and MIP along the continuum of the db-IPS and tractography. The latter also revealed "false positive" but plausible connections awaiting histologic validation.

Thalamic projections to the macaque caudal ventrolateral prefrontal areas 45A and 45B.

We studied the sources of thalamic projections to the caudal ventrolateral prefrontal areas 45A and 45B, which display markedly distinct cortical connections [M. Gerbella et al. (2010) Cereb. Cortex, 20, 141-168], and compared them with those to area 8/FEF (frontal eye field). Both areas 45A and 45B were the targets of highly predominant projections from the mediodorsal nucleus (MD) and of additional projections, mostly from the magnocellular ventral anterior and the medial pulvinar nucleus. The projection profiles from different MD subdivisions clearly distinguished these two areas from one another and from area 8/FEF. Area 45A was the target of predominant projections from parvicellular MD and of minor, albeit robust, projections from magnocellular MD. The opposite was true for area 45B: magnocellular MD was the major source of projections and parvicellular MD contributed minor, albeit robust, projections. Furthermore, area 45B, but not area 45A, was targeted by robust projections from multiform MD, the principal thalamic nucleus for area 8/FEF. These results provide further evidence for the distinctiveness of areas 45A and 45B, and support the idea that area 45B is affiliated with the frontal oculomotor system, challenging the proposed homology of this area with part of the human language-related area 45 (rostral part of Broca's region). Furthermore, the present data provide evidence for potentially robust trans-thalamic (via magnocellular MD) afferent, as well as direct and reciprocal, amygdaloid connections of areas 45A and 45B, suggesting the contribution of emotional information to the differential role of these two areas in non-spatial information processing.