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.

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.

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.

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.

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.

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.

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.

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).

Reproducing macaque lateral grasping and oculomotor networks using resting state functional connectivity and diffusion tractography.

Cortico-cortical networks involved in motor control have been well defined in the macaque using a range of invasive techniques. The advent of neuroimaging has enabled non-invasive study of these large-scale functionally specialized networks in the human brain; however, assessing its accuracy in reproducing genuine anatomy is more challenging. We set out to assess the similarities and differences between connections of macaque motor control networks defined using axonal tracing and those reproduced using structural and functional connectivity techniques. We processed a cohort of macaques scanned in vivo that were made available by the open access PRIME-DE resource, to evaluate connectivity using diffusion imaging tractography and resting state functional connectivity (rs-FC). Sectors of the lateral grasping and exploratory oculomotor networks were defined anatomically on structural images, and connections were reproduced using different structural and functional approaches (probabilistic and deterministic whole-brain and seed-based tractography; group template and native space functional connectivity analysis). The results showed that parieto-frontal connections were best reproduced using both structural and functional connectivity techniques. Tractography showed lower sensitivity but better specificity in reproducing connections identified by tracer data. Functional connectivity analysis performed in native space had higher sensitivity but lower specificity and was better at identifying connections between intrasulcal ROIs than group-level analysis. Connections of AIP were most consistently reproduced, although those connected with prefrontal sectors were not identified. We finally compared diffusion MR modelling with histology based on an injection in AIP and speculate on anatomical bases for the observed false negatives. Our results highlight the utility of precise ex vivo techniques to support the accuracy of neuroimaging in reproducing connections, which is relevant also for human studies.

Projections to the putamen from neurons located in the white matter and the claustrum in the macaque.

Continuing investigations of corticostriatal connections in rodents emphasize an intricate architecture where striatal projections originate from different combinations of cortical layers, include an inhibitory component, and form terminal arborizations which are cell-type dependent, extensive, or compact. Here, we report that in macaque monkeys, deep and superficial cortical white matter neurons (WMNs), peri-claustral WMNs, and the claustrum proper project to the putamen. WMNs retrogradely labeled by injections in the putamen (four injections in three macaques) were widely distributed, up to 10 mm antero-posterior from the injection site, mainly dorsal to the putamen in the external capsule, and below the premotor cortex. Striatally projecting labeled WMNs (WMNsST) were heterogeneous in size and shape, including a small GABAergic component. We compared the number of WMNsST with labeled claustral and cortical neurons and also estimated their proportion in relation to total WMNs. Since some WMNsST were located adjoining the claustrum, we wanted to compare results for density and distribution of striatally projecting claustral neurons (ClaST). ClaST neurons were morphologically heterogeneous and mainly located in the dorsal and anterior claustrum, in regions known to project to frontal, motor, and cingulate cortical areas. The ratio of ClaST to WMNsST was about 4:1 averaged across the four injections. These results provide new specifics on the connectional networks of WMNs in nonhuman primates, and delineate additional loops in the corticostriatal architecture, consisting of interconnections across cortex, claustralstriatal and striatally projecting WMNs.

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.

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.

Large-scale temporo-parieto-frontal networks for motor and cognitive motor functions in the primate brain.

The extent to which neural circuits and mechanisms underlying sensory, motor, and cognitive cortical functions in the human brain are shared with those of other animals, especially non-human primates, is currently a key issue in the field of comparative neuroscience. Cortical functions result from the conjoint function of different, reciprocally connected areas working together as large-scale functionally specialized networks, which can be investigated in human subjects thanks to the development of non-invasive functional and connectional imaging techniques. In spite of their limitations in terms of spatial and temporal resolution, these techniques make it possible to address the issue of how and to what extent the neural mechanisms for different cortical functions differ from those of non-human primates. Indeed, 30 million years of independent evolution have resulted in significant differences between the brains of humans and macaques, which are the experimental model system phylogenetically closest to humans for obtaining highly detailed anatomical and functional information on the organization of cortical networks. In the macaque brain, architectonic, connectional, and functional data have provided evidence for functionally specialized large-scale cortical networks involving temporal, parietal, and frontal areas. These networks appear to play a primary role in controlling different aspects of motor and cognitive motor functions, such as hand action organization and recognition, or oculomotor behavior and gaze processing. In the present review, based on the comparison of these data with data from human studies, we will argue that there is clear evidence for human counterparts of these networks. These human and macaque putatively homolog networks appear to share phylogenetically older neural mechanisms, which, in the evolution of the human lineage, could have been exploited and differentiated, resulting in the emergence of human-specific higher-order cognitive functions. These considerations are fully in line with the notion of "neural reuse" in primate evolution.

Cortical and subcortical connections of parietal and premotor nodes of the monkey hand mirror neuron network.

Mirror neurons (MNs) are a class of cells originally discovered in the monkey ventral premotor cortex (PMv) and inferior parietal lobule (IPL). They discharge during both action execution and action observation and appear to play a crucial role in understanding others' actions. It has been proposed that the mirror mechanism is based on a match between the visual description of actions, encoded in temporal cortical regions, and their motor representation, provided by PMv and IPL. However, neurons responding to action observation have been recently found in other cortical regions, suggesting that the mirror mechanism relies on a wider network. Here we provide the first description of this network by injecting neural tracers into physiologically identified IPL and PMv sectors containing hand MNs. Our results show that these sectors are reciprocally connected, in line with the current view, but IPL MN sectors showed virtually no direct connection with temporal visual areas. In addition, we found that PMv and IPL MN sectors share connections with several cortical regions, including the dorsal and mesial premotor cortex, the primary motor cortex, the secondary somatosensory cortex, the mid-dorsal insula and the ventrolateral prefrontal cortex, as well as subcortical structures, such as motor and polysensory thalamic nuclei and the mid-dorsal claustrum. We propose that each of these regions constitutes a node of an "extended network", through which information relative to ongoing movements, social context, environmental contingencies, abstract rules, and internal states can influence MN activity and contribute to several socio-cognitive functions.

Computational Architecture of the Parieto-Frontal Network Underlying Cognitive-Motor Control in Monkeys.

The statistical structure of intrinsic parietal and parieto-frontal connectivity in monkeys was studied through hierarchical cluster analysis. Based on their inputs, parietal and frontal areas were grouped into different clusters, including a variable number of areas that in most instances occupied contiguous architectonic fields. Connectivity tended to be stronger locally: that is, within areas of the same cluster. Distant frontal and parietal areas were targeted through connections that in most instances were reciprocal and often of different strength. These connections linked parietal and frontal clusters formed by areas sharing basic functional properties. This led to five different medio-laterally oriented pillar domains spanning the entire extent of the parieto-frontal system, in the posterior parietal, anterior parietal, cingulate, frontal, and prefrontal cortex. Different information processing streams could be identified thanks to inter-domain connectivity. These streams encode fast hand reaching and its control, complex visuomotor action spaces, hand grasping, action/intention recognition, oculomotor intention and visual attention, behavioral goals and strategies, and reward and decision value outcome. Most of these streams converge on the cingulate domain, the main hub of the system. All of them are embedded within a larger eye-hand coordination network, from which they can be selectively set in motion by task demands.

The macaque lateral grasping network: A neural substrate for generating purposeful hand actions.

In primates, neural mechanisms for controlling skilled hand actions primarily rely on sensorimotor transformations. These transformations are mediated by circuits linking specific inferior parietal with ventral premotor areas in which sensory coding of objects' features automatically triggers appropriate hand motor programs. Recently, connectional studies in macaques showed that these parietal and premotor areas are nodes of a large-scale cortical network, designated as "lateral grasping network," including specific temporal and prefrontal sectors involved in object recognition and executive functions, respectively. These data extend grasping models so far proposed in providing a possible substrate for interfacing perceptual, cognitive, and hand-related sensorimotor processes for controlling hand actions based on object identity, goals, and memory-based or contextual information and for the contribution of motor signals to cognitive motor functions. Human studies provided evidence for a possible counterpart of the macaque lateral grasping network, suggesting that in primate evolution the neural mechanisms for controlling hand actions described in the macaque have been retained and exploited for the emergence of human-specific motor and cognitive motor capacities.

Functional anatomy of the macaque temporo-parieto-frontal connectivity.

The primate parietal lobe is primarily dedicated to the processing of sensory information for the guidance of motor behavior, based on the integration of sensory with motor signals (sensorimotor transformations), mediated by specific, strong, and reciprocal connections with the motor cortex. Sensorimotor transformations have been regarded as an automatic process carried out independently from the temporal cortex, which is considered the location where sensory information is used for perceptual processes. However, both human and non-human primate studies have shown interactions between these two regions in different aspects of sensorimotor and cognitive processes. Connectional studies in macaques have provided a detailed description of the possible neural substrate for these interactions. Specifically, temporo-parietal connections almost exclusively involve the inferior parietal lobule (IPL) and display a fine topographic organization, providing the substrate for the role of the macaque IPL in "perception-based" control of motor behavior. Particularly, more rostral IPL areas are involved in motor and cognitive motor functions related to hand action organization and oculomotor control as well as in action and intention understanding, whereas more caudal IPL areas are involved in multisensory integration for the construction of space representations for guiding arm and eye motor behavior. Temporal and IPL-interconnected areas also share connections with specific ventral frontal areas and are thus part of large-scale cortical networks in which the various nodes are linked through "dorsal" temporo-parieto-frontal and "ventral" temporo-frontal pathways. Anatomical and functional studies suggest homologies between human and macaque temporo-parieto-frontal connectivity; they also suggest that higher-order functions of the human IPL could have evolved from the exploitation and adaptation of phylogenetically older neural mechanisms that occur in macaque brains. Thus, connectional data from macaque studies appear essential for understanding human brain mechanisms, even in cases of cognitive abilities undeveloped in other animals, and for interpreting clinical data, including disconnection syndromes.

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.

Connections of the macaque Granular Frontal Opercular (GrFO) area: a possible neural substrate for the contribution of limbic inputs for controlling hand and face/mouth actions.

We traced the connections of the macaque Granular Frontal Opercular (GrFO) area, located in the rostralmost part of the frontal opercular margin, and compared them with those of the caudally adjacent dorsal opercular (DO) and precentral opercular (PrCO) areas. Area GrFO displays strong connections with areas DO, PrCO, and ventrolateral prefrontal (VLPF) area 12l, and even more with the mostly hand-related ventral premotor (PMv) area F5a. Other connections involve the mostly face/mouth-related PMv area F5c, the arm-related area F6/pre-SMA, the hand-related fields of VLPF areas 46v and 12r, and area SII, mostly the hand representation. Furthermore, area GrFO shows rich connectivity with several components of the limbic system including orbitofrontal areas 12o, 12m, and 11, the agranular and dysgranular insula, the agranular cingulate area 24, and the amygdala. Thalamic afferents originate primarily from the parvocellular and the magnocellular subdivisions of the mediodorsal nucleus and from midline and intralaminar nuclei. This connectivity pattern clearly distinguishes area GrFO from areas DO and PrCO, characterized by a connectivity mostly involving oral sensorimotor and gustatory areas/subcortical structures. The present data suggest, based on connectivity patterns, an involvement of area GrFO in the cortical circuits for controlling goal-directed hand and face/mouth actions. In this context, area GrFO could represent a gateway for the access of limbic inputs, for example about subjective values, emotional significance of stimuli or internal states, to the PMv areas involved in selecting appropriate goal-directed hand and mouth/face actions.