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.

Anatomo-functional basis of emotional and motor resonance elicited by facial expressions.

Simulation theories predict that the observation of other's expressions modulates neural activity in the same centres controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization (emotional resonance). Here we investigated the role of frontal/insular regions in the processing of observed emotional expressions by combining intracranial recording, electrical stimulation and effective connectivity. First, we intracranially recorded from prefrontal, premotor or anterior insular regions of 44 patients during the passive observation of emotional expressions, finding widespread modulations in prefrontal/insular regions (anterior cingulate cortex, anterior insula, orbitofrontal cortex and inferior frontal gyrus) and motor territories (Rolandic operculum and inferior frontal junction). Subsequently, we electrically stimulated the activated sites, finding that (i) in the anterior cingulate cortex and anterior insula, the stimulation elicited emotional/interoceptive responses, as predicted by the 'emotional resonance model'; (ii) in the Rolandic operculum it evoked face/mouth sensorimotor responses, in line with the 'motor resonance' model; and (iii) all other regions were unresponsive or revealed functions unrelated to the processing of facial expressions. Finally, we traced the effective connectivity to sketch a network-level description of these regions, finding that the anterior cingulate cortex and the anterior insula are reciprocally interconnected while the Rolandic operculum is part of the parieto-frontal circuits and poorly connected with the former. These results support the hypothesis that the pathways hypothesized by the 'emotional resonance' and the 'motor resonance' models work in parallel, differing in terms of spatio-temporal fingerprints, reactivity to electrical stimulation and connectivity patterns.

Ventrolateral prefrontal neurons of the monkey encode instructions in the 'pragmatic' format of the associated behavioral outcomes.

The prefrontal cortex plays an important role in coding rules and producing context-appropriate behaviors. These processes necessarily require the generation of goals based on current context. Indeed, instructing stimuli are prospectively encoded in prefrontal cortex in relation to behavioral demands, but the coding format of this neural representation is, to date, largely unknown. In order to study how instructions and behaviors are encoded in prefrontal cortex, we recorded the activity of monkeys (Macaca mulatta) ventrolateral prefrontal neurons in a task requiring to perform (Action condition) or withhold (Inaction condition) grasping actions on real objects. Our data show that there are neurons responding in different task phases, and that the neuronal population discharge is stronger in the Inaction condition when the instructing cue is presented, and in the Action condition in the subsequent phases, from object presentation to action execution. Decoding analyses performed on neuronal populations showed that the neural activity recorded during the initial phases of the task shares the same type of format with that recorded during the final phases. We propose that this format has a pragmatic nature, that is instructions and goals are encoded by prefrontal neurons as predictions of the behavioral outcome.

Activation of Cerebellum, Basal Ganglia and Thalamus During Observation and Execution of Mouth, hand, and foot Actions.

Humans and monkey studies showed that specific sectors of cerebellum and basal ganglia activate not only during execution but also during observation of hand actions. However, it is unknown whether, and how, these structures are engaged during the observation of actions performed by effectors different from the hand. To address this issue, in the present fMRI study, healthy human participants were required to execute or to observe grasping acts performed with different effectors, namely mouth, hand, and foot. As control, participants executed and observed simple movements performed with the same effectors. The results show that: (1) execution of goal-directed actions elicited somatotopically organized activations not only in the cerebral cortex but also in the cerebellum, basal ganglia, and thalamus; (2) action observation evoked cortical, cerebellar and subcortical activations, lacking a clear somatotopic organization; (3) in the territories displaying shared activations between execution and observation, a rough somatotopy could be revealed in both cortical, cerebellar and subcortical structures. The present study confirms previous findings that action observation, beyond the cerebral cortex, also activates specific sectors of cerebellum and subcortical structures and it shows, for the first time, that these latter are engaged not only during hand actions observation but also during the observation of mouth and foot actions. We suggest that each of the activated structures processes specific aspects of the observed action, such as performing internal simulation (cerebellum) or recruiting/inhibiting the overt execution of the observed action (basal ganglia and sensory-motor thalamus).

Investigating form and content of emotional and non-emotional laughing.

As cold actions (i.e. actions devoid of an emotional content), also emotions are expressed with different vitality forms. For example, when an individual experiences a positive emotion, such as laughing as expression of happiness, this emotion can be conveyed to others by different intensities of face expressions and body postures. In the present study, we investigated whether the observation of emotions, expressed with different vitality forms, activates the same neural structures as those involved in cold action vitality forms processing. To this purpose, we carried out a functional magnetic resonance imaging study in which participants were tested in 2 conditions: emotional and non-emotional laughing both conveying different vitality forms. There are 3 main results. First, the observation of emotional and non-emotional laughing conveying different vitality forms activates the insula. Second, the observation of emotional laughing activates a series of subcortical structures known to be related to emotions. Furthermore, a region of interest analysis carried out in these structures reveals a significant modulation of the blood-oxygen-leveldependent (BOLD) signal during the processing of different vitality forms exclusively in the right amygdala, right anterior thalamus/hypothalamus, and periaqueductal gray. Third, in a subsequent electromyography study, we found a correlation between the zygomatic muscles activity and BOLD signal in the right amygdala only.

Specific tractography differences in autism compared to developmental coordination disorder.

About 85% of children with autism spectrum disorder (ASD) experience comorbid motor impairments, making it unclear whether white matter abnormalities previously found in ASD are related to social communication deficits, the hallmark of ASD, or instead related to comorbid motor impairment. Here we aim to understand specific white matter signatures of ASD beyond those related to comorbid motor impairment by comparing youth (aged 8-18) with ASD (n = 22), developmental coordination disorder (DCD; n = 16), and typically developing youth (TD; n = 22). Diffusion weighted imaging was collected and quantitative anisotropy, radial diffusivity, mean diffusivity, and axial diffusivity were compared between the three groups and correlated with social and motor measures. Compared to DCD and TD groups, diffusivity differences were found in the ASD group in the mid-cingulum longitudinal and u-fibers, the corpus callosum forceps minor/anterior commissure, and the left middle cerebellar peduncle. Compared to the TD group, the ASD group had diffusivity differences in the right inferior frontal occipital/extreme capsule and genu of the corpus callosum. These diffusion differences correlated with emotional deficits and/or autism severity. By contrast, children with DCD showed unique abnormality in the left cortico-spinal and cortico-pontine tracts.Trial Registration All data are available on the National Institute of Mental Health Data Archive: https://nda.nih.gov/edit_collection.html?id=2254 .

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).

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.

Connectional gradients underlie functional transitions in monkey pre-supplementary motor area.

The pre-supplementary motor area F6 is involved in a variety of functions in multiple domains, from planning/withholding goal-directed actions in space to rule-based cognitive processes and social interactions. Yet, the neural machinery underlying this functional heterogeneity remains unclear. Here, we measured local population dynamics in different rostro-caudal sites of cytoarchitectonically verified area F6 in two monkeys during spatial, contextual and motor processes, both in individual and social conditions. Then, we correlated multimodal population tuning with local anatomical connectivity revealed by neural tracer injections into the functionally characterized sites. We found stronger tuning for object position relative to the monkey in the rostral portion of area F6 than in its caudal part, which in turn exhibits stronger tuning to self and other's (observed) action. Functional specificities were associated with a rostro-caudal transition in connectivity strength from lateral prefrontal cortex, pregenual anterior cingulate cortex and associative striatum (rostrally), to dorso-ventral premotor areas and the motor putamen (caudally). These findings suggest that the functional heterogeneity of the pre-supplementary area F6 is accounted for by gradual transitions in functional properties grounded on local cortico-cortical and cortico-striatal connectional specificities.

The neural bases of vitality forms.

Unlike emotions, which are short-lasting events accompanied by viscero-motor responses, vitality forms are continuous internal states that modulate the motor behaviors of individuals and are devoid of the autonomic modifications that characterize real emotions. Despite the importance of vitality forms in social life, only recently have neurophysiological studies been devoted to this issue. The first part of this review describes fMRI experiments, showing that the dorso-central insula is activated during the execution, the perception and the imagination of arm actions endowed with different vitality forms as well as during the hearing and the production of speech conveying vitality forms. In the second part, we address the means by which the dorso-central insula modulates the networks for controlling action execution and how the sensory and interoceptive information is conveyed to this insular sector. Finally, we present behavioral data showing the importance of vitality forms in social interactions.

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.

Pathways for smiling, disgust and fear recognition in blindsight patients.

The aim of the present review is to discuss the localization of circuits that allow recognition of emotional facial expressions in blindsight patients. Because recognition of facial expressions is function of different centers, and their localization is not always clear, we decided to discuss here three emotional facial expression - smiling, disgust, and fear - whose anatomical localization in the pregenual sector of the anterior cingulate cortex (pACC), anterior insula (AI), and amygdala, respectively, is well established. We examined, then, the possible pathways that may convey affective visual information to these centers following lesions of V1. We concluded that the pathway leading to pACC, AI, and amygdala involves the deep layers of the superior colliculus, the medial pulvinar, and the superior temporal sulcus region. We suggest that this visual pathway provides an image of the observed affective faces, which, although deteriorated, is sufficient to determine some overt behavior, but not to provide conscious experience of the presented stimuli.

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.

Motor and emotional behaviours elicited by electrical stimulation of the human cingulate cortex.

The cingulate cortex is a mosaic of different anatomical fields, whose functional characterization is still a matter of debate. In humans, one method that may provide useful insights on the role of the different cingulate regions, and to tackle the issue of the functional differences between its anterior, middle and posterior subsectors, is intracortical electrical stimulation. While previous reports showed that a variety of integrated behaviours could be elicited by stimulating the midcingulate cortex, little is known about the effects of the electrical stimulation of anterior and posterior cingulate regions. Moreover, the internal arrangement of different behaviours within the midcingulate cortex is still unknown. In the present study, we extended previous stimulation studies by retrospectively analysing all the clinical manifestations induced by intracerebral high frequency electrical stimulation (50 Hz, pulse width: 1 ms, 5 s, current intensity: average intensity of 2.7 ± 0.7 mA, biphasic) of the entire cingulate cortex in a cohort of 329 drug-resistant epileptic patients (1789 stimulation sites) undergoing stereo-electroencephalography for a presurgical evaluation. The large number of patients, on one hand, and the accurate multimodal image-based localization of stereo-electroencephalography electrodes, on the other hand, allowed us to assign specific functional properties to modern anatomical subdivisions of the cingulate cortex. Behavioural or subjective responses were elicited from the 32.3% of all cingulate sites, mainly located in the pregenual and midcingulate regions. We found clear functional differences between the pregenual part of the cingulate cortex, hosting the majority of emotional, interoceptive and autonomic responses, and the anterior midcingulate sector, controlling the majority of all complex motor behaviours. Particularly interesting was the 'actotopic' organization of the anterior midcingulate sector, arranged along the ventro-dorsal axis: (i) whole-body behaviours directed to the extra-personal space, such as getting-up impulses, were elicited ventrally, close to the corpus callosum; (ii) hand actions in the peripersonal space were evoked by the stimulation of the intermediate position; and (iii) body-directed actions were induced by the stimulation of the dorsal branch of the cingulate sulcus. The caudal part of the midcingulate cortex and the posterior cingulate cortex were, in contrast, poorly excitable, and mainly devoted to sensory modalities. In particular, the caudal part of the midcingulate cortex hosted the majority of vestibular responses, while posterior cingulate cortex was the principal recipient of visual effects. We will discuss our data in the light of current controversies on the role of the cingulate cortex in cognition and emotion.

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.

The extended object-grasping network.

Grasping is the most important skilled motor act of primates. It is based on a series of sensorimotor transformations through which the affordances of the objects to be grasped are transformed into appropriate hand movements. It is generally accepted that a circuit formed by inferior parietal areas AIP and PFG and ventral premotor area F5 represents the core circuit for sensorimotor transformations for grasping. However, selection and control of appropriate grip should also depend on higher-order information, such as the meaning of the object to be grasped, and the overarching goal of the action in which grasping is embedded. In this review, we describe recent findings showing that specific sectors of the ventrolateral prefrontal cortex are instrumental in controlling higher-order aspects of grasping. We show that these prefrontal sectors control the premotor cortex through two main gateways: the anterior subdivision of ventral area F5-sub-area F5a-, and the pre-supplementary area (area F6). We then review functional studies showing that both F5a and F6, besides being relay stations of prefrontal information, also play specific roles in grasping. Namely, sub-area F5a is involved in stereoscopic analysis of 3D objects, and in planning cue-dependent grasping activity. As for area F6, this area appears to play a crucial role in determining when to execute the motor program encoded in the parieto-premotor circuit. The recent discovery that area F6 contains a set of neurons encoding specific grip types suggests that this area, besides controlling "when to go", also may control the grip type, i.e., "how to go". We conclude by discussing clinical syndromes affecting grasping actions and their possible mechanisms.

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.

Extending the Cortical Grasping Network: Pre-supplementary Motor Neuron Activity During Vision and Grasping of Objects.

Grasping relies on a network of parieto-frontal areas lying on the dorsolateral and dorsomedial parts of the hemispheres. However, the initiation and sequencing of voluntary actions also requires the contribution of mesial premotor regions, particularly the pre-supplementary motor area F6. We recorded 233 F6 neurons from 2 monkeys with chronic linear multishank neural probes during reaching-grasping visuomotor tasks. We showed that F6 neurons play a role in the control of forelimb movements and some of them (26%) exhibit visual and/or motor specificity for the target object. Interestingly, area F6 neurons form 2 functionally distinct populations, showing either visually-triggered or movement-related bursts of activity, in contrast to the sustained visual-to-motor activity displayed by ventral premotor area F5 neurons recorded in the same animals and with the same task during previous studies. These findings suggest that F6 plays a role in object grasping and extend existing models of the cortical grasping network.

Single Neurons in the Insular Cortex of a Macaque Monkey Respond to Skin Brushing: Preliminary Data of the Possible Representation of Pleasant Touch.

Pleasant touch may serve as a foundation for affiliative behavior, providing a mechanism for the formation and maintenance of social bonds among conspecifics. In humans, this touch is usually referred to as the caress. Dynamic caressing performed on the hairy skin with a velocity of 1-10 cm/s is perceived as being pleasant and determines positive cardio-physiological effects. Furthermore, imaging human studies show that affiliative touch activates the posterior insular cortex (pIC). Recently, it was demonstrated that pleasant touch in monkeys (i.e., sweeping in a grooming-like manner) is performed with velocities similar to those characteristics of human caress (9.31 cm/s), and causes similarly positive autonomic effects, if performed with velocity of 5 cm/s and 10 cm/s, but not lower or higher. Due to similarities between the human caress and non-human primate sweeping, we investigated for the first time whether single neurons of the perisylvian regions (secondary somatosensory cortex [SII] and pIC) of a rhesus monkey can process sweeping touch differently depending on the stimulus speed. We applied stimulation with two speeds: one that optimally induces positive cardio-physiological effects in the monkey who receives it, and includes the real speed of sweep (5-15 cm/s, sweep fast), and a non-optimal speed (1-5 cm/s, sweep slow). The results show that single neurons of insular cortex differently encode the stimulus speed. In particular, even the majority of recorded somatosensory neurons (82.96%) did not discriminate the two speeds, a small set of neurons (16.59%) were modulated just during the sweep fast. These findings represent the first evidence that single neurons of the non-human primates insular cortex can code affiliative touch, highlighting the similarity between human and non-human primates' social touch systems. This study constitutes an important starting point to carry out deeper investigation on neuronal processing of pleasant sweeping in the central nervous system.