Brain activation during processing of mouth actions in patients with disorders of consciousness.

In the past 2 decades, several attempts have been made to promote a correct diagnosis and possible restorative interventions in patients suffering from disorders of consciousness. Sensory stimulation has been proved to be useful in sustaining the level of arousal/awareness and to improve behavioural responsiveness with a significant effect on oro-motor functions. Recently, action observation has been proposed as a stimulation strategy in patients with disorders of consciousness, based on neurophysiological evidence that the motor cortex can be activated not only during action execution but also when actions are merely observed in the absence of motor output, or during listening to action sounds and speech. This mechanism is provided by the activity of mirror neurons. In the present study, a group of patients with disorders of consciousness (11 males, 4 females; median age: 55 years; age range: 19-74 years) underwent task-based functional MRI in which they had, in one condition, to observe and listen to the sound of mouth actions, and in another condition, to listen to verbs with motor or abstract content. In order to verify the presence of residual activation of the mirror neuron system, the brain activations of patients were compared with that of a group of healthy individuals (seven males, eight females; median age: 33.4 years; age range: 24-65 years) performing the same tasks. The results show that brain activations were lower in patients with disorders of consciousness compared with controls, except for primary auditory areas. During the audiovisual task, 5 out of 15 patients with disorders of consciousness showed only residual activation of low-level visual and auditory areas. Activation of high-level parieto-premotor areas was present in six patients. During the listening task, three patients showed only low-level activations, and six patients activated also high-level areas. Interestingly, in both tasks, one patient with a clinical diagnosis of vegetative state showed activations of high-level areas. Region of interest analysis on blood oxygen level dependent signal change in temporal, parietal and premotor cortex revealed a significant linear relation with the level of clinical functioning, assessed with coma recovery scale-revised. We propose a classification of the patient's response based on the presence of low-level and high-level activations, combined with the patient's functional level. These findings support the use of action observation and listening as possible stimulation strategies in patients with disorders of consciousness and highlight the relevance of combined methods based on functional assessment and brain imaging to provide more detailed neuroanatomical specificity about residual activated areas at both cortical and subcortical levels.

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.

Heart Rate Fractality Disruption as a Footprint of Subthreshold Depressive Symptoms in a Healthy Population.

Objective: Psychopathology (and depression in particular) is a cardiovascular risk factor independent from any co-occurring pathology. This link is traced back to the mind-heart-body connection, whose underlying mechanisms are still not completely known. To study psychopathology in relation to the heart, it is necessary to observe the autonomic nervous system, which mediates among the parts of that connection. Its gold standard of evaluation is the study of heart rate variability (HRV). To investigate whether any association exists between the HRV parameters and sub-threshold depressive symptoms in a sample of healthy subjects. Method: In this cross-sectional study, two short-term HRV recordings (5 min - supine and sitting) have been analyzed in 77 healthy subjects. Here we adopted a three-fold approach to evaluate HRV: a set of scores belonging to the time domain; to the frequency domain (high, low, and very low frequencies) and a set of 'nonlinear' parameters. The PHQ-9 (Patient Health Questionnaire-9) scale was used to detect depressive symptoms. Results: Depressive symptoms were associated only with a parameter from the non-linear approach and specifically the long-term fluctuations of fractal dimensions (DFA-α2). This association remained significant even after controlling for age, gender, BMI (Body-Mass-Index), arterial hypertension, anti-hypertensive drugs, dyslipidemia, and smoking habits. Moreover, the DFA-α2 was not affected by the baroreflex (postural change), unlike other autonomic markers. Conclusions: Fractal analysis of HRV (DFA-α2) allows then to predict depressive symptoms below the diagnostic threshold in healthy subjects regardless of their health status. DFA-α2 may be considered as an imprint of subclinical depression on the heart rhythm.

Structural connectivity associated with the sense of body ownership: a diffusion tensor imaging and disconnection study in patients with bodily awareness disorder.

The brain mechanisms underlying the emergence of a normal sense of body ownership can be investigated starting from pathological conditions in which body awareness is selectively impaired. Here, we focused on pathological embodiment, a body ownership disturbance observed in brain-damaged patients who misidentify other people's limbs as their own. We investigated whether such body ownership disturbance can be classified as a disconnection syndrome, using three different approaches based on diffusion tensor imaging: (i) reconstruction of disconnectome maps in a large sample (N = 70) of stroke patients with and without pathological embodiment; (ii) probabilistic tractography, performed on the age-matched healthy controls (N = 16), to trace cortical connections potentially interrupted in patients with pathological embodiment and spared in patients without this pathological condition; (iii) probabilistic 'in vivo' tractography on two patients without and one patient with pathological embodiment. The converging results revealed the arcuate fasciculus and the third branch of the superior longitudinal fasciculus as mainly involved fibre tracts in patients showing pathological embodiment, suggesting that this condition could be related to the disconnection between frontal, parietal and temporal areas. This evidence raises the possibility of a ventral self-body recognition route including regions where visual (computed in occipito-temporal areas) and sensorimotor (stored in premotor and parietal areas) body representations are integrated, giving rise to a normal sense of body ownership.

Visual response of ventrolateral prefrontal neurons and their behavior-related modulation.

The ventral part of lateral prefrontal cortex (VLPF) of the monkey receives strong visual input, mainly from inferotemporal cortex. It has been shown that VLPF neurons can show visual responses during paradigms requiring to associate arbitrary visual cues to behavioral reactions. Further studies showed that there are also VLPF neurons responding to the presentation of specific visual stimuli, such as objects and faces. However, it is largely unknown whether VLPF neurons respond and differentiate between stimuli belonging to different categories, also in absence of a specific requirement to actively categorize or to exploit these stimuli for choosing a given behavior. The first aim of the present study is to evaluate and map the responses of neurons of a large sector of VLPF to a wide set of visual stimuli when monkeys simply observe them. Recent studies showed that visual responses to objects are also present in VLPF neurons coding action execution, when they are the target of the action. Thus, the second aim of the present study is to compare the visual responses of VLPF neurons when the same objects are simply observed or when they become the target of a grasping action. Our results indicate that: (1) part of VLPF visually responsive neurons respond specifically to one stimulus or to a small set of stimuli, but there is no indication of a "passive" categorical coding; (2) VLPF neuronal visual responses to objects are often modulated by the task conditions in which the object is observed, with the strongest response when the object is target of an action. These data indicate that VLPF performs an early passive description of several types of visual stimuli, that can then be used for organizing and planning behavior. This could explain the modulation of visual response both in associative learning and in natural behavior.

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.

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.

The mirror mechanism in the parietal lobe.

The mirror mechanism is a basic mechanism that transforms sensory representations of others' actions into motor representations of the same actions in the brain of the observer. The mirror mechanism plays an important role in understanding actions of others. In the present chapter we discuss first the basic organization of the posterior parietal lobe in the monkey, stressing that it is best characterized as a motor scaffold, on the top of which sensory information is organized. We then describe the location of the mirror mechanism in the posterior parietal cortex of the monkey, and its functional role in areas PFG, and anterior, ventral, and lateral intraparietal areas. We will then present evidence that a similar functional organization is present in humans. We will conclude by discussing the role of the mirror mechanism in the recognition of action performed with tools.

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.

Neural Coding for Action Execution and Action Observation in the Prefrontal Cortex and Its Role in the Organization of Socially Driven Behavior.

The lateral prefrontal cortex (LPF) plays a fundamental role in planning, organizing, and optimizing behavioral performance. Neuroanatomical and neurophysiological studies have suggested that in this cortical sector, information processing becomes more abstract when moving from caudal to rostral and that such processing involves parietal and premotor areas. We review studies that have shown that the LPF, in addition to its involvement in implementing rules and setting behavioral goals, activates during the execution of forelimb movements even in the absence of a learned relationship between an instruction and its associated motor output. Thus, we propose that the prefrontal cortex is involved in exploiting contextual information for planning and guiding behavioral responses, also in natural situations. Among contextual cues, those provided by others' actions are particularly relevant for social interactions. Functional studies of macaques have demonstrated that the LPF is activated by the observation of biological stimuli, in particular those related to goal-directed actions. We review these studies and discuss the idea that the prefrontal cortex codes high-order representations of observed actions rather than simple visual descriptions of them. Based on evidence that the same sector of the LPF contains both neurons coding own action goals and neurons coding others' goals, we propose that this sector is involved in the selection of own actions appropriate for reacting in a particular social context and for the creation of new action sequences in imitative learning.

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.

Action observation activates neurons of the monkey ventrolateral prefrontal cortex.

Prefrontal cortex is crucial for exploiting contextual information for the planning and guidance of behavioral responses. Among contextual cues, those provided by others' behavior are particularly important, in primates, for selecting appropriate reactions and suppressing the inappropriate ones. These latter functions deeply rely on the ability to understand others' actions. However, it is largely unknown whether prefrontal neurons are activated by action observation. To address this issue, we recorded the activity of ventrolateral prefrontal (VLPF) neurons of macaque monkeys during the observation of videos depicting biological movements performed by a monkey or a human agent, and object motion. Our results show that a population of VLPF neurons respond to the observation of biological movements, in particular those representing goal directed actions. Many of these neurons also show a preference for the agent performing the action. The neural response is present also when part of the observed movement is obscured, suggesting that these VLPF neurons code a high order representation of the observed action rather than a simple visual description of it.

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.

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.

A shared neural network for emotional expression and perception: an anatomical study in the macaque monkey.

Over the past two decades, the insula has been described as the sensory "interoceptive cortex". As a consequence, human brain imaging studies have focused on its role in the sensory perception of emotions. However, evidence from neurophysiological studies in non-human primates have shown that the insula is also involved in generating emotional and communicative facial expressions. In particular, a recent study demonstrated that electrical stimulation of the mid-ventral sector of the insula evoked affiliative facial expressions. The present study aimed to describe the cortical connections of this "affiliative field". To this aim, we identified the region with electrical stimulation and injected neural tracers to label incoming and outgoing projections. Our results show that the insular field underlying emotional expression is part of a network involving specific frontal, cingulate, temporal, and parietal areas, as well as the amygdala, the basal ganglia, and thalamus, indicating that this sector of the insula is a site of integration of motor, emotional, sensory and social information. Together with our previous functional studies, this result challenges the classic view of the insula as a multisensory area merely reflecting bodily and internal visceral states. In contrast, it supports an alternative perspective; that the emotional responses classically attributed to the insular cortex are endowed with an enactive component intrinsic to each social and emotional behavior.

Movement-related activity during goal-directed hand actions in the monkey ventrolateral prefrontal cortex.

Grasping actions require the integration of two neural processes, one enabling the transformation of object properties into corresponding motor acts, and the other involved in planning and controlling action execution on the basis of contextual information. The first process relies on parieto-premotor circuits, whereas the second is considered to be a prefrontal function. Up to now, the prefrontal cortex has been mainly investigated with conditional visuomotor tasks requiring a learned association between cues and behavioural output. To clarify the functional role of the prefrontal cortex in grasping actions, we recorded the activity of ventrolateral prefrontal (VLPF) neurons while monkeys (Macaca mulatta) performed tasks requiring reaching-grasping actions in different contextual conditions (in light and darkness, memory-guided, and in the absence of abstract learned rules). The results showed that the VLPF cortex contains neurons that are active during action execution (movement-related neurons). Some of them showed grip selectivity, and some also responded to object presentation. Most movement-related neurons discharged during action execution both with and without visual feedback, and this discharge typically did not change when the action was performed with object mnemonic information and in the absence of abstract rules. The findings of this study indicate that a population of VLPF neurons play a role in controlling goal-directed grasping actions in several contexts. This control is probably exerted within a wider network, involving parietal and premotor regions, where the role of VLPF movement-related neurons would be that of activating, on the basis of contextual information, the representation of the motor goal of the intended action (taking possession of an object) during action planning and execution.

Grasping actions and social interaction: neural bases and anatomical circuitry in the monkey.

The study of the neural mechanisms underlying grasping actions showed that cognitive functions are deeply embedded in motor organization. In the first part of this review, we describe the anatomical structure of the motor cortex in the monkey and the cortical and sub-cortical connections of the different motor areas. In the second part, we review the neurophysiological literature showing that motor neurons are not only involved in movement execution, but also in the transformation of object physical features into motor programs appropriate to grasp them (through visuo-motor transformations). We also discuss evidence indicating that motor neurons can encode the goal of motor acts and the intention behind action execution. Then, we describe one of the mechanisms-the mirror mechanism-considered to be at the basis of action understanding and intention reading, and describe the anatomo-functional pathways through which information about the social context can reach the areas containing mirror neurons. Finally, we briefly show that a clear similarity exists between monkey and human in the organization of the motor and mirror systems. Based on monkey and human literature, we conclude that the mirror mechanism relies on a more extended network than previously thought, and possibly subserves basic social functions. We propose that this mechanism is also involved in preparing appropriate complementary response to observed actions, allowing two individuals to become attuned and cooperate in joint 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.