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Cerebellar outputs originate from the dentate nucleus (DN), project to the primary motor cortex (M1) via the motor thalamus, control M1 activity, and play an essential role in coordinated movements. However, it is unclear when and how the cerebellar outputs contribute to M1 activity. To address this question, we examined the response of M1 neurons to electrical stimulation of the DN and M1 activity during performance of arm-reaching tasks. Based on response patterns to DN stimulation, M1 neurons were classified into facilitation-, suppression-, and no-response-types. During tasks, not only facilitation- and suppression-type M1 neurons, but also no response-type M1 neurons increased or decreased their firing rates in relation to arm reaching movements. However, the firing rates of facilitation- and suppression-type neurons were higher than those of no-response-type neurons during both inter-trial intervals and arm reaching movements. These results imply that cerebellar outputs contribute to both spontaneous and movement-related activity in the M1, which help to maintain muscle tones and execute coordinated movements, although other inputs also contribute to movement-related activity. Pharmacological inactivation of the DN supports this notion, in that DN inactivation reduced both spontaneous firing rates and movement-related activity in the M1.

The thalamic reticular nucleus (TRN) collects inputs from the cerebral cortex and thalamus and, in turn, sends inhibitory outputs to the thalamic relay nuclei. This unique connectivity suggests that the TRN plays a pivotal role in regulating information flow through the thalamus. Here, we analyzed the roles of TRN neurons in visually guided reaching movements. We first used retrograde transneuronal labeling with rabies virus, and showed that the rostro-dorsal sector of the TRN (TRNrd) projected disynaptically to the ventral premotor cortex (PMv). In other experiments, we recorded neurons from the TRNrd or PMv while monkeys performed a visuomotor task. We found that neurons in the TRNrd and PMv showed visual-, set-, and movement-related activity modulation. These results indicate that the TRNrd, as well as the PMv, is involved in the reception of visual signals and in the preparation and execution of reaching movements. The fraction of neurons that were non-selective for the location of visual signals or the direction of reaching movements was greater in the TRNrd than in the PMv. Furthermore, the fraction of neurons whose activity increased from the baseline was greater in the TRNrd than in the PMv. The timing of activity modulation of visual-related and movement-related neurons was comparable in TRNrd and PMv neurons. Overall, our data suggest that TRNrd neurons provide motor thalamic nuclei with inhibitory inputs that are predominantly devoid of spatial selectivity, and that these signals modulate how these nuclei engage in both sensory processing and motor output during visually guided reaching behavior. This article is protected by copyright. All rights reserved.

The caudal cingulate motor area (CMAc) and the supplementary motor area (SMA) play important roles in movement execution. The present study examined the neural mechanisms underlying these roles by investigating local field potentials (LFPs) from these areas while monkeys pressed buttons with either their left or right hand. During hand movement, power increases in the high-gamma (80–120 Hz) and theta (3–8 Hz) bands and a power decrease in the beta (12–30 Hz) band were observed in both the CMAc and SMA. High-gamma and beta activity in the SMA predominantly represented contralateral hand movements, whereas activity in the CMAc preferentially represented movement of either hand. Theta activity in both brain regions most frequently reflected movement of either hand, but a contralateral hand bias was more evident in the SMA than in the CMAc. An analysis of the relationships of the laterality representations between the high-gamma and theta bands at each recording site revealed that, irrespective of the hand preference for the theta band, the high-gamma band in the SMA preferentially represented contralateral hand movement, whereas the high-gamma band in the CMAc represented movement of either hand. These findings suggest that the input-output relationships for ipsilateral and contralateral hand movements in the CMAc and SMA differ in terms of their functionality. The CMAc may transform the input signals representing general aspects of movement into commands to perform movements with either hand, whereas the SMA may transform the input signals into commands to perform movement with the contralateral hand.

The primate frontal lobe processes diverse motor information in parallel through multiple motor-related areas. For example, the supplementary motor area (SMA) is mainly involved in internally-triggered movements, whereas the premotor cortex (PM) is highly responsible for externally-guided movements. The primary motor cortex (M1) deals with both aspects of movements to execute a single motor behavior. To elucidate how the cortical motor system is structured to process a variety of information, the laminar distribution patterns of signals were examined between SMA and M1, or PM and M1 in macaque monkeys by using dual anterograde tract-tracing. Dense terminal labeling was observed in layers 1 and upper 2/3 of M1 after one tracer injection into SMA, another tracer injection into the dorsal division of PM resulted in prominent labeling in the deeper portion of layer 2/3. Weaker labeling was also visible in layer 5 in both cases. On the other hand, inputs from M1 terminated in both the superficial and the deep layers of SMA and PM. The present data indicate that distinct types of motor information are arranged in M1 in a layer-specific fashion to be orchestrated through a microcircuit within M1.

The primary motor cortex is located in Brodmann area 4 at the most posterior part of the frontal lobe. The primary motor cortex corresponds to an output stage of motor signals, sending motor commands to the brain stem and spinal cord. Brodmann area 6 is rostral to Brodmann area 4, where multiple higher-order motor areas are located. The premotor area, which is located in the lateral part, is involved in planning and executing action based on sensory signals. The premotor area contributes to the reaching for and grasping of an object to achieve a behavioral goal. The supplementary motor area, which occupies the mesial aspect, is involved in planning and executing actions based on internalized or memorized signals. The supplementary motor area plays a central role in bimanual movements, organizing multiple movements, and switching from a routine to a controlled behavior. Thus, Brodmann areas 4 and 6 are considered as central motor areas in the cerebral cortex, in which the idea of an action is transformed to an actual movement in a variety of contexts.

The globus pallidus (GP) communicates with widespread cortical areas that support various functions, including motivation, cognition and action. Anatomical tract-tracing studies revealed that the anteroventral GP communicates with the medial prefrontal and orbitofrontal cortices, which are involved in motivational control; the anterodorsal GP communicates with the lateral prefrontal cortex, which is involved in cognitive control; and the posterior GP communicates with the frontal motor cortex, which is involved in action control. This organization suggests that distinct subdivisions within the GP play specific roles. Neurophysiological studies examining GP neurons in monkeys during behavior revealed that the types of information coding performed within these subdivisions differ greatly. The anteroventral GP is characterized by activities related to motivation, such as reward seeking and aversive avoidance; the anterodorsal GP is characterized by activity that reflects cognition, such as goal decision and action selection; and the posterior GP is characterized by activity associated with action preparation and execution. Pathophysiological studies have shown that GABA-related substances or GP lesions result in abnormal activity in the GP, which causes site-specific behavioral and motor symptoms. The present review article discusses the anatomical organization, physiology and pathophysiology of the three major GP territories in nonhuman primates and humans.

Lines of evidence indicate that both the ventrolateral prefrontal cortex (vlPFC) (areas 45/12) and dorsal premotor cortex (PMd) (rostral F2 in area 6) are crucially involved in conditional visuomotor behavior, in which it is required to determine an action based on an associated visual object. However, virtually no direct projections appear to exist between the vlPFC and PMd. In the present study, to elucidate possible multisynaptic networks linking the vlPFC to the PMd, we performed a series of neuroanatomical tract-tracing experiments in macaque monkeys. First, we identified cortical areas that send projection fibers directly to the PMd by injecting Fast Blue into the PMd. Considerable retrograde labeling occurred in the dorsal prefrontal cortex (dPFC) (areas 46d/9/8B/8Ad), dorsomedial motor cortex (dmMC) (F7 and presupplementary motor area), rostral cingulate motor area, and ventral premotor cortex (F5 and area 44), whereas the vlPFC was virtually devoid of neuronal labeling. Second, we injected the rabies virus, a retrograde transneuronal tracer, into the PMd. At 3 days after the rabies injections, second-order neurons were labeled in the vlPFC (mainly area 45), indicating that the vlPFC disynaptically projects to the PMd. Finally, to determine areas that connect the vlPFC to the PMd indirectly, we carried out an anterograde/retrograde dual-labeling experiment in single monkeys. By examining the distribution of axon terminals labeled from the vlPFC and cell bodies labeled from the PMd, we found overlapping labels in the dPFC and dmMC. These results indicate that the vlPFC outflow is directed toward the PMd in a multisynaptic fashion through the dPFC and/or dmMC.

The dorsal premotor cortex residing in the dorsolateral aspect of area 6 is a rostrocaudally elongated area that is rostral to the primary motor cortex (M1) and caudal to the prefrontal cortex. This region, which is subdivided into rostral [pre-dorsal premotor cortex (pre-PMd)] and caudal [dorsal premotor cortex proper (PMd)] components, probably plays a central role in planning and executing actions to achieve a behavioural goal. In the present study, we investigated the functional specializations of the pre-PMd, PMd, and M1, because the synthesis of the specific functions performed by each area is considered to be essential. Neurons were recorded while monkeys performed a conditional visuo-goal task designed to include separate processes for determining a behavioural goal (reaching towards a right or left potential target) on the basis of visual object instructions, specifying actions (direction of reaching) to be performed on the basis of the goal, and preparing and executing the action. Neurons in the pre-PMd and PMd retrieved and maintained behavioural goals without encoding the visual features of the visual object instructions, and subsequently specified the actions by multiplexing the goals with the locations of the targets. Furthermore, PMd and M1 neurons played a major role in representing the action during movement preparation and execution, whereas the contribution of the pre-PMd progressively decreased as the time of the actual execution of the movement approached. These findings revealed that the multiple processing stages necessary for the realization of an action to accomplish a goal were implemented in an area-specific manner across a functional gradient from the pre-PMd to M1 that included the PMd as an intermediary.

The temporal structuring of multiple events is essential for the purposeful regulation of behavior. We investigated the role of the lateral prefrontal cortex (LPFC) in transforming external signals of multiple sensory modalities into information suitable for monitoring successive events across behavioral phases until an intended action is prompted and then initiated. We trained monkeys to receive a succession of 1 s visual, auditory, or tactile sensory signals separated by variable intervals and to then release a key as soon as the fourth signal appeared. Thus, the animals had to monitor and update information about the progress of the task upon receiving each signal preceding the key release in response to the fourth signal. We found that the initial, short-latency responses of LPFC neurons reflected primarily the sensory modality, rather than the phase or progress of the task. However, a task phase-selective response developed within 500 ms of signal reception, and information about the task phase was maintained throughout the presentation of successive cues. The task phase-selective activity was updated with the appearance of each cue until the planned action was initiated. The phase-selective activity of individual neurons reflected not merely a particular phase of the task but also multiple successive phases. Furthermore, we found combined representations of task phase and sensory modality in the activity of individual LPFC neurons. These properties suggest how information representing multiple phases of behavioral events develops in the LPFC to provide a basis for the temporal regulation of behavior.

We examined the organization of multisynaptic projections from the basal ganglia (BG) to the dorsal premotor area in macaques. After injection of the rabies virus into the rostral sector of the caudal aspect of the dorsal premotor area (F2r) and the caudal sector of the caudal aspect of the dorsal premotor area (F2c), second-order neuron labeling occurred in the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Labeled GPi neurons were found in the caudoventral portion after F2c injection, and in the dorsal portion at the rostrocaudal middle level after F2r injection. In the SNr, F2c and F2r injections led to labeling in the caudal or rostral part, respectively. Subsequently, third-order neuron labeling was observed in the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the striatum. After F2c injection, labeled neurons were observed over a broad territory in the GPe, whereas after F2r injection, labeled neurons tended to be restricted to the rostral and dorsal portions. In the STN, F2c injection resulted in extensive labeling over the nucleus, whereas F2r injection resulted in labeling in the ventral portion only. After both F2r and F2c injections, labeled neurons in the striatum were widely observed in the striatal cell bridge region and neighboring areas, as well as in the ventral striatum. The present results revealed that the origins of multisynaptic projections to F2c and F2r in the BG are segregated in the output stations of the BG, whereas intermingling rather than segregation is evident with respect to their input station.

In the caudal part of the dorsal premotor cortex of macaques (area F2), both anatomical and physiological studies have identified two rostrocaudally separate sectors. The rostral sector (F2r) is located medial to the genu of the arcuate sulcus, and the caudal sector (F2c) is located lateral to the superior precentral dimple. Here we examined the sites of origin of projections from the cerebellum to F2r and F2c. We applied retrograde transsynaptic transport of a neurotropic virus, CVS-11 of rabies virus, in macaque monkeys. Three days after rabies injections into F2r or F2c, neuronal labeling was found in the deep cerebellar nuclei mainly of the contralateral hemisphere. After the F2r injection, labeled cells were distributed primarily in the caudoventral portion of the dentate nucleus, whereas cells labeled after the F2c injection were distributed in the rostrodorsal portion of the dentate nucleus, and in the interpositus and fastigial nuclei. Four days after rabies injections, Purkinje cells were densely labeled in the lateral part of the cerebellar cortex. After the F2r injection, Purkinje cell labeling was confined to Crus I and II, whereas the labeling seen after the F2c injection was located broadly from lobules III to VIII, including Crus I and II. These results have revealed that F2c receives inputs from broader areas of the cerebellum than F2r, and that distinct portions of the deep cerebellar nuclei and the cerebellar cortex send major projections to F2r and F2c, suggesting that F2c and F2r may be under specific influences of the cerebellum.

Previous reports have indicated that the premotor cortex (PM) uses visual information for either direct guidance of limb movements or indirect specification of action targets at a conceptual level. We explored how visual inputs signaling these two different categories of information are processed by PM neurons. Monkeys performed a delayed reaching task after receiving two different sets of visual instructions, one directly specifying the spatial location of a motor target (a direct spatial-target cue) and the other providing abstract information about the spatial location of a motor target by indicating whether to select the right or left target at a conceptual level (a symbolic action-selection cue). By comparing visual responses of PM neurons to the two sets of visual cues, we found that the conceptual action plan indicated by the symbolic action-selection cue was represented predominantly in dorsal PM (PMd) neurons with a longer latency (150 ms), whereas both PMd and ventral PM (PMv) neurons responded with a shorter latency (90 ms) when the motor target was directly specified with the direct spatial-target cue. We also found that excited, but not inhibited, responses of PM neurons to the direct spatial-target cue were biased toward contralateral preference. In contrast, responses to the symbolic action-selection cue were either excited or inhibited without laterality preference. Taken together, these results suggest that the PM constitutes a pair of distinct circuits for visually guided motor act; one circuit, linked more strongly with PMd, carries information for retrieving action instruction associated with a symbolic cue, and the other circuit, linked with PMd and PMv, carries information for directly specifying a visuospatial position of a reach target.

The dorsal and ventral premotor areas, together with the primary motor cortex, are believed to have major roles in preparing and executing limb movements. Recent studies have expanded our knowledge of the dorsal and ventral premotor areas, which occupy the lateral part of area 6 in the frontal cortex. It is becoming clear that these two premotor areas, through involvement in distinct cortical networks, take part in unique aspects of motor planning and decision making. New lines of evidence also implicate the lateral premotor areas in planning motor behavior and selecting actions.

The ventral premotor cortex (PMv), occupying the ventral aspect of area 6 in the frontal lobe, has been implicated in action planning and execution based on visual signals. Although the PMv has been characterized by cortico-cortical connections with specific subregions of the parietal and prefrontal cortical areas, a topographical input/output organization between the PMv and the basal ganglia (BG) still remains elusive. In the present study, retrograde transneuronal labelling with the rabies virus was employed to identify the origins of multisynaptic projections from the BG to the PMv. The virus was injected into the forelimb region of the PMv, identified in the ventral aspect of the genu of the arcuate sulcus, in macaque monkeys. The survival time after the virus injection was set to allow either the second- or third-order neuron labelling across two or three synapses. The second-order neurons were observed in the ventral portion (primary motor territory) and the caudodorsal portion (higher-order motor territory) of the internal segment of the globus pallidus. Subsequently, the third-order neurons were distributed in the putamen caudal to the anterior commissure, including both the primary and the higher-order motor territories, and in the ventral striatum (limbic territory). In addition, they were found in the dorsolateral portion (motor territory) and ventromedial portion (limbic territory) of the subthalamic nucleus, and in the external segment of the globus pallidus including both the limbic and motor territories. These findings indicate that the PMv receives diverse signals from the primary motor, higher-order motor and limbic territories of the BG.

The caudal cingulate motor area (CMAc) and the supplementary motor area (SMA) play important roles in movement execution. The present study aimed to characterize the functional organization of these regions during movement by investigating laterality representations in the CMAc and SMA of monkeys via an examination of neuronal activity during a button press movement with either the right or left hand. Three types of movement-related neuronal activity were observed: 1) with only the contralateral hand, 2) with only the ipsilateral hand, and 3) with either hand. Neurons in the CMAc represented contralateral and ipsilateral hand movements to the same degree, whereas neuronal representations in the SMA were biased toward contralateral hand movement. Furthermore, recording neuronal activities using a linear-array multicontact electrode with 24 contacts spaced 150 μm apart allowed us to analyze the spatial distribution of neurons exhibiting particular hand preferences at the submillimeter scale. The CMAc and SMA displayed distinct microarchitectural organizations. The contralateral, ipsilateral, and bilateral CMAc neurons were distributed homogeneously, whereas SMA neurons exhibiting identical hand preferences tended to cluster. These findings indicate that the CMAc, which is functionally organized in a less structured manner than the SMA is, controls contralateral and ipsilateral hand movements in a counterbalanced fashion, whereas the SMA, which is more structured, preferentially controls contralateral hand movements.

We examined neuronal activity in the dorsal and ventral premotor cortex (PMd and PMv, respectively) to explore the role of each motor area in processing visual signals for action planning. We recorded neuronal activity while monkeys performed a behavioral task during which two visual instruction cues were given successively with an intervening delay. One cue instructed the location of the target to be reached, and the other indicated which arm was to be used. We found that the properties of neuronal activity in the PMd and PMv differed in many respects. After the first cue was given, PMv neuron response mostly reflected the spatial position of the visual cue. In contrast, PMd neuron response also reflected what the visual cue instructed, such as which arm to be used or which target to be reached. After the second cue was given, PMv neurons initially responded to the cue's visuospatial features and later reflected what the two visual cues instructed, progressively increasing information about the target location. In contrast, the activity of the majority of PMd neurons responded to the second cue with activity reflecting a combination of information supplied by the first and second cues. Such activity, already reflecting a forthcoming action, appeared with short latencies (

The dorsolateral prefrontal cortex (DLPFC) possesses cortico-cortical connections with the parietal and premotor cortices that are involved in visuomotor control of actions. Studies have shown that the DLPFC, especially the caudal part, has a crucial role in cognitive control of motor behavior, and that it uses spatial information in conjunction with information such as object identity, behavioral rules, and rewards. Current anatomical and physiological studies indicate that the DLPFC may not be a single entity. Anatomical studies show that preferential anatomical connections exist between subregions of the DLPFC and the parietal/premotor cortices. Physiological studies based on data obtained from monkeys performing a variety of cognitive tasks report region-specific neuronal activity within the DLPFC. In this article, I review evidence for functional segregation within the DLPFC and postulate that at least two distinct subregions, i.e., the dorsal and ventral parts, can be identified.

We explored functional differences between the supplementary and presupplementary motor areas (SMA and pre-SMA, respectively) systematically with respect to multiple behavioral factors, ranging from the retrieval and processing of associative visual signals to the planning and execution of target-reaching movement. We analyzed neuronal activity while monkeys performed a behavioral task in which two visual instruction cues were given successively with a delay: one cue instructed the location of the reach target, and the other instructed arm use (right or left). After a second delay, the monkey received a motor-set cue to be prepared to make the reaching movement as instructed. Finally, after a GO signal, it reached for the instructed target with the instructed arm. We found the following apparent differences in activity: 1) neuronal activity preceding the appearance of visual cues was more frequent in the pre-SMA; 2) a majority of pre-SMA neurons, but many fewer SMA neurons, responded to the first or second cue, reflecting what was shown or instructed; 3) in addition, pre-SMA neurons often reflected information combining the instructions in the first and second cues; 4) during the motor-set period, pre-SMA neurons preferentially reflected the location of the target, while SMA neurons mainly reflected which arm to use; and 5) when executing the movement, a majority of SMA neurons increased their activity and were largely selective for the use of either the ipsilateral or contralateral arm. In contrast, the activity of pre-SMA neurons tended to be suppressed. These findings point to the functional specialization of the two areas, with respect to receiving associative cues, information processing, motor behavior planning, and movement execution.

We examined how the transformation of coordinates from visual to motor space is reflected by neuronal activity in the ventral premotor cortex (PMv) of monkeys. Three monkeys were trained to reach with their right hand for a target that appeared on a screen. While performing the task, the monkeys wore prisms that shifted the image of the target 10°, left or right, or wore no prisms, for a block of 200 trials. The nine targets were located in the same positions in visual space regardless of whether the prisms were present. Wearing the prisms required the monkeys to initiate a movement in a direction that was different from the apparent target location. Thus using the prisms, we could dissociate visual space from motor space. While the monkey performed the behavioral task, we recorded neuronal activity in the left PMv and primary motor cortex (MI), and various kinds of task-related neuronal activity were found in the motor areas. These included neurons that changed their activity during a reaction time (RT) period (the period between target presentation and movement onset), which were called “movement-related neurons” and selected for analysis. In these neurons, activity during a movement time (MT) period was also compared. Using general linear models for our statistical analysis, the neurons were then classified into four types: those whose activity was consistently dependent on location of targets in the visual coordinates regardless of whether the prisms were present or absent (V type); those that were consistently dependent on target location in the motor coordinates only; those that had different activity for both of the motor and visual coordinates; and those that had nondifferential activity for the two types of coordinates. The proportion of the four types of the neurons differed significantly between the PMv and MI. Most remarkably, neurons with V-type activity were almost exclusively recorded in the PMv and were almost exclusively found during the RT period. Such activity was never observed in an electromyogram of the working forelimb. Based on these observations, we postulate that the V and other types may represent the various intermediate stages of the transformation of coordinates and that the PMv plays a crucial role in transforming coordinates from visual to motor space.

We compared neuronal activity in the dorsal and ventral premotor areas (PMd and PMv, respectively) when monkeys were preparing to perform arm-reaching movements in a motor-set period before their actual execution. They were required to select one of four possible movements (reaching to a target on the left or right, using either the left or right arm) in accordance with two sets of instruction cues, followed by a delay period, and a subsequent motor-set period. During the motor-set period, the monkeys were required to get ready for a movement-trigger signal to start the arm-reach promptly. We analyzed the activity of 211 PMd and 109 PMv neurons that showed selectivity for the combination of the two instruction cues during the motor-set period. A majority (53%) of PMd neurons exhibited activity significantly tuned to both target location and arm use, and an approximately equal number of PMd neurons showed selectivity to either forthcoming arm use or target location. In contrast, 60% of PMv neurons showed selectivity for target location only and not for arm use. These findings point to preference in the use of neuronal activity in the two areas: preparation for action in the PMd and preparation for target acquisition in the PMv.

Visually guided action is generated via multiple modes of information processing. Here, we discuss three modes of neural processing underlying visually guided action. The first mode involves direct visuo-action association. In this mode, an action is planned to reach and grasp a target based on information about the target position (for reaching) and shape (for grasping). The network connecting the premotor and parietal cortices plays a central role in this mode. The second mode involves conditional visuo-action association. In this mode, a particular action is selected based on a rule associating a visual feature with an action. The third mode involves conditional visuo-goal association. In this mode, a visual signal is associated with a behavioral goal, but not with an action. A particular action is subsequently selected to meet this goal. Areas on the route from the inferotemporal cortex to the dorsal premotor cortex, such as the prefrontal cortex and basal ganglia, play a role in achieving conditional visuo-action and conditional visuo-goal associations. In summary, our analysis suggests the involvement of multiple brain networks converging on the premotor cortex in the three modes of neural processing utilized for generating visually guided action.

Recent studies have presented evidence that the prefrontal cortex plays a crucial role in every aspect of the cognitive processes necessary for behavioral planning: processing and integration of perceived or memorized information, associative learning, reward-based behavioral control, behavioral selection/decision-making and behavioral guidance. We propose that the creation of novel information is the means by which the prefrontal cortex operates to achieve executive control over behavioral planning. The prefrontal cortex is the site of operation of nodal points, where neural circuits integrate currently available or memorized information to generate the information that is necessary to perform an action. The prefrontal cortex also regulates the flow of information through multiple nodes to meet behavioral demands.

The dorsal aspect of the globus pallidus (GP) communicates with the prefrontal cortex and higher-order motor areas, indicating that it plays a role in goal-directed behavior. We examined the involvement of dorsal GP neurons in behavioral goal monitoring and maintenance, essential components of executive function. We trained two macaque monkeys to choose a reach target based on relative target position in a spatial goal task or a target shape in an object-goal task. The monkeys were trained to continue to choose a certain behavioral goal when reward volume was constant and to switch the goals when the volume began to decrease. Because the judgment for the next goal was made in the absence of visual signals, the monkeys were required to monitor and maintain the chosen goals during the reaching movement. We obtained three major findings. (1) GP neurons reflected more of the relative spatial position than the shape of the reaching target during the spatial goal task. During the object-goal task, the shape of the reaching object was represented more than the relative position. (2) The selectivity of individual neurons for the relative position was enhanced during the spatial goal task, whereas the object-shape selectivity was enhanced during the object-goal task. (3) When the monkeys switched the goals, the selectivity for either the position or shape also switched. Together, these findings suggest that the dorsal GP is involved in behavioral goal monitoring and maintenance during execution of goal-oriented actions, presumably in collaboration with the prefrontal cortex.

This study examined neuronal activity in the prefrontal cortex (PF) involved in the process of motor selection in accordance with two behavioral rules. We trained two monkeys to select a target based on the integration of memorized and current sensory information. Initially, a sample cue (triangle or circle) appeared at one of three locations (top, left, or right) for 1 s. After a 3-s delay, one of two types of choice cue appeared. The first type asked the monkeys to reach for a target by matching the location (location-matching task). The second type asked the monkeys to reach for a target by matching the shape (shape-matching task). The choice cue for location matching consisted of either three circles or three triangles, and the choice cue for shape matching consisted of a circle and a triangle. When the color of the choice cue changed from red to green 1.5 s later (GO signal), the monkeys touched the correct object to obtain a reward. We found cue-, delay-, choice-, and movement-related neuronal activity in the lateral prefrontal cortex. During the sample cue presentation and delay periods, we found selective neuronal activity for the location or shape of the sample cue. Shape-selective neurons were located more anteriorly in the ventral bank of the principal sulcus and inferior convexity area, whereas location-selective neurons were more posteriorly. After the choice cue appeared, we found three main types of neuronal activity in the critical period when the subject selected the future target: 1) activity reflecting past sensory information (the location or shape of the sample cue presented 3 s earlier), 2) activity selective for the configuration of the current choice cue, and 3) activity reflecting the properties (location or shape) of the future target. During the motor-response period, we found neuronal activity selective for the location or shape of the reaching target. When muscimol was microinjected into the ventral bank of principal sulcus and inferior convexity area, the performance of both tasks was impaired. Furthermore, we found that the wealth of neuronal activity in the PF that seemed to play a role in motor selection was rarely seen in the primary motor cortex.

Reacquisition deficits in prism adaptation after muscimol microinjection into the ventral premotor cortex of monkeys. A small amount of muscimol (1 μl; concentration, 5 μg/μl) was injected into the ventral and dorsal premotor cortex areas (PMv and PMd, respectively) of monkeys, which then were required to perform a visually guided reaching task. For the task, the monkeys were required to reach for a target soon after it was presented on a screen. While performing the task, the monkeys’ eyes were covered with left 10°, right 10°, or no wedge prisms, for a block of 50–100 trials. Without the prisms, the monkeys reached the targets accurately. When the prisms were placed, the monkeys initially misreached the targets because the prisms displaced the visual field. Before the muscimol injection, the monkeys adapted to the prisms in 10–20 trials, judging from the horizontal distance between the target location and the point where the monkey touched the screen. After muscimol injection into the PMv, the monkeys lost the ability to readapt and touched the screen closer to the location of the targets as seen through the prisms. This deficit was observed at selective target locations, only when the targets were shifted contralaterally to the injected hemisphere. When muscimol was injected into the PMd, no such deficits were observed. There were no changes in the reaction and movement times induced by muscimol injections in either area. The results suggest that the PMv plays an important role in motor learning, specifically in recalibrating visual and motor coordinates.

Multiple loop circuits interconnect the basal ganglia and the frontal cortex, and each part of the cortico-basal ganglia loops plays an essential role in neuronal computational processes underlying motor behavior. To gain deeper insight into specific functions played by each component of the loops, we compared response properties of neurons in the globus pallidus (GP) with those in the dorsal premotor cortex (PMd) and the ventrolateral and dorsolateral prefrontal cortex (vlPFC and dlPFC) while monkeys performed a behavioral task designed to include separate processes for behavioral goal determination and action selection. Initially, visual signals instructed an abstract behavioral goal, and seconds later, a choice cue to select an action was presented. When the instruction cue appeared, GP neurons started to reflect visual features as early as vlPFC neurons. Subsequently, GP neurons began to reflect goals informed by the visual signals no later than neurons in the PMd, vlPFC, and dlPFC, indicating that the GP is involved in the early determination of behavioral goals. In contrast, action specification occurred later in the GP than in the cortical areas, and the GP was not as involved in the process by which a behavioral goal was transformed into an action. Furthermore, the length of time representing behavioral goal and action was shorter in the GP than in the PMd and dlPFC, indicating that the GP may play an important role in detecting individual behavioral events. These observations elucidate the involvement of the GP in goal-directed behavior.

© 2012 Takada et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Organization of Two Cortico–Basal Ganglia Loop Circuits That Arise from Distinct Sectors of the Monkey Dorsal Premotor Cortex

The medial temporal lobe (MTL) is responsible for various mnemonic functions, such as association/conjunction memory. The lateral prefrontal cortex (LPFC) also plays crucial roles in mnemonic functions and memory-based cognitive behaviors, for example, decision-making. Therefore, it is considered that the MTL and LPFC connect with each other and cooperate for the control of cognitive behaviors. However, there exist very weak, if any, direct inputs from the MTL to the LPFC. Employing retrograde transsynaptic transport of rabies virus, we investigated the organization of disynaptic bottom-up pathways connecting the MTL and the inferotemporal cortex to the LPFC in macaques. Three days after rabies injections into dorsal area 46, a large number of labeled neurons were observed in the MTL, such as the hippocampal formation (including the entorhinal cortex), the perirhinal cortex, and the parahippocampal cortex. In contrast, a majority of the labeled neurons were located in the inferotemporal cortex following rabies injections into ventral area 46 and lateral area 12. Rabies injections into lateral area 9/area 8B labeled only a small number of neurons in the MTL and the inferotemporal cortex. The present results indicate that, among the LPFC, dorsal area 46 is the main target of disynaptic inputs from the MTL.

Lines of evidence indicate that both the ventrolateral prefrontal cortex (vlPFC) (areas 45/12) and dorsal premotor cortex (PMd) (rostral F2 in area 6) are crucially involved in conditional visuomotor behavior, in which it is required to determine an action based on an associated visual object. However, virtually no direct projections appear to exist between the vlPFC and PMd. In the present study, to elucidate possible multisynaptic networks linking the vlPFC to the PMd, we performed a series of neuroanatomical tract-tracing experiments in macaque monkeys. First, we identified cortical areas that send projection fibers directly to the PMd by injecting Fast Blue into the PMd. Considerable retrograde labeling occurred in the dorsal prefrontal cortex (dPFC) (areas 46d/9/8B/8Ad), dorsomedial motor cortex (dmMC) (F7 and presupplementary motor area), rostral cingulate motor area, and ventral premotor cortex (F5 and area 44), whereas the vlPFC was virtually devoid of neuronal labeling. Second, we injected the rabies virus, a retrograde transneuronal tracer, into the PMd. At 3 days after the rabies injections, second-order neurons were labeled in the vlPFC (mainly area 45), indicating that the vlPFC disynaptically projects to the PMd. Finally, to determine areas that connect the vlPFC to the PMd indirectly, we carried out an anterograde/retrograde dual-labeling experiment in single monkeys. By examining the distribution of axon terminals labeled from the vlPFC and cell bodies labeled from the PMd, we found overlapping labels in the dPFC and dmMC. These results indicate that the vlPFC outflow is directed toward the PMd in a multisynaptic fashion through the dPFC and/or dmMC.

The hallmark of higher-order brain functions is the ability to integrate and associate diverse sets of information in a flexible manner. Thus, fundamental knowledge about the mechanisms underlying of information in the brain can be obtained by examining the neural mechanisms involved in the generation of an appropriate motor command based on perceived sensory signals. In this review article, we have focused on the involvement of the neuronal networks centered at the lateral aspect of the frontal cortex in the process of motor selection and motor planning based on visual signals. We have initially discussed the role of the lateral prefrontal cortex in integrating multiple sets of visual signals to select a reach target and the participation of the premotor cortex in retrieving and integrating diverse sets of motor information, such as where should one reach out or which arm is to be used. Next, based on the results of the studies on ideomotor apraxia, we have hypothesized that there are at least 2 distinct levels of neural representation (virtual level and physical level). We have reviewed the evidence supporting the operation of 2 distinct classes of neuronal activities corresponding to these 2 levels. In conclusion, we propose that the frontal cortex initially processes information across sensory and motor domains at the virtual level to generate information about a forthcoming motor action (virtual action plan) and that this information is subsequently transformed into a motor command, such as muscle activity or movement direction, for an actual body movement at the physical level (physical motor plan). This proposed framework may be useful for explaining the diverse clinical conditions caused by brain lesions as well as for clarifying the neural mechanisms underlying the integration of perception and action.

We examined the organization of multisynaptic projections from the basal ganglia (BG) to the dorsal premotor area in macaques. After injection of the rabies virus into the rostral sector of the caudal aspect of the dorsal premotor area (F2r) and the caudal sector of the caudal aspect of the dorsal premotor area (F2c), second-order neuron labeling occurred in the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Labeled GPi neurons were found in the caudoventral portion after F2c injection, and in the dorsal portion at the rostrocaudal middle level after F2r injection. In the SNr, F2c and F2r injections led to labeling in the caudal or rostral part, respectively. Subsequently, third-order neuron labeling was observed in the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the striatum. After F2c injection, labeled neurons were observed over a broad territory in the GPe, whereas after F2r injection, labeled neurons tended to be restricted to the rostral and dorsal portions. In the STN, F2c injection resulted in extensive labeling over the nucleus, whereas F2r injection resulted in labeling in the ventral portion only. After both F2r and F2c injections, labeled neurons in the striatum were widely observed in the striatal cell bridge region and neighboring areas, as well as in the ventral striatum. The present results revealed that the origins of multisynaptic projections to F2c and F2r in the BG are segregated in the output stations of the BG, whereas intermingling rather than segregation is evident with respect to their input station.

Early studies on cortical motor areas have been centered on their somatotopical organization: a reasonable direction of research from the standpoint of skeletomotor control of limb and body movements. On the primary motor cortex, anatomical and physiological studies revealed aspects of somatotopical organization in progressively finer scales. Earlier studies were directed at elucidating the fine-grain modular organization of the primary motor cortex. Later studies, however, emphasized the diversity of output organization in individual part of the cortex, even at a single-cell level. At present, there is no convincing evidence for the existence of microstructures representing any form of unitary function. As for nonprimary motor areas, the existence of somatotopical organization has been inferred based on anatomical studies and on studies utilizing microstimulation. In the supplementary motor area, the body-part representation is broadly organized rostrocaudally in the order of face, forelimb and hindlimb areas, although with an extensive overlap of each area. In contrast, somatotopy is not apparent in the presupplemenetary motor area; effector-independent control of motor behavior seems to be dominant in this area. In the premotor cortex, motor acts involving the hindlimb appears to be much less represented than actions involving hand-arm and face. Overall, in considering the workings of nonprimary areas, aspects of motor behavior involving sensorial guidance, action-selection, or visuomotor association appear to be of primary importance rather than the determination of body parts to be used.

Multiple premotor areas exist in the medial frontal cortex of humans and monkeys. These areas, together with other cortical and subcortical areas, constitute two major networks: one for oculomotor control and the other for the control of limb movements. Individual areas, on one hand, are characterized by specific aspects of functional properties. On the other hand, they work cooperatively for planning, organizing, monitoring, as well as generating movements. This article reviews structural and functional organization of the medial premotor areas, and discuss clinical relevance of basic findings on each area.

Before preparing to initiate a forthcoming motion, we often acquire information about the future action without specifying actual motor parameters. The information for planning an action at this conceptual level can be provided with verbal commands or nonverbal signals even before the associated motor targets are visible. Under these conditions, the information signifying a virtual action plan must be transformed to information that can be used for constructing a motor plan to initiate specific movements. To determine whether the premotor cortex is involved in this process, we examined neuronal activity in the dorsal premotor cortex (PMd) of monkeys performing a behavioral task designed to isolate the behavioral stages of the acquisition of information for a future action and the construction of a motor plan. We trained the animals to receive a symbolic instruction (color and shape of an instruction cue) to determine whether to select the right or left of targets to reach, despite the physical absence of targets. Subsequently, two targets appeared on a screen at different locations. The animals then determined the correct target (left or right) based on the previous instruction and prepared to initiate a reaching movement to an actual target. The experimental design dissociated the selection of the right/left at an abstract level (action plan) from the physical motor plan. Here, we show that activity of individual PMd neurons initially reflects a virtual action plan transcending motor specifics, before these neurons contribute to a transformation process that leads to activity encoding a motor plan.

The lateral prefrontal cortex is critically involved in broad aspects of executive behavioral control. Early studies emphasized its role in the short-term retention of information retrieved from cortical association areas and in the inhibition of prepotent responses. Recent studies of subhuman primates and humans have revealed the role of this area in more general aspects of behavioral planning. Novel findings of neuronal activity have specified how neurons in this area take part in selective attention for action and in selecting an intended action. Furthermore, the involvement of the lateral prefrontal cortex in the implementation of behavioral rules and in setting multiple behavioral goals has been discovered. Recent studies have begun to reveal neuronal mechanisms for strategic behavioral planning and for the development of knowledge that enables the planning of macrostructures of event-action sequences at the conceptual level.

This chapter focuses on the differential involvement of multiple areas of the lateral frontal cortex in rule‐based behavior. It presents evidence obtained from physiological and anatomical studies of monkeys and discusses the specific role played by each area from the viewpoint of a hierarchical network within the lateral frontal cortex. It introduces several key types of neuronal activity found in the prefrontal, premotor, and primary motor cortices of macaque monkeys performing a variety of rule‐based behaviors, such as following location‐matching rules or shape‐matching rules.

The cerebral cortex is interconnected with two major subcortical structures: the basal ganglia and the cerebellum. How and where cerebellar circuits interact with basal ganglia circuits has been a longstanding question. Using transneuronal transport of rabies virus in macaques, we found that a disynaptic pathway links an output stage of cerebellar processing, the dentate nucleus, with an input stage of basal ganglia processing, the striatum.

We examined the cellular activity in the rostral cingulate motor area (CMAr) with respect to multiple behavioral factors that ranged from the retrieval and processing of associative visual signals to the planning and execution of instructed actions. We analyzed the neuronal activity in monkeys while they performed a behavioral task in which 2 visual instruction cues were given successively with an intervening delay. One cue instructed the location of the target to be reached; the other cue instructed which arm was to be used. After a second delay, the monkey received a motor-set cue to be prepared to initiate the motor task in accordance with instructions. Finally, after a go signal, the monkey reached for the instructed target with the instructed arm. We found that the activity of neurons in the CMAr changed profoundly throughout the behavioral task, which suggested that the CMAr participated in each of the behavioral processing steps. However, the neuronal activity was only modestly selective for the spatial location of the visual signal. We also found that selectivity for the instructional information delivered with the signals (target location and arm use) was modest. Furthermore, during the motor-set and movement periods, few CMAr neurons exhibited selectivity for such motor parameters as the location of the target or the arm to be used. The abundance and robustness of the neuronal activity within the CMAr that reflected each step of the behavioral task and the modest selectivity of the same cells for sensorimotor parameters are strikingly different from the preponderance of selectivity that we have observed in other frontal areas. Based on these results, we propose that the CMAr participates in monitoring individual behavioral events to keep track of the progress of required behavioral tasks. On the other hand, CMAr activity during motor planning may reflect the emergence of a general intention for action.

We compared how neurons in the dorsal and ventral regions of the dorsolateral prefrontal cortex (dl-PFC) participate in processing 2 sets of sensory signals, given at intervals, to generate plans for future actions. For the first set of visual signals, neurons in the ventral region of dl-PFC responded preferentially to the visuospatial properties of the signal, whereas neurons in the dorsal region of dl-PFC were involved primarily in retrieving information from the signal, such as the location of the target or which arm to use. For the second set of visual signals, most ventral dl-PFC neurons reflected either the sensory properties of the signals or the information retrieved from each signal. By contrast, dorsal neurons were involved more in integrating information about the target location and which arm to use to reach the target, thereby generating information that could be used to plan future actions. Thus sensorimotor transformations in the dorsolateral PFC appear to be time-variant and region-selective.

The premotor cortex (PM) in the bilateral lateral hemisphere of nonhuman primates and the human has been implicated in the sensorial guidance of movements. This is in contrast to more medial motor areas that are involved more in the temporal structuring of movements based on memorized information. The PM is further subdivided into dorsal (PMd) and ventral (PMv) parts. In this chapter, we describe our attempts to find differences in the use of these two areas in a nonhuman primate for programming future motor actions based on visual signals. We show that neurons in the PMv are involved primarily in receiving visuospatial signals and in specifying the spatial location of the target to be reached. In contrast, neurons in the PMd are involved more in integrating information about which arm to use and the target to be reached. Thus, PMd neurons are more implicated than those of the PMv in the preparation for a future motor action.

The premotor cortex (PM) in the bilateral lateral hemisphere of nonhuman primates and the human has been implicated in the sensorial guidance of movements. This is in contrast to more medial motor areas that are involved more in the temporal structuring of movements based on memorized information. The PM is further subdivided into dorsal (PMd) and ventral (PMv) parts. In this chapter, we describe our attempts to find differences in the use of these two areas in a nonhuman primate for programming future motor actions based on visual signals. We show that neurons in the PMv are involved primarily in receiving visuospatial signals and in specifying the spatial location of the target to be reached. In contrast, neurons in the PMd are involved more in integrating information about which arm to use and the target to be reached. Thus, PMd neurons are more implicated than those of the PMv in the preparation for a future motor action.

To plan an action, we must first select an object to act on and the body part (or parts) to use to accomplish our intention. To plan the motor task of reaching, we specify both the target to reach for and the arm to use. In the process of planning and preparing a motor task, information about the motor target and the arm to use must be integrated before a motor program can be formulated to generate the appropriate limb movement. One of the structures in the brain that is probably involved in integrating these two sets of information is the premotor area in the cerebral cortex of primates. The lateral sector of the dorsal premotor cortex is known to receive both visual and somatosensory input, and we show here that neurons in this area gather information about both the target and the body part, while subsequent activity specifies the planned action.