The role of the human ventral premotor cortex in counting successive stimuli

Adult humans have the ability to count large numbers of successive stimuli exactly. What brain areas underlie this uniquely human process? To identify the candidate brain areas, we first used functional magnetic resonance imaging, and found that the upper part of the left ventral premotor cortex was preferentially activated during counting of successive sensory stimuli presented 10–22 times, while the area was not activated during small number counting up to 4. We then used transcranial magnetic stimulation to assess the necessity of this area, and found that stimulation of this area preferentially disrupted subjects’ exact large number enumeration. Stimulation to the area affected neither subjects’ number word perception nor their ability to perform a non-numerical sequential letter task. While further investigation is necessary to determine the precise role of the left ventral premotor cortex, the results suggest that the area is indispensably involved for large number counting of successive stimuli, at least for the types of tasks in this study.     

Inactivation of the ventral premotor cortex biases the laterality of motoric choices

The visual, tactile, and motor properties of neurons in the ventral premotor cortex (PMv) suggest that the PMv plays an important role in the interaction of the face and upper extremities with visual objects, a function that might be disrupted by inactivation of the PMv. The behavior of three rhesus monkeys was, therefore, examined while the PMv was reversibly inactivated by intracortical injection of muscimol. Unilateral PMv inactivation produced no overt deficit in a monkey's ability to reach out and grasp a food morsel with either hand, nor did the monkey have difficulty in extracting a food morsel from a narrow well or in performing a visually cued individuated finger movement task. Unilateral PMv inactivation did bias the laterality of the monkeys' motoric choices, however. When two equivalent food morsels were presented simultaneously to the monkey's right and left, the likelihood that the monkey would make motoric responses contralateral to the inactivated PMv was reduced. After PMv muscimol injections, a monkey was less likely to initially turn its head contralaterally to inspect food morsels, less likely to reach for the food morsel with its contralateral hand, and less likely to take the morsel on its contralateral side. Catch trials in which a food morsel was present only on one side showed that the monkey was aware of the contralateral food morsels and was able to turn its head contralaterally and to use its contralateral arm and hand promptly and accurately. These observations suggest that, when equivalent visual objects for behavioral interaction are present bilaterally, the PMv plays a role in choosing the side to which motoric responses will be directed and the body part that will be deployed as the response effector.     

Differential involvement of neurons in the dorsal and ventral premotor cortex during processing of visual signals for action planning

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 (<400 ms) and persisted throughout the delay period. In addition, both the PMv and PMd showed bilateral representation on visuospatial information and motor-target or effector information. These results further elucidate the functional specialization of the PMd and PMv during the processing of visual information for action planning.     

Facilitation from ventral premotor cortex of primary motor cortex outputs to macaque hand muscles

We demonstrate that in the macaque monkey there is robust, short-latency facilitation by ventral premotor cortex (area F5) of motor outputs from primary motor cortex (M1) to contralateral intrinsic hand muscles. Experiments were carried out on two adult macaques under light sedation (ketamine plus medetomidine HCl). Facilitation of hand muscle electromyograms (EMG) was tested using arrays of fine intracortical microwires implanted, respectively, in the wrist/digit motor representations of F5 and M1, which were identified by previous mapping with intracortical microstimulation. Single pulses (70-200 microA) delivered to F5 microwires never evoked any EMG responses, but small responses were occasionally seen with double pulses (interval: 3 ms) at high intensity. However, both single- and double-pulse stimulation of F5 could facilitate the EMG responses evoked from M1 by single shocks. The facilitation was large (up to 4-fold with single and 12-fold with double F5 shocks) and occurred with an early onset, with significant effects at intervals of only 1-2 ms between conditioning F5 and test M1 stimuli. A number of possible pathways could be responsible for these effects, although it is argued that the most likely mechanism would be the facilitation, by cortico-cortical inputs from F5, of corticospinal I wave activity evoked from M1. This facilitatory action could be of considerable importance for the coupling of grasp-related neurons in F5 and M1 during visuomotor tasks.     

Effects of small ischemic lesions in the primary motor cortex on neurophysiological organization in ventral premotor cortex

After a cortical lesion, cortical areas distant from the site of injury are known to undergo physiological and anatomical changes. However, the mechanisms through which reorganization of distant cortical areas is initiated are poorly understood. In a previous publication, we showed that the ventral premotor cortex (PMv) undergoes physiological reorganization after a lesion destroying the majority of the primary motor cortex (M1) distal forelimb representation (DFL). After large lesions destroying >50% of the M1 DFL, the PMv DFL invariably increased in size, and the amount of the increase was positively correlated with the size of lesion. To determine whether lesions destroying <50% of the M1 DFL followed a similar trajectory, we documented PMv reorganization using intracortical microstimulation techniques after small, ischemic lesions targeting subregions within the M1 DFL. In contrast to earlier results, lesions resulted in a reduction of the PMv DFL regardless of their location. Further, because recent anatomical findings suggest a segregation of PMv connectivity with M1, we examined two lesion characteristics that may drive alterations in PMv physiological reorganization: location of the lesion with respect to PMv connectivity and relative size of the lesion. The results suggest that after a lesion in the M1 DFL, the induction of representational plasticity in PMv, as evaluated using intracortical microstimulation, is related more to the size of the lesion than to the disruption of its intracortical connections.     

The ventral premotor cortex (vPM) and resistance to interference

The authors tested a patient suffering from a circumscribed lesion of the right frontal operculum (FO) in 3 experiments of visual attention involving spatial orienting, maintenance of task-relevant priorities, and control of interference from new and old task-irrelevant items. The authors found that spatial orienting and active maintenance of priorities were intact, but there were difficulties in controlling interference from new and old irrelevant items. These results suggest that the FO is necessary for the direct control of interference, but its lesion alone is not enough to disturb spatial orienting processes or active maintenance of task priorities. The authors discuss the results in light of a hybrid cognitive model of attention.     

Movement-related neuronal activity reflecting the transformation of coordinates in the ventral premotor cortex of monkeys

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 degrees, 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.     

Modulation of primary motor cortex outputs from ventral premotor cortex during visually guided grasp in the macaque monkey

Area F5, in the ventral premotor cortex of the macaque monkey, plays a critical role in determining the hand shape appropriate for grasp of a visible object. F5 neurones show increased firing for particular types of grasp, and inactivation of F5 produces deficits in visually guided grasp. But how is F5 activity transformed into the appropriate pattern of hand muscle activity for efficient grasp? Here we investigate the pathways that may be involved by testing the effect of single stimuli delivered through microwires chronically implanted in area F5 and in primary motor cortex (M1) of two macaque monkeys. The EMG responses from M1 test (T) stimulation were recorded from 4–11 contralateral hand, digit and arm muscles during reach-to-grasp of visually presented objects. Conditioning (C) stimulation of F5, at intensities subthreshold for motor effects, caused strong modulation (over twofold) of M1 test (T) responses. The pattern of facilitation was specific. First, facilitation of the T response was particularly evident at short C–T intervals of −1 to 1 ms. Second, this facilitation was only present in some muscles and during reach-to-grasp of a subset of objects; it did not appear to be simply related to the level of EMG activity in the muscles at the moment of cortical stimulation or indeed to the upcoming contribution of that muscle during grasp. At later C–T intervals (1–6 ms), F5 stimulation caused significant suppression of the test M1 response. The results are in keeping with the concept that during visually guided grasp, F5 modulates corticospinal outputs from M1 in a muscle- and grasp-specific manner.     

Reacquisition deficits in prism adaptation after muscimol microinjection into the ventral premotor cortex of monkeys

A small amount of muscimol (1 microl; concentration, 5 microg/microl) 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 degrees, right 10 degrees, 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.     

Selective modulation of interactions between ventral premotor cortex and primary motor cortex during precision grasping in humans

In humans, the rostral part of the ventral premotor cortex (PMv), the homologue of F5 in monkeys, is known to be critically involved in shaping the hand to grasp objects. How does information about hand posture, that is processed in PMv, give rise to appropriate motor commands for transmission to spinal circuits controlling the hand? Whereas PMv is crucial for skilled visuomotor control of the hand, PMv sends relatively few direct corticospinal projections to spinal segments innervating hand muscles and the most likely route for PMv to contribute to the control of hand shape is through cortico-cortical connections with primary motor cortex (M1). If this is the case, we predicted that PMv–M1 interactions should be modulated specifically during precision grasping in humans. To address this issue, we investigated PMv–M1 connections by means of paired-pulse transcranial magnetic stimulation (TMS) and compared whether they were differentially modulated at rest, and during precision versus power grip. To do so, TMS was applied over M1 either in isolation or after a conditioning stimulus delivered, at different delays, over the ipsilateral PMv. For the parameters of TMS tested, we found that, at rest, PMv exerted a net inhibitory influence on M1 whereas, during power grip, this inhibition disappeared and was converted into a net facilitation during precision grip. The finding that, in humans, PMv–M1 interactions are selectively modulated during specific types of grasp provides further evidence that these connections play an important role in control of the hand.     

Neuronal activities in the ventral premotor cortex during a visually guided jaw movement in monkeys

Neuronal activities in the ventral part of the premotor cortex (PMv) and the primary motor cortex (MI) were analyzed during a visually guided jaw movement task. Based on the type of neuronal activity observed, when monkeys closed or opened their mouths in response to a visual stimulus, PMv neurons could be classified into three categories: (1) signal-related neurons, which transiently responded to visual stimuli, (2) movement-related neurons which were time-locked to jaw opening and/or jaw closing movements, and (3) set related neurons which exhibited gradually increasing activities while jaw position was maintained. However, all MI neurons exhibited movement-related activities and responded differently between the closing and opening dynamic phases. These results suggest that PMv neurons may be involved in motor preparation, initiation and control of jaw movements and task behavior based on visual information, and that MI neurons may be involved in controlling jaw movements, especially contraction of the masticatory muscles.     

Laterality of movement-related activity reflects transformation of coordinates in ventral premotor cortex and primary motor cortex of monkeys

The ventral premotor cortex (PMv) and the primary motor cortex (MI) of monkeys participate in various sensorimotor integrations, such as the transformation of coordinates from visual to motor space, because the areas contain movement-related neuronal activity reflecting either visual or motor space. In addition to relationship to visual and motor space, laterality of the activity could indicate stages in the visuomotor transformation. Thus we examined laterality and relationship to visual and motor space of movement-related neuronal activity in the PMv and MI of monkeys performing a fast-reaching task with the left or right arm, toward targets with visual and motor coordinates that had been dissociated by shift prisms. We determined laterality of each activity quantitatively and classified it into four types: activity that consistently depended on target locations in either head-centered visual coordinates (V-type) or motor coordinates (M-type) and those that had either differential or nondifferential activity for both coordinates (B- and N-types). A majority of M-type neurons in the areas had preferences for reaching movements with the arm contralateral to the hemisphere where neuronal activity was recorded. In contrast, most of the V-type neurons were recorded in the PMv and exhibited less laterality than the M-type. The B- and N-types were recorded in the PMv and MI and exhibited intermediate properties between the V- and M-types when laterality and correlations to visual and motor space of them were jointly examined. These results suggest that the cortical motor areas contribute to the transformation of coordinates to generate final motor commands.     

Corticocortical inputs to the dorsal and ventral aspects of the premotor cortex of macaque monkeys.

Recent cytoarchitectonic, histochemical and physiological studies have shown that the lateral part of area 6 (the premotor cortex) of macaque monkeys can be divided into at least two subregions, each of which is considered to play an important role in motor control. One lies in the dorsal aspect of the premotor cortex (PMd) medial to the spur of the arcuate sulcus, and the other in the ventral aspect of the premotor cortex (PMv) lateral to it. Since there is little information on the corticocortical inputs to the PMd, wheat-germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was injected into both the PMd and PMv to study corticocortical inputs to these two regions, and the distribution of retrogradely labeled cells was compared. When WGA-HRP was injected into the region immediately lateral to the superior precentral sulcus within the PMd, retrogradely labeled neurons were found in area 6 lying in the mesial wall possibly corresponding to the supplementary motor area (SMA), areas 24 and 23 of the cingulate cortex, rostral region of area 4, and area 5 (area PEa). In contrast, when WGA-HRP was injected into the PMv immediately caudal to the arcuate sulcus and lateral to the spur of the arcuate sulcus, the labeled cells were found in area 7 (areas POa, PF, PFG), area 5 (area PEa), area PFop (secondary somatosensory area), SMA, the cingulate cortex (areas 24), caudal region of area 4 in the rostral bank of the central sulcus, and area 3a. It appears that the differences in the corticocortical inputs contribute to specialization of the PMd and PMv for their differential roles in motor control.     

Representation of body identity and body actions in extrastriate body area and ventral premotor cortex

Although inherently linked, body form and body action may be represented in separate neural substrates. Using repetitive transcranial magnetic stimulation in healthy individuals, we show that interference with the extrastriate body area impairs the discrimination of bodily forms, and interference with the ventral premotor cortex impairs the discrimination of bodily actions. This double dissociation suggests that whereas extrastriate body area mainly processes actors' body identity, premotor cortex is crucial for visual discriminations of actions.     

Tuning of ventral premotor cortex neurons to distinct observed grasp types: a TMS-priming study

The ventral premotor cortex is known to be involved in the observation of others' actions. We tested the tuning properties of neuronal populations in the premotor cortex to distinct observed hand-object interactions with a transcranial magnetic stimulation (TMS)-priming protocol. Participants were asked to classify as "fast" or "slow" target pictures preceded by prime pictures both representing a spectrum of grasp types from precision grip (PG) to whole-hand grasp (WHG). Single TMS pulses time-locked to targets were delivered over the left ventral premotor (L-PMv) and left dorsal premotor (L-PMd) cortices or as sham stimulation. Without TMS and with sham stimulation, a clear priming effect was observed as a shortening of reaction times and as a bias towards the priming grasp type in the classification responses. The perceptual advantage of priming was reversed by TMS over PMv but not over PMd. According to the TMS-priming paradigm, these results show that distinct neural populations in L-PMv but not in L-PMd are selectively tuned to different observed grasp types as PG or WHG.     

The functions of the medial premotor cortex

Monkeys with medial premotor cortex (MPC) lesions are impaired on a simple learned task that requires them to raise their arm at their own pace. However, they can succeed on this task if they are given tones to guide performance. In the externally paced task the tones could aid performance in several ways. They tell the animal when to act (trigger), they remind the animal that food is available and so motivate (predictor), and they remind the animal of what to do (instruction). Monkeys with MPC lesions can respond quickly to visual cues (experiment 1), and they can respond as well as normal monkeys when there is no immediate trigger (experiment 2). They are also quick to relearn a task in which external cues tell them what to do (experiment 5). However, they are poor at selecting between movements on a simple motor sequence task (experiment 3), and they are poor at changing between two movements (experiment 4). On these tasks there were cues to act as triggers and predictors, but there were no external instructions. We conclude that the reason why animals with MPC lesions perform better with external cues is that these cues act as instructions. The cues prompt retrieval of the appropriate action. This is true whether the task requires the animal to perform one action (experiments 1 and 2) or to select between actions (experiments 3 and 4).     

Selectivity for grip type and action goal in macaque inferior parietal and ventral premotor grasping neurons

Grasping objects requires the selection of specific grip postures in relation to the objects' physical properties. Furthermore, grasping acts can be embedded in actions aimed at different goals, depending on the context in which the action is performed. Here we assessed whether information on grip and action type integrate at the single-neuron level within the parieto-frontal motor system. For this purpose, we trained three monkeys to perform simple grasp-to-eat and grasp-to-place actions, depending on contextual cues, in which different grip types were required in relation to target features. We recorded 173 grasping neurons: 86 from the inferior parietal area PFG and 87 from the ventral premotor area F5. Results showed that most neurons in both areas are selective for grip type, but the discharge of many of them, particularly in PFG, appears to differ in relation to action context. Kinematics data and control experiments indicated that neuronal selectivity appears more likely to depend on the action goal triggered by the context than on specific contextual elements. The temporal dynamics of grip and goal selectivity showed that grasping neurons reflect first "how" the object has to be grasped (grip), to guide and monitor the hand shaping phase, and then "why" the action is performed (goal), very likely to facilitate subsequent motor acts following grasping. These findings suggest that, in the parieto-frontal system, grip types and action goals are processed by both parallel and converging pathways, and area PFG appears to be particularly relevant for integrating this information for action organization.     

Activity in ventral and dorsal premotor cortex in response to predictable force-pulse perturbations in a precision grip task

This study compared the responses of ventral and dorsal premotor cortex (PMv and PMd) neurons to predictable force-pulse perturbations applied during a precision grip. Three monkeys were trained to grasp an unseen instrumented object between the thumb and index finger and to lift and hold it stationary within a position window for 2-2.5 s. The grip and load forces and the object displacement were measured on each trial. Single-unit activity was recorded from the hand regions in the PMv and PMd. In some conditions a predictable perturbation was applied to the object after 1,500 ms of static holding, whereas in other conditions different random combinations of perturbed and unperturbed trials were given. In the perturbed conditions, some were randomly and intermittently presented with a warning flash, whereas some were unsignaled. The activities of 198 cells were modulated during the task performance. Of these cells, 151 were located in the PMv, and 47 were located in the PMd. Although both PMv and PMd neurons had similar discharge patterns, more PMd neurons (84 vs. 43%) showed early pregrip activity. Forty of 106 PMv and 10/30 PMd cells responded to the perturbation with reflexlike triggered reactions. The latency of this response was always <100 ms with a mean of about 55 ms in both the PMv and the PMd. In contrast, 106 PMv and 30 PMd cells tested with the perturbations, only 9 and 10%, respectively, showed significant but nonspecific adaptations to the perturbation. The warning stimulus did not increase the occurrence of specific responses to the perturbation even though 21 of 42 cells related to the grip task also responded to moving visual stimuli. The responses were retinal and frequently involved limited portions of both foveal and peripheral visual fields. When tested with a 75 x 5.5-cm dark bar on a light background, these cells were sensitive to the direction of movement. In summary, the periarcuate premotor area activity to related to predictable force-pulse perturbations seems to reflect a general increase in excitability in contrast to a more specific anticipatory activity such as recorded in the cerebellum. In spite of the strong cerebello-thalamo-cortical projections, the results of the present study suggest that the cortical premotor areas are not involved in the elaboration of adaptive internal models of hand-object dynamics.     

Cue familiarity is represented in monkey medial prefrontal cortex during visuomotor association learning

To examine functional roles of the medial prefrontal cortex (mPFC) in visuomotor association learning, neuronal activity in the mPFC of a behaving monkey was recorded during this learning. The monkey was presented a cueing visual stimulus, and required to push, pull or turn a manipulator according to the cue following a delay period. Under the control condition, three cues (circle, triangle and square) instructed the monkey to the three responses in a block of trials. After 2 months of training the animal was familiar with these cue-response associations. Under the learning condition, two of the three familiar cues and one novel cue were presented in a block. The monkey initially did not know what the novel cue instructed at first and learned a new cue-response association by trial and error. Neurons in the mPFC showed marked responses to cue presentation, and cue responses changed depending on whether cues were familiar or novel. A group of mPFC neurons responded to novel cues, but not to familiar cues. Another group of neurons responded to familiar cues, but not to novel cues. In a subgroup of these familiar cue-selective neurons, cue response was increased under the learning condition compared to the control condition. These results suggest that mPFC neurons differentiate between familiar and novel instructions, and that the neurons responsive to familiar stimuli enhance their modulations when both familiar and novel instructions have to be processed during task performance.