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Distinctions between dorsal and ventral premotor areas: anatomical connectivity and functional properties
Distinctions between dorsal and ventral premotor areas: anatomical connectivity and functional properties Eiji Hoshi and Jun Tanji 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. Addresses Tamagawa University Research Institute, Tamagawa. Gakuen 6-1-1 Machida, Tokyo 194-8610, Japan Corresponding author: Tanji, Jun ([email protected])
Cortical non-primary motor areas At least seven non-primary motor areas involved in controlling arm movements, such as reaching and grasping, have been delineated in the frontal cortex of primates (Figure 2) [1,2,3]. Of these, four are in Brodmann’s area 6: the dorsal and ventral premotor areas (PMd and PMv), which are caudal to the arcuate sulcus and rostral to the M1, and the supplementary motor and pre-supplementary motor areas (SMA and pre-SMA), which are in the superior frontal gyrus. In addition, there are three non-primary motor areas in the banks of the cingulate sulcus: the rostral cingulate motor area (CMAr) in area 24c, the dorsal cingulate motor area (CMAd) in area 6c, and the ventral cingulate motor area (CMAv) in area 23c [4]. Here, we focus on the PMd and PMv (for a description of the anatomy of these premotor areas, see [5]).
Current Opinion in Neurobiology 2007, 17:234–242 This review comes from a themed issue on Cognitive neuroscience Edited by Keiji Tanaka and Takeo Watanabe Available online 20th February 2007 0959-4388/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.conb.2007.02.003
Introduction To achieve voluntary actions, many motor areas in the medial and lateral frontal cortex must work cooperatively. In this review, we examine the role of the lateral premotor cortex in multiple stages of controlling motor behavior (Figure 1). At the stage of preparing and executing planned movements, neurons in the lateral premotor cortex are engaged in a manner that is not readily distinguishable from that of neurons in the primary motor cortex (M1). However, when we consider behavioral stages that occur before motor preparation, neuronal activity in the premotor areas seems to differ from that in the M1. During the past two years, studies have revealed unique aspects of neuronal activity in the premotor cortex at two stages: planning actions based on available information, and selecting appropriate actions from potential options. Interestingly, neuronal activity exhibits distinct properties in the dorsal and ventral premotor areas. Taking this into account, along with the anatomical connectivity that characterizes each area, we propose a new concept — direct versus indirect sensorimotor processing — as a core aspect of operations that involve these areas. Current Opinion in Neurobiology 2007, 17:234–242
Involvement of the PMd and PMv in motor preparation and execution Involvement of the PMd in motor preparation was first described as set-related activity, which is defined as a neuronal activity that starts once a forthcoming movement is instructed and continues until the movement is executed [6,7]. According to this definition, if a visual cue is used to instruct motor preparation to capture a target in space, PMd activity reflects the motor significance of the instructional cue rather than its sensory or attentional significance [8]. Subsequently, it was shown that setrelated activity reflects movement parameters, such as direction, amplitude and speed of arm movements (e.g. [9–13]). Recent reports on the variability of discharges of PMd neurons during the set period, and the effects of microstimulation on the PMd [14,15], provide convincing evidence that the preparatory activity in the PMd facilitates the initiation of arm movements according to predetermined motor parameters. A recent study [16] that dissociated three motor variables required for the preparation of arm movements (target location, and the starting positions of the hand and eye) reported that PMd neurons encode the relative positions of the target, hand and eye, rather than the hand position in the eyecentered reference frame, as do neurons in the medial intraparietal cortex. At the stage of motor execution, neurons in the PMd exhibit activity that closely resembles that in the M1, suggesting that the PMd is involved in executing movements [17]. For example, PMd neurons seem to represent the direction of targets to be reached with the arm, and the preferred direction of these neurons rotates as the workspace shifts, as do the preferred directions of neurons www.sciencedirect.com
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Figure 1
Figure 2
Multiple stages in controlling motor behavior. This figure shows how inputs to motor areas of the brain are processed to specify a motor output. When an input provides a complete motor instruction, subjects can prepare the instructed movement before executing it. By contrast, when only partial motor instructions are given, a planning process, in which the instructions are collected and integrated, is necessary to construct an action in advance of its preparation and execution. In more demanding cases, subjects must select an action from multiple options in advance of planning, preparing and executing it. Multiple arrows pointing to planning and selection indicate a fact that multiple sets of information must be handled in these processes.
in the M1 [18]. Furthermore, the activity of PMd and M1 neurons is greatly influenced by arm orientation and hand trajectory [19]. Involvement of the PMv in preparing and executing arm movements has also been established. Although neuronal activity at this stage might seem similar to that in the M1, recent studies have revealed that the functional properties of the neuronal activities in the two areas are different. Kakei et al. [20] examined neuronal activity while a monkey made wrist movements under three different forearm postures, which enabled the authors to dissociate movement parameters related to an intrinsic coordinate frame from those related to an extrinsic frame. They found that 94% of PMv neurons were selective for the direction of movement in space, independent of posture, suggesting that the PMv encodes wrist movements in the extrinsic frame of reference. Subsequent reports extended this concept to whole-arm movements by showing that PMv neurons reflect the trajectory of motion in the visual space [21] and the direction of image motion [22], rather than the direction of the moving arm. Kurata and Hoshi [23] used shift-prisms to dissociate the motor space from the visual space with reference to which monkeys reached a target in space, and found three groups of PMv neurons that represented the target location in the visual space, the motor space, or both. They proposed that the PMv is involved in transforming the target information in space into motor information required for reaching, thus matching the visual space to the motor space. Other studies have found that two regions of the premotor areas (area F5 in PMv and area www.sciencedirect.com
Cortical motor areas in the macaque monkey. (a) Medial view upside-down. (b) Lateral view. Rostral is to the left in both panels. The central sulcus (CeS), arcuate sulcus (AS), principal sulcus (PS) and cingulate sulcus (CiS) are shown unfolded. The fundus of each sulcus is depicted by a broken line. In the frontal cortex, seven nonprimary motor areas are labeled: the dorsal and ventral premotor areas (PMd and PMv, respectively); the supplementary and presupplementary motor areas (SMA and pre-SMA, respectively); and the rostral, dorsal and ventral cingulate motor areas (CMAr, CMAd and CMAv, respectively). Only those areas of the PMd and PMv that represent the arm are shown. The PMd and PMv are highlighted because we focus on these areas in this review. The arm area of the primary motor cortex (M1) is also shown for reference. Three protogradations (directions of progressive cortical differentiation) in the frontal cortex of primates identified by Sanides [41] are indicated using colored arrows: the medial protogradation (orange), which originates in the cingulate gyrus; the lateral protogradation (green), which originates in the insular cortex; and the most recent protogradation in the evolution (blue), which originates in the central sulcus. Scale bar, 10 mm.
F2vr in PMd) are involved in preparing and executing grasping movements of three-dimensional objects [24,25]. They reported three classes of neurons that were selective for both the type of grasping movement (prehension) and for wrist orientation: purely motor neurons, visually modulated neurons and visuomotor neurons. These differed in the degree of response to object presentation or a grasping movement. Together, these results suggest that the PMv helps prepare and Current Opinion in Neurobiology 2007, 17:234–242
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Figure 3
Distinct response properties of neurons in the PMv and PMd. (a) Temporal sequence of behavioral events. (i) A trial in which an instruction for which arm to use (‘arm’) is followed by an instruction for which target to reach for (‘target’). (ii) A trial in which the two instructions were given in
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execute distal, in addition to proximal, arm movements, and stress its role in the visual guidance of movements for reaching a target in space or grasping an object [26,27]. Several studies have examined the structural and functional relationships of the premotor areas to the cortical motor areas and the spinal cord. Dum and Strick [3] revealed that the PMv, PMd and M1 send outputs to the spinal cord, and that all three areas are densely interconnected without area-specific differences [28]. Dancause et al. [29] showed that representation of a distal forelimb in the PMv is interconnected with both the distal and proximal areas of the M1. On the basis of physiological studies, Shimazu et al. [30] reported that microstimulation of the PMv facilitates output from the M1 to motor neurons in the spinal cord, although the PMv itself has little effect on them, suggesting that motor output from the PMv is largely mediated by the M1. It remains unknown how and to what extent activity in the premotor areas influences other motor areas or structures in the brainstem or spinal cord.
Action planning Motor planning is necessary to decide what to do and which action to perform, and the participation of the premotor areas, especially the PMd, is crucial for this process. Here, the term ‘planning’ refers to a process in which multiple sets of information on actions are collected and integrated to establish an intended action. A useful approach in examining this process experimentally is to give multiple partial motor instructions successively — that is, to require subjects to retrieve multiple instructions in a stepwise manner, and integrate them. Riehle and Requin [31] pioneered this approach by revealing that PMd neurons respond not only to the appearance of a motor instruction that specifies the
direction and amplitude of arm movements but also to the appearance of a partial instruction that specifies either direction or amplitude alone. Kurata extended this finding by presenting two sets of instructions on the direction and amplitude of wrist movements separately, before the overt movement began [9]. He showed that PMd neurons initially retrieve partial motor information on the direction and on the amplitude, which they then integrate. These two reports showed that the PMd is involved in deciding which movement to perform by combining necessary information. Subsequently, a detailed analysis of the action planning process in the PMd was performed by systematically examining neuronal activity in each of the necessary steps: reception of visuospatial signals, retrieval of information that specifies components of action, and integration of action-component information to establish an intended action [32,33,34]. To plan an action, two major behavioral factors must be specified: the effector to perform an action, and the target for that action. As an experimental model for action planning, Hoshi and Tanji [32] developed a behavioral task in which two instructions for arm use (effector information) and target location (spatial information) were given in two steps (Figure 3a) to plan a reaching action. They found that the PMd neurons promptly retrieved information about arm use and target location from visual instruction cues. Subsequently, when both instructions were given, PMd activity reflected a process in which the two sets of information were integrated to specify an action. These results point to a key role for the PMd in retrieving component information for constructing an action, and integrating the information necessary for action planning. In this respect, findings in monkey and human subjects are congruent. Beurze et al. [35] examined human cortical areas activated during action planning, using a
(Figure 3 Legend Continued ) the reverse order. When a monkey placed one hand on each touch pad and gazed at a fixation point (illustrated here as the central black dot on each rectangle), the first instruction (the first cue; 400 ms duration) was presented. This instruction contained information about either the target location or which arm to use. A small, colored cue superimposed on the central fixation point indicated the type of instruction — that is, whether it was an instruction for target location or arm use. A green square indicated an arm-use instruction, whereas a blue cross indicated a target-location instruction. At the same time, a white square appeared to the left or right of the fixation point and indicated laterality of arm use (for arm-use-related instructions) or target location (for target-related instructions). After the subsequent delay period (the first delay), which lasted 1200 ms, the second instruction (the second cue; 400 ms duration) was given to complete the information required for the subsequent action. After the second delay (1200 ms), squares appeared on each side of the fixation point (the set cue; 1000 ms duration), instructing the monkey to prepare to reach for the target when the fixation point disappeared (the ‘go’ signal). If the monkey subsequently reached for the instructed target with the instructed arm, it received a reward. The order of appearance of the target and arm instructions was alternated in a block of 20 trials, and laterality was randomized within each block. A series of five 250 Hz tones after a reward signaled reversal of instruction orders. (b) An example of PMv neuronal activity presented with raster displays and plots of spike density functions (SDFs). Each panel selectively illustrates activity of a PMv neuron in one of eight possible sequences of two instructions. Gray areas (from left to right) represent when the first, second and set cues were presented. Tic marks on the x-axis are at 400 ms intervals. First and second instructions are shown above each panel: right arm (RA); left arm (LA); right target (RT); and left target (LT). Spike density functions (Gaussian kernel, s = 20 ms, mean SE) are shown below each raster display. Raster plots and spike density functions were aligned to the onset of the first and second instructions, and to the onset of the set cue. The y-axis represents the instantaneous firing rate. This PMv neuron reflected mainly the left position of the white square that appeared in the instructional cues, soon after the appearance of the first and second cues. In addition, in the latter part of the second delay period, activity started to reflect the future reach target location (left), regardless of arm use. Of the eight possible sequences of the first and second cues, only four are illustrated. (c) An example of neuronal activity in the PMd. Display formats are as in (b). All eight sequences of the first and second cues are illustrated. This neuron showed brief visual responses when the first cue indicated right target reach. During the first delay period, the activity was greater when the first cue indicated the use of the left arm. After the appearance of the second cue, this neuron showed greater activity when the animal was required to reach the right target. Used, with permission, from [34]. www.sciencedirect.com
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behavioral task similar to one used for monkeys. They found that the activity in the PMd specified both the spatial location of a target and the effector to be selected for planned action, and also reflected processes of target– arm integration.
Decision for action selection Several studies have examined the involvement of the premotor areas in the process of selecting an appropriate action from multiple options. Ohbayashi et al. [36] investigated PMd involvement in decision making for saccadic eye movements. In the task, the first and second cues instructed the two potential saccadic targets, and the third cue indicated whether the saccades should be made in the visually displayed or reversed order. They found that PMd neurons temporarily hold information on the location of two cues and, subsequently, reflect the saccade targets after the third cue. Another group of neurons responded to the third cue only when monkeys were judging the order of saccades. These findings suggest that the PMd is involved in selecting an appropriate saccade by converting sequential spatial information about cues into information necessary to select the directions of planned sequential saccades. Cisek and Kalaska [37] reported that the PMd neurons initially represented potential reach directions, and subsequently represented the direction of the selected reach target. They proposed that multiple reach options are initially specified in the PMd and then gradually eliminated in competition for overt execution. Cisek [38] further developed a theoretical model that accounts for how an action is specified from potential actions by multiple cortical areas. Romo et al. [39] trained monkeys to compare two mechanical vibrations applied sequentially to the fingertip and report their decision by pushing a medial or lateral button. They found that PMv neurons initially retrieved signals given by each of the two vibration stimuli, and later represented an action selected by the monkeys. Wallis and Miller [40] found that PMd neurons initially reflected whether the behavioral rule was for matching or non-matching, and thereafter reflected the selected motor response. Taken together, these reports suggest that the premotor areas are involved in the selection of the appropriate action from the potential options in the process of converting sensory information into action.
Dorsal and ventral premotor areas are involved in different networks Sanides [41] proposed a theory on the evolution of the structure of the cerebral cortex and its phylogenetic differentiation, identifying three protogradations (directions of progressive cortical differentiation) in the frontal cortex of primates (Figure 2): the medial, originating in the cingulate gyrus; the lateral, originating in the insular cortex; and the most recent protogradation in the evolution, originating in the central sulcus. In this schema, the medial and lateral protogradations give rise to the PMd Current Opinion in Neurobiology 2007, 17:234–242
and PMv, respectively. The architectonic concept of evolution of the two areas from separate sources has interesting implications for anatomical connectivity [42]. Input sources from the dorsolateral prefrontal cortex are different: the PMd receives main inputs from its dorsal area, whereas the PMv receives inputs from its ventral area [5,43–45]. Input sources from the parietal cortex are also different: the PMd receives main inputs from the superior parietal lobule [46,47], whereas the PMv receives inputs from the inferior parietal lobule [48]. Thus, neuroanatomical considerations suggest that the PMd and PMv are involved in networks that are, at least to some extent, distinct [49–51]. Lesion studies substantiate this view. Ablation of the PMv was found to cause deficits in attending to peripersonal space [52]. Subsequent studies reported impairments in orienting on the side contralateral to the lesion [53], in executing visual tracking with wrist movements [54], and in remapping between the visual and motor space when prisms were introduced to shift how visual information reached the eyes [55]. Deficits in grasping objects, without any paralysis of finger movements, were also reported following lesion of the PMv [56]. These findings suggest that an important function of the PMv is to match the motor act directly with sensory inputs, such as matching the movement of the wrist or whole body with the location of a target or matching a grasping movement with the three-dimensional feature of the target. The mirror neuron system [57,58,59], which matches a viewed act with an actual self movement, might be categorized as a variant of direct matching between sensory information and a motor act. By contrast, lesion studies on the PMd revealed impairments in conditional motor behavior [54,60,61].
Direct comparison of neuronal activity in the PMv and PMd during action performance Because the PMd and PMv are involved in distinct networks, it is possible that their functional roles in motor control are, at least in part, fundamentally different. Indeed, several studies have reported functional differences between the PMd and PMv. Boussaoud and Wise [62,63] examined activity in PMd and PMv neurons while monkeys were performing a behavioral task that dissociated the representation for the visuospatial position of a cue from the visuomotor representation of arm movements. In this landmark study, they found that a majority of the PMd neurons represented the motor significance of visual signals, whereas the PMv neurons preferentially reflected the visuospatial information of the visual cue. Subsequent studies suggested that the PMd is more involved in representing motor information instructed by an arbitrary visual signal [64–67]. This process might be a crucial component of conditional motor behavior, requiring subjects to associate a sensory signal with a motor act in an arbitrary manner [64,68]. In a recent study, www.sciencedirect.com
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Xiao et al. [69] examined activity during a preparatory period and found that PMv neurons are less sensitive to the dynamics of the forthcoming movement than are PMd neurons. By contrast, the movement-related activity in the PMv was sensitive to the dynamics (such as force). Xiao et al. concluded that the representation of action in the PMv shifts from kinematics (such as direction) to dynamics when the reaching movement is initiated, whereas in the PMd, the shift occurs during the set period. Hoshi and Tanji [34] compared the response properties of neurons in the PMd and PMv while monkeys were performing the aforementioned task (Figure 3a). Consistent with the report by Boussaoud and Wise [62,63], the PMv neurons preferentially reflected visuospatial features of the cue, rather than the motor instruction (Figure 3b). In addition, the spatial preference between visual responses and the action target was often congruent. For example, during the late second delay period between presentation of second and set cues in this task (Figure 3b), activity in the PMv neurons was greater in response to the left reach target, whereas visual responses in these neurons were greater in response to left visual cues. In addition to three distinct groups of PMd neurons involved in the planning process (as discussed in the previous section), Hoshi and Tanji identified a group of PMd neurons that have intermediate function between
motor information retrieval and action formulation. A typical example of neuronal activity is shown in Figure 3c. This neuron showed brief visual responses when the first cue indicated right target reach. During the delay period that followed presentation of the first cue, the activity was greater when the first cue indicated the use of the left arm. After the appearance of the second cue, this neuron showed greater activity when the animal prepared to reach for the right target than for the left [34].
Direct versus indirect sensorimotor processing in the PMv and PMd Taking into consideration all of the reports discussed in previous sections, we propose that a core aspect of the functional differences between the PMd and PMv can be explained in terms of direct versus indirect sensorimotor processing. Figure 4a illustrates the concept of neuronal processes that operate in direct sensorimotor processing in the PMv. This schematic diagram shows the basic operation of a neuronal circuit that receives sensory inputs that inform the animal about a target, and sends outputs of motor commands that match the sensory input. In the case of grasping movements, the three-dimensional features of the target object are the sensory inputs, and the motor commands for digit configurations are the motor output [25]. In the case of reaching movements, the target location in the visual space corresponds to the input, and the target location in the motor space
Figure 4
Two modes of sensorimotor processing. (a) Direct sensorimotor processing in the PMv. This schematic diagram shows the basic operation of a neuronal circuit that receives sensory inputs about a target and sends outputs of motor commands that match the sensory input. Each level of shadings indicates a group of neurons that preferentially represent distinct sensory inputs, intermediates and motor outputs. (b) Indirect sensorimotor processing in the PMd. This schematic diagram shows the basic operation of a neuronal circuit that receives partial motor information as inputs and integrates them via intermediates. Finally, the motor outputs correspond to a motor act. Neuronal activity shown in Figure 3c can work as a part of the intermediates. www.sciencedirect.com
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corresponds to the output [23]. Figure 4b represents indirect sensorimotor processing in the PMd. As shown in this schematic diagram, the basic operation of a neuronal circuit has three stages: to receive inputs that specify partial motor information, such as target location and arm use; to integrate the inputs in intervening intermediate nodes; and to send outputs. The neuron shown in Figure 3c serves as an intermediate node because it selectively retrieves motor information from the first cue and then, after the second cue, integrates the two instructions on arm use and target location. The motor outputs correspond to a motor act, such as a specific combination of arm use and target location [32]. The arbitrary sensorimotor mapping required for conditional motor behavior can be viewed as requiring indirect sensorimotor processing in the PMd, because the sensory signal does not directly indicate action. This is in contrast to the direct sensorimotor processing, which is deemed to require participation of the PMv. Indeed, Cisek and Kalaska [70] showed that PMd neurons discharged when subjects were looking at a learned, conditional visuomotor task that was being performed by others, in addition to when the subject was performing the task itself.
Conclusions The PMd and PMv, which have distinct evolutionary origins, constitute largely separate cortical networks that are interconnected by different regions of the prefrontal cortex and parietal cortex. As inferred from neuroanatomical considerations, the PMd and PMv are involved in different aspects of selecting and planning motor behavior, and in preparing and executing movements. We propose that the functional specificity of the PMd and PMv can be explained by a cardinal concept of direct versus indirect sensorimotor processing. In direct sensorimotor processing, the PMv receives information on a motor target and sends outputs to achieve an action that directly matches the information. By contrast, the PMd has a major role in indirect sensorimotor processing, retrieving multiple sets of motor information from sensory signals, and integrating components of a required action to formulate a motor program for the intended action.
Acknowledgements This work was supported by the 21st Century Center of Excellence Program from the Japanese Society for the Promotion of Science, a Grant-in-Aid for Scientific Research on Priority Areas — Integrative Brain Research — from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT; 18019032 and 16067101), and a Grant-in-Aid for Young Scientists (A) from MEXT (18680035).
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34. Hoshi E, Tanji J: Differential involvement of neurons in the dorsal and ventral premotor cortex during processing of visual signals for action planning. J Neurophysiol 2006, 95:3596-3616. This paper showed that the PMd is involved in action planning, whereas the PMv reflects visuospatial features of instruction signals and reach targets.
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35. Beurze SM, De Lange FP, Toni I, Medendorp WP: Integration of target and effector information in the human brain during reach planning. J Neurophysiol 2007, 97:188-199. This paper, along with [34], revealed that the PMd of both humans and non-human primates has a crucial role in planning reaching movements. 36. Ohbayashi M, Ohki K, Miyashita Y: Conversion of working memory to motor sequence in the monkey premotor cortex. Science 2003, 301:233-236. 37. Cisek P, Kalaska JF: Neural correlates of reaching decisions in dorsal premotor cortex: specification of multiple direction choices and final selection of action. Neuron 2005, 45:801-814. www.sciencedirect.com
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Cortical non-primary motor areas At least seven non-primary motor areas involved in controlling arm movements, such as reaching and grasping, have been delineated in the frontal cortex of primates (Figure 2) [1,2,3]. Of these, four are in Brodmann’s area 6: the dorsal and ventral premotor areas (PMd and PMv), which are caudal to the arcuate sulcus and rostral to the M1, and the supplementary motor and pre-supplementary motor areas (SMA and pre-SMA), which are in the superior frontal gyrus. In addition, there are three non-primary motor areas in the banks of the cingulate sulcus: the rostral cingulate motor area (CMAr) in area 24c, the dorsal cingulate motor area (CMAd) in area 6c, and the ventral cingulate motor area (CMAv) in area 23c [4]. Here, we focus on the PMd and PMv (for a description of the anatomy of these premotor areas, see [5]).
Current Opinion in Neurobiology 2007, 17:234–242 This review comes from a themed issue on Cognitive neuroscience Edited by Keiji Tanaka and Takeo Watanabe Available online 20th February 2007 0959-4388/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.conb.2007.02.003
Introduction To achieve voluntary actions, many motor areas in the medial and lateral frontal cortex must work cooperatively. In this review, we examine the role of the lateral premotor cortex in multiple stages of controlling motor behavior (Figure 1). At the stage of preparing and executing planned movements, neurons in the lateral premotor cortex are engaged in a manner that is not readily distinguishable from that of neurons in the primary motor cortex (M1). However, when we consider behavioral stages that occur before motor preparation, neuronal activity in the premotor areas seems to differ from that in the M1. During the past two years, studies have revealed unique aspects of neuronal activity in the premotor cortex at two stages: planning actions based on available information, and selecting appropriate actions from potential options. Interestingly, neuronal activity exhibits distinct properties in the dorsal and ventral premotor areas. Taking this into account, along with the anatomical connectivity that characterizes each area, we propose a new concept — direct versus indirect sensorimotor processing — as a core aspect of operations that involve these areas. Current Opinion in Neurobiology 2007, 17:234–242
Involvement of the PMd and PMv in motor preparation and execution Involvement of the PMd in motor preparation was first described as set-related activity, which is defined as a neuronal activity that starts once a forthcoming movement is instructed and continues until the movement is executed [6,7]. According to this definition, if a visual cue is used to instruct motor preparation to capture a target in space, PMd activity reflects the motor significance of the instructional cue rather than its sensory or attentional significance [8]. Subsequently, it was shown that setrelated activity reflects movement parameters, such as direction, amplitude and speed of arm movements (e.g. [9–13]). Recent reports on the variability of discharges of PMd neurons during the set period, and the effects of microstimulation on the PMd [14,15], provide convincing evidence that the preparatory activity in the PMd facilitates the initiation of arm movements according to predetermined motor parameters. A recent study [16] that dissociated three motor variables required for the preparation of arm movements (target location, and the starting positions of the hand and eye) reported that PMd neurons encode the relative positions of the target, hand and eye, rather than the hand position in the eyecentered reference frame, as do neurons in the medial intraparietal cortex. At the stage of motor execution, neurons in the PMd exhibit activity that closely resembles that in the M1, suggesting that the PMd is involved in executing movements [17]. For example, PMd neurons seem to represent the direction of targets to be reached with the arm, and the preferred direction of these neurons rotates as the workspace shifts, as do the preferred directions of neurons www.sciencedirect.com
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Figure 1
Figure 2
Multiple stages in controlling motor behavior. This figure shows how inputs to motor areas of the brain are processed to specify a motor output. When an input provides a complete motor instruction, subjects can prepare the instructed movement before executing it. By contrast, when only partial motor instructions are given, a planning process, in which the instructions are collected and integrated, is necessary to construct an action in advance of its preparation and execution. In more demanding cases, subjects must select an action from multiple options in advance of planning, preparing and executing it. Multiple arrows pointing to planning and selection indicate a fact that multiple sets of information must be handled in these processes.
in the M1 [18]. Furthermore, the activity of PMd and M1 neurons is greatly influenced by arm orientation and hand trajectory [19]. Involvement of the PMv in preparing and executing arm movements has also been established. Although neuronal activity at this stage might seem similar to that in the M1, recent studies have revealed that the functional properties of the neuronal activities in the two areas are different. Kakei et al. [20] examined neuronal activity while a monkey made wrist movements under three different forearm postures, which enabled the authors to dissociate movement parameters related to an intrinsic coordinate frame from those related to an extrinsic frame. They found that 94% of PMv neurons were selective for the direction of movement in space, independent of posture, suggesting that the PMv encodes wrist movements in the extrinsic frame of reference. Subsequent reports extended this concept to whole-arm movements by showing that PMv neurons reflect the trajectory of motion in the visual space [21] and the direction of image motion [22], rather than the direction of the moving arm. Kurata and Hoshi [23] used shift-prisms to dissociate the motor space from the visual space with reference to which monkeys reached a target in space, and found three groups of PMv neurons that represented the target location in the visual space, the motor space, or both. They proposed that the PMv is involved in transforming the target information in space into motor information required for reaching, thus matching the visual space to the motor space. Other studies have found that two regions of the premotor areas (area F5 in PMv and area www.sciencedirect.com
Cortical motor areas in the macaque monkey. (a) Medial view upside-down. (b) Lateral view. Rostral is to the left in both panels. The central sulcus (CeS), arcuate sulcus (AS), principal sulcus (PS) and cingulate sulcus (CiS) are shown unfolded. The fundus of each sulcus is depicted by a broken line. In the frontal cortex, seven nonprimary motor areas are labeled: the dorsal and ventral premotor areas (PMd and PMv, respectively); the supplementary and presupplementary motor areas (SMA and pre-SMA, respectively); and the rostral, dorsal and ventral cingulate motor areas (CMAr, CMAd and CMAv, respectively). Only those areas of the PMd and PMv that represent the arm are shown. The PMd and PMv are highlighted because we focus on these areas in this review. The arm area of the primary motor cortex (M1) is also shown for reference. Three protogradations (directions of progressive cortical differentiation) in the frontal cortex of primates identified by Sanides [41] are indicated using colored arrows: the medial protogradation (orange), which originates in the cingulate gyrus; the lateral protogradation (green), which originates in the insular cortex; and the most recent protogradation in the evolution (blue), which originates in the central sulcus. Scale bar, 10 mm.
F2vr in PMd) are involved in preparing and executing grasping movements of three-dimensional objects [24,25]. They reported three classes of neurons that were selective for both the type of grasping movement (prehension) and for wrist orientation: purely motor neurons, visually modulated neurons and visuomotor neurons. These differed in the degree of response to object presentation or a grasping movement. Together, these results suggest that the PMv helps prepare and Current Opinion in Neurobiology 2007, 17:234–242
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Figure 3
Distinct response properties of neurons in the PMv and PMd. (a) Temporal sequence of behavioral events. (i) A trial in which an instruction for which arm to use (‘arm’) is followed by an instruction for which target to reach for (‘target’). (ii) A trial in which the two instructions were given in
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execute distal, in addition to proximal, arm movements, and stress its role in the visual guidance of movements for reaching a target in space or grasping an object [26,27]. Several studies have examined the structural and functional relationships of the premotor areas to the cortical motor areas and the spinal cord. Dum and Strick [3] revealed that the PMv, PMd and M1 send outputs to the spinal cord, and that all three areas are densely interconnected without area-specific differences [28]. Dancause et al. [29] showed that representation of a distal forelimb in the PMv is interconnected with both the distal and proximal areas of the M1. On the basis of physiological studies, Shimazu et al. [30] reported that microstimulation of the PMv facilitates output from the M1 to motor neurons in the spinal cord, although the PMv itself has little effect on them, suggesting that motor output from the PMv is largely mediated by the M1. It remains unknown how and to what extent activity in the premotor areas influences other motor areas or structures in the brainstem or spinal cord.
Action planning Motor planning is necessary to decide what to do and which action to perform, and the participation of the premotor areas, especially the PMd, is crucial for this process. Here, the term ‘planning’ refers to a process in which multiple sets of information on actions are collected and integrated to establish an intended action. A useful approach in examining this process experimentally is to give multiple partial motor instructions successively — that is, to require subjects to retrieve multiple instructions in a stepwise manner, and integrate them. Riehle and Requin [31] pioneered this approach by revealing that PMd neurons respond not only to the appearance of a motor instruction that specifies the
direction and amplitude of arm movements but also to the appearance of a partial instruction that specifies either direction or amplitude alone. Kurata extended this finding by presenting two sets of instructions on the direction and amplitude of wrist movements separately, before the overt movement began [9]. He showed that PMd neurons initially retrieve partial motor information on the direction and on the amplitude, which they then integrate. These two reports showed that the PMd is involved in deciding which movement to perform by combining necessary information. Subsequently, a detailed analysis of the action planning process in the PMd was performed by systematically examining neuronal activity in each of the necessary steps: reception of visuospatial signals, retrieval of information that specifies components of action, and integration of action-component information to establish an intended action [32,33,34]. To plan an action, two major behavioral factors must be specified: the effector to perform an action, and the target for that action. As an experimental model for action planning, Hoshi and Tanji [32] developed a behavioral task in which two instructions for arm use (effector information) and target location (spatial information) were given in two steps (Figure 3a) to plan a reaching action. They found that the PMd neurons promptly retrieved information about arm use and target location from visual instruction cues. Subsequently, when both instructions were given, PMd activity reflected a process in which the two sets of information were integrated to specify an action. These results point to a key role for the PMd in retrieving component information for constructing an action, and integrating the information necessary for action planning. In this respect, findings in monkey and human subjects are congruent. Beurze et al. [35] examined human cortical areas activated during action planning, using a
(Figure 3 Legend Continued ) the reverse order. When a monkey placed one hand on each touch pad and gazed at a fixation point (illustrated here as the central black dot on each rectangle), the first instruction (the first cue; 400 ms duration) was presented. This instruction contained information about either the target location or which arm to use. A small, colored cue superimposed on the central fixation point indicated the type of instruction — that is, whether it was an instruction for target location or arm use. A green square indicated an arm-use instruction, whereas a blue cross indicated a target-location instruction. At the same time, a white square appeared to the left or right of the fixation point and indicated laterality of arm use (for arm-use-related instructions) or target location (for target-related instructions). After the subsequent delay period (the first delay), which lasted 1200 ms, the second instruction (the second cue; 400 ms duration) was given to complete the information required for the subsequent action. After the second delay (1200 ms), squares appeared on each side of the fixation point (the set cue; 1000 ms duration), instructing the monkey to prepare to reach for the target when the fixation point disappeared (the ‘go’ signal). If the monkey subsequently reached for the instructed target with the instructed arm, it received a reward. The order of appearance of the target and arm instructions was alternated in a block of 20 trials, and laterality was randomized within each block. A series of five 250 Hz tones after a reward signaled reversal of instruction orders. (b) An example of PMv neuronal activity presented with raster displays and plots of spike density functions (SDFs). Each panel selectively illustrates activity of a PMv neuron in one of eight possible sequences of two instructions. Gray areas (from left to right) represent when the first, second and set cues were presented. Tic marks on the x-axis are at 400 ms intervals. First and second instructions are shown above each panel: right arm (RA); left arm (LA); right target (RT); and left target (LT). Spike density functions (Gaussian kernel, s = 20 ms, mean SE) are shown below each raster display. Raster plots and spike density functions were aligned to the onset of the first and second instructions, and to the onset of the set cue. The y-axis represents the instantaneous firing rate. This PMv neuron reflected mainly the left position of the white square that appeared in the instructional cues, soon after the appearance of the first and second cues. In addition, in the latter part of the second delay period, activity started to reflect the future reach target location (left), regardless of arm use. Of the eight possible sequences of the first and second cues, only four are illustrated. (c) An example of neuronal activity in the PMd. Display formats are as in (b). All eight sequences of the first and second cues are illustrated. This neuron showed brief visual responses when the first cue indicated right target reach. During the first delay period, the activity was greater when the first cue indicated the use of the left arm. After the appearance of the second cue, this neuron showed greater activity when the animal was required to reach the right target. Used, with permission, from [34]. www.sciencedirect.com
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behavioral task similar to one used for monkeys. They found that the activity in the PMd specified both the spatial location of a target and the effector to be selected for planned action, and also reflected processes of target– arm integration.
Decision for action selection Several studies have examined the involvement of the premotor areas in the process of selecting an appropriate action from multiple options. Ohbayashi et al. [36] investigated PMd involvement in decision making for saccadic eye movements. In the task, the first and second cues instructed the two potential saccadic targets, and the third cue indicated whether the saccades should be made in the visually displayed or reversed order. They found that PMd neurons temporarily hold information on the location of two cues and, subsequently, reflect the saccade targets after the third cue. Another group of neurons responded to the third cue only when monkeys were judging the order of saccades. These findings suggest that the PMd is involved in selecting an appropriate saccade by converting sequential spatial information about cues into information necessary to select the directions of planned sequential saccades. Cisek and Kalaska [37] reported that the PMd neurons initially represented potential reach directions, and subsequently represented the direction of the selected reach target. They proposed that multiple reach options are initially specified in the PMd and then gradually eliminated in competition for overt execution. Cisek [38] further developed a theoretical model that accounts for how an action is specified from potential actions by multiple cortical areas. Romo et al. [39] trained monkeys to compare two mechanical vibrations applied sequentially to the fingertip and report their decision by pushing a medial or lateral button. They found that PMv neurons initially retrieved signals given by each of the two vibration stimuli, and later represented an action selected by the monkeys. Wallis and Miller [40] found that PMd neurons initially reflected whether the behavioral rule was for matching or non-matching, and thereafter reflected the selected motor response. Taken together, these reports suggest that the premotor areas are involved in the selection of the appropriate action from the potential options in the process of converting sensory information into action.
Dorsal and ventral premotor areas are involved in different networks Sanides [41] proposed a theory on the evolution of the structure of the cerebral cortex and its phylogenetic differentiation, identifying three protogradations (directions of progressive cortical differentiation) in the frontal cortex of primates (Figure 2): the medial, originating in the cingulate gyrus; the lateral, originating in the insular cortex; and the most recent protogradation in the evolution, originating in the central sulcus. In this schema, the medial and lateral protogradations give rise to the PMd Current Opinion in Neurobiology 2007, 17:234–242
and PMv, respectively. The architectonic concept of evolution of the two areas from separate sources has interesting implications for anatomical connectivity [42]. Input sources from the dorsolateral prefrontal cortex are different: the PMd receives main inputs from its dorsal area, whereas the PMv receives inputs from its ventral area [5,43–45]. Input sources from the parietal cortex are also different: the PMd receives main inputs from the superior parietal lobule [46,47], whereas the PMv receives inputs from the inferior parietal lobule [48]. Thus, neuroanatomical considerations suggest that the PMd and PMv are involved in networks that are, at least to some extent, distinct [49–51]. Lesion studies substantiate this view. Ablation of the PMv was found to cause deficits in attending to peripersonal space [52]. Subsequent studies reported impairments in orienting on the side contralateral to the lesion [53], in executing visual tracking with wrist movements [54], and in remapping between the visual and motor space when prisms were introduced to shift how visual information reached the eyes [55]. Deficits in grasping objects, without any paralysis of finger movements, were also reported following lesion of the PMv [56]. These findings suggest that an important function of the PMv is to match the motor act directly with sensory inputs, such as matching the movement of the wrist or whole body with the location of a target or matching a grasping movement with the three-dimensional feature of the target. The mirror neuron system [57,58,59], which matches a viewed act with an actual self movement, might be categorized as a variant of direct matching between sensory information and a motor act. By contrast, lesion studies on the PMd revealed impairments in conditional motor behavior [54,60,61].
Direct comparison of neuronal activity in the PMv and PMd during action performance Because the PMd and PMv are involved in distinct networks, it is possible that their functional roles in motor control are, at least in part, fundamentally different. Indeed, several studies have reported functional differences between the PMd and PMv. Boussaoud and Wise [62,63] examined activity in PMd and PMv neurons while monkeys were performing a behavioral task that dissociated the representation for the visuospatial position of a cue from the visuomotor representation of arm movements. In this landmark study, they found that a majority of the PMd neurons represented the motor significance of visual signals, whereas the PMv neurons preferentially reflected the visuospatial information of the visual cue. Subsequent studies suggested that the PMd is more involved in representing motor information instructed by an arbitrary visual signal [64–67]. This process might be a crucial component of conditional motor behavior, requiring subjects to associate a sensory signal with a motor act in an arbitrary manner [64,68]. In a recent study, www.sciencedirect.com
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Xiao et al. [69] examined activity during a preparatory period and found that PMv neurons are less sensitive to the dynamics of the forthcoming movement than are PMd neurons. By contrast, the movement-related activity in the PMv was sensitive to the dynamics (such as force). Xiao et al. concluded that the representation of action in the PMv shifts from kinematics (such as direction) to dynamics when the reaching movement is initiated, whereas in the PMd, the shift occurs during the set period. Hoshi and Tanji [34] compared the response properties of neurons in the PMd and PMv while monkeys were performing the aforementioned task (Figure 3a). Consistent with the report by Boussaoud and Wise [62,63], the PMv neurons preferentially reflected visuospatial features of the cue, rather than the motor instruction (Figure 3b). In addition, the spatial preference between visual responses and the action target was often congruent. For example, during the late second delay period between presentation of second and set cues in this task (Figure 3b), activity in the PMv neurons was greater in response to the left reach target, whereas visual responses in these neurons were greater in response to left visual cues. In addition to three distinct groups of PMd neurons involved in the planning process (as discussed in the previous section), Hoshi and Tanji identified a group of PMd neurons that have intermediate function between
motor information retrieval and action formulation. A typical example of neuronal activity is shown in Figure 3c. This neuron showed brief visual responses when the first cue indicated right target reach. During the delay period that followed presentation of the first cue, the activity was greater when the first cue indicated the use of the left arm. After the appearance of the second cue, this neuron showed greater activity when the animal prepared to reach for the right target than for the left [34].
Direct versus indirect sensorimotor processing in the PMv and PMd Taking into consideration all of the reports discussed in previous sections, we propose that a core aspect of the functional differences between the PMd and PMv can be explained in terms of direct versus indirect sensorimotor processing. Figure 4a illustrates the concept of neuronal processes that operate in direct sensorimotor processing in the PMv. This schematic diagram shows the basic operation of a neuronal circuit that receives sensory inputs that inform the animal about a target, and sends outputs of motor commands that match the sensory input. In the case of grasping movements, the three-dimensional features of the target object are the sensory inputs, and the motor commands for digit configurations are the motor output [25]. In the case of reaching movements, the target location in the visual space corresponds to the input, and the target location in the motor space
Figure 4
Two modes of sensorimotor processing. (a) Direct sensorimotor processing in the PMv. This schematic diagram shows the basic operation of a neuronal circuit that receives sensory inputs about a target and sends outputs of motor commands that match the sensory input. Each level of shadings indicates a group of neurons that preferentially represent distinct sensory inputs, intermediates and motor outputs. (b) Indirect sensorimotor processing in the PMd. This schematic diagram shows the basic operation of a neuronal circuit that receives partial motor information as inputs and integrates them via intermediates. Finally, the motor outputs correspond to a motor act. Neuronal activity shown in Figure 3c can work as a part of the intermediates. www.sciencedirect.com
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corresponds to the output [23]. Figure 4b represents indirect sensorimotor processing in the PMd. As shown in this schematic diagram, the basic operation of a neuronal circuit has three stages: to receive inputs that specify partial motor information, such as target location and arm use; to integrate the inputs in intervening intermediate nodes; and to send outputs. The neuron shown in Figure 3c serves as an intermediate node because it selectively retrieves motor information from the first cue and then, after the second cue, integrates the two instructions on arm use and target location. The motor outputs correspond to a motor act, such as a specific combination of arm use and target location [32]. The arbitrary sensorimotor mapping required for conditional motor behavior can be viewed as requiring indirect sensorimotor processing in the PMd, because the sensory signal does not directly indicate action. This is in contrast to the direct sensorimotor processing, which is deemed to require participation of the PMv. Indeed, Cisek and Kalaska [70] showed that PMd neurons discharged when subjects were looking at a learned, conditional visuomotor task that was being performed by others, in addition to when the subject was performing the task itself.
Conclusions The PMd and PMv, which have distinct evolutionary origins, constitute largely separate cortical networks that are interconnected by different regions of the prefrontal cortex and parietal cortex. As inferred from neuroanatomical considerations, the PMd and PMv are involved in different aspects of selecting and planning motor behavior, and in preparing and executing movements. We propose that the functional specificity of the PMd and PMv can be explained by a cardinal concept of direct versus indirect sensorimotor processing. In direct sensorimotor processing, the PMv receives information on a motor target and sends outputs to achieve an action that directly matches the information. By contrast, the PMd has a major role in indirect sensorimotor processing, retrieving multiple sets of motor information from sensory signals, and integrating components of a required action to formulate a motor program for the intended action.
Acknowledgements This work was supported by the 21st Century Center of Excellence Program from the Japanese Society for the Promotion of Science, a Grant-in-Aid for Scientific Research on Priority Areas — Integrative Brain Research — from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT; 18019032 and 16067101), and a Grant-in-Aid for Young Scientists (A) from MEXT (18680035).
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