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Imaging the premotor areas Nathalie Picard* and Peter L Strick†

Recent imaging studies of motor function provide new insights critically on a clear definition of the location and boundaries into the organization of the premotor areas of the . of these cortical areas. Thus, one focus of our review The pre- and the rostral portion of synthesizes the new data that is relevant to this issue. the dorsal premotor , the ‘pre-PMd’, are, in many respects, more like prefrontal areas than motor areas. Recent Medial wall data also suggest the existence of separate functional divisions Pre-supplementary motor area and supplementary in the rostral cingulate zone. motor area In monkeys, it is now established that area 6 on the medial Addresses wall of the contains two separate areas: the supple- Department of Neurobiology, University of Pittsburgh School of mentary motor area proper (SMA) in the caudal portion of Medicine, W1640 Biomedical Science Tower, 200 Lothrop Street, area 6, and the pre-SMA in the rostral portion (Figure 1a; Pittsburgh, PA 15261, USA reviewed in [2,4]). The SMA and pre-SMA are equivalent *e-mail: [email protected] †e-mail: [email protected] to fields F3 and F6 described by Matelli et al. [5]. In humans, the level of the anterior commissure (VCA line) Current Opinion in Neurobiology 2001, 11:663–672 [6] marks the border between the two areas. The division 0959-4388/01/$ — see front matter of medial area 6 into two distinct fields is based on a © 2001 Elsevier Science Ltd. All rights reserved. collection of anatomical and functional data [2,4]. Because Abbreviations the pre-SMA was born out of a premotor area — the tradi- CCZ caudal cingulate zone tional SMA of Woolsey et al. [7] — the common perception CMAd dorsal cingulate motor area is that the pre-SMA is also a motor area. However, the CMAr rostral cingulate motor area connectivity and physiology of the pre-SMA suggest that it CMAv ventral cingulate motor area is more like a prefrontal area than a motor area. Prefrontal FEF frontal eye field fMRI functional magnetic resonance imaging areas provide cognitive, sensory or motivational inputs for M1 primary motor behavior, whereas the motor areas are concerned PMd dorsal premotor cortex with more concrete aspects of movement (e.g. muscle PMv ventral premotor cortex patterns). Two important differences in the anatomical RCZ rostral cingulate zone RCZa anterior rostral cingulate zone connections of the SMA and pre-SMA support this view. RCZp posterior rostral cingulate zone First, only the SMA is directly connected to M1 and to the SMA supplementary motor area [1,8–11]. Second, only the pre-SMA is inter- VCA line level of the anterior commissure connected with the [12–14]. These anatomical features, among others, are reflected by differ- Introduction ential patterns of activity in the SMA and pre-SMA [4]. Large regions of the brain located on the lateral surface and In neuroimaging studies, the pre-SMA/SMA distinction is on the medial wall of each hemisphere participate in the the clearest example of an anatomical and functional generation and control of movement. The premotor areas dissociation that emerged from the primate model [2]. In in the frontal lobe have the anatomical substrate to the following, we describe recent findings that provide influence motor output, both through connections with the further support for this dissociation. (M1) and through direct projections to the spinal cord (e.g. [1]). In monkeys, the frontal lobe Initially, studies in monkeys suggested that the pre-SMA contains six well-defined premotor areas (Figure 1a). The has involved in learning sequential movements [15–17]. presence of analogous areas in humans has been inferred This motor view of pre-SMA function was supported by from functional imaging studies (Figure 1b) [2,3]. the observation that, in humans, activation of the pre-SMA However, the definition of premotor areas in humans is increased in parallel to acquisition of a motor sequence still evolving. Some associations between anatomy and task [18]. In contrast, SMA activation during the same task function proposed in the past [2] have been validated by was related simply to aspects of motor execution. More recent imaging data, and other associations are emerging. recent studies by the same group have resulted in a modi- fied view of pre-SMA function. Sakai et al. [19] recently In this review, we present the results of salient imaging compared pre-SMA activation in closely matched tasks studies that have helped to increase our understanding of that all required visuo–motor associations, but varied in the underlying anatomical and functional organization of motor and perceptual sequence components. Activation of the premotor areas. Much recent effort in the field of func- the pre-SMA occurred in all tasks related to visuo–motor tional imaging has been to examine brain regions involved association demands rather than to sequential components. in cognitive operations. The interpretation of activations In fact, pre-SMA activation was greatest in the conditional in premotor cortex during cognitive operations depends task, in which non-sequential responses were arbitrarily 664 Motor systems

Figure 1

(a)Pre- (b) Motor areas of the frontal lobe in monkeys SMA SMA Pre- SMA M1 (a) and homologous areas in the human (b). SMA In humans, the border between areas 6 and 4 M1 on the lateral surface is located in the anterior CCZ bank of the central [65]. For illustration, CMAd RCZp CMAr CMAv RCZa the border is drawn on the surface of the hemisphere along the (bottom, white dotted line). Except for the most medial portion, M1 does not occupy the precentral . Pictures of the monkey brain courtesy of Richard P Dum; pictures of the reproduced with permission from [93]. PMd M1 Pre- PMd PMd FEF

M1 PMv F7 F2 F1 FEF 44 45 PMv F4 F5

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determined by the color of visual cues, and showed a motor preparation, during working memory delays of a relative decrease in sequential paradigms. This important match to sample task [26] (Figure 2c). In addition, the study shows conclusively that activation of the pre-SMA in pre-SMA showed transient activation associated with shifts these tasks has little to do with motor sequence learning of attention to visual object features (shape, color, location) per se. Instead, pre-SMA activation occurs in association in a card sorting task [27]. Attending to various features of with establishing or retrieving visuo–motor associations visual stimuli was found to activate the pre-SMA equally in (see also [20,21]). The activity in the pre-SMA in associa- another context [28]. These results suggest that pre-SMA tion with visually cued changes between motor sequences function is more closely related to processing or mainte- [22,23] may also be due to the role of the pre-SMA in nance of relevant sensory information than response retrieving visuo–motor associations. selection or production.

Additional studies have extended the involvement of Overall, neuroimaging studies leave no doubt that the the pre-SMA to associations based on auditory stimuli pre-SMA is fundamentally different from the SMA. [24••,25] (Figure 2a). Visual and auditory versions of a con- Activation of the SMA, caudal to the VCA line, is observed ditional choice reaction time paradigm generated pre-SMA primarily in relation to aspects of movement behavior. In activations of equal magnitude [25]. Thus, the contribu- contrast, pre-SMA activation, rostral to the VCA line, is tion of the pre-SMA to sensory–motor associations is associated with cognitive aspects of a variety of tasks (see modality-independent. In addition, the contribution of also [29–34]). These findings, together with anatomical the pre-SMA appears to be effector-independent. Similar results, suggest that the pre-SMA might be functionally regions are activated in conditional manual motor [24••,25] considered a region of prefrontal cortex. and oculomotor tasks [21] (Figure 2b). This is consistent with the poor somatotopic organization of the pre-SMA [2] Cingulate motor areas and supports the view that the pre-SMA operates at a more The contains three separate motor areas in abstract level. In contrast, SMA activation displayed only primates: the rostral cingulate motor area (CMAr), the cau- movement-related activation in visual or auditory tasks. dal cingulate motor area in the ventral bank of the sulcus (CMAv) and the caudal cingulate motor area in the dorsal It must be emphasized that pre-SMA activation during bank of the sulcus (CMAd; Figure 1a). We have proposed conditional motor behaviors was not due to response [2] that corresponding areas are also present in humans: a selection or preparation [19,24••]. In fact, activation patterns rostral cingulate zone (RCZ) with two subdivisions (anterior: of the pre-SMA during non-conditional behavior suggest RCZa, and posterior: RCZp) and a caudal cingulate that its contribution to sensory–motor association is zone (CCZ; Figure 1b). The anatomical variability of the detached from motor aspects of the task. For example, the cingulate sulcus in humans complicates functional analysis pre-SMA displayed sustained activation, independent of of this region [35–37]. As a consequence, a degree of Imaging the premotor areas Picard and Strick 665

Figure 2

Anatomical and functional distinction of the (a)Pre- (b) (c) SMA SMA and the pre-SMA in three different tasks. SMA SMA SEF (a) Top: activation in the SMA and pre-SMA during an auditory conditional task; bottom: selective activation in the pre-SMA during an CCZ auditory–motor association task. Reproduced with permission from [24••]. (b) Top: Activation in the (SEF) during Pre- Pre- Pre- visually guided saccades; bottom: selective SMA SMA SMA activation of the pre-SMA for a mixed condition of compatible and incompatible (Stroop-like) RCZ conditional saccades. Reproduced with permission from [21]. (c) Top: motor-related activations in the SMA and CCZ; bottom: sustained activation during working memory Current Opinion in Neurobiology delay in the pre-SMA and RCZ. Reproduced with permission from [26].

uncertainty in the definition of the cingulate motor areas Two theories predominate about the overall function of remains. However, on the basis of results from recent this region of cortex: ‘conflict monitoring’ [43] and ‘atten- experiments, consistent patterns of activation are found in tion/selection for action’ [44]. The first theory emphasizes the CCZ, and a new view of the RCZ is emerging. the evaluative function of the RCZ, whereas the second emphasizes its motor function ([45•], but see also [46]). The CCZ, which appears to be comparable to the CMAd How do these two theories and functions relate to the of monkeys, is activated primarily in relation to movement motor area(s) in the RCZ? We propose that they reflect the execution ([2,3,26,38••], see also [39]). Painful stimuli properties of two different functional regions: conflict activate an area in or near the CCZ ventral to the area monitoring within the RCZa and selection for action with- associated with movement execution [38••]. Thus, differ- in the RCZp. For example, a series of imaging studies that ent functional areas may exist for movement and for were carefully designed to control conflict monitoring, painful stimuli. The site of movement-related activation in found activation in the ‘anterior cingulate’ cortex the CCZ is remarkably similar across studies. For example, [43,45•,47,48•]. On average, the sites of these activations in two different studies, finger movements activate virtually were located 24 mm ± 7 mm (mean ± standard deviation) identical sites in the CCZ [26,38••] (Figure 2c). In anterior to the VCA line (Table 1). This location corre- addition, activation in the CCZ is consistently separable sponds to the RCZa, which may correspond to the CMAr from that in the SMA. These observations reinforce the of monkeys [2]. In contrast, when some of the same inves- view that the CCZ is distinct from the SMA, despite the tigators used a similar paradigm that did not specifically proximity of the two areas and their tendency to be co- dissociate conflict monitoring from response selection, activated during manual tasks [40]. In the monkey, the they found response-related activation in the area of the functional dissociation of the CMAd from the SMA occurs ‘anterior cingulate’ cortex, located 1 mm anterior to the under specific behavioral conditions [41]. Thus, future VCA line [49]. This site corresponds to the RCZp, which studies are likely to find important functional differences may correspond to the CMAv of monkeys [2]. between the human CCZ and SMA. The results of other imaging studies can be interpreted Recent studies confirm that movement leads to activation within the same anatomical–functional framework. Two in the RCZ, rostral to the VCA line [26,38••]. Movement- groups of investigators, using single subject analysis, found related activation in this region is best demonstrated in multiple foci of activation in the ‘anterior cingulate’ cortex analyses of single subjects [3,37,38••], presumably during word generation tasks that involved response selec- because of anatomical variability. The activation in these tion [37,42] (Figure 3a). In both instances, the major site of studies is clustered near the cingulate sulcus or its activation was located largely within the RCZp. Tasks that ramifications. Similarly, the RCZ activation associated can be interpreted as involving both conflict processing and with a word generation task is located in or near the response selection (versions of Go/NoGo and STOP tasks) cingulate or paracingulate sulci and never extends onto evoked distinct sites of activation in the ‘anterior cingulate’ the cingulate gyrus [37]. Thus, some motor and cognitive cortex [50•,51]. In a Go/NoGo task, different cues (e.g. functions may share a common substrate within the RCZ. green or red stimuli) each determine a particular response In contrast, activations related to attention or arousal are (Go or NoGo). Thus, this task is similar to a conditional located at more rostral and ventral locations [38••,42], visuo–motor association task. Because only one cue is pre- which are probably outside the RCZ on the cingulate sented for each response to produce (no interference) and gyrus proper. because a cue is always associated with a single response, 666 Motor systems

Figure 3 Table 1

Talairach coordinates [6] of activation sites in the RCZ. (a) Pre- Ref Task Type x y z SMA [43] Flanker task: previous trial type effect Conflict –2 31 29 [45•] Stroop task: high conflict & low control Conflict 0 15 41 vs low conflict & high control RCZ [47] Verb generation: high vs low response Conflict 3 28 29 competition [48•] Flanker task: congruency x expectancy Conflict –8 22 32 [92] Delayed recognition: high interference Conflict 6 22 43 vs no interference • VCA [50 ] STOP task vs control Conflict 6 25 37 (b) (STOP task vs control) & (Go/NoGo Conflict & 3 31 37 vs control) selection 3 14 42 [50•] Go/NoGo vs control Selection –3 0 42 • RCZa [50 ] Go/NoGo vs STOP task Selection –6 0 42 [51] Go/NoGo vs Go Selection 4 16 46

sulcus: the CCZ and two subdivisions within the RCZ. The CCZ appears to be activated during simple motor tasks, whereas the RCZa and the RCZp appear to be differentially involved in conflict monitoring and response selection. Overall, proposals about the RCZ are founded on a relatively Current Opinion in Neurobiology small number of studies. Further research is necessary to fully define the function(s) of these cortical regions. Anatomical and functional division of the RCZ. (a) Activation during free word generation. The dashed line separates activations located in the pre- Lateral surface SMA and in the RCZ. Reproduced with permission from [37]. (b) Activation related to conflict monitoring. Brain images from the two The dorsal part of the lateral premotor cortex studies were matched in size in the anterior–posterior axis. Dotted lines in In monkeys, the dorsal part of the lateral premotor cortex (b) represent the estimated locations of levels indicated in (a). Activations (PMd) has been divided into rostral (F7, PMdr) and caudal related to conflict monitoring are located at the rostral edge of activations (F2, PMd ) subdivisions [5,52], on the basis of anatomical found during word generation. This topography suggests that the RCZa is c involved in conflict monitoring (evaluative function) whereas the RCZp is and physiological differences (Figure 1a). These differences involved in response selection. Note that all cingulate activations are in are analogous to those that generate the pre-SMA/SMA sulci, not on the cingulate gyrus, supporting the view that they overlap split. In fact, in a number of important respects, the caudal with cingulate motor areas. Reproduced with permission from [43]. portion of the PMd has much in common with the SMA proper. Both areas project to the primary motor cortex and directly to the spinal cord [1,8,52,53]. Neither area has conflict is negligible in Go/NoGo tasks in which response substantial interconnections with prefrontal cortex [14]. selection is required. Activation in the RCZ during the Neurons in both regions are primarily involved in aspects of Go/NoGo task was located, on average, 7.5 ± 9 mm in front motor control [4]. In contrast, the rostral portion of the PMd of the VCA line (Table 1). This site falls within the RCZp has much in common with the pre-SMA. Neither of these [2]. In addition, activation in the RCZp was larger during areas projects to the primary motor cortex or to the spinal the Go/NoGo task than during the STOP task. In STOP cord [1,8,52,53]. Instead, both regions are interconnected tasks, a cued Go response is prevented by the delayed with areas of prefrontal cortex and with the reticular forma- presentation of a second cue signaling NoGo. Thus, STOP tion [4,14,54]. Interestingly, neither the pre-SMA nor the tasks present a high degree of response conflict because PMdr appears to have substantial interconnections with the contradictory instructions determine the subject’s response. SMA proper or with the caudal portion of the PMd The RCZ activation in STOP tasks, like that in other high [11,13,55]. Furthermore, the results of neuronal recording conflict tasks, was located in a separate focus 25 mm rostral and functional imaging studies suggest that the pre-SMA to the VCA line (in the RCZa) [50•] (Table 1). and the rostral portion of the PMd are more involved in cognitive than in motor processes (see below). On the basis In sum, these data support the existence of at least three of these findings, we believe that there is heuristic value in functional areas in the anterior portion of the cingulate adopting a new terminology to refer to these cortical areas. Imaging the premotor areas Picard and Strick 667

Figure 4

Anatomical and functional division of (a) (b) dorsolateral area 6. (a) Top: activation of the PMd PMd proper during execution of finger flexion/extension movements; bottom: activation of the pre-PMd during imagined movements of the fingers. Reproduced with permission from [31]. (b) Activation of the Pre- pre-PMd related to spatial attention/memory is PMd shown in red, activation of the PMd on the related to movement preparation is shown in yellow, and the overlap is shown in green. Reproduced with permission from [59••]. Pre- PMd PMd

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We suggest that the rostral portion of the PMd (F7) be located on average 8.1 mm rostral to the center of M1 termed the pre-PMd, and that the caudal portion of the activation in the same subjects [31,32,60–64]. This value is PMd (F2) be termed the PMd proper. This terminology strikingly similar to the location of the hand representation more clearly reflects the parallels between these areas and on the precentral gyrus. In humans, the precentral gyrus the pre-SMA and SMA proper. corresponds to the premotor cortex (area 6) [65], which is 8.8 mm anterior to the hand representation in the central Recent studies in monkeys further support the distinction sulcus [66]. Over a relatively large number of studies, the between the pre-PMd and the PMd proper. Parietal cells average of the absolute coordinates for movement-related that project to the pre-PMd convey eye movement signals, activation in the PMd and the location of the hand repre- whereas those that project to the PMd convey hand move- sentation on the precentral gyrus [66] are very similar ment signals [56,57]. The two subdivisions can be further (Table 2). Conversely, activations related to higher-order characterized on the basis of their differential involvement processing (e.g. conditional visuo–motor associations, in oculomotor control [58]. Eye movements are evoked by response selection or motor imagery) are located in the pre- stimulation of pre-PMd, whereas predominantly limb and PMd an average of 22.9 mm anterior to movement-related body movements are evoked from the PMd. Similarly, activation in M1 [25,31,61,67]. neurons in the pre-PMd are more active during a saccade task than during a limb movement task. In contrast, the The rostro-caudal gradient of activation across the reverse is the case for neurons in the PMd. Thus, there is pre-PMd–PMd is most convincingly demonstrated within ample evidence that the pre-PMd and the PMd are subjects [24••,25,31,59••,61,67–69] (Figure 4). For exam- anatomically and physiologically distinct [59••]. ple, activation that specifically relates to sensory–motor association in an auditory conditional task is restricted to The functional distinction between the pre-PMd and the the rostral edge of area 6 [24••]. The site of this activation PMd has not always been obvious in imaging studies of is likely to be in the pre-PMd, rather than in the PMd. human subjects. However, we have found that a consistent Similarly, activation in other conditional motor tasks is pattern emerges when M1 activation related to hand move- located in the pre-PMd, 18–26 mm anterior to movement- ment is used as an ‘anchor point’ and activations in related activation in M1 [25,67] (Table 2). In addition, premotor cortex, relating to other more cognitive types of rostral portions of area 6 in the pre-PMd are activated movement in the same subjects, are measured in relation to during the presentation of visual cues or movement imag- this point. The data in Table 2 illustrates that, in a recent ination, whereas caudal portions of area 6 in the PMd are group of studies, movement performance tasks produced activated during movement preparation or execution activations more caudally in the PMd than more cognitively [59••,61,69]. This interpretation is compatible with the demanding tasks. Movement-related activations were response properties of neurons seen in recording studies of 668 Motor systems

Table 2

Talairach coordinates [6] of activation sites in the PMd relative to movement-related activations in M1*.

Refs Contrast Type PMd M1 ∆y ∆z x, y, z x, y, z

[25] Choice RT (auditory mode): (control-rest)∩(response uncertainty-rest)∩ Movement-related –42,–18,48 (time uncertainty-rest)∩(dual uncertainty-rest) Choice RT (auditory mode): response uncertainty-control Higher-order –54,6,46 24 –2 Choice RT (auditory mode): time uncertainty-control Higher-order –50,4,42 22 –6 Choice RT (auditory mode): dual uncertainty-control Higher-order –52,6,48 24 0 Choice RT (visual mode): (control-rest)∩(response uncertainty-rest)∩ (time uncertainty-rest)∩(dual uncertainty-rest) Movement-related –36,–16,50 Choice RT (visual mode): response uncertainty-control Higher-order –50,8,50 24 0 Choice RT (visual mode): time uncertainty-control Higher-order –44,2,50 18 0 Choice RT (visual mode): dual uncertainty-control Higher-order –52,10,46 26 –4 [31] Finger movement-rest Movement-related –36,–3,66 –42,–18,66 15 0 42,–3,60 39,–15,63 12 –3 Imagined finger movement-rest Higher-order –42,3,51 21 –15 42,6,57 21 –6 (finger movement-rest)-(imagined movement-rest) Movement-related –36,–6,69 –42,–18,69 12 0 24,–9,75 39,–15,63 6 12 (imagined movement-rest)-(finger movement-rest) Higher-order –42,3,51 21 –15 48,9,48 24 –15 [32] Self-paced finger movement-rest Movement-related –12,–14,60 –34,–18,56 4 4 [60] Object manipulation-rest Movement-related –40,–16,52 –46,–32,50 16 2 [61] Event-related: finger movement period Movement-related –38,–4,60 36,–20,58 16 2 –36,–8,54 12 –4 Event-related: instruction & delay periods Higher-order –18,6,70 26 12 [62] Conditional visual-perceptual control Movement-related –34,–14,62 –42,–28,52 14 10 [63] Hand movement-rest Movement-related 32,–29,64 32,–29,54 0 10 [64] Hand reaching: (eye-arm-jump & eye-arm-stationary)-(eye-jump & eye-stationary) Movement-related –41,–23,62 –39,–29,63 6 –1 –53,–29,50 –35,–27,53 –2 –3 Hand reaching: (eye-arm-stationary)-(eye-stationary) Movement-related –41,–23,62 –36,–23,53 0 9 –57,–21,48 2 –5 [67] Conditional grip-mandatory grip Higher-order –33,–3,48 –33,–27,55 24 –7

Average† (n=14) Movement-related 37.3,–14.4, 38.2,–22.2, 8.1 2.4 60.3 56.9 Standard deviation† 10.9,9.3,7.4 4.0,5.9,6.5 6.5 5.8 Average† (n=13) Higher-order 43.9,5.0,50.6 22.9 –4.8 Standard deviation† 10.1,3.5,7.1 2.4 7.9

[66] High resolution fMRI & 3D reconstruction: finger movement-rest Movement-related –35.5,–14.6, –36.6,–23.4, 8.8 8.5 Average (n=5) 65.3 56.8 Standard deviation 6.0,4.5,5.6 7.6,4.1,9.4

*Only hand movement tasks were considered in this comparison. †Absolute values used for calculation of x averages and standard deviations. ∩, intersection. awake trained monkeys [59••,70,71]. The PMd contains a The ventral part of the lateral premotor cortex high proportion of neurons that display set- and move- In monkeys, the ventral part of the lateral premotor cortex ment-related activity. In contrast, neurons in the pre-PMd (PMv) lies in area 6 below the spur of the arcuate sulcus are more responsive to sensory cues, and fewer are active (Figure 1a). The PMv, like the PMd proper, is densely inter- in relation to movement. Thus, neuroimaging studies and connected with M1. In addition, the portion of the PMv in neuron properties indicate that the PMd is primarily and adjacent to the caudal bank of the arcuate sulcus contains involved in aspects of movement preparation or generation neurons that project directly to the spinal cord [1,53]. There (see also [72,73]), whereas the functions of the pre-PMd is general agreement that the PMv in humans lies ventral to are more closely related to cognitive processes than to the frontal eye field (FEF). However, the precise location and motor processes. boundaries of the PMv in humans is uncertain [3,74•]. Imaging the premotor areas Picard and Strick 669

Matelli et al. [75] suggest that the PMv of monkeys consists a somatotopically organized pattern of activation that of two cytoarchitectonic fields, F4 and F5 (Figure 1a). The involved all of the premotor cortex on the lateral surface connections of F4 with posterior parietal cortex and the (i.e. both the PMd and the presumed PMv). These authors responses properties of F4 neurons have led Rizzolatti also observed activation in or near Broca’s area in the action et al. [76] to suggest that F4 is involved in ‘transforming observation tasks. Thus, the relationship between the object locations into appropriate movements towards activation in area 44 and that observed in portions of area 6 is them’ (see also [77]). This hypothesis has not been unclear. Importantly, these results indicate that the human explored by imaging studies in humans. Furthermore, the PMv can’t be identified solely by the presence of activation location or even the existence of a human equivalent of during movement observation tasks. In summary, on the the monkey F4 remains to be established. basis of previous data, it is not possible to establish a defi- nite correspondence between the functional subdivisions of The F5 portion of the PMv has received more attention. the monkey PMv and the inferior frontal areas in humans. Rizzolatti et al. [76] have described two types of neurons in monkey F5 that have unique responses to visual stimuli: Conclusions ‘canonical’ and ‘mirror’ neurons [4,76,78,79]. Canonical neu- The data presented in this review help to clarify the location rons respond to the visual presentation of three-dimensional and boundaries of the premotor areas in the frontal lobe of objects of different size and shape. The motor responses of humans. For many of these areas, there is a clear correspon- these neurons are limited to specific goal-directed actions dence with a specific premotor area in the monkey. For towards these three-dimensional objects. Canonical neurons other regions, such as the motor fields in inferior frontal are largely found in the portion of the PMv that is buried in cortex, the correspondence with areas in the monkey brain the bank of the arcuate sulcus. Mirror neurons are active remains to be established. Two regions have generally been when a monkey watches someone else perform a specific considered to be motor fields: the rostral part of area 6 on the action, and when the monkey executes a similar action. medial wall of the hemisphere (pre-SMA), and the rostral Mirror neurons are largely found in the portion of the PMv part of area 6 on the dorsal surface (pre-PMd). However, that is on the cortical surface, caudal to the arcuate sulcus. both these areas display activation that is more closely related to cognitive than to motor processes. Thus, it might The unique properties of mirror neurons have prompted be more appropriate to consider the pre-SMA and the the search for the equivalent of F5 in human subjects. pre-PMd as functional components of prefrontal cortex, Neuroimaging studies have generated conflicting results rather than as premotor areas. In other cases, cognitive and on this issue. In a recent meta-analysis, Grèzes and Decety motor functions appear to have a common anatomical [74•] failed to find conclusive evidence for neuronal activ- substrate. The RCZa, which may correspond to the CMAr ity in inferior frontal areas, including ventral portions of of monkeys, is involved in ‘conflict monitoring’. The RCZp, area 6, during action observation. In contrast, other studies which may correspond to the CMAv of monkeys, appears to have reported activation of area 44 during imitation and be involved in response selection. Other premotor areas, observation of finger movements [80,81], as well as when including the SMA proper, the PMd proper and the CCZ objects are gripped and manipulated [60,82,83]. This has are involved in various aspects of movement generation and led some investigators to suggest that area 44, which has control. Overall, we feel that it is important to continue to traditionally been considered part of Broca’s area, is the seek correspondences between motor areas in the monkey human equivalent of the monkey F5 [76,84]. and human cortex, as this will result in important insights into the functional organization of the frontal lobe. Other results raise doubts over this conclusion. Amunts et al. [85] found considerable variation in the location of Acknowledgements the border between area 44 and rostro-ventral area 6, and Our work is supported by the Veterans Administration Medical Research and Rehabilitation Research and Development Services (PL Strick), and noted that this border cannot be determined solely on the United States Public Health Service grant NS24328 (PL Strick). basis of gyral and sulcal landmarks. Area 44 is strongly activated during tasks that involve silent or covert speech References and recommended reading (e.g. [86–88]). Thus, it is possible that activation of area 44 Papers of particular interest, published within the annual period of review, have been highlighted as: during action observation, in some cases, reflects internal • • of special interest verbalization of the observed action (e.g. [74 ]). This view •• of outstanding interest is compatible with the absence of activation in Broca’s area 1. Dum RP, Strick PL: The origin of corticospinal projections from the during the observation of meaningless hand gestures that premotor areas in the frontal lobe. J Neurosci 1991, 11:667-689. cannot be named [89,90]. However, verbalization alone 2. Picard N, Strick PL: Medial wall motor areas: a review of their cannot account for all activations related to action observa- location and functional activation. Cereb Cortex 1996, 6:342-353. tion, which are also found in parts of premotor cortex 3. Fink GR, Frackowiak RSJ, Pietrzyk U, Passingham RE: Multiple clearly outside of Broca’s area [74•,89–91]. nonprimary motor areas in the human cortex. J Neurophysiol 1997, 77:2164-2174. A recent report by Buccino et al. [91] indicates that obser- 4. Geyer S, Matelli M, Luppino G, Zilles K: Functional neuroanatomy of the primate isocortical motor system. Anat Embryol 2000, vation of recognizable face, hand or foot actions resulted in 202:443-474. 670 Motor systems

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