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J Neurosci. Author manuscript; available in PMC 2010 July 27.
Published in final edited form as:
PMCID: PMC2880444
EMSID: UKMS28614

A network centered on ventral premotor cortex exerts both facilitatory and inhibitory control over primary motor cortex during action reprogramming

Abstract

Ventral premotor cortex (PMv) is widely accepted to exert an important influence over primary motor cortex (M1) when hand movements are made. Although study of these interactions has typically focused on their excitatory nature, given its strong connections with both ventral and opercular frontal regions, one feature of PMv's influence over M1 may be inhibitory. Paired-pulse transcranial magnetic stimulation (ppTMS) was used to examine functional interactions between human PMv and M1 during the selection and reprogramming of a naturalistic goal-directed action. One of two cylinders was illuminated on each trial. It was then grasped and picked up. On some trials, however, subjects had to re-program the action as the illuminated cylinder was switched off and the other illuminated simultaneously with reach initiation. At a neurophysiological level, the PMv paired-pulse effect (PPE) on M1 corticospinal activity was facilitatory after the initial target presentation and during movement initiation. When reprogramming was required however, the PPE became strongly inhibitory. This context-dependent change from facilitation to inhibition occurred within 75ms of the change of target. Behaviorally, PMv-M1 ppTMS disrupted reprogramming. Diffusion-weighted magnetic resonance image (DW-MRI) scans were taken of each subject. Intersubject differences in the facilitation–inhibition contrast of PMv–M1 interactions were correlated with fractional anisotropy of white-matter in ventral prefrontal, premotor, and intraparietal brain areas. These results suggest that a network of brain areas centered on PMv inhibits M1 corticospinal activity associated with undesired movements when action plans change.

Keywords: PMv, parietal cortex, prefrontal cortex, TMS, DTI, grasping, inhibition

INTRODUCTION

PMv is a likely source of influence over M1 during grasping. In monkeys, M1 receives dense input from PMv (Godschalk et al., 1984; Dum and Strick, 2005), and stimulation of PMv modulates M1-corticospinal excitability under anesthesia (Shimazu et al., 2004) and during reaching and grasping (Prabhu et al., 2009). Additionally, PMv is also a likely source of inhibitory influence over M1. Amongst premotor areas, PMv is the recipient of the densest projections from lateral prefrontal cortex, especially from opercular and ventral prefrontal cortex (PFv; Dum and Strick, 2005).

PFv plays an important attentional role and determines what stimuli are relevant for behavior (Everling et al., 2002; Rushworth et al., 2005b). When an action-relevant stimulus changes, PMv may be well placed to reprogram the action, making it more appropriate for the new context. Moreover, a growing body of work implicates inferior frontal cortex in the inhibition of action. Although discussion of these data has primarily focused on more rostral frontal cortex, PMv also falls within the critical region reported (Aron et al., 2004; Forstmann et al., 2008). Finally, PMv connects and interacts with intraparietal sulcal (IPS) regions (Verhagen et al., 2008, Rushworth et al., 2005a) involved in the redirection and change of actions (Desmurget et al., 1999; Rushworth et al., 2001; Glover et al., 2005; Tunik et al., 2005).

Functional interactions between premotor cortex and M1 during action selection can be measured at sub-second timescales in humans with ppTMS (Koch et al., 2006; Boorman et al., 2007). In a baseline condition, a single TMS “test” pulse is applied over M1 (spTMS) and a motor evoked potential (MEP) is measured. On some trials, a preceding “conditioning” pulse is applied milliseconds earlier over another brain area, and its impact on the size of the MEP elicited by the same “test” pulse is measured. Conditioning pulses over dorsal premotor cortex (PMd) or pre-supplementary motor area (pre-SMA) cause a facilitatory PPE 75-125ms after cues instructing subjects to make movements (Koch et al., 2006; O'Shea et al., 2007; Mars et al., 2009). Although M1 facilitation by several premotor regions has been reported in ppTMS action selection experiments, reports of an inhibitory influence have not been prominent. Inhibitory control of M1 by premotor cortex during action selection may be contextually-gated however, and thus more evident when the selected action must be changed and reprogrammed.

The aim of the current experiment was to examine PMv-M1 interactions during reprogramming of naturalistic grasping actions at three levels: (1) neurophysiological interactions, (2) behavior, and (3) related anatomical connections. The focus was on whether task-mandated reprogramming of grasping behavior is associated with M1-corticospinal inhibition at a neurophysiological level, and whether inter-subject variance in this inhibition can be explained by differences in the connectivity between PMv and remote brain regions. To assess these relationships, the impact of PMv-M1 ppTMS on grasping kinematics was measured, and DW-MRI brain scans were performed.

METHODS

Subjects

14 healthy, right-handed adults (9 females) participated in the experiment. All subjects received T1-weighted structural MRI scans, with 13 also receiving DW-MRI scans. 6 healthy, right-handed adults (3 females) participated in a control experiment. Written informed consent was obtained for all subjects prior to participation in accordance with a project approval from the National Research Ethics Service (Oxford RECC, No.05-Q1606-96).

Behavioral Task

Subjects were seated in a darkened room, and performed reaching and grasping movements with their right hand, cued by the illumination of one of two concentrically arranged cylinders (15 and 65 mm diam.) placed in front of them at a distance of 30 cm (starting position to origin; Glover et al., 2005). Reaction and movement times, as well as kinematic data for the thumb, index finger and wrist were recorded. Each trial was initiated once a touch-bar was depressed with the right hand. Following a variable delay of 5-7s (uniformly distributed), a single cylinder was illuminated. Subjects responded by reaching out and grasping it with their thumb and index finger, before lifting it out of its pedestal. On most trials, the cued cylinder remained illuminated throughout the entire response (stay). On some trials (40%) however, the cued cylinder was switched once the touch-bar was released. This switch forced subjects to update their grasp aperture to accommodate the new target cylinder (switch).

A majority of trials were accompanied by either spTMS to left M1, or ppTMS to right PMv followed by left M1 8ms later. In both cases, the test-pulse was applied at 75 or 100ms after the initial cylinder illumination (CI+75ms or CI+100ms; pre-movement condition), or following movement onset (MO+75ms or MO+100ms; peri-movement condition). An inter-hemispheric ppTMS configuration was used because it was unclear if both TMS coils could be reliably positioned over PMv and M1 within a single hemisphere in all subjects. A total of 160 trials were performed with spTMS, ppTMS, and no-TMS trials pseudorandomly interleaved within the same session. Subjects received spTMS on 60 trials, ppTMS on 60 trials, and no-TMS on 40 trials. The 8ms conditioning-test pulse interval, 75ms and 100ms visual cue-to-TMS test-pulse latencies, and inter-hemispheric application of ppTMS have been shown to be appropriate in previous studies of premotor-M1 interactions (Koch et al., 2006; O'Shea et al., 2007; Davare et al., 2008).

TMS and Electromyography (EMG) Recordings

TMS was applied using two Magstim200 (The Magstim Company Ltd) magnetic stimulators. A 50mm figure-of-eight coil applied conditioning pulses over right PMv, and a 70mm figure-of-eight coil applied test-pulses over left M1. The M1 “hot-spot” was identified as the scalp location where stimulation reliably evoked the largest MEP amplitude in the FDI muscle of the right hand, with the intensity set to produce single-pulse MEPs of ~1mV at rest. The PMv coil location was determined using an MRI-aligned frameless stereotaxic neuronavigation system (Brainsight, Rogue Research Inc.), and adjusted with respect to individual sulcal landmarks to be immediately posterior to the inferior precentral sulcus. The mean Montreal Neurological Institute (MNI) location across the subject group was 55.4,14.7,29.5, which lies centrally within the region previously defined as PMv in the human brain (Mayka et al., 2006) and just posterior to the precentral operculum (Germann et al., 2005). PMv TMS was set at 110% of the resting motor threshold (RMT) for that hemisphere (suprathreshold conditioning pulses were used as in other inter-hemispheric ppTMS experiments: Koch et al., 2006; O'Shea et al., 2007; Mars et al., 2009), defined as the intensity at which a small MEP (~50μV peak-to-peak amplitude) was evoked by stimulating M1 on 5 of 10 consecutive trials (Rossini et al., 1994). TMS coils were positioned tangential to the skull at the stimulation site, with the M1 coil angled at approximately 45° (handle pointing posteriorly), and the PMv coil angled at 90° relative to the midline (handle pointing anteriorly; Figure 1). Coil positions were fixed in place by adjustable metal arms and monitored throughout the experiment.

Figure 1
(A) Behavioral task. spTMS or ppTMS was applied during most trials while subjects responded with their right hand (large cylinder stay trial shown in example). Either the large or small cylinder illuminated to initiate each trial. On stay trials the same ...

EMG was recorded from the first dorsal interosseus (FDI) and abductor pollicis brevis (APB) muscles of the right hand using a bipolar surface Ag-AgCl electrode montage. Responses were band-pass filtered between 10-1000 Hz, with an additional 50 Hz notch filter, sampled at 5000 Hz, and recorded using a CED 1902 amplifier, a CED micro 1401 Mk.II A/D converter, and a PC running Spike2 (Cambridge Electronic Design, Cambridge, UK).

Analysis of electrophysiological data was based on peak-to-peak amplitudes of the MEPs measured on TMS trials. Trials in which the test pulse failed to elicit a reliable MEP were discarded from the analysis. MEP data from trials where all task parameters, except for cylinder size, were identical were combined and analyzed together. Because TMS coil placement and stimulator intensity were optimized for the FDI, we focus on these.

A control experiment examined whether PPEs of PMv-M1 ppTMS were specific to that region or whether similar PPEs were found when both conditioning and test pulses were applied over left M1 using identical stimulation parameters.

Kinematic Recordings

A Fastrack (Polhemus, Inc.) motion analysis system was used to record Cartesian position data from three transmitters, which were attached to the finger nails of the right thumb and index finger, and adjacent to the ulnar styloid process of the right wrist. The system samples sequentially from the available transmitters at 120 Hz, so that data for each individual transmitter was actually obtained at 40 Hz. Kinematic recording was initiated 500ms prior to cylinder illumination, and raw Cartesian data was stored for offline analysis performed with custom MATLAB (The MathWorks Inc.) software.

The time-series for each channel were corrected for TMS-related artifacts, and aligned in time via cubic spline interpolation, with the aligned data upsampled to 120 Hz for each channel. The grasp aperture time-series was then computed as the Euclidean distance between the thumb and index finger position at each time-point. Event code markers associated with the EMG data were then used to align the grasping aperture and EMG data in time. The movement onset and offset were determined for each trial. To determine movement onset, the tangential displacement time-series with respect to the initial position was calculated for the wrist channel, and from this, the velocity profile was determined by computing the first derivative with respect to time and smoothing using a 200ms-wide gaussian (FWHM=0.94) kernel. The onset was defined as the first point before the observed maximum velocity, in which the velocity exceeded 0.05 cm/s. The movement offset was marked by an event code recorded when the illuminated cylinder was touched.

The grasp aperture from movement onset to offset was then time-normalized by resampling via spline interpolation. The resulting series was made up of 100 time-points representing the percentage of the movement completed. For trials in which TMS was delivered, the time-normalized location of the TMS test-pulse was determined as well. Individual subject data was then averaged across trials for each type of kinematic×TMS condition, and pooled across the group. 95% confidence intervals for the group mean were then computed using a bootstrap technique, repeated 10,000 times.

Diffusion Weighted MRI (DWI-MRI)

We acquired diffusion-weighted (3 acquisitions of 60 directions, b-value 1000s×mm−2, 2×2×2 mm3 voxels, 72 slices) and T1-weighted data using a 1.5T Siemens Sonata MR scanner (Tomassini et al., 2007). The FMRIB Software Library (FSL; http://www.fmrib.ox.ac.uk/fsl) was used to analyze these data. Fractional anisotropy (FA) was computed with the FMRIB Diffusion Toolbox (FDT). All subjects' FA data were then coregistered to the FMRIB58_FA template in MNI152 standard space, using the FNIRT nonlinear registration tool. A mean FA image was created and then skeletonized using an FA threshold of 0.2. Voxel-wise statistical analysis of the FA data was then performed using Tract-Based Spatial Statistics (TBSS; Smith et al., 2006) from. With TBSS, each subject's aligned FA image was projected onto the mean skeleton by searching perpendicular from the skeleton for maximum FA values. This step allows for the statistical comparison of FA values from homologous regions of the FA map. Between-subject variance in FA from these homologous regions were then related to between-subject variance in observed physiological (stay – switch PPE contrast at MO+75ms and MO+100ms) and behavioral (grasp aperture distance between large cylinder stay and small-to-large cylinder switch trials measured at 50% of MT for ppTMS applied at MO+75ms) effects, by using each as a GLM regressor in TBSS (Boorman et al., 2007). The resulting voxel-wise statistical images were thresholded at P≤0.005. Individual clusters consisting of 30 or more voxels were then masked, and the average FA within the cluster was determined for each subject. The average FA values were then correlated with the MEP effect-size to determine the correlation coefficient for the cluster.

RESULTS

Physiological effects of PMv-M1 ppTMS

Task-related PMv-M1 PPEs were indexed by Z-scores computed as the difference of the mean ppTMS minus spTMS MEP magnitudes divided by the pooled standard deviation. Thus, the reported PPEs are relative to the observed within-subject variance for each condition (Figure 2; see Supplementary Information 1 for an alternative analysis approach). During the pre-movement period, a two-way ANOVA [Muscle (APB vs. FDI) × Time (CI+75 vs. CI+100 ms)] revealed a significant Muscle×Time interaction (F1,13=5.02;P<0.05). One-sample t-tests confirmed a significant facilitatory PPE for the FDI at CI+100ms (t13=3.04;P<0.01). During the peri-movement period, a three-way ANOVA [Muscle (APB vs. FDI) × Context (switch vs. stay) × Time (MO+75ms vs. MO+100 ms)] showed a significant main effect of Context (F1,13=5.66;P<0.05), a Muscle×Time interaction (F1,13=15.60;P<0.01), and a Context×Time interaction (F1,13=5.17;P<0.05). Again, subsequent one-sample t-tests revealed a significant facilitatory PPE for the FDI at MO+75ms during stay trials (t13=2.86;P<0.01). Alternatively, during switch trials this PPE became inhibitory, which was significant at both MO+75ms (t13=−2.45;P<0.05) and MO+100ms (t13=−2.184;P<0.05). Cylinder size was not associated with any differences in these effects.

Figure 2
PMv-M1 ppTMS facilitated M1 corticospinal activity during the pre-movement period and in the peri-movement stay condition. However, the PPE switched to peri-movement inhibition when the action had to be inhibited and reprogrammed on switch trials. Example ...

A similar pattern of PMv-M1 PPEs were observed in MEPs recorded from the APB muscle (Supplementary Figure 1) during the pre-movement period. As in the FDI muscle, one-sample t-tests confirmed a significant facilitatory PPE for the APB at CI+100ms (t13=2.388;p<0.05). Differences between the two muscles were observed during the peri-movement period, however. Here, one-sample t-tests for the APB muscle did not show a significant ppTMS facilitation of MEPs during stay trials (both t13≤1.903; both p≥0.079). During switch trials, the APB did show a significant inhibition at MO+75ms (t13=−3.49;p<0.01), similar to the effect observed in FDI. Thus, some of the significant facilitation and inhibition effects observed for FDI, also appeared to be present for APB, while others were absent. Although these observations might represent differential involvement of FDI and APB at specific points of the task, the design of this study does not assess this question. The primary reason for this is that the selected stimulation parameters (including the location of left M1 stimulation, and right PMv and left M1 stimulation intensities) were optimized based only on the FDI response. Thus, nonoptimal stimulation parameters for the APB muscle cannot be ruled out as a source of these differences.

Behavioral effects of PMv stimulation

Since the direction (facilitation or inhibition) of significant PPEs for PMv-M1 ppTMS was related to the task context (stay or switch) at MO+75ms, the analysis of related kinematic effects also focused on trials at this time-point. It has previously been shown that action reprogramming is particularly vulnerable to disruptive TMS applied to the parietal cortex shortly after the cylinder switch occurs on small-to-large switch trials (Glover et al., 2005). Therefore, it was expected that PMv-M1 ppTMS might also particularly disrupt grasping reprogramming on small-to-large cylinder switch trials.

Indeed, the application of PMv-M1 ppTMS at MO+75ms caused a specific delay in grasp aperture adjustments on small-to-large cylinder switch trials, relative to no-TMS or spTMS applied at this time (Figure 3A-C). This was quantitatively assessed by comparing the GAD between large cylinder stay and small-to-large cylinder switch trials (Figure 3D) at three points throughout the movement. A 2-factor ANOVA [TMS (no-TMS vs. spTMS vs. ppTMS) × Normalized Time (25% vs. 50% vs. 75%)] revealed significant main effects for TMS (F1.70,22.14=11.70;p<0.001), and Normalized Time (F2,26=10.06;p<0.001). The TMS× Normalized Time (F3.90,50.67=4.51;p<0.01) interaction was significant as well. Paired-sample t-tests showed a significantly greater GAD for ppTMS trials at the 50% time-point than for the no-TMS (t13=−6.99;p<0.001) or spTMS (t13=−3.20;p<0.01) conditions. There were no significant differences observed between the no-TMS and spTMS conditions (t13=−1.05;p=0.31) at this time-point, and none observed between TMS conditions at the other two (25% or 75%).

Figure 3
PMv-M1 ppTMS led to slower reprogramming on small-to-large cylinder switch trials (A), relative to the spTMS (B) or no-TMS conditions (C). This delay is quantified by the |stay – Switch| grasp aperture difference (GAD; D). Similar, albeit non-significant, ...

Anatomical connections associated with physiological and behavioral effects of PMv-M1 ppTMS

A number of white-matter regions were found in which FA correlated with between-subject differences in the stay – switch PPE contrast at MO+75ms and MO+100ms (Supplementary Table 1), with the largest clusters emerging in the vicinity of PFv and IPS in the right hemisphere. Overlapping clusters were found in the right PFv adjacent to the inferior frontal sulcus and the frontal operculum (Figure 4A) at both MO+75ms and MO+100ms. The largest region of correlation, near the right IPS (Figure 4C), only emerged at the later MO+100ms time period (Figure 4C) as did a smaller region of correlation near right PMv (Figure 4B). In relation to behavioural effects, adjacent right IPS (Figure 4D) and PMv (Figure 4E) clusters showed as significant correlation between FA and GAD measured at 50% of MT (~300-400ms after the MO+100ms time-point).

Figure 4
White-matter FA relationships with physiological (A-C) and behavioral (D-E) effects produced by PMv-M1 ppTMS. Clusters highlighting regions that showed differential PPEs relative to the behavioral context (stay vs. switch) emerged in (A) PFv at MO+75ms, ...

Control Experiment and Analyses

A control experiment confirmed that the differential, context-based PMv-M1 PPEs were specific to that interaction and could not be explained by simple superposition of the conditioning and test pulses over left M1. When both the conditioning pulse and test pulse were applied through the same coil over left M1, the same three-way ANOVA [Muscle (APB vs. FDI) × Context (switch vs. stay) × Time (MO+75ms vs. MO+100 ms)] used to compare peri-movement conditions in the main experiment revealed no significant main (all F1,5≤1.304; all p≥0.305) or interaction effects (all F1,5≤3.829; all p≥0.108). As the conditioning pulse over left M1 appeared to exert a facilitatory effect on test pulse for all conditions in both muscles, a three-way ANOVA [TMS (single vs. paired-pulse) × Context (switch vs. stay) × Time (MO+75ms vs. MO+100 ms)] was performed on the raw data in each muscle to assess this statistically. As expected, both the FDI (F1,5=21.967;p<0.01) and APB (F1,5=21.696;p<0.01) muscles showed only a significant main effect for TMS.

Furthermore, data from the main experiment suggest that the change from facilitation to inhibition cannot be attributed to a change in excitability in the M1 region during action reprogramming. A two-way ANOVA [Context (stay vs. switch) × Time (MO+75 vs. MO+100 ms)] assessing differences in MEP magnitude during trials in which single pulses were applied over M1, revealed no significant main (Context: F1,13=0.206;p=0.657; Time: F1,13=1.704;p=0.214) or interaction (F1,13=0.002;p=0.966) effects.

Another potential confound, particularly when measuring MEPs during movement, could be related to systematic differences in background EMG activity between conditions at the time when TMS was applied. To address this, a three-way ANOVA [TMS (single pulse vs. paired-pulse) × Context (stay vs. switch) × Time (MO+75ms vs. MO+100ms)] was conducted for the root mean square (RMS) of the background EMG in a 100ms window ending 10ms prior to the application of the TMS test pulse (so that the conditioning pulse artifact was not included for paired-pulse trials). No significant main (all F1,13≤2.571; all p≥0.133) or interaction (all F1,13≤2.985; all p≥0.108) effects were found for this comparison. Therefore, MEP amplitude effects were not confounded with differences in FDI muscle contraction states.

Finally, reaction (RT) and movement time (MT) were calculated and statistically compared for peri-movement conditions (Supplementary Figure 2). Three-way ANOVAs [TMS (single vs. paired-pulse) × Context (switch vs. stay) × Time (MO+75ms vs. MO+100 ms)] were performed on both measures. For RT, the results of the ANOVA showed no significant main or interaction effects (p≥0.185). For MT, there was a significant main effect for Time (p<0.05), while no other effects were significant (p≥0.179).

DISCUSSION

The combination of three methods, ppTMS, kinematic recordings, and DW-MRI, provides a detailed picture of functional interactions that occur during action reprogramming. First, it was shown that physiological interactions between PMv and M1 change with behavioral context. While PMv facilitated M1 activity during the preparation and execution of a normal movement, it inhibited M1 activity when the initial action had to be suppressed and a new one selected. Furthermore, with ppTMS it was possible to probe functional interactions at a high temporal resolution and to show that this change in the PPE happened within 75ms of the change in task context.

Previous studies have reported task-related facilitation of M1 corticospinal activity by PMd (Koch et al., 2006; O'Shea et al., 2007), PMv (Davare et al., 2008), and pre-SMA (Mars et al., 2009). Although there has been evidence for a change to an inhibitory influence when interpulse-interval or stimulation intensity are varied, these differential effects have not always been clear during motor task performance. By contrast, the present study showed that a change in behavioral context is sufficient to cause a complete reversal of the influence exerted by PMv over M1 (within the same subject and test session), even in the absence of a change in stimulation parameters. The change from facilitation to inhibition cannot be explained by a change in local excitability within left M1, as spTMS applied over M1 on both switch and stay trials elicited similar sized MEPs. Similarly, paired microwire stimulation of PMv and M1 in macaques has also been shown to exert both facilitatory and inhibitory effects on MEPs during grasping movements (Prabhu et al., 2009). In humans, the muscle-specific nature of these PPEs appears to depend on each muscle's functional role during the particular grasping movement being made (Davare et al., 2008). Here, similar patterns of PPEs emerged regardless of whether subjects were switching to or from the large or small cylinder. As a similar precision grasp was used for all trials, the FDI played a relatively constant functional role throughout the experiment.

Activity in inferior frontal cortex (extending into PMv) increases when people inhibit actions, and lesions or disruptive TMS applied to this region impair the ability to withhold movements (Aron et al., 2004; Forstmann et al., 2008). Although it has been suggested that PMv exerts an inhibitory physiological influence over other brain areas, including M1 (Aron et al., 2004), the degree to which inhibition of action at a behavioral level can be related to inhibition at a physiological level has been difficult to ascertain. The present findings demonstrate that PMv does indeed exert an inhibitory influence over M1 when an action has to be inhibited and reprogrammed. Moreover, the short latency of the inhibitory influence, just 8ms elapsed between the PMv and M1 pulses, suggests that it occurs in a relatively direct manner that need not depend on a multi-synaptic route via the basal ganglia, as has been speculated.

An attempt was also made to assess the impact this inhibitory physiological effect had on behavior. Although the applied stimulation was not optimized to disrupt performance, it still caused a reduction in grasp aperture adjustments measured at the mid-point of the movement on switch trials. In PMv, unlike M1, populations of neurons encode different grasping movements not just before movement but throughout the course of movement (Umilta et al., 2007). One interpretation of the PMv switch effect is that, under circumstances where reprogramming is required, PMv generates a specific pattern of inhibition across M1 that leads to decreased activity in M1 corticospinal neurons associated with the initial movement. This selective inhibition beneficially minimizes the inertial consequences of the initial action on any alternative movement being made. When TMS is applied to PMv in the same context, the TMS pulse augments the inhibitory influence of PMv but may induce a non-specific pattern of inhibition over M1 that leads to temporary inhibition of all on-going movements. Although the behavioral impact of TMS depends on the direction of size change, similar patterns of neurophysiological change were seen regardless of cylinder size.

Consistent with the idea that PFv and opercular frontal regions influence PMv during reprogramming through the selection of task-relevant information, we observed that FA in a region adjacent to the inferior frontal sulcus was significantly correlated with between-subject differences in the size of PMv's context-dependent influence on M1. Furthermore, overlapping PFv clusters emerged for the physiological regressor at both MO+75ms and MO+100ms, but none emerged for the kinematic regressor which was measured approximately 300–400ms following the MO+100ms time-point. By contrast, similar PMv and IPS clusters only showed significant correlations with the physiological regressor at MO+100ms, and the kinematic regressor. This suggests that PFv plays an early role in influencing PMv during reprogramming and that, as the action evolves, PMv and IPS emerge as major influences over M1.

One caveat related to the interpretation of these data is that if actions are represented in a hierarchical framework (Majdandzic et al., 2009; Rosenbaum et al., 2007), then one might argue that the action reprogramming required by this task was related to the kinematics of the action rather than a complete change in every aspect of the intended final goal state. Given PMv's importance in representing the kinematics of grasping movements (Majdandzic et al., 2009) it is unclear whether similar effects would be seen if other aspects of the action had been reprogrammed instead. An important point is that while PMv's influence during action reprogramming may depend on input from PFv, this is only one part of an extended circuit of brain regions that influence action reprogramming. The size of PMv's context-dependent inhibitory influence was also correlated with other prominent regions of FA. The sagittal stratum, adjacent to the IPS, is the bundle mediating connections to the pons and cerebellum. Smaller regions of FA near premotor cortex itself were found, as well. All of these regions have been implicated in on-line updating of hand position and movement trajectories (Desmurget et al., 1999; Rushworth et al., 2001; Glover et al., 2005; Tunik et al., 2005; Lee and van Donkelaar, 2006).

Even if PMv does mediate action inhibition, it is clear that its influence is not confined to such a role. In fact, a second novel finding was that PMv exerted a protracted excitatory influence over M1 corticospinal activity even when reprogramming was not required. ppTMS investigations of PMd and pre-SMA have suggested that these regions exert their major influence over M1 in a transitory manner between 75 and 125ms after the presentation of the cue instructing movement (Koch et al., 2006, O'Shea et al., 2007, Mars et al., 2009). By contrast, little has been known of how PMv-M1 interactions evolve during the course of an action. PMv stimulation facilitated M1 activity at the end of the movement preparation period, as well as after movement onset occurred. Such a protracted influence is consistent with PMv facilitation of M1 even when subjects maintain static hand postures (Davare et al., 2008), and with demonstrations that other areas in the PMv network influence movement even when the need for updating is not explicitly manipulated (Tunik et al., 2008).

In conclusion, PMv exerts a protracted influence over M1that can rapidly change between facilitation and inhibition depending on behavioral context. Inhibition of M1 corticospinal activity is mediated by an interconnected network of areas spanning prefrontal, premotor and parietal cortex when actions are inhibited and reprogrammed.

Supplementary Material

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ACKNOWLEDGEMENTS

This work was supported by the Medical Research Council UK (MFSR), the award of a Marie Curie Intra-European Fellowship within the sixth European Community Framework Programme (RBM), and the intramural program of the NINDS.

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