Dorsal premotor cortex exerts state-dependent causal influences on activity in contralateral primary motor and dorsal premotor cortex

Abstract

During voluntary action, dorsal premotor cortex (PMd) may exert influences on motor regions in both hemispheres, but such interregional interactions are not well understood. We used transcranial magnetic stimulation (TMS) concurrently with event-related functional magnetic resonance imaging to study such interactions directly. We tested whether causal influences from left PMd upon contralateral (right) motor areas depend on the current state of the motor system, involving regions engaged in a current task. We applied short bursts (360 ms) of high- or low-intensity TMS to left PMd during single isometric left-hand grips or during rest. TMS to left PMd affected activity in contralateral right PMd and primary motor cortex (M1) in a state-dependent manner. During active left-hand grip, high (vs. low)-intensity TMS led to activity increases in contralateral right PMd and M1, whereas activity decreases there due to TMS were observed during no-grip rest. Analyses of condition-dependent functional coupling confirmed topographically specific stronger coupling between left PMd and right PMd (and right M1), when high-intensity TMS was applied to left PMd during left-hand grip. We conclude that left PMd can exert state-dependent interhemispheric influences on contralateral cortical motor areas relevant for a current motor task.

Figure 1

Experimental setup and main effects of grip task. A. Grip-force manipulandum and screen display for grip (arrow to left) and nogrip (central cross) trials. During grip trials, a yellow target bar indicated the required force level of 20% maximum voluntary contraction. The actual force exerted was indicated online by a red column. Participants were instructed to generate a non-ballistic force matching the displayed target bar using a gentle pace without major corrective movements. TMS was applied in a train, starting 900 ms after presentation of the target force bar, so as to overlap with performance of the grip. B. Schematic of EPI-TMS pulse synchronization. On each trial, TMS was applied at one of two intensities (110% resting motor threshold or 70% active motor threshold). TMS pulses were applied every 90 ms during the waiting time between EPI navigator echoes and EPI data readout. Every slice was perturbed equally often throughout a scanning session. TMS pulses were temporally separated from any slice selection gradients or excitation pulses (fat saturation pulse, trigger pulse, RF pulse, slice selection gradient, refocusing gradient, navigator echo) and EPI data readout-gradients. C. Simple fMRI main effects of grip > nogrip, irrespective of TMS. Results of the group random effects analysis are projected onto a transparent schematic of the MNI template brain and on a transverse section (z=54) of the averaged normalized structural scans of all participants. The height threshold was set at T > 4, uncorrected for multiple comparisons across whole brain, and the extent (or cluster) threshold set at P < 0.05, corrected for multiple comparisons across whole brain. Left hand grip evoked activity in right primary motor cortex, extending into adjacent dorsal and ventral premotor cortex, plus primary and secondary somatosensory cortex. Additional activity increases were found in superior parietal cortex and intraparietal sulcus, reflecting the visuomotor processing involved in hand grip-trials. Note that we focused imaging largely on the dorsal part of the brain. Therefore, any ventral visual activations due to visual aspects of the grip task were outside the field of view. R = right.

Figure 2

Local effect of TMS stimulation on BOLD signal from left PMd Region of interest (ROI) analysis for TMS_high > TMS_low, irrespective of grip, in an a priori defined ROI (sphere of 15 mm diameter, illustrated by the white circle) centered around the site of stimulation in the left PMd (x,y,z: -24, -14, 62). TMS_high vs TMS_low induced more activity in this area (P < 0.05, corrected for multiple comparisons at the cluster level within ROI). Thus, TMS at 110% of resting motor threshold evoked a local activity increase, relative to stimulation at the low intensity (70% active motor threshold). Activations are projected onto the average normalized structural scans of all participants. R = right.

Figure 3

Interaction between TMS intensity and current motor state for BOLD signals. A. SPMs showing a significant interaction [(TMS_highnogrip - TMS_lownogrip) - (TMS_high-grip - TMS_low-grip)] in right PMd contralateral to TMS stimulation (x,y,z: 34, -16, 58; assigned to Area 6 with a 60% probability, [Eickhoff and others 2006]) and right M1 (36, -26, 62; assigned to Area 4a with a 60% probability). These same regions were also modulated by the grip task (i.e. were active during left-hand grip), see Table 1, Figure 1C. B. SPM parameter estimates showing that TMS_high to left PMd at rest led to a relative activity decrease in contralateral PMd and M1 (BA4a), as compared to TMS_low. By contrast, when applied during active left-hand grip, TMS_high to left PMd now led instead to a relative increase in activity in these regions. This illustrates the state-dependent influence of left PMD TMS on contralateral motor areas which are implicated in hand movement control. C. Regions implicated in the grip task that also show changes in functional coupling (as revealed by an independent psychophysiological interaction analysis) with the site of TMS stimulation (left PMd), as a function of event-related condition. A significant context-dependent covariation with left (stimulated) PMd was revealed in two similar clusters as for the SPM interaction analysis, located in contralateral right PMd (x, y, z = 36, -14, 56) and right M1 (x, y, z = 36, -24, 64). Thus, the functional coupling between left PMd and right PMd and right M1 was stronger for TMS_high versus TMS_low during grip than during no-grip. Results are projected onto the average normalized structural scans of all participants (random effects analysis, corrected for multiple comparisons across the whole brain at T>4 and extent (cluster) threshold of P < 0.05). R = right.