Cortical and subcortical interactions during action reprogramming and their related white matter pathways

Franz-Xaver Neubert, Rogier B Mars, Ethan R Buch, Etienne Olivier, Matthew F S Rushworth, Franz-Xaver Neubert, Rogier B Mars, Ethan R Buch, Etienne Olivier, Matthew F S Rushworth

Abstract

The right inferior frontal gyrus (rIFG) and the presupplementary motor area (pre-SMA) have been identified with cognitive control-the top-down influence on other brain areas when nonroutine behavior is required. It has been argued that they "inhibit" habitual motor responses when environmental changes mean a different response should be made. However, whether such "inhibition" can be equated with inhibitory physiological interactions has been unclear, as has the areas' relationship with each other and the anatomical routes by which they influence movement execution. Paired-pulse transcranial magnetic stimulation (ppTMS) was applied over rIFG and primary motor cortex (M1) or over pre-SMA and M1 to measure their interactions, at a subsecond scale, during either inhibition and reprogramming of actions or during routine action selection. Distinct patterns of functional interaction between pre-SMA and M1 and between rIFG and M1 were found that were specific to action reprogramming trials; at a physiological level, direct influences of pre-SMA and rIFG on M1 were predominantly facilitatory and inhibitory, respectively. In a subsequent experiment, it was shown that the rIFG's inhibitory influence was dependent on pre-SMA. A third experiment showed that pre-SMA and rIFG influenced M1 at two time scales. By regressing white matter fractional anisotropy from diffusion-weighted magnetic resonance images against TMS-measured functional connectivity, it was shown that short-latency (6 ms) and longer latency (12 ms) influences were mediated by cortico-cortical and subcortical pathways, respectively, with the latter passing close to the subthalamic nucleus.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
(A) Behavioral task required participants to respond with the left or right index finger in response to visual stimuli presented on a computer screen. Each trial started with the presentation of two peripheral flankers (red and green, sides random). A center cue taking the color of one of the flankers appeared 450–600 ms later. Participants had to respond with the finger of the hand on the side of the congruent flanker color. The center cue took the same color for trains of three to seven trials. Hence, on each trial, participants could prepare a movement based on their knowledge of the identity of the center cue on the previous trial. However, after taking the same color for a series of trials, the center cue color changed. This manipulation meant that there were two types of trials: stay trials, in which the fixation square turned into the same color as in the previous trial, thus allowing the participants to exert the already prepared response, and switch trials, in which the fixation square turned into a different color from that in the previous trial, thus requiring participants to inhibit an already prepared response and to reprogram their action plans. (B) Time course of the rIFG/M1 interaction experiments. Pulses were delivered through two coils. The conditioning (Cond.) coil (gray) was placed over rIFG, and the test coil was placed over left M1. ppTMS was applied at different SOAs after center cue color onset in the “rIFG/M1 SOA experiment” or at a single SOA but with different IPLs in the rIFG/M1 IPL experiment and pre-SMA/M1 IPL experiment. (C) Schematic representation of the setup, with the gray conditioning coil placed over rIFG and black test coil placed over the left M1. (D) Coil placements on Montreal Neurological Institute (MNI) brain. Circular symbols indicate individual participants’ stimulation locations. Ellipsoids represent 95% confidence limits of the mean group stimulation location. Red and blue ellipsoids show coil location for the “rIFG/M1 interaction experiment.” Green, yellow, and pink ellipsoids show locations for the rIFG/M1 IPL experiment and pre-SMA/M1 IPL experiment.
Fig. 2.
Fig. 2.
Time course of frontal/M1 interactions. ppTMS and spTMS MEP ratios are plotted for each SOA between central fixation color change and TMS delivery. (A) MEP ratios for switch (gray) and stay (black) trials shown for rIFG/M1 interactions pooled over both hands. (B) Similar information for pre-SMA data from Mars et al. (12), adapted with permission of the Society for Neuroscience. (C) rIFG/M1 interactions separately for trials in which right and left hand responses were executed. Asterisks indicate significant inhibition compared with the single-pulse baseline. (D) rIFG/M1 interactions before and after 15 min of 1-Hz TMS over pre-SMA.
Fig. 3.
Fig. 3.
(A) Pre-SMA/M1 (black) and rIFG/M1 (gray) MEP ratios during action reprogramming at different IPLs, plotted for right hand responses only (asterisks indicate significant modulation from the single-pulse baseline). Clusters showing significant correlations between individual FA and MEP effect sizes are displayed on the MNI brain [pre-SMA: green (6 ms) and red (12 ms); rIFG: yellow (6 ms) and blue (12 ms)]. (B) Comparison of two connectivity networks derived from the pre-SMA (green) and the rIFG (yellow) at 6-ms IPI, showing dorsomedial cortical white matter. (C) Cross-correlation matrices for pre-SMA/M1 (Left) and rIFG/M1 (Right) functional connectivity effects at different IPLs. ppTMS and spTMS MEP effects are correlated across different IPLs and plotted with their Pearson correlation coefficient. The 6- and 12-ms effects are sufficiently uncorrelated so as to be separate regressors in a multiple regression model. (D) Comparison of two composite connectivity networks derived from pre-SMA (red) and rIFG (blue) at 12-ms IPL, showing white matter in the vicinity of the global pallidus and STN.
Fig. 4.
Fig. 4.
Bars show the number connections from probabilistic diffusion tractography that passed through the STN ROIs (Upper). Tracts were derived from clusters of significant correlation between FA and TMS effect size in the IPL experiments (pre-SMA, Left; rIFG, Right) and the two different IPLs (light gray = 6 ms, dark gray = 12 ms). It can be seen that tracts were significantly more likely to pass through or near STN at the 12-ms IPL only.

Source: PubMed

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