Motivational tuning of fronto-subthalamic connectivity facilitates control of action impulses

Abstract

It is critical for survival to quickly respond to environmental stimuli with the most appropriate action. This task becomes most challenging when response tendencies induced by relevant and irrelevant stimulus features are in conflict, and have to be resolved in real time. Inputs from the pre-supplementary motor area (pre-SMA) and inferior frontal gyrus (IFG) to the subthalamic nucleus (STN) are thought to support this function, but the connectivity and causality of these regions in calibrating motor control has not been delineated. In this study, we combined off-line noninvasive brain stimulation and functional magnetic resonance imaging, while young healthy human participants performed a modified version of the Simon task. We show that impairing pre-SMA function by noninvasive brain stimulation improved control over impulsive response tendencies, but only when participants were explicitly rewarded for fast and accurate responses. These effects were mediated by enhanced activation and connectivity of the IFG-STN pathway. These results provide causal evidence for a pivotal role of the IFG-STN pathway during action control. Additionally, they suggest a parallel rather than hierarchical organization of the pre-SMA-STN and IFG-STN pathways, since interruption of pre-SMA function can enhance IFG-STN connectivity and improve control over inappropriate responses.

Keywords: Simon task; TMS; fMRI; motor control; pre-SMA; reward.

Figure 1.

Experimental task and behavioral results. a, Experimental task. During fMRI, subjects performed a Simon task, which required subjects to make a correct response while suppressing an inappropriate response. On each trial a cue was presented on either the left or right side of the screen. Depending on the color of the cue, participants had to respond with a button press of the index or middle finger of their right hand. When one cue dimension (e.g., color) alternated between trials, while the other cue dimension (e.g., spatial position) was repeated (incompatible trials), there was an increased risk of impulsive inappropriate responses compared with consecutive trials where both cue dimensions change or stay the same (compatible trials). The level of motivation was manipulated by the presence or absence of a financial incentive. Participants could win a monetary reward in 50% of the trials, which were indicated by a coin instead of a circle. b, Mean RTs after sham (left) and real rTMS (right). Error bars indicate SEM. c, Mean accuracy rates after sham (left) and real rTMS (right) for fast responses. Trials were divided into slow and fast responses after a median split. The gray box shows a selective improvement in accuracy after real rTMS for trials with a high level of response conflict (incompatible trials) and a high level of motivation (rewarding context). Error bars indicate SEM.

Figure 2.

fMRI covariance analysis. Regions showing significant correlation with individual differences in the reward-related benefit in accuracy. For illustration purposes only, the SPM is thresholded at P_uncorrected < 0.005 and the rTMS-induced behavioral benefit is plotted against the rTMS-induced change in neural activity of, respectively, left IFG (ρ: 0.769) and left STN (ρ: 0.776). L, left; R, right.

Figure 3.

BMS. a, Models that were compared using BMS. The models differed with regards to the modulated connection (pre-SMA–STN, IFG—STN, or both) and the experimental modulator (Prospect-of-reward, TMS, or both). We also created a null model (M-1), which postulated that no connections were modulated. The models did not differ with regards to endogenous coupling (A-matrix) or driving inputs (C-matrix; set to pre-SMA). b, Comparison of all considered models. There was strong evidence for the model postulating that both Prospect-of-reward and TMS modulated the connection from IFG to STN (model 9). c, Model parameters. Endogenous coupling (A-matrix) is indicated by yellow lines connecting the different regions. Contextual modulation (B-matrix; effect of Reward and TMS) is indicated by red lines modulating IFG–STN. The yellow arrow entering the network via pre-SMA indicates the driving inputs (compatible and incompatible trials). Coupling values are given in mean (SD).

Figure 4.

Hierarchical multiple linear regression analysis. a, Illustration of the predictors. The original regression model included modulation of neural activity in IFG and STN as observed in the covariance-based fMRI analysis (R² = 0.762). Entering connectivity values from the DCM analysis reflecting modulation of coupling by Prospect-of-reward and TMS (B-matrix) significantly improved model predictions of the behavioral benefit (reward-related benefit in accuracy after rTMS) with an R²-change of 0.124 (p = 0.036). The independent variables (predictors) of the regression model are marked in red. b, Regression model predictions. The regression model comprising modulation of activity and connectivity of the IFG-STN pathway predicted >88% variance of the behavioral benefit (p < 0.001).