Modulating Inhibitory Action Control Systems With Subthalamic Nucleus Stimulation

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Neurological (Parkinson's and Huntington's diseases) and neuropsychiatric disorders (Attention-Deficit Hyperactivity Disorder, Tourette syndrome) associated with frontal-basal ganglia dysfunction are accompanied by deficits in stopping or suppressing actions. Action inhibition deficits can have devastating effects and have been linked to clinical motor symptoms (e.g., falling, freezing, dyskinetic movements), poor functional skills (e.g., driving), and behavioral disorders (e.g., poor impulse control). Unfortunately, there are few options for treatment deficits in inhibitory control. One potential way to modulate inhibitory control processes is direct stimulation of relevant neural circuitries. Specifically, it is possible to stimulate a key node in the brain's inhibitory control circuitry, the subthalamic nucleus (STN), and directly modulate inhibitory control capabilities, including improving them. The STN is linked to two distinct forms of inhibitory control: (1) a stopping control mechanism that rapidly inhibits an initiated or ongoing action (2) a conflict control mechanism that selectively suppresses strong initial motor impulses that conflict and interfere with goal-directed actions. Our recent work and preliminary data lead to the hypothesis that these control mechanisms can be directly modulated and improved by stimulating the STN in patients with Parkinson's disease (PD). Moreover, our preliminary findings are strongly suggestive that modulating these distinct forms of inhibitory control requires stimulating in different STN subterritories. Additionally, a proposed, but scarcely tested idea is that inhibitory control mechanisms involve a predominantly right hemisphere circuitry. These state of findings leads to our specific hypotheses that inhibitory control circuitries can be directly modulated and improved by stimulating in distinct subregions and hemispheres in the STN. We propose experiments to systematically test the precise relationship between STN neural circuitry and inhibitory action control mechanisms. We propose novel interrogations of STN substructures and neurophysiology to define links between inhibitory control mechanisms and STN subterritories and hemispheres. In Specific Aim 1, we use innovative electrode localization and stimulation methods (both post-operatively as well as in the operating room) to test the hypothesis that stimulating dorsal and ventral subregions in the left and right STN produce dissociable effects on stopping control and on conflict control mechanisms. In Specific Aim 2, we investigate the relationships between inhibitory control mechanisms and STN neurophysiology by recording single unit neural activity in bilateral STN during intraoperative placement of DBS electrodes in PD patients. While the cognitive neuroscience of inhibitory control deficits in PD will benefit directly from this work, the project is designed with broader applications in mind as the neurosurgical community explores how DBS in the STN and other basal ganglia structures can improve inhibitory control deficits in individuals with Huntington's disease, Tourette's syndrome, and other neuropsychiatric disorders associated with basal ganglia circuitry dysfunction.