Resolving the paradoxical effects of subthalamic deep-brain stimulation on inhibitory motor control

University Of Iowa, Iowa City IA

Investigators

Linked publications & trials

Abstract

ABSTRACT Parkinson’s disease (PD) is the most common hypokinetic movement disorder. It is characterized by an over- inhibited motor system, which results in bradykinesia, tremor, and stiffness of gait. Deep-brain stimulation (DBS) is the primary neurosurgical treatment of PD. It commonly targets the subthalamic nucleus (STN) of the basal ganglia, the primary inhibitory node in the motor system. One purported mechanism underlying STN DBS is that it reduces STN’s inhibitory influence, thereby moving the pathologically inhibited motor system back to a more typical excitation-inhibition balance. However, this is only one of the many competing explanations for the mechanism underlying STN DBS’ therapeutic effect. To adjudicate between these explanations, there is a critical need to precisely assess the inhibitory motor control function of the STN. The premier method to assess inhibitory motor control is the stop-signal task (SST), in which inhibition is needed to periodically stop an already-initiated action. Converging evidence shows that STN activity correlates with the ability to successfully stop an action in the SST. As such, the SST is the ideal method to assess the mechanism(s) underlying STN DBS, as it links STN activity with its purported function. The prediction is straightforward: if DBS indeed reduces STN’s inhibitory influence, it should impair SST performance. However, existing work has produced a highly contradictory, paradoxical picture of STN DBS’ effect on motor inhibition: while some studies do show the predicted pattern, other studies show the exact opposite: DBS seemingly improves action-stopping. The current proposal asks a very simple question: How can this be? Previous work has not been able to answer that question, partially because small sample sizes prevented the investigation of individual differences, and partially because methods to assess some key variables did not exist. The core hypothesis of the current work is that DBS’s effects on motor inhibition are mediated by DBS lead placement (Aim 1), cortico-STN connectivity (Aims 1 & 2), and/or task-related cortical dynamics (Aim 3). We propose to investigate these aspects in a large sample of N=100 PD patients, who will perform two sessions of the SST – On and Off DBS. In Aim 1, we will reconstruct the exact location of the implanted STN leads, as well as the associated structural connectivity to the rest of the brain, and test whether changes in motor inhibition are related to systematic variation in either. In Aim 2, we will investigate the same for cortico-STN functional / effective connectivity, as assessed using EEG and a new method for concurrent task-related LFP recordings. In Aim 3, we will focus on local cortical activity measured by EEG to test if secondary network-effects of DBS contribute to different effects on motor inhibition. If successful, this work would provide unprecedented insights into STN’s role in inhibitory motor control, resolve an unaddressed paradox in existing work, lay the methodological groundwork for the comprehensive, causal study of cortico-subcortical circuits and human behavior, and provide novel insights into the mechanism(s) underlying STN DBS.