Optimizing Repetitive Transcranial Magnetic Stimulation Protocols for Motor Function

Abstract

Humans are incredibly adept at reaching for and manipulating objects – tasks vital for daily activities of independent living. Restoration of motor function after a neurological disorder like Parkinson’s disease or stroke is critical to the rehabilitation process. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that can affect neural activity and produce lasting changes in cortical physiology, making it a useful tool for studying the brain network that controls motor function. However, the effects of rTMS on the brain and behavior across the lifespan are highly variable and not fully understood, which limits its application in both basic research and clinical settings. This dissertation aims to investigate factors that contribute to the development of optimal rTMS protocols for promoting plasticity in a parietal-frontal network that mediates movement processes. The central hypothesis is that controlling the brain state during repeated, spaced, network-targeted stimulation will improve motor function and performance. I tested the central hypothesis by pursuing the three following specific aims. Aim 1 examines whether a network-targeted rTMS approach that leverages individual-specific functional parietal-motor pathways of the motor control network for skilled reach-to-grasp actions will maximize stimulation specificity. Aim 2 investigates the impact of stimulation dosage on motor excitability and performance by varying the number of rTMS sessions focused on a defined reach-to-grasp network in the motor system. Aim 3 tests the notion that the functional context of brain activity (i.e., brain state) during parietal stimulation can modulate interactions with functionally connected motor regions to alter plasticity associated with skilled motor control of hand actions. The first study describes a multi-focal TMS method to measure and manipulate functional interactions between parietal and motor regions with two coils, providing insight into the cortical reach-to-grasp network connectivity and its alteration at a system level. The second study investigates age-related changes in functional interactions between parietal and motor regions, revealing decreased facilitation of parietal-motor functional connections and its association with age-related decline in the neural control of movement. The third study demonstrates the cumulative dose-dependent effect on excitability in the motor cortex after repeated spaced rTMS to the parietal-motor pathway involved in reach-to-grasp control in young adults. The fourth study examines the application of a multiple-dose rTMS protocol to the parietal-motor pathway in older adults, demonstrating the challenges of augmenting plasticity induction with rTMS for the aging brain. The fifth study investigates how modulating cerebellar activity in the reach-to-grasp control network impacts subsequent stimulation responses downstream in the parietal-motor pathway. Lastly, the sixth study investigates the impact of controlling the brain state during parietal rTMS with a reach-to-grasp task on motor excitability and skilled motor performance, highlighting the potential of behavioral-induced brain states to amplify rTMS effects on functionally specific neural populations and pathways associated with motor function. Together, these studies demonstrate effective, functionally specific, and lasting changes to the parietal-motor network that support motor function. Leveraging these insights can better guide the plasticity mechanisms of motor control and inform the design of targeted interventions that can transition from research settings to widespread clinical practice. These studies could lead to targeted neuromodulation strategies to combat age-related sensorimotor declines and restore neuromotor abilities lost to neurological disorders like Parkinson’s disease and stroke.