Factors Contributing to Rigidity Expression and Response to Pallidal Deep Brain Stimulation in People with Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic cells in the substantia nigra, buildup of alpha-synuclein in specific regions of the brain, and the emergence of cardinal motor symptoms including rigidity, slowness of movement, tremor, and gait dysfunction. Despite these shared characteristics, there is a great deal of heterogeneity in symptom presentation and response to therapies within the population of individuals with PD. Understanding the driving factors behind this heterogeneity is crucial for developing targeted and effective therapies for the disease and improving outcomes for those living with Parkinson’s disease. In this dissertation, two studies are described: 1) an investigation into the effects of rapid eye movement (REM) sleep without atonia (RSWA) on the presentation of rigidity in a population of individuals with mild-to-moderate Parkinson’s disease and 2) the development and implementation of a computational model of pallidal deep brain stimulation (GP-DBS) to identify neural pathways associated with rigidity suppression in individuals with PD. Both studies utilize a quantitative measure of rigidity as a tool to assess symptom severity. In the first study, our findings demonstrate that people with mild to moderate PD and RSWA have dysfunctional regulation of muscle tone during both sleep and wakefulness. The results show that the presence of RSWA is associated with increased forearm rigidity magnitude and symmetry. In the second study, a patient-specific computational model of GP-DBS was developed and implemented. By combining pathway activation estimates from the model with quantitative measurements of rigidity, the analyses identified the internal capsule as an important pathway for reducing parkinsonian rigidity. In particular, profound decreases in rigidity were associated with activation of internal capsule fibers projecting from Brodmann’s area 6, which contains axons from premotor cortex and supplementary motor area. The results of these studies reveal the importance of understanding factors like RSWA that may drive heterogeneity in PD, while also identifying potential pipelines for developing symptom-specific targets for treatment.