Parkinson’s disease (PD) and dystonia are neurologic conditions with complex etiologies, significant disability, and limited treatment options. This dissertation explores the role of anti-inflammatory medication use in genetically mediated PD risk, outcomes of deep brain stimulation surgery in isolated dystonia, and a novel neuromodulation therapy for acquired dystonia in cerebral palsy (CP).The first study analyzed non-steroidal anti-inflammatory drug (NSAID) exposure in asymptomatic pathogenic variant carriers of LRRK2 and GBA1 variants -the most common genetic risk factors for PD- using longitudinal data from the Parkinson’s Progression Marker Initiative (PPMI). NSAID use was not significantly associated with progression of parkinsonian markers, though wide confidence intervals and measurement challenges underscored the need for larger, detailed studies. The second study characterized short- and long-term DBS outcomes in isolated dystonia using a large, two-decade, single-center cohort. DBS consistently improved symptoms, disability, and quality of life in over 80% of patients. Favorable predictors of one-year outcomes included shorter disease duration, lower baseline severity, and having a TOR1A variant. While outcomes were generally similar between GPi and STN targets, STN stimulation was associated with greater improvement in cervical symptoms, and to a more rapid improvement. The third study explored safety and preliminary efficacy of cerebellar DBS in young patients with dyskinetic CP. Given limited success with traditional DBS targets in this condition, the cerebellum represents a promising alternative due to its role in dystonia networks and relative sparing in CP pathology. The study presents the protocol for an ongoing, single-center series of N-of-1 clinical trials with intracranial recordings and neuroimaging. Together, these studies address critical gaps in the understanding and management of neurodegenerative and neurodevelopmental disorders, paving the way for more effective, targeted interventions and improved patient outcomes.
