Project Summary/Abstract Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) is an established therapy for PD patients with motor fluctuations and dyskinesias. While STN DBS is an effective treatment for motor symptoms, it can produce unintended side effects cognition including executive function, language and attention deficits which affect quality of life and independence. Developing an individualized STN DBS approach which optimizes patient selection prior to surgery and enhances specificity when targeting neural networks is significant because it has the potential to reduce DBS induced cognitive decline. The research proposed in this K99/R00 Pathway to Independence Award will lay the groundwork needed to establish this approach by determining 1) how limited cognitive reserve prior to surgery and 2) how direct DBS interference with cognitive networks contribute to cognitive decline. Cholinergic and dopaminergic network hubs (i.e., the Nucleus Basalis of Meynert; NBM, and striatum) support cognition, however, these regions degenerate in PD and may be indirectly modulated by STN stimulation. Thus, the central objective of this proposal is to determine how vulnerability (K99) and the direct modulation (R00) of the NBM, and striatal networks contribute to cognitive decline in individuals with STN DBS. NBM/striatal vulnerability will be measured using diffusion kurtosis imaging (DKI) which reflects microstructural changes associated with the progressive degeneration of neuronal tissue. Network interference will be measured by assessing the change in NBM/striatal connectivity using combined DBS-fMRI which allows functional MRI data to be collected while simultaneously cycling stimulation. The central hypothesis of this proposal is that pre-surgical microstructural integrity (K99) and DBS induced interference (R00) of the NBM, and striatal networks will be associated with greater cognitive decline. Preliminarily data demonstrates that reduced mean kurtosis of diffusion within the NBM and striatum are associated with reduced executive function and language deficits in those with PD. In the 2-year mentored K99 phase of this proposal, I will establish the relationship between NBM/striatal microstructure and cognition (Aim 1) and cognitive decline 1-year following STN-DBS surgery (Aim 2). To accomplish these aims I will collect DKI and longitudinal neurocognitive data from 50 participants with PD planning to undergo clinical STN-DBS treatment. Additionally, I will receive training in DBS as a research tool, neurocognitive testing, combined DBS-fMRI and DKI analysis/interpretation. This will be facilitated by my mentoring team which includes DKI co-developer Dr. Jens Jensen (Primary Mentor) and DBS neurologist Dr. Gonzalo Revuelta (Co-mentor). After securing a tenure track faculty position, I will transition into the R00 phase of the award to investigate the relationship between STN-DBS modulation of the NBM/striatal networks and cognitiv...