7. PROJECT SUMMARY/ABSTRACT Cognitive impairment in Parkinson's disease (PD) drives substantial disability and US healthcare spending, yet further understanding of the multiple possible mechanisms is needed in order to develop treatments. Cognitive deficits in PD are associated with cholinergic denervation mediated through regional α4β2 nicotinic cholinergic receptor (α4β2-nAChR) binding changes. Animal evidence implicates the same receptors in the generation of brain oscillations that are a mechanism of normal brain function. Abnormal oscillations in the β band or phase- amplitude coupling (PAC) between β and γ frequencies correlate with motor symptoms in PD. Abnormal oscillations also exist in brain regions and networks associated with cognitive functions. Our overall objective of this exploratory R21 is to understand the relationship between α4β2-nAChR signaling and pathological brain oscillations in regions involved in cognitive impairment in PD. With converging evidence for the role of α4β2- nAChR's in PD-related cognitive dysfunction and slow oscillations, we hypothesize that defective signaling through α4β2-nAChR's is related to pathological oscillations and oscillation coupling and is one mechanism of cognitive impairment in PD. The proposed study combines cognitive testing, molecular imaging of α4β2- nAChR's with a unique radioligand ([18F]XTRA) with good signal-to-noise characteristics for imaging cortical and hippocampal regions, and intracranial recordings from STN and subdural electrodes over cortical regions known to a) be involved in the cognitive deficits seen in PD, b) have elevated β oscillation power in PD, and c) show abnormal α4β2-nAChR availability in PD. Aim 1 is to determine whether α4β2-nAChR availability in persons with PD positively correlates with the cortical β power or β-γ phase-amplitude coupling and STN- cortex coherence as measured by intracranial recordings over regions involved in cognition during deep brain stimulation (DBS) surgery. We hypothesize: 1) Higher α4β2-nAChR availability (BPND) in the left DLPFC and right parietal cortex will be associated with higher β power and β-γ PAC recorded via a subdural electrode strip in these regions at rest, adjusting for age; and 2) Higher α4β2-nAChR availability will be associated with greater subthalamic nucleus (STN) β power locally and β phase coherence with the left DLPFC and right parietal cortex, regions associated with cognitive dysfunction in PD. Aim 2 is to evaluate whether α4β2-nAChR availability and β band power or β-γ phase-amplitude coupling over the DLPFC and parietal cortices are associated with executive and visuospatial dysfunction in PD, where we hypothesize: 1) Higher α4β2-nAChR availability and LFP β band power and/or β-γ PAC in the left DLPFC will correlate with worse problem-solving, working memory, and set-shifting, and in the right parietal cortex, with worse visuospatial perception, and 2) Higher associative STN LFP β band power and α4β2-nAChR a...