# The role of cortical nicotinic receptors in pathological brain oscillations in Parkinson's disease cognitive impairment

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $204,688

## Abstract

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...

## Key facts

- **NIH application ID:** 10774326
- **Project number:** 5R21NS128391-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Kelly Alexander Mills
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2023-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10774326

## Citation

> US National Institutes of Health, RePORTER application 10774326, The role of cortical nicotinic receptors in pathological brain oscillations in Parkinson's disease cognitive impairment (5R21NS128391-02). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10774326. Licensed CC0.

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