Study Rationale:
Anxiety, depression, reduced motivation, and impaired cognition are common symptoms in Parkinson’s disease (PD), often occurring early in its course, before deficits in movement. The brain circuits responsible for these psychiatric symptoms remain poorly understood, but clinical findings in PD patients with deep-brain stimulation (DBS) of a region called the subthalamic nucleus (STN) may provide important clues. While often highly effective for treating motor symptoms, STN DBS can have unintended and variable effects on psychiatric symptoms, ranging from elevated mood to worsening anxiety, depression, motivation, and cognition. This variability between individuals likely depends on DBS stimulation settings and location within the STN and its neighboring brain structures.
Hypothesis:
We hypothesize that the abnormal activities of distinct cellular subtypes in the STN and the neighboring para-subthalamic nucleus (pSTN) contribute to specific psychiatric symptoms in PD, including anxiety, depression, reduced motivation, and impaired cognition, and therefore represent potential targets for therapeutic intervention.
Study Design:
We will use multiple state-of-the-art approaches in humans and mice to determine the properties, connections, functions, and malfunctions of STN and pSTN cellular subtypes in health and PD. We will 1) identify the locations and patterns of STN DBS that modulate psychiatric symptoms in PD patients 2) refine the boundaries of the STN and pSTN in the human brain through mapping of STN and pSTN subtype molecular markers 3) determine how STN and pSTN subtypes regulate mood, motivation, and cognition in control and PD model mice, and whether manipulation of their activity improves psychiatric symptoms.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Understanding how STN and pSTN cell subtypes contribute to specific psychiatric symptoms in PD may assist interpretation of fMRI, microelectrode, and EEG measurements and neuropsychiatric evaluations in patients, leading to informed individualized interventions involving DBS and/or drug-based treatments.
Next Steps for Development:
The data provided here could be used to inform new treatments for the psychiatric symptoms of PD using DBS and/or administration of drugs that selectively target STN and/or pSTN subtypes and their associated circuits.