Unraveling the Mechanisms of Cognitive and Affective Symptoms in Parkinson’s Disease: Towards Personalized Therapeutic Interventions

Context: Parkinson's disease (PD) is a complex neurodegenerative disorder characterized not only by motor symptoms like tremors and stiffness but also by cognitive and affective impairments such as attention and decision-making challenges and depression. These non-motor symptoms significantly impact patients' quality of life, functional abilities, and overall well-being. Despite their profound effects, cognitive and affective symptoms in PD remain poorly understood and inadequately addressed in clinical practice.
Challenge: The challenge lies in the multifaceted nature of cognitive and affective symptoms in PD, which often go unrecognized or untreated due to diagnostic challenges and the subjective nature of self-report measures. Crucially, there is no effective therapy. This gap in understanding and management not only exacerbates patients' suffering but also increases healthcare utilization and caregiver burden.
This project will address these challenges by pursuing three main objectives:

Mechanistic Elucidation: Through multimodal assessment methods, including advanced neurophysiological recording, the project aims to unravel the underlying mechanisms of cognitive and affective symptoms in PD.
Biomarker Identification: The project aims to identify biomarkers for the early detection and objective assessment of cognitive and affective symptoms in PD. By correlating neural features with symptom severity over time, the research seeks to develop reliable biomarkers that can facilitate timely intervention and personalized treatment strategies.
Innovative Therapeutic Paradigm Development: Building on preliminary findings, the project will explore a novel Deep Brain Stimulation (DBS) paradigm that specifically targets cognitive and affective symptoms in PD. By modulating neural circuits implicated in non-motor symptoms using a novel stimulation paradigm, the research aims to optimize therapeutic outcomes while maintaining optimal effects on motor symptoms. This innovative approach has the potential to transform PD treatment by offering precise, targeted interventions tailored to individual patients' needs.

Methods: This project encompasses 2 work packages.
Work package 1:
PD Patients will undergo comprehensive assessments in clinic before and after DBS activation. These assessments include neuropsychological evaluations and recording of brain dynamics using DBS devices with sensing capabilities during resting and computer tasks. Additionally, patients will undergo at-home recording of neural signals and symptom tracking using the DBS device with sensing capability, wearable devices, and smartphone-based tasks, aiming to capture symptom fluctuations.
Work Package 2:
Individuals with PD will undergo a randomized controlled trial with a cross-over design. Patients will be randomly allocated to two groups, receiving either conventional 130 Hz DBS or a novel Dual Frequency DBS paradigm in alternating periods. Standardized neuropsychological tests and measures of neuropsychiatric symptoms will be assessed in clinic at baseline, 3 months, and 6 months. Additionally, at-home assessments will include weekly cognitive tests, affective symptoms and motor symptom severity assessments using a smartphone-based app and wearable devices during the treatment periods.
 
Potential Applications and Benefits: The outcomes of this research have significant implications for healthcare, society, and the wider research community. By elucidating the neurobiological basis of cognitive and affective symptoms in PD, the project could lead to more accurate diagnosis, personalized treatment strategies, and improved quality of life for patients. The findings will inform our understanding and management of neuropsychiatric disorders beyond PD, contributing to advancements in neuroscience and personalized medicine. Overall, this project represents a pioneering effort to address a critical unmet need in PD research and care, with far-reaching implications for patient well-being and healthcare outcomes.