Ultrasound-Based Characterization of Functional Connectivity and Evaluation of Effects of Focused Ultrasound Neuromodulation in a rapidly progressing murine model of Parkinson’s Disease

• Applicant: Dr. Jonas Bendig
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Experimental and Theoretical Network Neuroscience
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523020841

Parkinson's disease (PD) is a neurodegenerative disease affecting over 10 million people worldwide. Its hallmark motor symptoms - tremors, stiffness, and slowness of movement -as well as non-motor symptoms like cognitive decline, depression, and autonomic dysfunction are associated with disrupted neuronal activity and connectivity in key brain regions. Understanding how these disruptions evolve and testing new therapeutic strategies is crucial for advancing treatment. This project focuses on investigating whole-brain functional connectivity and assessing the potential of focused ultrasound (FUS) neuromodulation as a novel intervention in a rapidly progressing murine model of PD. Traditional imaging methods like functional MRI (fMRI) have significantly advanced our understanding of brain connectivity changes in PD. However, their use is limited in preclinical studies due to the need for anesthesia, which alters neural activity, and constraints on behavioral testing in MRI environments. To overcome these challenges, we utilize 4D functional ultrasound imaging (fUSi), a technique offering high spatiotemporal resolution to map brain activity in awake, freely behaving animals. The project is built around a recently developed genetic mouse model of PD, which replicates critical aspects of human disease progression, including mitochondrial dysfunction and motor symptoms responsive to L-DOPA therapy. This model enables longitudinal assessments of brain connectivity as the disease advances. By pairing this model with fUSi, we aim to comprehensively map changes in brain network connectivity over time and under different conditions, such as L-DOPA treatment and FUS neuromodulation. FUS neuromodulation is a non-invasive technology capable of precisely targeting deep brain regions. It has shown promise in preclinical studies for reducing motor deficits, modulating neuronal activity, and stimulating dopamine release. In this project, we will explore whether FUS can induce lasting improvements in both functional and structural connectivity, using complementary methods such as fiber photometry to measure neuronal activity and dopamine release, and diffusion-weighted MRI to evaluate structural changes. Key research objectives include: 1. Mapping changes in whole-brain connectivity in the PD model longitudinally and compared to healthy controls. 2. Investigating whether FUS neuromodulation can normalize disrupted connectivity and neuronal activity in PD. 3. Validating FUS-induced changes in connectivity with independent methods such as fiber photometry and structural imaging. By integrating advanced imaging techniques and neuromodulation methods, this project aims to provide a deeper understanding of how PD disrupts brain networks and evaluate the potential of FUS as a therapeutic tool. The findings could contribute to the development of novel treatments for PD and other neurodegenerative disorders.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Elisa Evgenia Konofagou, Ph.D.