Monday, May 19, 2025
5/19/2025
Mechanisms of Noninvasive Ultrasonic Neuromodulation of Parkinsonian Neural Circuits - PROJECT SUMMARY/ABSTRACT: Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to debilitating motor symptoms such as bradykinesia, rigidity, and tremor. Current treatments, such as dopamine replacement therapy and deep brain stimulation, provide symptomatic relief but do not halt disease progression or offer sustained efficacy. Consequently, there is a shift toward non-invasive neuromodulation techniques such as low-intensity focused transcranial ultrasound (TUS). Recent clinical studies, including those by Co-Sponsor Dr. Robert Chen, have shown that theta burst TUS can improve motor symptoms in PD patients by increasing motor cortex excitability and reducing bradykinesia. However, the precise mechanisms by which TUS modulates neural activity and cellular dynamics remain unclear. Our recent research using cellular calcium imaging demonstrated that TUS at specific pulse repetition frequencies (PRFs) can selectively activate neuron populations in the motor cortex of awake mice, indicating that TUS can precisely influence neural circuits. The goal of this proposal is to investigate how TUS modulates neuronal activity with subcellular spatial resolution and millisecond temporal resolution in the awake mammalian brain. First, we will examine how different TUS PRFs modulate the membrane voltage of individual neurons in the motor cortex and striatum of awake mice using kilohertz voltage imaging. We hypothesize that TUS will effectively entrain neuronal oscillations and modulate membrane voltage, providing the first direct experimental evidence on how TUS modulates individual neurons in the awake mammalian brain. Our preliminary results show that TUS can entrain individual neuron membrane voltage in the motor cortex at 10 Hz and 40 Hz (Aim 1). Secondly, I will directly measure the effect of theta burst (5 Hz PRF, used clinically by Dr. Chen) and beta burst (10 Hz in mice) TUS on dopamine terminals in the striatum and its downstream targets, the striatal cholinergic interneurons using simultaneous calcium and voltage imaging. By targeting TUS to the cortico-basal ganglia-thalamic loop, we aim to demonstrate how TUS influences dopaminergic transmission and neuronal dynamics, hypothesizing that TUS leads to simultaneous activation of pre-synaptic dopamine terminals and post-synaptic cholinergic interneurons (Aim 2). Such results will provide direct experimental evidence on the pre- and post-synaptic effect of TUS, providing important insights on the fundamental principles underlying TUS neuromodulation. Finally, we will explore the effects of TUS on behavior and neuronal activity in a PD mouse model. Using a dopamine depletion PD model, we will assess TUS-evoked changes in dopamine terminals, cholinergic interneuron membrane voltage, locomotion, and dopamine neuron survival. We anticipate that TUS at theta frequencies will improve motor function and enhance dopamine neuron survival (Aim 3). This research will provide critical insights into the mechanisms of TUS neuromodulation, paving the way for its clinical application in PD treatment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).