Pedunculopontine Nucleus Transcranial Ultrasound Stimulation as a Treatment of Freezing of Gait in Parkinson's Disease

To evaluate the safety, tolerability and effectiveness of Pedunculopontine nucleus transcranial ultrasound stimulation (PPN-TUS) in reducing freezing of gait (FOG) in Parkinson's disease (PD) patients using advanced gait analyses and patient-reported quality of life outcomes. Investigate changes in brain functional connectivity caused by PPN-TUS using resting state functional magnetic (rsfMRI) and Arterial Spin Labelling (ASL). The study will recruit 25 PD patients with FOG and 25 healthy controls, matched for age and sex, in a randomized, cross-over design. Visit 1: Obtain anatomical MRI for TUS planning and rsfMRI for functional connectivity analysis in PD patients with FOG. This session also includes baseline clinical evaluation, kinematic gait analysis in the ON-medication state. Between Visits 1 and 2: Structural MRI data of each participant will be processed using BabelBrain software to configure the TUS parameters. The depth required to stimulate the PPN will be calculated, and a precise model of the pressure distribution and thermal dynamics of the TUS based on individual skull thickness and geometry will be created. Visits 2-4: The TUS will be applied using a 4-element NeuroFUS LT system (BrainBox Neuro Ltd., UK). This system allows for adjustments of the focus point of the ultrasound, which in essence changes the stimulation depth. Participants receive excitatory, inhibitory, or sham TUS for three sets of sonication, targeting the PPN bilaterally, with each stimulation set separated by one hour (accelerated TUS). We will be using excitatory and inhibitory protocols since DBS has complex excitatory and inhibitory effects and it is not known whether excitatory or inhibitory protocols will be most effective. The type of sonication (excitatory, inhibitory, or sham) will be the same within a visit but different across visits. The visits will be spaced at least a week apart to allow for a washout period. The stimulation will target both left and right PPN, sonicating each side sequentially with a 1-minute break in between to allow adjustment of the transducer. The order of which side is to be stimulated first will be counterbalanced across participants. Both hemispheres will be stimulated with the same condition (e.g., both sham if it is a sham session). Functional connectivity using rsfMRI and clinical assessments will be measured pre- and post-sonication. Healthy subjects will undergo MRI study in one session to establish the normal range for rsfMRI and CBF measured by ASL. This will allow us to establish whether the rsfMRI and CBF findings in PD patients at baseline are normal and whether TUS of PPN normalize these patterns.