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

This study is investigating the use of transcranial ultrasound stimulation (TUS) on the Pedunculopontine nucleus (PPN) in changing freezing of gait in people with Parkinson's disease. The PPN is noted to be involved in voluntary movements, locomotion, and muscle tone. This will be assessed by patient-reported outcomes and analyzing the gait. The study will also investigate the effects of the stimulation on the PPN and surrounding connectivity by using magnetic resonance imaging (MRI).

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; Freezing of Gait Symptoms in Parkinson Disease
• Intervention / Treatment: Device: Excitatory Stimulation; Device: Inhibitory Stimulation; Device: Sham

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julian Kwok; Phone Number: 2708 416-603-5800; Email: julian.kwok@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Recruiting
      • Toronto Western Hospital
      • Contact: Julian Kwok; Phone Number: 2708 416-603-5800; Email: julian.kwok@uhn.ca
      • Principal Investigator: Robert Chen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 18-90 years of age
• Confirmed diagnosis of a movement disorder with Freezing of Gait
• Stable dopaminergic medication dose for a minimum of 4 weeks

Exclusion Criteria:

• History of stroke or seizure
• Comorbid dementia
• Scored below 22 on the Montreal Cognitive Assessment (MoCA)
• Has intracranial implant(s) or device(s)
• Has an implanted cardiac pacemaker or implantable cardioverter-defibrillator (ICD)
• Has a previous surgical intervention to treat the movement disorder such as lesioning or a DBS system in place.
• Presence of metal implanted in body that is contraindicated in TMS/MRI
• Pregnancy
• Major depression/psychiatric disorder that in the opinion of the Investigator will affect patient's understanding of study procedures and willingness to abide by all procedures during the course of the study
• Is on antipsychotics, marijuana, or other recreational drugs that affect the nervous system
• Major musculoskeletal or neuromuscular disease or disorder of the hands, wrists and limbs
• Major systemic illness or infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1; All participants will receive excitatory, inhibitory, and sham stimulation to the PPN. The order that they receive it is randomized across Visits 2 - 4. All stimulation within a visit will be the same.	Device: Excitatory Stimulation; Excitatory Stimulation to the PPN; Device: Inhibitory Stimulation; Inhibitory Stimulation to the PPN; Device: Sham; Sham stimulation to PPN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New Freezing of Gait Questionnaire		Occurs twice at Visits 2, 3, and 4. For each of those visits, it will be conducted once before stimulation and another after stimulation.
Timed Up-and-Go Task		Occurs twice at Visits 2, 3, and 4. For each of those visits, it will be conducted once before stimulation and another after stimulation.
ZenoTM Walkway	Mat that detects pressure data during standing and walking to evaluate gait such as speed, profile, step time, step length, strid time, stride length, and more.	Occurs twice at Visits 2, 3, and 4. For each of those visits, it will be conducted once before stimulation and another after stimulation.

Collaborators and Investigators

• Sponsor: Robert Chen
• Investigators: Principal Investigator: Robert Chen, MD, University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: February 22, 2026
• First Submitted That Met QC Criteria: July 5, 2026
• First Posted (Actual): July 10, 2026

Study Record Updates

• Last Update Posted (Actual): July 10, 2026
• Last Update Submitted That Met QC Criteria: July 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parkinson Disease
• Other Study ID Numbers: 20-5740 #8

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No