Optimizing Parameters of Low-Intensity Focused Ultrasound for Pallidal Modulation in Huntington's Disease

Low-Intensity Focused Ultrasound Stimulation of the External Globus Pallidus in Huntington's Disease: A Phase I/II Safety and Feasibility Trial

The purpose of this research study is to determine the optimal pulse repetition frequency of low-intensity focused ultrasound that is safe and effective in improving motor symptoms in patients with Huntington's disease.

Study Overview

• Status: Recruiting
• Conditions: Huntington Disease
• Intervention / Treatment: Device: Low-Intensity Focused Ultrasound Stimulation（LIFU）

Detailed Description

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by HTT gene CAG repeat expansion. Early degeneration of striatal neurons projecting to the external globus pallidus (GPe) leads to abnormal basal ganglia circuitry and impaired motor control, resulting in involuntary movements and other motor symptoms. Current treatments are symptomatic only, with no disease-modifying therapies available. Deep brain stimulation targeting the globus pallidus has shown efficacy but is invasive and associated with significant adverse events.

Low-intensity focused ultrasound (LIFU) enables non-invasive, deep, and millimeter-precise neuromodulation. It has been applied in various neurological and psychiatric disorders with favorable safety and efficacy, demonstrating potential for neuromodulation of basal ganglia circuits.

This phase I/II adaptive dose-finding prospective interventional study evaluates the safety and efficacy of LIFU targeting the external globus pallidus in patients with Huntington's disease. Using MRI-derived individualized head models and real-time neuronavigation, the study employs a Bayesian optimal interval (BOIN) design with three pulse repetition frequencies: 10 Hz, 50 Hz, and 100 Hz. Patients are enrolled in sequential cohorts of three, with dose escalation guided by a utility-based approach integrating safety and efficacy data. Each patient receives ten LIFU sessions over five consecutive days, with two sessions daily. Motor function, cognitive function, functional assessments, and magnetic resonance imaging are evaluated before the first treatment session and after the final treatment session.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xin-Yuan Chen; Phone Number: +86 15005065282; Email: fychenxinyuan@fjmu.edu.cn
• Study Contact Backup: Name: Li-Zhu Wu; Phone Number: +86 18459867658; Email: 1809225097@qq.com

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China
      • Recruiting
      • Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical University
      • Contact: Xin-Yuan Chen; Phone Number: +86 15005065282; Email: fychenxinyuan@fjmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18 to 75 years (inclusive)
2. Genetically confirmed Huntington's disease with HTT CAG repeat length of 40 or greater
3. Unified Huntington's Disease Rating Scale Total Maximal Chorea score of 8 or higher on a scale of 0 to 28, with higher scores indicating more severe chorea
4. Huntington's Disease Integrated Staging System stage 2 or 3
5. Willing to participate and provide informed consent
6. Have a reliable caregiver available
7. No severe cognitive impairment that would preclude reliable reporting of adverse events or efficacy during treatment

Exclusion Criteria:

1. History of self-injury, aggressive behavior, or unstable psychiatric disorders
2. History of head injury or neurosurgical procedure
3. Presence of intracranial implants, metallic foreign bodies, cochlear implants, or cardiac pacemakers
4. Severe systemic disease, pregnancy, or breastfeeding
5. Contraindications to magnetic resonance imaging, ultrasound, or anesthesia
6. Prior treatment with electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, or other neuromodulation therapies within the past 3 years
7. Severe brain atrophy with unclear external globus pallidus structure on MRI
8. Concurrent participation in another interventional clinical trial
9. Any other condition that, in the opinion of the investigator, would preclude participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 10 Hz LIFU Group; Low-Intensity Focused Ultrasound (LIFU), PRF 10 Hz	Device: Low-Intensity Focused Ultrasound Stimulation（LIFU）; This is not a traditional three-arm parallel trial but a Stage I/II dose-finding study using an adaptive design. Participants are dynamically assigned to three pulse repetition frequency levels (10 Hz, 50 Hz, 100 Hz) based on predefined rules, rather than fixed randomization. The study adopts a two-stage utility-based Bayesian optimal interval (U-BOIN) design: Stage I: Dose decisions are based solely on dose-limiting toxicity (DLT) incidence. Participants are enrolled in cohorts of three. Based on observed DLTs, the next cohort's dose is determined (escalate/stay/de-escalate). Stage II: When any dose group reaches 6 participants or the highest dose is explored, safety and efficacy data are integrated to calculate a utility value. Subsequent cohorts are assigned to the dose group with the highest utility value. The study stops when any dose group reaches 12 participants or total enrollment reaches 24. Not all three dose levels may be utilized. Allocation is not fixed a priori.
Experimental: 50 Hz LIFU Group; Low-Intensity Focused Ultrasound (LIFU), PRF 50 Hz	Device: Low-Intensity Focused Ultrasound Stimulation（LIFU）; This is not a traditional three-arm parallel trial but a Stage I/II dose-finding study using an adaptive design. Participants are dynamically assigned to three pulse repetition frequency levels (10 Hz, 50 Hz, 100 Hz) based on predefined rules, rather than fixed randomization. The study adopts a two-stage utility-based Bayesian optimal interval (U-BOIN) design: Stage I: Dose decisions are based solely on dose-limiting toxicity (DLT) incidence. Participants are enrolled in cohorts of three. Based on observed DLTs, the next cohort's dose is determined (escalate/stay/de-escalate). Stage II: When any dose group reaches 6 participants or the highest dose is explored, safety and efficacy data are integrated to calculate a utility value. Subsequent cohorts are assigned to the dose group with the highest utility value. The study stops when any dose group reaches 12 participants or total enrollment reaches 24. Not all three dose levels may be utilized. Allocation is not fixed a priori.
Experimental: 100 Hz LIFU Group; Low-Intensity Focused Ultrasound (LIFU), PRF 100 Hz	Device: Low-Intensity Focused Ultrasound Stimulation（LIFU）; This is not a traditional three-arm parallel trial but a Stage I/II dose-finding study using an adaptive design. Participants are dynamically assigned to three pulse repetition frequency levels (10 Hz, 50 Hz, 100 Hz) based on predefined rules, rather than fixed randomization. The study adopts a two-stage utility-based Bayesian optimal interval (U-BOIN) design: Stage I: Dose decisions are based solely on dose-limiting toxicity (DLT) incidence. Participants are enrolled in cohorts of three. Based on observed DLTs, the next cohort's dose is determined (escalate/stay/de-escalate). Stage II: When any dose group reaches 6 participants or the highest dose is explored, safety and efficacy data are integrated to calculate a utility value. Subsequent cohorts are assigned to the dose group with the highest utility value. The study stops when any dose group reaches 12 participants or total enrollment reaches 24. Not all three dose levels may be utilized. Allocation is not fixed a priori.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Incidence of Dose-Limiting Toxicity (DLT)	DLT refers to the occurrence of any of the following six events during LIFU treatment: Second-degree scalp burn;; Clinical seizure;; Worsening of chorea or new movement disorder;; Significant deterioration of the patient's mood or mental status (e.g., anxiety, depression, hallucinations, excessive sleepiness);; Severe autonomic dysfunction, such as marked blood pressure fluctuations, abnormal heart rate, or respiratory distress;; Imaging-related safety events: new or significantly enlarged brain edema, new microbleeds, new infarcts, or structural abnormalities in the treatment area on post-treatment cranial MRI compared with baseline, deemed clinically significant by both radiologists and clinicians.	At any point during or immediately following intervention on day of LIFUS application
Efficacy: Change in Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS)	The Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) evaluates motor impairment in Huntington's disease. Score range: 0-124 Higher scores indicate more severe motor impairment Response is defined as a reduction of ≥4 points from baseline.	Baseline and within 2 days after completing the 5-day LIFU treatment
Comprehensive Benefit-Risk: Utility	Utility is a composite measure integrating dose-limiting toxicity (DLT) and efficacy response to quantify the overall benefit-risk balance for each dose group. During the trial, the Utility value for each dose group is dynamically calculated using the U-BOIN design platform. In Stage II, the Utility value determines dose allocation for subsequent cohorts. At study completion, the dose group with the highest Utility value is identified as the optimal biological dose.	Within 2 days after completing the 5-day LIFU treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Global Impression of Change (PGI-C)	The Patient Global Impression of Change (PGI-C) is a patient-reported scale assessing perceived change in overall condition after treatment. Score range: 1-7 Lower scores indicate greater improvement	Within 2 days after completing the 5-day LIFU treatment
Clinical Global Impression of Change (CGI-C)	The Clinical Global Impression of Change (CGI-C) is a clinician-rated scale assessing overall change in the patient's clinical status. Score range: 1-7 Lower scores indicate greater improvement	Within 2 days after completing the 5-day LIFU treatment
Change in Unified Huntington's Disease Rating Scale Chorea Score	The UHDRS Chorea Score evaluates severity of choreiform movements. Score range: 0-28 Higher scores indicate more severe chorea	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Symbol Digit Modalities Test (SDMT)	The Symbol Digit Modalities Test (SDMT) is a cognitive assessment of processing speed and attention. Score range: 0-110 (number of correct matches within 90 seconds) Higher scores indicate better cognitive function	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Controlled Oral Word Association Test (COWAT)	The Controlled Oral Word Association Test (COWAT) assesses verbal fluency and executive function. Score range: 0-unlimited (total number of words generated across three trials, each 60 seconds) Higher scores indicate better verbal fluency and executive function	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Stroop Interference Test Score	The Stroop Interference Test assesses cognitive inhibition and executive function. Score range: 0-unlimited (number of correct responses on the interference task within a time limit) Higher scores indicate better cognitive function	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Functional Independence Scale	The Functional Independence Scale assesses a patient's level of independence in daily activities. Score range: 0-100 Higher scores indicate greater independence	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Total Functional Capacity (TFC)	The Total Functional Capacity (TFC) scale is a component of the Unified Huntington's Disease Rating Scale (UHDRS) that assesses functional capacity. Score range: 0-13 Higher scores indicate better functional capacity	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Functional Assessment Score	The Functional Assessment Score is a component of the Unified Huntington's Disease Rating Scale (UHDRS) that assesses the patient's ability to perform specific tasks. Score range: 0-25 Higher scores indicate better functional ability	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Serum Neuron-Specific Enolase (NSE)	Serum Neuron-Specific Enolase (NSE) is a biomarker of neuronal injury. Unit of measure: ng/mL Higher levels indicate more neuronal damage	Baseline and within 2 days after completing the 5-day LIFU treatment
Change in Multimodal Magnetic Resonance Imaging (MRI) Parameters	Change from baseline in structural and functional brain connectivity metrics as assessed by multimodal MRIto evaluate the neuromodulatory effects of LIFU.	Baseline and within 2 days after completing the 5-day LIFU treatment

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Fujian Medical University

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2026
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 31, 2026
• First Posted (Actual): April 7, 2026

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Huntington Disease; brain stimulation; low intensity focused ultrasound; ultrasonic stimulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Huntington Disease
• Other Study ID Numbers: MRCTA,ECFAH of FMU[2025]738-1

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