Overview
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.
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.
Eligibility
Inclusion Criteria:
- Aged 18 to 75 years (inclusive)
- Genetically confirmed Huntington's disease with HTT CAG repeat length of 40 or greater
- 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
- Huntington's Disease Integrated Staging System stage 2 or 3
- Willing to participate and provide informed consent
- Have a reliable caregiver available
- No severe cognitive impairment that would preclude reliable reporting of adverse events or efficacy during treatment
Exclusion Criteria:
- History of self-injury, aggressive behavior, or unstable psychiatric disorders
- History of head injury or neurosurgical procedure
- Presence of intracranial implants, metallic foreign bodies, cochlear implants, or cardiac pacemakers
- Severe systemic disease, pregnancy, or breastfeeding
- Contraindications to magnetic resonance imaging, ultrasound, or anesthesia
- 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
- Severe brain atrophy with unclear external globus pallidus structure on MRI
- Concurrent participation in another interventional clinical trial
- Any other condition that, in the opinion of the investigator, would preclude participation
