Spinocerebellar Ataxia Type 3
Conditions
Keywords
Transcranial Temporal Interference stimulation, Spinocerebellar ataxia type 3, Cerebellar dentate nucleus, Stimulation difference frequency, Individualized head modeling
Brief summary
The purpose of this research study is to identify the optimal biological dose for tTIS that targets DN in SCA3 while achieving the best possible balance between therapeutic efficacy and safety.
Detailed description
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN3 gene. Selective degeneration of neurons in the cerebellar dentate nucleus (DN) leads to abnormal cerebellar outflow circuitry and impaired motor control, resulting in progressive gait ataxia, dysarthria and other motor symptoms. Current treatments are symptomatic only, with no disease-modifying therapies available. Deep brain stimulation targeting the dentate nucleus has shown efficacy but is invasive and associated with significant adverse events. Transcranial temporal interference stimulation (tTIS) enables non-invasive, deep and spatially precise neuromodulation. It has been applied in various neurological and psychiatric disorders with favorable safety and efficacy, demonstrating potential for neuromodulation of deep cerebellar circuits. This phase I/II adaptive dose-finding prospective interventional study evaluates the safety and efficacy of tTIS targeting the cerebellar dentate nucleus in patients with spinocerebellar ataxia type 3. Using MRI-derived individualized head models and real-time neuronavigation, the study employs a utility-based Bayesian optimal interval (U-BOIN) design with three difference frequencies: 30 Hz, 40 Hz, and 70 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 tTIS sessions over two consecutive weeks, with one session daily. Motor function, balance function, activities of daily living, and multimodal magnetic resonance imaging are evaluated before the first treatment session and after the final treatment session.
Interventions
Participants assigned to this intervention arm receive transcranial temporal interference stimulation (tTIS) with a difference frequency (Δf) of 30Hz/40Hz/70 Hz. Before treatment, individualized electric field modeling is performed based on each participant's 3D-T1 MRI data to optimize electrode placement and stimulation parameters. The stimulation target is the bilateral cerebellar dentate nuclei. A personalized finite element head model is generated, and electrode positions are determined through simulation-based optimization to achieve focused interference electric fields at the target region. During each treatment session, tTIS is delivered using two carrier frequencies of 2000 Hz and 2030Hz/2040Hz/2070 Hz, with a current intensity of 2.0 mA (zero-to-peak). Each session lasts 20 minutes. Treatment is administered twice daily, 5 days per week, for a total of 10 sessions.
Sponsors
First Affiliated Hospital of Fujian Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. A physician-diagnosed SCA3 according to diagnostic criteria, with definite clinical symptoms and confirmed genetic testing; 2. Age 18-75 years; 3. Baseline total score of SARA: 8-30 points (inclusive); SARA gait function subscore: 2-6 points (inclusive); 4. Willing to participate and provide informed consent; 5. Have a reliable caregiver available; 6. No severe cognitive impairment that would preclude reliable reporting of adverse events or efficacy during treatment.
Exclusion criteria
1. History of seizures or convulsions, or a seizure within 6 months prior to enrolment; 2. History of severe traumatic brain injury or intracranial neurosurgery; 3. Presence of cardiac pacemakers, cochlear implants, intracranial implanted electronic devices, or other MRI-contraindicated ferromagnetic implants; 4. Severe cognitive impairment (Mini-Mental State Examination \[MMSE\] score ≤ 9) or severe visual, auditory, or speech dysfunction preventing cooperation with scale assessments and study procedures; 5. Pregnant or lactating women, or women of childbearing age not using reliable contraception; 6. Previous neuromodulation treatment (e.g., rTMS or tDCS) within the past year; 7. Skin breakdown or inflammation at the electrode placement site, or known allergy to conductive gel or electrode patch adhesives; 8. Currently participating in other interventional clinical trials, or planning to participate in other trials that might affect the outcome assessment of this study during the study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Incidence of Dose-Limiting Toxicity (DLT) | At any point during or immediately following intervention on day of tTIS application | DLT event is defined as any one of the following 5 categories: 1. Grade Ⅱ (moderate) or higher adverse events per the NCI-CTCAE grading criteria\[1\] that require topical or non-invasive intervention, such as skin burns (skin breakdown, blister formation); 2. Clinically observable seizures during stimulation; 3. Severe headache with vomiting, confusion, or severe dizziness leading to syncope; 4. Severe sleep disturbance with psychiatric abnormalities (anxiety, depression, hallucinations, etc.); 5. New brain lesions on imaging, or decreased apparent diffusion coefficient (ADC) values in the subcortex beneath the stimulation site. References \[1\] Antal A, et al. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines (2017-2025: An update) - endorsed by the European Society for Brain Stimulation (ESBS) and by the International Federation for Clinical Neurophysiology (IFCN). Clin Neurophysiol. 2026. 184: 2111436 |
| Efficacy: To assess the proportion of patients with SARA improvement (decrease) of at least 1.5 from baseline after 5 days | Baseline and within 24 hours after completing the 5-day tTIS treatment | The Scale for the Assessment and Rating of Ataxia (SARA) evaluates the severity of ataxia symptoms, including gait, posture, speech, and limb kinetic functions. Score range: 0-40 Higher scores indicate more severe ataxia. Response is defined as a reduction of ≥1.5 points from baseline. |
| Comprehensive Benefit-Risk: Utility | Within 24 hours after completing the 5-day tTIS treatment | 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. |
Countries
China
Contacts
CONTACTXin-Yuan Chen
CONTACTKai-Xiong Chen
Outcome results
None listed