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.
A physician-diagnosed SCA3 according to diagnostic criteria, with definite clinical symptoms and confirmed genetic testing;
Age 18-75 years;
Baseline total score of SARA: 8-30 points (inclusive); SARA gait function subscore: 2-6 points (inclusive);
Willing to participate and provide informed consent;
History of seizures or convulsions, or a seizure within 6 months prior to enrolment;
History of severe traumatic brain injury or intracranial neurosurgery;
Presence of cardiac pacemakers, cochlear implants, intracranial implanted electronic devices, or other MRI-contraindicated ferromagnetic implants;
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;
Sequential
Transcranial Temporal Interference Stimulation (tTIS)
DeviceParticipants 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.
Safety: Incidence of Dose-Limiting Toxicity (DLT)
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
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
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.
The International Cooperative Ataxia Rating Scale (ICARS)
The International Cooperative Ataxia Rating Scale (ICARS) assesses the severity of cerebellar ataxia across four subscales: posture and gait disturbances, limb kinetic functions, speech disorders, and oculomotor disorders. Total score range: 0-100 Higher scores indicate more severe ataxia impairment.
The European Quality of Life 5-Dimension (EQ-5D)
The European Quality of Life 5-Dimension Utility Index Score (EQ-5D Utility Index) assesses health-related quality of life across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Participants' health states are described using a five-digit code, with values ranging from 11111 (no problems in any dimension) to 33333 (extreme problems in all dimensions). The health state code is converted into a utility index score using population-specific preference weights. The score is anchored at 1.0 for full health, with lower values indicating poorer health status; values below 0 may occur for health states considered worse than death depending on the applicable value set.
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
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
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