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Optimizing Parameters of Transcranial Temporal Interference Stimulation for Spinocerebellar Ataxia Type 3

2026年8月31日 更新者：Xinyuan Chen、First Affiliated Hospital of Fujian Medical University

Efficacy and Safety of Transcranial Temporal Interference Stimulation of the Cerebellar Dentate Nucleus Using Individualized Head Modeling in Patients With Spinocerebellar Ataxia Type 3

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.

研究概览

地位

尚未招聘

条件

干预/治疗

详细说明

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.

研究类型

介入性

注册 (估计的)

24

阶段

  • 不适用

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习联系方式

研究联系人备份

学习地点

  • 中国
    • Fujian
      • Fuzhou、Fujian、中国
        • Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical University
        • 接触：

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

  • 成人
  • 年长者

接受健康志愿者

不

描述

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.

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：治疗
  • 分配：非随机化
  • 介入模型：顺序分配
  • 屏蔽：单身的

武器和干预

参与者组/臂
干预/治疗
实验性的：30 Hz Difference Frequency tTIS
Transcranial Temporal Interference Stimulation (tTIS) uses a difference frequency (Δf) of 30 Hz.
设备：Transcranial Temporal Interference Stimulation (tTIS)

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.
实验性的：40 Hz Difference Frequency tTIS
Transcranial Temporal Interference Stimulation (tTIS) uses a difference frequency (Δf) of 40 Hz.
设备：Transcranial Temporal Interference Stimulation (tTIS)

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.
实验性的：70 Hz Difference Frequency tTIS
Transcranial Temporal Interference Stimulation (tTIS) uses a difference frequency (Δf) of 70 Hz.
设备：Transcranial Temporal Interference Stimulation (tTIS)

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.

研究衡量的是什么？

主要结果指标

结果测量
措施说明
大体时间
Safety: Incidence of Dose-Limiting Toxicity (DLT)
大体时间：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
At any point during or immediately following intervention on day of tTIS application
Efficacy: To assess the proportion of patients with SARA improvement (decrease) of at least 1.5 from baseline after 5 days
大体时间：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.
Baseline and within 24 hours after completing the 5-day tTIS treatment
Comprehensive Benefit-Risk: Utility
大体时间：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.
Within 24 hours after completing the 5-day tTIS treatment

其他结果措施

结果测量
措施说明
大体时间
The International Cooperative Ataxia Rating Scale (ICARS)
大体时间：Baseline and within 24 hours after completing the 5-day tTIS treatment

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.
Baseline and within 24 hours after completing the 5-day tTIS treatment
The European Quality of Life 5-Dimension (EQ-5D)
大体时间：Baseline and within 24 hours after completing the 5-day tTIS treatment

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.
Baseline and within 24 hours after completing the 5-day tTIS treatment
Patient Global Impression of Change (PGI-C)
大体时间：Within 24 hours after completing the 5-day tTIS treatment

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 24 hours after completing the 5-day tTIS treatment
Clinical Global Impression of Change (CGI-C)
大体时间：Within 24 hours after completing the 5-day tTIS treatment

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 24 hours after completing the 5-day tTIS treatment
Change in Multimodal Magnetic Resonance Imaging (MRI) Parameters
大体时间：Baseline and within 24 hours after completing the 5-day tTIS treatment
Multimodal magnetic resonance imaging (MRI), including structural MRI (sMRI), resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI), is performed to evaluate cerebral structural and functional alterations.
Baseline and within 24 hours after completing the 5-day tTIS treatment
Functional Near-Infrared Spectroscopy (fNIRS) assesses hemodynamic changes
大体时间：Baseline and within 24 hours after completing the 5-day tTIS treatment

Functional Near-Infrared Spectroscopy (fNIRS) assesses hemodynamic changes by measuring regional cerebral oxygenation in the cerebellar and motor cortical regions.

Changes in oxygenation signals reflect alterations in regional neural activity through neurovascular coupling.
Baseline and within 24 hours after completing the 5-day tTIS treatment

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

First Affiliated Hospital of Fujian Medical University

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (估计的)

2026年8月7日

初级完成 (估计的)

2026年11月30日

研究完成 (估计的)

2027年2月28日

研究注册日期

首次提交

2026年7月29日

首先提交符合 QC 标准的

2026年7月31日

首次发布 (实际的)

2026年8月4日

研究记录更新

最后更新发布 (实际的)

2026年9月1日

上次提交的符合 QC 标准的更新

2026年8月31日

最后验证

2026年8月1日

更多信息

与本研究相关的术语

关键字

其他相关的 MeSH 术语

其他研究编号

  • MRCTA,ECFAH of FMU[2026]803

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)？

不

药物和器械信息、研究文件

研究美国 FDA 监管的药品

不

研究美国 FDA 监管的设备产品

不

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