A Randomized Controlled Trial Exploring the Efficacy of Temporal Interference Stimulation for Negative Symptoms and Cognitive Impairment in Schizophrenia
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 74
- 试验地点
- 2
- 主要终点
- Change in the Positive and Negative Syndrome Scale Negative Symptom Subscale Score
研究概览
简要总结
This randomized, double-blind, sham-controlled trial aims to evaluate the efficacy and safety of dorsal anterior cingulate cortex-targeted temporal interference stimulation in individuals with schizophrenia. Participants will be randomly assigned to receive either active or sham stimulation for 10 sessions over two consecutive weeks. The primary outcome is the change in negative symptoms, assessed using the Negative Symptom Subscale of the Positive and Negative Syndrome Scale. Cognitive performance, detailed dimensions of negative symptoms, psychosocial functioning, quality of life, and treatment-related adverse events will also be evaluated. Neuroimaging assessments will be conducted before and after the intervention to explore potential neural mechanisms underlying the clinical effects of temporal interference stimulation.
详细描述
Background and Scientific Rationale Persistent negative symptoms and cognitive difficulties remain major barriers to recovery in schizophrenia, often showing insufficient improvement with standard antipsychotic treatments. Transcranial temporal interference stimulation (tTIS) represents a novel non-invasive neuromodulation technique capable of reaching deeper brain structures without direct activation of overlying superficial cortical tissue. This trial focuses on targeting the dorsal anterior cingulate cortex (dACC), a critical node in the prefrontal-cingulate-striatal network involved in cognitive control, performance monitoring, and motivational processes. Study Design and Participants This study is a parallel-group, participant- and outcome-assessor-blinded, sham-controlled randomized clinical trial. A total of 74 eligible participants with a confirmed diagnosis of schizophrenia, who exhibit clinically meaningful negative symptoms and objective cognitive impairment, will be enrolled. Participants will be randomly assigned in a 1:1 ratio to receive either active dACC-targeted tTIS or sham stimulation.
ntervention ProceduresActive tTIS: Stimulation is delivered via a NervioX-1000 stimulator using two scalp electrode pairs targeting the dACC. The system applies two high-frequency carrier currents (2000 Hz and 2006 Hz) to generate a lower-frequency 6-Hz amplitude-modulated envelope field at the target region. Current intensity is titrated to participant tolerance and does not exceed 3.6 mA per channel. The treatment course consists of ten 30-minute sessions administered on consecutive weekdays over two weeks. Sham tTIS: The control group receives a sensory-matched simulation utilizing identical electrode montages and visit schedules. To ensure the integrity of the double-blind design, the sham condition features only brief ramp-up and ramp-down periods at the beginning and end of the session to mimic the transient scalp sensations of active treatment, with no continuous current delivered in between. Individualized Optimization: Prior to the intervention, participant-specific finite-element head models are derived from T1-weighted anatomical MRI scans to optimize dACC targeting, guiding candidate electrode positions and electric-field distributions.
Assessments and Outcomes Comprehensive evaluations are conducted at three specific time points: before the first stimulation session (baseline/T0), immediately after the 10-session treatment course (T1), and 4 weeks after treatment completion (T2). Primary Endpoint: The primary objective is to evaluate the change in negative symptom severity, operationalized as the clinician-rated Positive and Negative Syndrome Scale negative symptom subscale (PANSS-NS) score. Secondary Clinical Endpoints: Key secondary measures include overall neurocognitive functioning assessed by the Brief Assessment of Cognition in Schizophrenia (BACS) composite z-score and the dimensional structure of negative symptoms via the Scale for the Assessment of Negative Symptoms (SANS) total score. Broader evaluations incorporate measures of general psychopathology, apathy, anhedonia, social functioning, depression, anxiety, and sleep quality. Behavioral Tracking: Cognitive control, conflict processing, and response inhibition are objectively quantified using computerized Go/No-Go paradigms and the Stroop color-word task. Mechanistic Neuroimaging Exploration: Resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) data are acquired pre- and post-intervention. These exploratory analyses aim to investigate treatment-related neural changes, tracking alterations in spontaneous brain activity and structural/functional connectivity to provide preliminary evidence of circuit-level mechanisms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All of the following criteria must be satisfied for enrolment:
- •A confirmed diagnosis of schizophrenia established according to the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5);
- •Age between 18 and 65 years, regardless of sex, with completion of at least junior secondary education and the capacity to undergo neurocognitive testing;
- •Clinically meaningful negative symptoms, operationalized as a PANSS negative symptom subscale (PANSS-NS) total score ≥ 20 with a rating of ≥ 3 on a minimum of one individual PANSS-NS item ; the PANSS positive symptom subscale score must additionally not exceed 19;
- •Objective cognitive impairment evidenced by an age- and sex-adjusted composite z-score of ≤ -1.0 on the Chinese version of the Brief Assessment of Cognition in Schizophrenia (BACS), reflecting performance at least one standard deviation below normative values derived from Mandarin-speaking populations;
- •Maintenance on an unchanged antipsychotic regimen - with no modification to medication type or dose - for at least 30 days prior to informed consent and continuing throughout the trial;
- •Voluntary agreement to participate, documented by written informed consent following thorough explanation of study objectives and procedures; where applicable, a legally authorized representative may provide or co-sign consent.
排除标准
- •Individuals will be ineligible if any of the following conditions apply:
- •A concurrent psychiatric diagnosis requiring active clinical management, including but not limited to major depressive episode or bipolar disorder, or the presence of a comorbid neurological disorder or serious physical illness;
- •Current or past substance use disorder, encompassing problematic consumption of alcohol or illicit substances;
- •A documented seizure disorder or marked electroencephalographic abnormalities, particularly epileptiform activity;
- •Evidence of structural brain pathology, including organic lesions, prior traumatic brain injury, or previous neurosurgical intervention;
- •Presence of ferromagnetic implants or any other contraindication to MRI or tTIS exposure, including intracranial metallic clips, implanted cardiac devices, or cochlear implants;
- •Current use of glucocorticoids or other pharmacological agents known to meaningfully alter cortical excitability;
- •Prior exposure to any neuromodulatory intervention - including modified electroconvulsive therapy (MECT), repetitive transcranial magnetic stimulation (TMS), or transcranial direct current stimulation (tDCS) - within the 30 days preceding enrolment.
研究组 & 干预措施
Sham tTIS
Participants assigned to this arm will receive sham transcranial temporal interference stimulation (tTIS). The sham condition will mirror the active intervention with respect to electrode montage, visit schedule, and session length (30 minutes per session across 10 consecutive weekdays). To reproduce the transient scalp sensations associated with treatment initiation and termination, brief ramp-up and ramp-down periods will be applied at the beginning and end of each visit. Between these two phases, no continuous current will be delivered.
干预措施: Sham Temporal Interference Stimulation (Device)
Active tTIS
Participants assigned to this arm will receive active transcranial temporal interference stimulation (tTIS) targeting the dorsal anterior cingulate cortex (dACC). The stimulation will be delivered using two scalp electrode pairs operating at 2000 Hz and 2006 Hz, resulting in a 6-Hz envelope frequency. Current intensity will be titrated to participant tolerance and will not exceed 3.6 mA per channel. The intervention will be administered for 30 minutes per session across 10 consecutive weekdays. Each session begins with a 10-second current ramp-up and ends with a 10-second ramp-down.
干预措施: Temporal Interference Stimulation (Device)
结局指标
主要结局
Change in the Positive and Negative Syndrome Scale Negative Symptom Subscale Score
时间窗: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
The Positive and Negative Syndrome Scale Negative Symptom Subscale (PANSS-NS) consists of 7 items. Each item is rated from 1 to 7, yielding a total score ranging from 7 to 49. Higher scores indicate greater severity of negative symptoms. The change from baseline to immediately after the intervention will be compared between the active and sham stimulation groups.
次要结局
- Change in the Scale for the Assessment of Negative Symptoms Total Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in the Temporal Experience of Pleasure Scale Total Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in the Personal and Social Performance Scale Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in the World Health Organization Quality of Life-BREF Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Incidence of Treatment-Emergent Adverse Events(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in Patient Health Questionnaire-9 (PHQ-9) Total Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Baseline Credibility/Expectancy Questionnaire (CEQ) Score(Baseline before the first stimulation session)
- Change in the Positive and Negative Syndrome Scale (PANSS) Total Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in Resting-State Functional Connectivity (rs-fMRI)(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in Go/No-Go Task Accuracy(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in Generalized Anxiety Disorder-7 (GAD-7) Total Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in Pittsburgh Sleep Quality Index (PSQI) Global Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in Stroop Color-Word Task Interference Effect(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in the Positive and Negative Syndrome Scale Positive Symptom Subscale Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in White Matter Structural Connectivity via Diffusion Tensor Imaging (DTI)(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in the Brief Assessment of Cognition in Schizophrenia Composite Score(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
- Change in the Apathy Evaluation Scale Total Scor(Baseline, immediately after the 2-week intervention, and at the 4-week follow-up)
研究者
Fan Wu
Attending Psychiatrist
Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University