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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
74
Participants will receive active temporal interference stimulation targeting the dorsal anterior cingulate cortex. Two high-frequency alternating currents at 2000 Hz and 2006 Hz will be delivered using an individualized electrode configuration determined by electric field modeling. Each session will last 30 minutes. Treatment will be administered five times per week for two consecutive weeks, for a total of 10 sessions.
Participants will receive sham temporal interference stimulation using the same electrode placement and session schedule as the active stimulation group. Brief ramp-up and ramp-down periods will be applied to mimic the sensations associated with active stimulation, but sustained temporal interference stimulation will not be delivered. Each session will last 30 minutes. Treatment will be administered five times per week for two consecutive weeks, for a total of 10 sessions.
Shanghai Pudong New Area Mental Health Center
Shanghai, China
RECRUITINGChange in the Positive and Negative Syndrome Scale Negative Symptom Subscale Score
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.
Time frame: 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
The Brief Assessment of Cognition in Schizophrenia (BACS) is a multidomain battery assessing overall neurocognitive functioning, including verbal learning and memory, working memory, psychomotor speed, verbal fluency, sustained attention and processing speed, and executive function. The constituent subtests include the List Learning Test, Digit Sequencing Task, Token Motor Task, Category Instances and Controlled Oral Word Association Test, Symbol Coding Task, and Tower of London Test. Domain scores are aggregated into a single composite z-score standardized against age- and sex-matched normative data. Lower values reflect greater cognitive impairment.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in the Scale for the Assessment of Negative Symptoms Total Score
The Scale for the Assessment of Negative Symptoms (SANS) provides a detailed characterization of negative symptomatology. It comprises 25 clinician-rated items spanning five domains: affective flattening or blunting, alogia, avolition-apathy, anhedonia-asociality, and attentional impairment. Each item is rated on a six-point scale ranging from 0 to 5. The item scores are summed to generate a total score, where higher values denote a more severe negative symptom profile.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in the Apathy Evaluation Scale Total Scor
The Apathy Evaluation Scale (AES-S) is a self-rated measure used to evaluate apathy. The scale consists of 18 items that probe the cognitive, affective, and behavioral dimensions of apathetic experiences over the preceding four weeks. Responses are summed to yield a total score ranging from 0 to 72. Higher scores indicate more severe apathy, meaning a worse outcome.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in the Temporal Experience of Pleasure Scale Total Score
The Temporal Experience of Pleasure Scale (TEPS) is used to evaluate hedonic experience by separately indexing the anticipatory and consummatory components of pleasure. The scale consists of 20 items, with each item rated on a six-point Likert scale ranging from 1 ("very false for me") to 6 ("very true for me"). Following the reverse-scoring of designated items, responses are summed to yield a total score, where lower values indicate greater anhedonia. Therefore, higher scores indicate a better outcome.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in the Personal and Social Performance Scale Score
The Personal and Social Performance Scale (PSP) is a clinician-administered tool used to evaluate real-world social functioning. It appraises four behavioral domains: engagement in socially constructive activities, interpersonal relationships, self-care, and disruptive or aggressive conduct. The total score spans from 1 to 100, with higher scores reflecting superior functional status.
Time frame: 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
Subjective quality of life will be assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF). This multidimensional instrument covers four domains: physical health, psychological well-being, social relationships, and environment. Higher scores within each domain reflect a more positive self-reported quality of life, meaning a better outcome.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Incidence of Treatment-Emergent Adverse Events
The incidence and severity of adverse events will be assessed throughout the study period, from baseline to the 4-week follow-up, to evaluate treatment safety and tolerability.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in Patient Health Questionnaire-9 (PHQ-9) Total Score
Current depressive symptomatology will be quantified using the Patient Health Questionnaire-9 (PHQ-9). It contains nine items, each rated on a scale from 0 to 3, yielding an aggregate score ranging from 0 to 27. Elevated scores reflect a more severe depressive burden.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Baseline Credibility/Expectancy Questionnaire (CEQ) Score
Participants' perceptions of the credibility of the intervention and their expectations regarding treatment benefit will be assessed using an adapted version of the Credibility/Expectancy Questionnaire (CEQ). Higher scores indicate greater perceived credibility and higher expectations for treatment benefit, which represents a more positive expectancy.
Time frame: Baseline before the first stimulation session
Change in the Positive and Negative Syndrome Scale (PANSS) Total Score
Broader psychopathological status will be assessed using the 30-item Positive and Negative Syndrome Scale (PANSS). Each of the 30 items is rated on a 1 to 7 ordinal scale, yielding a total score ranging from a minimum of 30 to a maximum of 210. Higher scores denote a more severe psychopathological profile, meaning a worse outcome.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in Resting-State Functional Connectivity (rs-fMRI)
Exploratory analyses will investigate treatment-related neural changes using resting-state functional MRI (rs-fMRI).
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in Go/No-Go Task Accuracy
Response inhibition will be evaluated with the computerized Go/No-Go paradigm. The derived index reported here is overall accuracy, calculated as the percentage of correct responses. Higher accuracy percentages indicate better response inhibition and cognitive control, meaning a better outcome.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in Generalized Anxiety Disorder-7 (GAD-7) Total Score
Anxiety over the preceding two weeks will be indexed by the Generalized Anxiety Disorder-7 scale (GAD-7). It comprises seven items, each scored from 0 to 3, which are summed to a maximum total score of 21. Higher totals denote greater anxiety severity.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in Pittsburgh Sleep Quality Index (PSQI) Global Score
Sleep disturbance will be quantified with the Pittsburgh Sleep Quality Index (PSQI). It is a 19-item self-report measure that generates a composite global score ranging from 0 to 21. Higher values indicate worse sleep quality.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
Change in Stroop Color-Word Task Interference Effect
Conflict processing and cognitive control will be evaluated using the Stroop color-word task. The primary metric evaluated is the Stroop interference effect, calculated based on the differences in reaction times between congruent and incongruent trials. A lower interference effect score indicates better conflict processing and cognitive control, meaning a better outcome.
Time frame: 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
The positive symptom subscale of the 30-item Positive and Negative Syndrome Scale (PANSS) will be evaluated to assess broader psychopathological status. Clinician-assigned ratings for the items in this subscale are each anchored on a 1 to 7 ordinal scale. Higher scores denote a more severe positive symptom profile, meaning a worse outcome.
Time frame: 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)
Exploratory analyses will investigate treatment-related neural changes using diffusion tensor imaging (DTI). Changes in white matter structural connectivity will be evaluated to assess neural target engagement.
Time frame: Baseline, immediately after the 2-week intervention, and at the 4-week follow-up
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