dACC-Targeted Temporal Interference for Negative and Cognitive Symptoms in Schizophrenia

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.