The goal of this clinical trial is to learn if sequential dual-site accelerated theta burst stimulation (SD-aTBS) targeting the frontoparietal network and default mode network works to improve cognitive function in adults with schizophrenia. It will also learn about the safety of SD-aTBS. The main questions it aims to answer are:
Does SD-aTBS improve cognitive function in participants with schizophrenia? What are the neurobiological mechanisms (brain network and synaptic plasticity changes) underlying the effects of SD-aTBS? Researchers will compare real SD-aTBS to sham stimulation to see if SD-aTBS is effective and safe for treating cognitive impairment in schizophrenia.
Participants will:
Receive real SD-aTBS or sham stimulation for 10 consecutive working days Complete clinical symptom assessments, cognitive function tests, MRI scans, and EEG recordings at baseline, after treatment, and 1 month after treatment Undergo SV2A-PET scans at baseline and 1 month after treatment
Age 18-35 years.
Meets the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed by the Structured Clinical Interview for DSM-5 (SCID-5).
Duration of illness ≤ 8 years.
Taking no more than 2 antipsychotic medications, with a stable antipsychotic dose for at least 4 weeks prior to enrollment, and no expected change in the medication regimen throughout the treatment and follow-up period.
Current or lifetime co-occurrence of any other DSM-5 psychiatric disorder.
Concurrent use of mood stabilizers, antidepressants, or excessive benzodiazepines (lorazepam equivalent > 2 mg/day).
Presence of severe or acute physical illness, including a history of epilepsy, traumatic brain injury, intracranial space-occupying or infectious disease, acute cardiovascular or cerebrovascular disease, acute respiratory disease, or acute hematologic disease.
Any contraindication to transcranial magnetic stimulation (TMS), PET scanning, or magnetic resonance imaging (MRI).
Parallel
Sequential Dual-Site Accelerated Theta Burst Stimulation (SD-aTBS)
DeviceSequential dual-site accelerated theta burst stimulation (SD-aTBS) delivers accelerated theta burst stimulation to two individually targeted brain regions - the frontoparietal network and the default mode network - in a sequential (site-by-site) manner, with stimulation delivered 5 times daily for 10 consecutive working days.
Sham Sequential Dual-Site Accelerated Theta Burst Stimulation
DeviceSham sequential dual-site accelerated theta burst stimulation uses the same coil positioning and stimulation parameters as the active SD-aTBS but delivers no effective cortical stimulation, serving as a sham control
Change in Global Cognitive Function as Measured by the Mean Composite T-Score Derived from 14 Neuropsychological Tests
Global cognitive function will be assessed using the mean of the standardized T-scores from 14 neuropsychological tests: the MATRICS Consensus Cognitive Battery (MCCB; 9 subtests) plus 5 supplementary tests - the Wisconsin Card Sorting Test 64-Item Version (WCST-64), the Color Trails Test I and II, the Stroop Color-Word Test, and the Paced Auditory Serial Addition Task (PASAT). Raw scores from all 14 tests will be converted to standardized T-scores (population mean of 50, standard deviation of 10), adjusted for age, sex, education, and city of childhood and current residence. A single composite T-score will be calculated as the mean of the 14 test T-scores. Higher scores indicate better cognitive function.
Change in Synaptic Density as Measured by [18F]SV2A-PET Standardized Uptake Value Ratio (SUVR)
Synaptic density will be assessed using \[18F\]SV2A positron emission tomography (SV2A-PET). The outcome is the change in the standardized uptake value ratio (SUVR), calculated with the centrum semiovale (white matter) as the reference region. Higher SUVR values indicate greater synaptic density.
Change in Psychotic Symptom Severity as Measured by the Positive and Negative Syndrome Scale (PANSS) Total Score
Psychiatric symptom severity will be assessed using the Positive and Negative Syndrome Scale (PANSS). The PANSS total score ranges from 30 to 210, with higher scores indicating more severe symptoms.
Change in Negative Symptom Severity as Measured by the Scale for the Assessment of Negative Symptoms (SANS) Total Score
Negative symptoms will be assessed using the Scale for the Assessment of Negative Symptoms (SANS). The SANS total score ranges from 0 to 125, with higher scores indicating more severe negative symptoms
Change in Treatment-Emergent Adverse Event Severity as Measured by the Treatment Emergent Symptom Scale (TESS) Total Score
Treatment-emergent adverse events will be assessed using the Treatment Emergent Symptom Scale (TESS), a 35-item clinician-rated scale. Each item is rated for severity on a 0-4 scale (0 = absent/not applicable, 4 = severe). The outcome is the change in TESS total severity score, with higher scores indicating greater adverse event burden.
Brain MRI Measures (High-Resolution T1-Weighted, Resting-State fMRI, Task-Based fMRI [n-back]，DTI)
Change in structural and functional MRI measures.
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