Multi-target TMS for Schizophrenia Negative Symptoms

Schizophrenia is a chronic and severe mental disorder. Although antipsychotic medications are effective for positive symptoms, they offer limited improvement for negative symptoms and cognitive deficits. Effective treatments for these symptoms are still lacking. To address current clinical bottlenecks, there is an urgent need to develop novel, effective treatment strategies. Repetitive transcranial magnetic stimulation (rTMS) is a recently developed neuromodulation technique. The latest evidence-based guidelines indicate that the level of evidence for rTMS in treating schizophrenia remains low (i.e., Level C evidence, possibly effective). However, the critical parameter of target selection has not received sufficient attention. This randomized controlled trial (RCT) is the first to evaluate the efficacy and safety of a multi-target TMS protocol targeting the Right Orbitofrontal Cortex (R-OFC), Left Dorsolateral Prefrontal Cortex (L-DLPFC), and Left Inferior Parietal Lobe (L-IPL) for negative symptoms of schizophrenia. MRI-guided neuronavigation will be used to localize targets in each subject. The intensity of TMS stimulations is set to 80-120% of resting motor threshold (RMT). A total of 50 TMS sessions will be administered. The stimulation sequence will be R-OFC (1 Hz) → L-DLPFC (iTBS) → L-IPL (iTBS). The first target (R-OFC) will receive 720 pulses at 1 Hz, while the second and third targets (L-DLPFC and L-IPL) will each receive 900 pulses of iTBS. Five sessions will be delivered per day for 10 consecutive working days, with a 60-minute interval between sessions. Clinical assessments, cognitive evaluations, and resting-state functional Magnetic Resonance Imaging (MRI) scans will be performed before and after TMS treatment.

Inclusion criteria

• Outpatients or inpatients at the Department of Psychiatry, Shanghai Mental Health Center;
• Meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for first-episode schizophrenia (diagnosed using the Structured Clinical Interview for DSM-5, SCID-5); disease duration less than 5 years at enrollment;
• Male or female aged 16-45 years;
• Education duration ≥ 9 years;
• Stable medication regimen for at least 6 weeks prior to baseline visit and throughout the study period; psychiatric symptoms generally stable within 1 month prior to baseline visit;
• Participants and their guardians can understand and sign written informed consent;
• Total score on the PANSS Negative Symptom subscale (PANSS-N) > 15, and at least one item score ≥ 3.

Exclusion criteria

• Current or lifetime psychiatric disorders as determined by SCID-5 assessment;
• Severe or unstable physical illnesses, including: neurological disorders (delirium, dementia, stroke, epilepsy, migraine, etc.), congestive heart failure, angina pectoris, myocardial infarction, arrhythmia, hypertension, hyperglycemia, malignant tumors, and immunocompromised conditions;
• Alcohol abuse within 30 days prior to the study or alcohol/drug dependence within 6 months prior to the study; participation in any clinical trial within 30 days prior to baseline;
• Pregnant or breastfeeding women;
• Intellectual disability (IQ < 70);
• No history of modified electroconvulsive therapy (mECT) within the past 6 months.