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 Left Dorsolateral Prefrontal Cortex (L-DLPFC), Left Inferior Parietal Lobe (L-IPL), and Right Orbitofrontal Cortex (R-OFC) for negative symptoms of schizophrenia. MRI-guided neuronavigation will be used to localize targets in each subject. Stimulation will be delivered at 100% of the resting motor threshold (RMT), with a total of 50 Theta Burst Stimulation (TBS) sessions, which include intermittent TBS (iTBS) and continuous TBS (cTBS). In the order of L-DLPFC (iTBS)→ L-IPL (iTBS) → R-OFC (cTBS), each target receives 600 pulses, for a total of 1800 pulses across three targets. Five sessions will be administered 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 TBS treatment.

• Change in cognitive function scores before and after intervention [Time frame: MATRICS Consensus Cognitive Battery (MCCB) will be measured at baseline (Day-4±2), immediately after the 50th session of TBS (Day 14), and 4 weeks ( Day 42) after completion of TBS treatment.]
• Change in positive symptom scores before and after intervention [Time frame: Positive symptoms will be measured at baseline (Day-4±2), immediately after the 50th session of TBS (Day 14), and at 1 week (Day 21), 2 weeks (Day 28), and 4 weeks ( Day 42) after completion of TBS treatment.]
• Change in general symptom scores before and after intervention [Time frame: General symptoms will be measured at baseline (Day-4±2), immediately after the 50th session of TBS (Day 14), and at 1 week (Day 21), 2 weeks (Day 28), and 4 weeks ( Day 42) after completion of TBS treatment.]
• Change in anxiety symptoms before and after intervention [Time frame: Anxiety symptoms will be measured at baseline (Day-4±2), immediately after the 50th session of TBS (Day 14), and at 1 week (Day 21), 2 weeks (Day 28), and 4 weeks ( Day 42) after completion of TBS treatment.]
• Depressive symptoms changes [Time frame: Depressive symptoms will be measured at baseline (Day-4±2), immediately after the 50th session of TBS (Day 14), and at 1 week (Day 21), 2 weeks (Day 28), and 4 weeks ( Day 42) after completion of TBS treatment.]
• Safety as measured by number of participants with Adverse Events [Time frame: Record the adverse events reported on that day after completing the day's TBS treatment. This should be done every day during the treatment period (Day 0 - Day 14)]
• Resting-state functional MRI (rsfMRI) scan [Time frame: Resting-state functional MRI will be measured at baseline (Day-4±2), immediately after the 50th session of TBS (Day 14), and 4 weeks ( Day 42) after completion of TBS treatment.]