The efficacy and safety of dual-target rTMS over dorsolateral prefrontal cortex (DLPFC) and cerebellum in the treatment of negative symptoms in first-episode schizophrenia: Protocol for a multicenter, randomized, double-blind, sham-controlled study.

Background and objective: The dorsolateral prefrontal cortex (DLPFC) - cerebellum circuit has been implicated in the pathogenesis of negative symptoms of schizophrenia (SZ). Both areas are considered separate targets for repetitive transcranial magnetic stimulation (rTMS) treatment, showing potential for improving negative symptoms. However, there is still a lack of research that targets both DLPFC and cerebellum simultaneously. In this study, we will explore the efficacy and safety of dual-target rTMS based on the DLPFC-cerebellum circuit in the treatment of negative symptoms in SZ. Methods: The study is a multicenter randomized, double-blind, and sham-controlled trial. First-episode schizophrenia is treated with adjunctive 1 Hz rTMS to the right DLPFC and intermittent theta burst stimulation (iTBS) to the cerebellum delivered sequentially in 20 sessions (active group) or a sham condition (sham group) along with antipsychotics. Clinical symptoms are assessed using the Positive and Negative Symptom Scale (PANSS) at baseline (T0), at the middle of the TMS intervention (after 10 sessions, T1), at the end of the intervention (after 20 sessions, T2), and at a 4-week follow-up after the intervention concludes (T3). Subjects will undergo magnetic resonance imaging (MRI) scans twice: once at baseline (T0) and again at the end of TMS intervention (T2). Comparisons of improvements in negative symptoms are conducted between the active and sham groups. Alterations in functional connectivity (FC) are also compared between both groups. Pearson or Spearman correlation analysis is performed to estimate the relationship between FC alteration and clinical symptom remission (PANSS negative subscale reduction scores and response rates, etc) depending on whether the data follows a normal distribution. In addition, potential neuroimaging biomarkers based on MRI associated with TMS treatment will be explored. Discussion: Positive results from this double-blind, sham-controlled, randomized study may optimize the TMS treatment strategy for SZ, particularly in managing negative symptoms. Clinicians can select TMS with increased confidence as a safe adjunctive treatment option. Furthermore, the findings of this trial may offer preliminary insights into the potential neuroimaging therapeutic mechanisms of TMS interventions targeting the prefrontal-cerebellar circuit.Trial registration: ClinicalTrials.govNCT04853485Primary sponsor: Jijun WANG (J. Wang), Principal Investigator: jijunwang27@163.com.