Neuronavigated dual-target transcranial magnetic stimulation for schizophrenia negative symptoms

Abstract Negative symptoms in schizophrenia severely impair function and quality of life, yet respond poorly to current therapies. This multicenter, randomized, double-blind, sham-controlled trial aimed to investigate the efficacy of neuronavigated dual-target repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (rDLPFC) and cerebellum for improving negative symptoms in early-stage psychosis (ClinicalTrials.gov Identifier: NCT04853485). Participants with first-episode schizophrenia or clinical high-risk for psychosis were enrolled from Shanghai Mental Health Center and Suzhou Guangji Hospital. Participants were randomly assigned to either a real or sham group under MRI-guided neuronavigation, targeting rDLPFC with 1Hz at 100% motor threshold(MT), cerebellar with intermittent theta burst stimulation(iTBS) at 120% MT for 20 consecutive days. Clinical assessments were conducted at baseline(T0), 10-session(T1), 20-session(T2) and one month after the intervention(T3). Cognition and MRI were evaluated at T0 and T2. The primary outcome was change of negative subscale score of the Positive and Negative Symptoms Scale(PANSS), while secondary outcomes included alterations in other PANSS subscale scores and fronto-cerebellar circuit functional connectivity. In total, 75 participants were included in the intention-to-treat analysis (36 active, 39 sham). The pre-specified primary linear mixed-effects analysis revealed a non-significant group-by-time interaction for PANSS negative subscale scores (F(3,174.6)=1.45, p=0.230). At the 4-week endpoint (T2), the nominal unadjusted between-group p-value was 0.049; after Sidak correction for multiple comparisons, the adjusted mean difference was −2.48 points (95% CI −4.99 to 0.03, adjusted p=0.150, Cohen’s d=−0.51). Descriptive uncorrected t-tests indicated greater negative-symptom reductions in the active group at T1 and T2, and the 4-week negative-symptom response rate (≥50% reduction) was higher under real rTMS (χ2=9.5, p=0.002). A significant group-by-time interaction was observed for PANSS positive subscale scores (F(3,172.0)=3.26, p=0.023). Both groups exhibited substantial within-group symptom improvement. Resting-state fMRI demonstrated group-by-time interactions within cerebello-temporal, parahippocampal, caudate, and parietal networks (FWE-corrected p<0.05), and negative-symptom change correlated with cerebello-caudate connectivity (r=0.33, p=0.026). These findings suggest neuronavigated dual-target rTMS over rDLPFC and cerebellum may be associated with numerical improvements in negative symptoms in early-stage psychosis.