A randomized controlled trial of adjunctive iTBS targeting the dorsomedial prefrontal cortex for anhedonia in schizophrenia: rationale and protocol design

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Abstract
Introduction: Anhedonia, a core negative symptom of schizophrenia, refers to the inability to experience pleasure from normally enjoyable activities. It significantly worsens prognosis and remains poorly addressed by current treatments. In recent years, repetitive transcranial magnetic stimulation (rTMS) has shown potential in treating anhedonia in depression and other disorders; however, its application to anhedonia in schizophrenia remains underexplored. This study aimed to evaluate the efficacy of rTMS targeting the dorsomedial prefrontal cortex (DMPFC) on anhedonia in patients with schizophrenia, and to explore its correlation with cognitive function and prefrontal activity. Methods: The present study is a randomized controlled trial that will include 82 patients with schizophrenia who meet DSM-5 diagnostic criteria and have a score of ≥12 on the Snaith-Hamilton Pleasure Scale (SHAPS). Eligible participants will be randomly allocated in a 1:1 ratio to either active or sham rTMS stimulation groups. The active group will receive a high-frequency rTMS intervention using an intermittent theta-burst stimulation (iTBS) protocol (20 trains x 10 pulses at 5 Hz, with an intensity of 90% of resting motor threshold) administered twice daily for 15 days. The sham group will receive a sham-stimulation regimen with the same parameters. All participants will be assessed using both the SHAPS and the Scale for the Assessment of Negative Symptoms (SANS) at three time points: baseline (T0), immediately post-treatment (T1), and 4-week follow-up (T2). In addition, the Wisconsin Card Sorting Test (WCST) and the dynamics of prefrontal oxygenated hemoglobin (Δoxy-Hb) monitored by functional near-infrared spectroscopy (fNIRS), will be assessed at T0, T1, and T2. Ethics and dissemination: The trial protocol complies with the principles of the Declaration of Helsinki and has been approved by the Ethics Committee of Zigong Mental Health Center (approval number: 20250801). The findings of this trial will be published and made publicly accessible in a peer-reviewed journal. Discussion: If the iTBS protocols targeting the DMPFC lead to positive changes in anhedonia symptoms in patients with schizophrenia, this would provide a new intervention strategy for negative symptoms. Furthermore, leveraging neuroimaging evidence from such studies could help optimize rTMS target selection and overall treatment strategies. Trial registration: ChiCTR2500107965.

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