Low-Frequency rTMS Modulates Small-World Network Properties in an AVH-Related Brain Network in Schizophrenia

Lin Zhang ¹ Li Guo ¹ Xiaohui Liu ¹ Jing Han ¹ Yuanqiang Zhu ² Chaozong Ma ¹ Ye Li ^1,3 Weiliang Ye ^1*

• ¹ Air Force Medical University, Xi'an, Shaanxi Province, China
• ² Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
• ³ No. 968 Hospital of PLA Joint Logistic Support Force, Jinzhou, Liaoning Province, China

BackgroundAuditory verbal hallucinations (AVH) are a core symptom of schizophrenia, often persisting despite pharmacological treatment. Low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the left temporoparietal junction (TPJ) has shown promise in alleviating AVH symptoms. However, the network-level effects, particularly changes in small-world properties reflecting local and global efficiency, remain incompletely understood. Previous studies have predominantly analyzed whole-brain networks, lacking specificity regarding AVH-related circuits.ObjectiveThis study aimed to investigate how low-frequency rTMS modulates small-world properties within a refined AVH-related network composed of 35 regions specifically implicated in hallucinations and treatment effects. Healthy controls (HCs) were included to determine whether rTMS normalizes network alterations. Additionally, responder vs. non-responder analysis assessed variability in treatment response.MethodsFifty schizophrenia patients with persistent AVH underwent 15 sessions of 1 Hz rTMS over the left TPJ. Resting-state fMRI data were collected pre- and post-treatment to assess functional connectivity within the AVH-related network. Small-worldness (σ), normalized clustering coefficient (γ), normalized characteristic path length (λ), functional segregation (Cp, El), and integration (Eg, Lp) were analyzed. Clinical symptom severity was assessed using the Auditory Hallucination Rating Scale (AHRS).ResultsAt baseline, schizophrenia patients exhibited disrupted small-world properties, with significantly lower σ, Cp, El, and Eg compared to healthy controls, indicating impaired local clustering and inefficient global communication. After rTMS, small-worldness (σ), local efficiency (El), and global efficiency (Eg) significantly improved. Functional connectivity analyses revealed reductions in hyperconnectivity between the right middle temporal gyrus and superior putamen, and between the left TPJ and left lateral prefrontal cortex. Responders showed greater connectivity changes correlated with AVH severity reduction, highlighting network modulation in treatment response.ConclusionThese findings support the network dysregulation model of AVH and demonstrate that rTMS partially restores AVH-related network efficiency. Inclusion of healthy controls confirmed the normalization of connectivity patterns following treatment. Network modulation correlated with clinical improvement, highlighting the potential for biomarker-driven, individualized neuromodulation in schizophrenia.