Yao Chenyang, Zhao Youjin, Zhang Qian, Zhao Ziyuan, Ai Kai, Zhang Bo, Lui Su
Department of Radiology, and Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, China.
Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Chengdu, China.
Schizophrenia (Heidelb). 2025 Feb 4;11(1):12. doi: 10.1038/s41537-025-00563-8.
Cerebellar dysfunction is a key aspect of schizophrenia, with the cerebello-thalamo-cortical (CTC) hyperconnectivity serving as a neural signature. Abnormalities in gamma-aminobutyric acid (GABA) and glutamate + glutamine (Glx) levels also contribute to this pathology. Transcranial magnetic stimulation (TMS) applied to the cerebellum shows potential in alleviating schizophrenia symptoms, possibly by modulating functional connectivity or neurotransmitter levels. This study aims to explore the immediate effects of cerebellar TMS on CTC circuitry and neurotransmitter levels to elucidate its therapeutic mechanisms in schizophrenia.The study involved 19 stable schizophrenia patients and 26 healthy controls, diagnosed according to DSM-V criteria and assessed for symptom severity using the Positive and Negative Syndrome Scale (PANSS). MRI scans were conducted pre- and post-TMS to detect changes in CTC functional connectivity, GABA, Glx, and Glx/GABA. Linear Mixed-Effects Model (LMEM) and two-sample tests were employed to analyze changes in these variables from baseline to post-TMS. Pearson's correlation analysis was conducted to examine the relationships among these variables and their association with PANSS scores. Mediation analyses were employed to investigate whether GABA and/or Glx serve as potential mediators of CTC hyperconnectivity in patients with schizophrenia. Schizophrenia patients exhibit CTC hyperconnectivity, which remains at a relatively stable level after cerebellar TMS. Compared to healthy controls, schizophrenia patients have significantly higher cerebellar GABA levels, and cerebellar GABA has a significant mediation effect on CTC hyperconnectivity in patients. The Glx/GABA ratio was associated with the severity of clinical symptoms in patients, and cerebellar TMS partially normalized this ratio. Our findings demonstrate that aberrant cerebellar GABA levels contribute to CTC hyperconnectivity in schizophrenia. Additionally, our study shows that cerebellar TMS can increase Glx levels in schizophrenia patients, leading to the normalization of the Glx/GABA ratio, which may contribute to the therapeutic effects of TMS in schizophrenia.
小脑功能障碍是精神分裂症的一个关键方面，小脑-丘脑-皮质（CTC）的过度连接是其神经特征。γ-氨基丁酸（GABA）和谷氨酸+谷氨酰胺（Glx）水平的异常也与这种病理状况有关。应用于小脑的经颅磁刺激（TMS）显示出缓解精神分裂症症状的潜力，可能是通过调节功能连接或神经递质水平。本研究旨在探讨小脑TMS对CTC回路和神经递质水平的即时影响，以阐明其在精神分裂症中的治疗机制。该研究纳入了19名病情稳定的精神分裂症患者和26名健康对照者，根据《精神疾病诊断与统计手册》第五版（DSM-V）标准进行诊断，并使用阳性和阴性症状量表（PANSS）评估症状严重程度。在TMS前后进行MRI扫描，以检测CTC功能连接、GABA、Glx以及Glx/GABA的变化。采用线性混合效应模型（LMEM）和双样本检验分析这些变量从基线到TMS后的变化。进行Pearson相关分析以检验这些变量之间的关系及其与PANSS评分的关联。采用中介分析来研究GABA和/或Glx是否作为精神分裂症患者CTC过度连接的潜在中介因素。精神分裂症患者表现出CTC过度连接，在小脑TMS后保持在相对稳定的水平。与健康对照者相比，精神分裂症患者的小脑GABA水平显著更高，并且小脑GABA对患者的CTC过度连接具有显著的中介作用。Glx/GABA比值与患者的临床症状严重程度相关，小脑TMS使该比值部分恢复正常。我们的研究结果表明，异常的小脑GABA水平导致精神分裂症患者的CTC过度连接。此外，我们的研究表明，小脑TMS可以提高精神分裂症患者的Glx水平，导致Glx/GABA比值恢复正常，这可能有助于TMS在精神分裂症中的治疗效果。
