Zhang Lin, Guo Li, Liu Xiaohui, Han Jing, Zhu Yuanqiang, Ma Chaozong, Li Ye, Ye Weiliang
Tenth Outpatient Department, 986th Hospital, Xijing Hospital, Air Force Medical University, Xi'an, China.
Department of Psychology, 986th Hospital, Xijing Hospital, Air Force Medical University, Xi'an, China.
Front Psychiatry. 2025 Apr 15;16:1578072. doi: 10.3389/fpsyt.2025.1578072. eCollection 2025.
Auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, often persisting despite pharmacological treatment. Repetitive transcranial magnetic stimulation (rTMS), particularly low-frequency rTMS targeting the left temporoparietal junction (TPJ), has shown promise in alleviating AVH symptoms by modulating dysfunctional brain connectivity. However, the network-level effects of rTMS remain incompletely understood, particularly in terms of small-world network properties, which provide insights into local and global network efficiency. Furthermore, most previous studies have analyzed whole-brain networks, lacking specificity regarding disease-relevant circuits.
This study aimed to investigate how low-frequency rTMS modulates the small-world network properties of a refined AVH-related network composed of 35 brain regions specifically implicated in hallucination generation and rTMS treatment effects, thereby providing a more targeted perspective on network reorganization. Healthy controls (HCs) were included as a reference to determine whether rTMS normalizes network alterations in schizophrenia. Additionally, a responder vs. non-responder analysis was conducted to assess individual variability in treatment response.
A total of 50 schizophrenia patients with persistent AVH underwent 15 sessions of 1 Hz rTMS over the left TPJ. Resting-state fMRI data were collected before and after treatment to assess functional connectivity within the predefined 35-region AVH-related network. small-worldness (σ), normalized clustering coefficient (γ), and normalized characteristic path length (λ), as well as functional segregation (clustering coefficient [Cp], local efficiency [El]) and functional integration (global efficiency [Eg], characteristic path length [Lp])-were analyzed before and after rTMS. Clinical symptom severity was assessed using the Auditory Hallucination Rating Scale (AHRS).
At baseline, schizophrenia patients exhibited disrupted small-world properties, with significantly lower σ, Cp, El, and Eg compared to healthy controls, reflecting impaired network organization, reduced local clustering, and inefficient global communication. Following rTMS, small-worldness (σ), local efficiency (El), and global efficiency (Eg) showed significant improvement, suggesting partial restoration of network efficiency. Functional connectivity analyses revealed significant reductions in hyperconnectivity between the right middle temporal gyrus (MTG) and superior putamen, as well as between the left TPJ and left lateral prefrontal cortex (LPFC). Notably, responders showed greater connectivity changes, which were correlated with AVH severity reduction, highlighting the role of network modulation in treatment response.
These findings support the network dysregulation model of AVH in schizophrenia and demonstrate that rTMS can modulate AVH-related connectivity, partially restoring network efficiency. The inclusion of HCs provides evidence that rTMS-induced changes align with normative network patterns, and the responder analysis suggests that connectivity modulation is linked to clinical improvement. This study offers new insights into the neurobiological mechanisms of rTMS treatment and underscores the need for biomarker-driven, individualized neuromodulation strategies for schizophrenia.
幻听是精神分裂症的核心症状，尽管进行了药物治疗，通常仍会持续存在。重复经颅磁刺激（rTMS），尤其是针对左侧颞顶联合区（TPJ）的低频rTMS，已显示出通过调节功能失调的脑连接来缓解幻听症状的潜力。然而，rTMS的网络水平效应仍未完全理解，特别是在小世界网络特性方面，这些特性有助于深入了解局部和全局网络效率。此外，以前的大多数研究都分析了全脑网络，缺乏对与疾病相关回路的特异性研究。
本研究旨在探讨低频rTMS如何调节由35个与幻觉产生和rTMS治疗效果特别相关的脑区组成的精细幻听相关网络的小世界网络特性，从而为网络重组提供更有针对性的视角。纳入健康对照（HCs）作为参考，以确定rTMS是否能使精神分裂症患者的网络改变恢复正常。此外，进行了反应者与非反应者分析，以评估治疗反应的个体差异。
共有50例患有持续性幻听的精神分裂症患者接受了15次针对左侧TPJ的1 Hz rTMS治疗。在治疗前后收集静息态功能磁共振成像（fMRI）数据，以评估预定义的35区幻听相关网络内的功能连接。分析了rTMS前后的小世界特性（σ）、归一化聚类系数（γ）和归一化特征路径长度（λ），以及功能分离（聚类系数[Cp]、局部效率[El]）和功能整合（全局效率[Eg]、特征路径长度[Lp]）。使用幻听评定量表（AHRS）评估临床症状严重程度。
在基线时，精神分裂症患者表现出小世界特性破坏，与健康对照相比，σ、Cp、El和Eg显著降低，反映出网络组织受损、局部聚类减少和全局通信效率低下。rTMS治疗后，小世界特性（σ）、局部效率（El）和全局效率（Eg）显示出显著改善，表明网络效率部分恢复。功能连接分析显示，右侧颞中回（MTG）与壳核之间以及左侧TPJ与左侧前额叶外侧皮质（LPFC）之间的过度连接显著减少。值得注意的是，反应者显示出更大的连接变化，这与幻听严重程度降低相关，突出了网络调节在治疗反应中的作用。
这些发现支持精神分裂症中幻听的网络失调模型，并表明rTMS可以调节与幻听相关的连接，部分恢复网络效率。纳入HCs提供了证据，表明rTMS诱导的变化与正常网络模式一致，反应者分析表明连接调节与临床改善相关。本研究为rTMS治疗的神经生物学机制提供了新的见解，并强调了对精神分裂症采用生物标志物驱动的个体化神经调节策略的必要性。
