基于记忆网络探索磁刺激对早期精神分裂症患者海马功能的调控作用

Episodic memory deficit, which plays an important role for the functional outcomes, is the core cognitive symptom of patients with schizophrenia, however, no effective interventions have been put forward in the clinical practice. Previous studies indicated that repetitive Transcranial Magnetic Stimulation (rTMS) targeting the left lateral parietal cortex (LPC) or right dorsolateral prefrontal cortex (DLPFC) could stimulate hippocampal neurogenesis, enhance the function of memory network, and accordingly improve the associative memory, which is the key component of episodic memory and mainly the function of hippocampus. Since the early stage is the critical period of interventions for schizophrenia, first-episode patients will be included in this study. First, we intend to use behavioral experiments to explore whether rTMS stimulation targeting left LPC or right DLPFC can improve the episodic memory deficit in schizophrenia patients. Second, the hippocampal neurogenesis and memory network will be examined pre- and post-rTMS stimulations by using multi-modal MRI techniques and molecular biology techniques, to determine the regulation effects of rTMS on the happocampal functions. Third, the relationship between the therapeutic effect of rTMS on episodic memory impairment in schizophrenia patients and the regulation effects of rTMS on hippocampal neurogenesis, synaptic plasticity and memory network will be further investigated. The present study could clarify the therapeutic effect and underlying mechanism of rTMS for episodic memory deficit in patients with first-episode schizophrenia, and probably new therapeutic target will be revealed, which is benificial to the functional outcomes of schizophrenia patients.

情景记忆缺陷是精神分裂症的核心认知症状，目前缺乏有效干预手段。研究发现应用重复经颅磁刺激（rTMS）对记忆网络中皮层脑区刺激可以促进海马神经发生，调控海马及其功能网络，提高联想记忆（反映海马功能的一种特殊情景记忆）。本项目以首发精神分裂症患者作为研究对象，结合神经心理学、多模态脑影像学技术研究：①rTMS刺激记忆网络中皮层脑区(左外侧顶叶皮层或右侧前额叶背外侧皮层)是否可以改善精神分裂症的情景记忆缺陷；②rTMS皮层刺激通过记忆网络如何改善精神分裂症的海马功能及其功能网络；③rTMS对精神分裂症情景记忆缺陷的治疗作用与海马功能改善（神经发生、突触可塑性及功能网络变化）的相关性，明确rTMS对精神分裂症情景记忆缺陷的疗效、作用机制及最佳干预模式。该项目有助于揭示精神分裂症的病理机制，为精神分裂症的记忆缺陷治疗及功能康复提供新的治疗靶点及实验依据。

情景记忆缺陷是精神分裂症的核心认知症状，目前缺乏有效干预手段。有研究发现应用 重复经颅磁刺激（rTMS）刺激记忆网络中的皮层脑区可以促进海马神经发生，调控海马及其功能网络，从而提高联想记忆（反映海马功能的一种特殊情景记忆）。本项目以精神分裂症患者作为研究对象，结合神经心理学及多模态脑影像学技术进行研究：① rTMS刺激记忆网络中皮层脑区(左外侧顶叶皮层或右侧前额叶背外侧皮层)是否可以改善精神分裂症的情景记忆（联想记忆）缺陷；② rTMS刺激记忆网络的皮层脑区是否可以改善精神分裂症的海马功能及其功能网络；③ rTMS对精神分裂症情景记忆缺陷的治疗作用与海马功能改善（神经发生、突触可塑性及功能网络变化）的相关性。结果发现：① 精神分裂症的视觉通道联想记忆及听觉通道联想记忆均受损，且视觉通道联想记忆的ROC曲线下面积最小（AUCVV=0.630, p=0.005），辨别力d’值明显小于听觉通道联想记忆d’值（p=0.021）。② rTMS干预可以改善精神分裂症的联想记忆缺陷，刺激右侧DLPFC可以改善视觉通道联想记忆，而刺激左侧LPC可以改善跨通道及视觉通道联想记忆。但rTMS刺激上述部位对精神分裂症的其他认知缺陷症状（MCCB测评）、阳性症状及阴性症状的疗效均不显著（组间差异均无统计学意义）。③ 以双侧海马作为种子点（ROI），分析海马与左侧LPC、右侧DLPFC的功能连接，结果发现精神分裂症患者左侧海马与左侧LPC的功能连接减弱，而右侧海马与右侧DLPFC的功能连接增强。④ rTMS刺激左侧LPC可以改善左侧LPC与左侧海马的功能连接/呈增强趋势，而刺激右侧DLPFC后右侧DLPFC与右侧海马的功能连接/呈增强趋势。⑤ 研究发现rTMS刺激对精神分裂症的海马神经新生产生促进作用，神经新生信号在治疗后出现并增强。本项目提示rTMS刺激左侧LPC或右侧DLPFC均可以改善海马的神经新生及功能连接，改善精神分裂症的联想记忆（视觉通道及跨通道）缺陷，为精神分裂症的记忆缺陷治疗及功能康复提供新的治疗靶点及实验依据。