认知与发展心理学研究室知识库

阴性症状和认知缺陷是精神分裂症的两个核心症状，也是治疗困难的症状。重复经颅磁刺激（repetitive transcranial magnetic stimulation, rTMS）是近年来用于治疗这两组症状的方法之一，由于其无创性及副作用小，在临床上有较大的推广价值。本研究将系统探讨 rTMS 对精神分裂症阴性症状和认知缺陷的治疗作用，并初步探索其产生疗效的神经机制。
本文包含两个研究。研究一对目前 rTMS 治疗精神分裂症阴性症状的文献进行了元分析，发现在控制安慰剂效应后，rTMS 对精神分裂症阴性症状的治疗效应值仍达中度（Cohen’s d 0.53），110%的运动阈值、10Hz、左侧背外侧前额叶、持续三周以上的治疗是最佳的治疗范式。研究二是一个双盲随机对照实验，包括三个部分。第一部分探讨 rTMS 对阴性症状总体和各个成分的疗效，发现对于病程短、治疗相对系统及时、阴性症状突出的青壮年精神分裂症患者，rTMS 对阴性症状总体治疗效果较明显，其中对情感平淡和意志缺乏效果更佳。但同时存在安慰剂效应。需要扩大样本进一步验证其治疗效应。阴性症状对功能结局有明确影响，其中快感缺失和意志缺乏的作用更为明显。在临床上评估阴性症状时，要注意服药剂量、抑郁和认知功能等混淆因素。第二部分探讨 rTMS 对认知功能总体和各个成分的疗效，研究发现，入组的精神分裂症患者，年龄较轻、病程短和治疗及时，均使用的是第二代抗精神病，认知损害程度较轻，且范围不大。rTMS治疗精神分裂症认知受损总体改善显著，改善主要表现在信息处理速度、词语学习、视觉学习和执行功能方面，但同时存在安慰剂效应。在控制安慰剂效应后，rTMS对迷宫测验所代表的执行功能领域仍表现出显著的治疗效应，效应值极高。第三部分探讨rTMS 治疗精神分裂症阴性症状和认知症状的脑机制，以阴性症状为主的精神分裂症患者存在广泛的灰质体积下降，以额叶和边缘系统更为突出。本研究对于精神分裂症患者白质完整性的结果尚无定论。以阴性症状为主的精神分裂症患者小世界属性下降可以初步确定，但短期的 rTMS 治疗对精神分裂症患者小世界属性改善不明显。rTMS 治疗阴性症状的改善可能与左侧背外侧前额叶的激活，左侧背外侧前额叶与前扣带回及壳核的连接增加，中央执行网络和突显网络的连接下降有关；迷宫成绩的改善可能与左侧背外侧前额叶的激活，海马旁回和颞上回及前扣带回的连接增加有关。
总结，rTMS 对精神分裂症阴性症状和认知缺陷均有一定改善作用，改善的主要领域有情感平淡、意志缺乏和执行计划功能。阴性症状的改善可能与中央执行控制网络和突显网络网络内及网络间的连接改变有关。 反映问题解决能力的迷宫成绩改善可能与负责计划功能和地形识别相关的脑区激活有关。

Negative symptoms  and cognitive  impairments  are two core  features  of schizophrenia,  that contribute mainly to the  treatment-refractory symptoms observed in this clinical group. Repetitive transcranial magnetic stimulation (rTMS) is considered to be a promising non-medical intervention for treating the negative and cognitive symptoms in schizophrenia because of its noninvasive nature and fewer side effects. The current dissertation aimed to explore the  therapeutic effects of rTMS on negative and cognitive symptoms. Moreover, it also aimed to explore if this observed behavioral changes would be associated with the corresponding changes in the brain structural and functional connectivity.  
The dissertation consists of two main parts.  In part 1, we conducted a meta-analysis of the effects of rTMS on negative symptoms. We found a moderate effect size (Cohen’s d 0.53) when sham-control was taken into account, also we found a 10 Hz setting, at least three consecutive weeks of treatment, treatment site at the left dorsolateral prefrontal cortex (DLPFC) and a 110% motor threshold (MT) were found to be the best rTMS parameters for the treatment of negative symptoms.  In part 2, a double-blind randomized controlled trial study was conducted to examine the clinical (behavioural) changes in negative symptoms and cognitive functions.. Firstly,, we investigated  the effects of rTMS on negative symptoms. The results showed that the treatment efficacy in the rTMS was significant for the  patients with schizophrenia who were younger,  with a  shorter duration of illness  and  duration of untreated psychosis,  and had predominant negative symptoms at baseline,  especially in the subdomains of affective flattening and avolition. However, the placebo effect was also observed in the sham control group. The functioning outcome was influenced by the negative symptoms, especially  by  anhedonia and avolition.  We should take into account the confounders of dosage of medication, depression and cognition when we evaluate the negative symptom in clinic. Then, we explored  the effects of rTMS on cognitive  function improvement.   The therapeutic effects of rTMS on  cognitive function were  also significant, especially in    the speed of  information processing, verbal learning, visual learning and executive function. However, similar effects were also  observed in the sham-control  group,  After controlling for the placebo effect observed in the sham-control group, we still found a significant improvement in Maze Test  in the rTMS experimental group.  Finally, we  further  explored  whether these observed changes in clinical symptoms and cognitive performances were associated with a corresponding change in the underlying neural mechanism. The results showed that the patients with predominant negative symptoms  demonstrated a significant reduction  in gray matter volume, especially in  the  frontal lobes  and limbic system. However, no significant changes were observed in white matter integrity by diffusion tensor imaging (DTI). . Resting-state analysis indicated that the small world property in the patients with predominant negative symptom was reduced. However,  such a small world property was not changed by  the  rTMS treatment. The improvement of negative symptoms by  the rTMS in our study was probably due to  the activations of the  left DLPFC, an  increased connectivity between  the  left DLPFC and  the anterior cingulate gyrus  and the  putamen,  a  decreased connectivity between the central executive network and insula of  the  salience network.    The improvement of Maze performance by rTMS in our study might be due to the activations of left DLPFC, an increased connectivity between the parahippocampus,the superior temporal gyrus,and the anterior cingulate gyrus.
In summary, rTMS  could  improve the negative symptoms and cognitive impairments  in patients with schizophrenia, especially in  affective flattening, avolition and problem solving  ability. The improvement of negative symptoms was likely related to the changes of the connectivity within the central executive network and  the  changes of the  connectivity between the central executive network and salience network.  The improvement of  problem solving ability (as observed in the Maze Test) might be  due to the activations  of brain area related topographical and planning.