脑可塑性对精神分裂症工作记忆训练效应的影响

Poor working memory performance is an essential feature of cognitive deficits in schizophrenia. Dysfunction and aberrant functional connection of dorsal lateral prefrontal cortex (DLPFC) with other related brain areas may be the critical neural basis of working memory deficits in these patients. Converging evidence revealed that cognitive training is an effective method to improve working memory function of schizophrenia. But the efficiency of working memory training should be enhanced to put this method to clinical application. Evidence from published work suggested that brain plasticity is a core effect predictor of cognitive training. It’s a promising way to enhance the efficiency and transfer effect of working memory remediation by inducing brain plasticity before cognitive training. Cumulative evidence showed that repetitive transcranial magnetic stimulation (rTMS) is the most commonly used experimental strategy to directly enhance neuronal plasticity in human brain. A multisite research conducted by present group had demonstrated working memory and brain function improvement by cognitive remediation therapy, but the effect size is moderate. So to enhance the behavior and brain plasticity effect of working memory training in schizophrenia, a union method of rTMS plus working memory training will be adopted for schizophrenia in this project. The hypothesis is that the enhanced brain plasticity induced by rTMS will promote the cognitive performance, brain function and structure changing caused by working memory training in patients with schizophrenia. In this study, a total number of 129 inpatients with schizophrenia will be recruited. All subjects will be divided randomly into three groups, rTMS group, rTMS plus working memory training group and false rTMS plus working memory training group. A serial cognitive tests which focus on working memory and functional (resting and task dependent), structural magnetic resonance imaging (MRI) scanning will be administrated before and after rTMS and working memory training. To explore the facilitative effect of rTMS on working memory training in cognitive and brain plasticity, difference among three groups in cognitive, functional, brain structural changing of working memory related brain, such as DLPFC will be analyzed. To our knowledge, this is the first study of rTMS plus working memory training to improve the cognitive function and brain plasticity in patients with schizophrenia. This project will give scientific suggestions for treating cognitive deficits which suffered by patients with schizophrenia.

工作记忆受损是精神分裂症认知缺陷最核心的表现之一，背外侧前额叶等脑区功能及功能连接异常是工作记忆受损的机制。认知训练可改善精神分裂症的工作记忆缺陷，但效应亟待提高。先改善工作记忆相关脑区可塑性，再予以工作记忆训练的方法有助于提升训练效果和迁移效应。项目组既往研究发现认知训练可改善工作记忆及相关脑区功能，但效应值不高，而研究提示rTMS可改变脑区的神经活动水平，引起可塑性变化，藉此，本研究将先用rTMS改变脑功能及可塑性，再予以工作记忆训练，以期提高训练效应，促进相应脑区功能及结构的可塑性变化。项目将入组129例患者，随机分入rTMS组，rTMS+工作记忆训练组，伪rTMS+工作记忆训练组，干预前后予以认知及MRI检测，通过分析各组干预前后工作记忆及背外侧前额叶等脑区功能和结构的变化，探讨rTMS所致脑可塑性改变对工作记忆训练效应的易化作用，为精神分裂症认知缺陷干预技术的发展提供科学依据。

工作记忆缺陷是精神分裂症认知缺陷中最突出的损害之一，通过认知训练的方法能在一定程度上改善精神分裂症患者的工作记忆，但总体效应待提高，如何提高工作记忆的训练效应是当前精神分裂症认知康复研究中最重要的领域之一。重复经颅磁刺激（rTMS）是目前最具循证基础的能改善大脑皮层可塑性的物理方法之一，在rTMS改善大脑皮层可塑性的基础上再予以工作记忆训练，将有望提高工作训练的临床效应。本项目入组88例精神分裂症患者，随机分成4组，每组22例。分别予以①rTMS+SRT（A组：rTMS+简单反应训练）；②rTMS+WMT（B组：rTMS+工作记忆训练）；③伪rTMS+SRT（C组：伪rTMS+简单反应训练）；④伪rTMS+WMT(D组，伪rTMS+工作记忆训练)。rTMS采用间歇θ波刺激（iTBS）方式，持续3分20秒。每次WMT或SRT持续45分钟左右，每组被试治疗均持续30次，每周5次，持续6周。所有被试治疗前后均采用精神分裂症认知功能成套测验共识版（MCCB）进行认知评估，同时运用阳性与阴性症状量表（PANSS）和简明阴性症状量表（BNSS）进行临床症状评估。. 统计分析表明，四组在MCCB词语流畅性分测验和加工速度维度的得分存在显著差异（P<0.05），在MCCB总分及符号编码、迷宫分测验的得分存在边缘显著（P<0.1）。进一步两两分析表明，B组、C组的MCCB总分在治疗后的改善显著优于A组。B组在MCCB工作记忆维度上的改善显著优于A组（P<0.05），其效应值为四组最高；B组和C组在MCCB精神运动速度维度上的得分在治疗后的改善均显著优于A组。B组在MCCB迷宫测验上的得分改善显著优于A组（P<0.05），B组和C组在MCCB符号编码测验上的得分改善均显著优于A组（P<0.5），其余组间比较无显著差异。四组临床症状（PANSS总分及各分量表分）在治疗前后均有显著改善，但组间差异无统计学意义（P>0.05）。. 本研究结果表明，rTMS联合工作记忆训练可显著改善精神分裂症患者的工作记忆，且其对整体认知功能的改善既高于单纯的rTMS刺激，也高于单纯的工作记忆训练，提示rTMS刺激对工作记忆训练具有一定的易化作用。这一结果对进一步提升传统认知训练的临床效应提供了易于推广应用的方法，也为精神分裂症物理治疗与社会心理干预的联合应用提供了循证基础。