抑郁症社会决策行为的脑网络基础及与5-HT系统基因多态性的关系

Major depressive disorder (MDD) is characterized with significant and pervasive impairments in social functioning. Understanding the physiological basis of social dysfunction is essential for preventing or ameliorating negative outcomes of patients with MDD and also helpful to find potential treatment target. This project aims to study brain networks underlying social decision-making behavior during a game theory paradigm in drug-free patients with MDD and their associations with genetic polymorphisms of 5-HT pathway. We will also explore the neural mechanism of genetic polymorphisms of 5-HT pathway mediating social decision-making in order to obtain a comprehensive understanding on the physiological basis of social dysfunction in MDD. Specifically, in Study 1 we will use a game theory paradigm (ultimatum game) to study social decision-making behavior of drug-free MDD patients and investigate its clinical correlates. In Study 2, we will use functional magnetic resonance imaging (fMRI) to investigate whether there are abnormalities in functional interactions between brain networks related to emotion and cognition during this social decision-making task in drug-free MDD patients compared to their matched normal controls. Study 3 aims to explore the relationship among genetic polymorphisms of 5-HT pathway, brain networks and social decision-making behavior in an independent large sample of healthy volunteers. Based on these findings, Study 4 will compare the relationship among genetic polymorphisms of 5-HT pathway, brain networks and social decision-making behavior in drug-free MDD patients with that in their matched healthy controls. The findings obtained in this project will improve our understanding on psychopathology of social dysfunction in MDD, will be helpful to find a new biomarker for prognosis evaluation of MDD, and will provide evidences for improving therapy and intervention of MDD.

抑郁症患者常存在显著而持久的社会功能障碍，理解这种社会功能障碍的生理基础，对于预防和缓解抑郁造成的负性结果，发现潜在的抑郁症干预靶标具有重要意义。本项目将以未服药抑郁症患者为主要研究对象，采用源自博弈论的社会决策范式研究其社会功能，从脑功能网络角度研究其社会决策行为的神经基础，探索5-HT系统基因多态性对决策相关脑网络的影响，进而从基因-脑-行为角度获得对抑郁症社会功能障碍生理基础的综合理解。具体而言：研究1将比较未服药抑郁症患者社会决策行为与正常对照的差异；研究2将采用fMRI技术，考察未服药抑郁症患者在社会决策情境中情绪和认知相关脑网络功能交互模式与正常对照的差异；研究3将在独立大样本正常人中研究5-HT系统基因多态性累积效应与社会决策行为及相关脑网络的关系；研究4将比较这种基因多态性累积效应与社会决策行为及相关脑网络的关系是否在未服药抑郁症患者与其正常对照之间存在差异。

抑郁症患者存在显著而持久的社会功能障碍，可表现为社会交互中决策行为异常。本项目从社会决策角度，采用fMRI技术和博弈论的研究范式(最后通牒博弈)，研究未服药抑郁症患者社会决策行为及其脑网络基础，探究遗传因素对社会决策行为及相关脑网络的影响，以期从基因-脑-行为角度获得对抑郁症社会功能障碍生理基础的综合理解。本项目主要研究内容包含以下几部分：未服药抑郁症患者社会决策行为的研究；未服药抑郁症患者社会决策行为的神经基础研究；正常人5-HT系统基因多态性与社会决策行为、脑网络关系的探索研究，及抑郁症患者基因-脑-行为关系的探索研究。我们发现未服药抑郁症患者公平决策行为异常，这种异常源于抑郁症患者公平感知和决策行为的关联减弱；抑郁症患者对遭遇不公平待遇的敏感性更高，其神经基础不同于正常对照；抑郁症患者公平决策相关的额颞叶脑区脑激活模式异常，以背外侧前额叶皮层、前脑岛、前扣带皮层为核心脑区的脑网络效应连接模式不同于正常对照，并且效应连接和拒绝率的相关模式也不同于正常对照；遗传因素对公平决策和公平特质的个体差异有中等程度贡献，感兴趣基因多态性（尤其是5-羟色胺通路TPH2(rs4570625)位点的基因多态性）影响公平决策行为和效应连接模式，但仍需进一步研究。本项目所取得研究成果有助于理解抑郁症患者社会功能障碍的生理基础，对于预防和缓解抑郁造成的负性结果、发现潜在抑郁症干预靶标具有一定意义。