抑郁症快感缺失的神经环路基础及其与多巴胺系统基因多态性关联机制

Anhedonia, which refers to markedly diminish interest or pleasure, is a potential trait marker for major depressive disorder (MDD). The presence of anhedonic symptoms haves been found to be associated with an inability to respond to positive reinforcers, leading to abnormal reward-based decision making and impairment in goal-directed behavior, and can predict poor treatment outcome in MDD. Clinical and neurobiological studies over the past ten years suggest that anhedonia is a core feature of reward deficits because the capacity to feel pleasure is a critical step during the normal processing of rewards. The recent literatures regarding the neural bases of the various aspects of reward processing have identified that specific neural circuits, especially in the mesolimbic dopamine system, are involved in the process of anhedonia. However, the precise mechanisms underlying anhedonia in MDD remains poorly understood..In the current study, using imaging genetics approach, we investigate the neural basis of structural and functional architectures of anhedonia in MDD subjects, explore the underlying mechanism of information integration of neural circuits that implicate in the anhedonia at the system level, and the difference of information integration capacity between subtypes of anhedonia (anticipatory and consummatory phase) by classifying the distinct clinical symptoms that involve in the anhedonia in MDD patients. In addition, we also examine the potential effects of dopamine system gene polymorphism [Catechol-O-methyl transferase (COMT) and dopamine transporter (DAT)] on the neural circuits of anhedonia in MDD patients. Our study will identify that 1) the distinct neural basis of constructs that distinguish anticipatory and consummatory phases of anhedonia in MDD; 2) the relationship between information integration capacity of subtypes of anhedonia and clinical phenotypes in MDD; 3) main and interactive effects of COMT and DAT gene polymorphisms on the neural circuits of anhedonia. All these findings will benefit to clarify the pathological mechanism of anhedonia in MDD, and reveal the potential mechanism underlying how anhedonia affects the development of MDD, and provide empirical evidences for the fact that anhedonia, as an endophenotype, can be used to early detect MDD patients and guide the individual-level treatment.

快感缺失是抑郁症的核心症状，是影响抑郁症发生、发展和转归的重要因素。利用遗传影像学策略，以快感缺失神经环路的结构基础和功能调控模式及其信息整合机制为核心，结合多模态神经影像学技术，多层面、多角度研究抑郁症患者快感缺失神经环路模式特征和调控机制，以及不同快感缺失亚型抑郁症患者信息整合的共同机制和专有特性，从系统水平揭示快感缺失神经环路结构和功能基础；结合基因分型，分析儿茶酚胺氧位甲基移位酶（COMT）和多巴胺转运体（DAT）基因多态性对快感缺失神经环路结构和功能的影响，从遗传通路水平分析多巴胺系统功能基因多态性对抑郁症快感缺失的潜在影响；结合神经心理学评估，揭示快感缺失神经环路在抑郁症发生发展中的变化规律，解析抑郁症快感缺失神经环路的整合机制及其与临床认知表型的关系，为明确抑郁症快感缺失的神经病理机制，并为后续随访研究寻找疾病特异性的神经环路特征及早期诊断的影像表征模型奠定基础。

快感缺失是抑郁症的核心症状，是影响抑郁症发生、发展和转归的重要因素。本课题利用多模态fMRI技术，研究首发抑郁症患者快感缺失神经环路的结构基础和功能连接模式特征：证实抑郁症患者奖赏神经环路结构基础与功能调控异常，奖赏环路障碍可能是抑郁症患者抑郁情绪、认知障碍及病程的共同神经病理学基础，对奖赏神经环路的调控可能有助于改善其抑郁情绪及认知障碍；结合神经经济学理论，我们证实奖赏网络与认知调控网络的环路基础、交互调控机制及其与行为学的相关性，发现奖赏神经环路与认知环路的共同神经环路基础、协同调控机制及其对快感缺失的影响；此外，我们还证实了杏仁核网络的异常及其与抑郁与焦虑严重程度的相关性，证实了抑郁与焦虑的共病基础；利用遗传影像学策略，以快感缺失神经环路的结构基础和功能调控机制为核心，从系统水平揭示遗传因素影响快感缺失神经环路的可能机制：结合基因分型，证实儿茶酚胺氧位甲基移位酶（COMT）基因多态性（Val/Met）对全脑功能网络呈现“U”调控机制；通过分析多巴胺通路主导基因多态性集聚效应，揭示多基因效应影响抑郁症快感缺失的神经环路基础：即多巴胺通路基因可能通过影响奖赏环路功能连接异常来影响抑郁症的临床症状，这些研究从遗传通路水平揭示多巴胺系统功能基因多态性对抑郁症快感缺失的潜在影响；结合图论分析技术，证实抑郁症患者呈现出较低的标准聚类系数及小世界性，默认网络的节点效率增高，而在海马及基底节网络的节点效率降低。右侧海马降低的节点效率在短期治疗后恢复正常。左侧海马的节点效率与抑郁症病情严重度呈负相关而与2周抗抑郁治疗的疗效呈正相关。提示抑郁症患者存在脑功能网络的拓扑性质改变。海马的节点效率改变与抑郁症状相关且可能是一个有效的短期抗抑郁治疗疗效的预测指标。最后，结合神经心理学评估，初步揭示快感缺失在抑郁症发病机制中的重要地位，解析抑郁症快感缺失神经环路的整合机制及其与临床认知表型的关系，为明确抑郁症快感缺失的神经病理机制，并为后续随访研究寻找疾病特异性的神经环路特征及早期诊断的影像表征模型奠定基础。