精神分裂症谱系的快感缺失：基于情感神经科学的脑成像研究

Negative symptoms have long been considered to be the common features of schizophrenia and there is a lack of effective medications for this domain of psychopathology. Anhedonia (an inability to experience pleasure) is a core negative symptom in schizophrenia that presents great challenge to available treatments and has significant bearings on prognosis. Recent advance in affective neuroscience and cognitive neuroscience now suggest negative symptoms, anhedonia in particular, is now better conceptualized as a 2-facet construct involving anticipatory and consummatory components. A potentially fruitful avenue is the newly developed tools capturing anticipatory and consummatory of pleasure experience ranging from self-reported checklist, laboratory-based tests, and interview-based clinical ratings. Very little is known about the relationship of the brain regions, the negative symptoms, and the corresponding changes of associations along the course of the illness. The proposed project will adopt the trajectory-based measures of structural and functional connectivity to examine negative symptoms, especially anhedonia in schizophrenia. These will facilitate a clearer understanding on whether anhedonia may serve as a vulnerability maker for schizophrenia and contribute to the development of potential intervention for this deficit. The newly developed clinical interview, the Clinical Assessment Interview for Negative Symptoms (CAINS) will be beneficial to clarify which factors are more effective for improving the anticipatory and consummatory components of negative symptoms in patients with prominent negative symptoms. The inclusion of bipolar disorders and major depressive disorders, based on the use of these new sets of tools, will help clarify the underlying differential neural mechanisms and psychopathology of negative symptoms observed in schizophrenia. The adoption of such a systematic and theoretical framework will revolutionize psychiatric clinical practice and research regime for schizophrenia. The potential impact of this project is profound and far-reaching.

阴性症状，特别是快感缺失，一直被认为是影响精神分裂症预后的显著特征，但目前仍没有有效的治疗药物。最新神经科学研究表明，快感缺失可分成期待和即时成分，这一发现对了解阴性症状的内在机制具有重要意义。本项目将会主要以精神分裂症患者为研究对象，采用最新的临床访谈工具（阴性症状临床评估访谈，CAINS）及行为实验方法，区分期待和即时成分，考察快感缺失相关的内在神经生物学机制。这将有利于更清晰地了解快感缺失能否作为精神分裂症的易感因素之一，并有助于发展针对该缺损的潜在干预措施。同时，本项目还将纳入双相障碍和抑郁症患者，尝试阐明快感缺失这一共同的临床表现在不同疾病之间的神经病理机制的异同。采用这样一个系统的、理论化的框架将会带来精神病学的临床实践和精神分裂症的研究方式的革新，其潜在的影响是深远的。

本项目基于快感缺失的即时性和期待性的双因素模型，综合自评量表、实验室行为测量、临床访谈以及脑成像等多种测量手段，对精神分裂症患者的快感缺失及其发展变化、相关的脑结构和脑功能异常进行系统考察。验证了新一代阴性症状访谈CAINS在我国精神分裂症患者中的信度和效度。采用系统评估方法从即时和期待的两因素角度考察了精神分裂症谱系（慢性、首发精神分裂症患者和高危群体）快感缺失的症状表现。精神分裂症患者及其未患病一级家属在期待金钱刺激时所表现出的背侧纹状体功能减弱则提示纹状体功能紊乱或先发于精神分裂症。通过脑体素水平的遗传度脑图谱测绘，结果发现双侧伏隔核在期待金钱奖赏时具有显著的遗传度。待金钱奖赏时的脑激活与愉快体验共享遗传信息。相关缺损可能是精神分裂症的内表型。最后通过跨临床诊断组别（精神分裂症、双相障碍和抑郁症）考察快感缺失特异性及其与行为、认知、社会功能以及相关脑结构和脑功能异常的关系，阐明快感缺失在精神分裂症、双相障碍和抑郁症患者之间的不同临床表现及内在机制。