Neuroimaging of Dimensional Reward Dysfunction in Adolescence

描述（由申请人提供）：快感缺乏症是多种破坏性精神疾病的核心。快感缺乏是精神分裂症的主要阴性症状之一，严重恶化患者的长期预后。在双相情感障碍中，快感缺乏也是周期性抑郁发作的一个核心特征，它产生了该疾病的大部分发病率。在精神分裂症和双相情感障碍中，快感缺乏的症状通常开始于青春期。无论潜在的临床诊断如何，快感缺乏与不良的治疗反应有关。一些研究和我们的初步数据已经将快感缺乏与大脑奖励系统的功能障碍联系起来。然而，关于奖励功能障碍是如何在青春期发展而产生快感缺乏的，我们所知甚少。早期识别快感缺乏症的生物学基础是治疗进展的必要条件。在这里，我建议利用我们正在进行的大规模RC2大机遇（“GO”）神经发育研究。我计划全面评估有精神病或双相情感障碍症状的GO参与者的后续样本中的快感缺乏症和奖励系统功能，并与典型发展的青少年进行比较。将采用专门的临床措施，奖励系统反应的专用成像，以及后续脑结构和功能连接的纵向神经成像。多元模式分析技术将用于整合高维成像数据，并产生基于大脑的快感缺乏症维度测量。我们希望证明快感缺乏症的存在与反应性降低和腹侧纹状体连接中断有关，腹侧纹状体是奖励系统的关键节点。在诊断类别的维度基础上，将快感缺乏与奖励系统功能障碍联系起来，与最近发布的NIMH研究领域标准密切相关。拟议的努力将产生新颖的科学成果，并为即将完成神经精神病学博士后研究的精神病学家候选人提供重要的培训。该申请建立在候选人对奖励系统功能的既定兴趣和大量神经成像经验的基础上，最近与GO研究有关。候选人将受到经验丰富的指导委员会的指导，该委员会由主要导师Raquel Gur博士领导，他是精神分裂症和精神病理学生物学基础研究方面的知名专家。Gur博士和其他申请导师将确保从拟议的培训计划中获得的经验将使候选人能够在青少年奖励系统功能障碍的神经科学方面建立一个独立的研究项目。

DESCRIPTION (provided by applicant): Anhedonia is at the center of multiple devastating psychiatric conditions. Anhedonia is one of the cardinal negative symptoms in schizophrenia, which substantially worsen long-term outcome in affected patients. In bipolar disorder, anhedonia is also a core feature of the cyclic depressive episodes that produce the majority of the morbidity of that illness. In both schizophrenia and bipolar disorder, symptoms of anhedonia often begin in adolescence. Regardless of the underlying clinical diagnosis, anhedonia is associated with poor treatment response. Several studies and our preliminary data have linked anhedonia to dysfunction of the brain's reward system. However, very little is yet known regarding how reward dysfunction develops in adolescence to produce anhedonia. Early identification of the biological substrates of anhedonia is needed for advances in treatment. Here, I propose to capitalize upon our ongoing large-scale RC2 Grand Opportunity ("GO") study of neurodevelopment. I plan to comprehensively assess anhedonia and reward system function in a follow-up sample of GO participants with symptoms of psychosis or bipolar disorder, compared to typically developing youths. Specialized clinical measures, dedicated imaging of reward system responses, and follow-up longitudinal neuroimaging of brain structure and functional connectivity will be applied. Multivariate pattern analysis techniques will be used to integrate high-dimensional imaging data and produce a brain-based, dimensional measure of anhedonia. We expect to demonstrate that the presence of anhedonia is related to diminished responsiveness and disrupted connectivity of the ventral striatum, a key node of the reward system. Relating anhedonia to reward system dysfunction on a dimensional basis across diagnostic categories coheres closely with the recently released NIMH Research Domain Criteria. The proposed effort will produce novel scientific results and additionally provide criticl training to the candidate, who is a psychiatrist finishing his post-doctoral neuropsychiatry fellowship. The application builds upon the candidate's established interest in reward system function and substantial neuroimaging experience, most recently with the GO study. The candidate will be mentored by an experienced mentorship committee, lead by primary mentor Dr. Raquel Gur, who is a renowned expert in schizophrenia and investigations of the biological basis of psychopathology. Dr. Gur and the other application mentors will assure that the experience resulting from the proposed training plan will enable the candidate to establish an independent research program in the neuroscience of reward system dysfunction in adolescence.