Examining Reward-Related Predictors and Mechanisms of Change in BA Treatment for Anhedonic Adolescents

 描述(申请人提供)：严重抑郁障碍(MDD)的患病率在儿童时期相对较低(即1-3%)，但在青春期大幅上升。由 到18岁时，大约15%的青少年将至少经历过一次MDD发作。越来越多的研究表明，奖赏回路的异常在青少年抑郁症状的发展和维持中发挥着关键作用。重要的是，这些奖赏回路的异常与快感缺失(即快感降低或对奖赏刺激的反应迟钝)有关。行为激活(BA)代表了一种有希望的-而且相对简单的-对青少年抑郁症的非药物干预，已经被证明在减轻症状和降低成人样本中的复发风险方面至少与认知行为疗法(CBT)一样有效。最近，BA在抑郁青少年中的应用出现了一些令人振奋的数据。BA可以被概念化为一种直接针对快感缺失的治疗方法。更具体地说，BA通过行为改变策略针对快感缺乏症，旨在逐步增加患者对奖励刺激的暴露和参与，并积极加强体验。鉴于这一治疗重点，BA可能对与相对较高水平的非享乐症状作斗争的青少年特别有益。因此，本研究将检验快感缺乏和奖赏功能在预测BA的治疗反应中的作用。此外，还将分析BA无快感症状改善背后的与奖励相关的神经和行为机制。为了检验假设，本研究从三个分析单元整合了对奖赏功能的评估：1)神经回路(即通过功能磁共振成像[fMRI]货币奖赏任务探测神经奖赏回路功能)，2)行为(即设计用于客观探索享乐行为的概率奖赏任务[PRT])和3)自我报告(即Snaith-Hamilton愉悦量表[Shaps]和生态瞬间评估[EMA])。除了拟议的研究外，为期四年的K23奖将允许候选人在三个互补领域发展能力。首先，参与者将在治疗前和治疗后接受fMRI检查，同时完成一项金钱奖励任务，探索奖励回路的运作。Diego Pizzagalli博士(Mentor)是使用功能磁共振成像研究抑郁症和快感缺乏症病理生理学的领导者，布莱斯·弗雷德里克博士(顾问)是麦克莱恩成像中心的首席物理学家，他们将在功能磁共振成像的获取、处理和分析方面提供关键培训 数据。这一培训将使应聘者发展必要的技能，将神经成像功能整合到他的抑郁症治疗研究计划中，以更深入地探索症状改善的潜在神经机制。除了个人指导和实践培训外，还将提供功能磁共振成像方法方面的课程，包括1)功能磁共振访问奖学金，这是由哈佛-麻省理工学院(MIT)健康科学与技术部(HST)的阿蒂努拉·A·马蒂诺斯中心提供的功能磁共振课程；2)通过麻省理工学院/马蒂诺斯健康科学与技术部提供的MATL for Medicine；3)为麻省理工学院的基础和临床研究人员提供的SPM8；以及4)通过MRI和马蒂诺斯中心提供的功能磁共振成像实现脑结构和功能的连通性。其次，为了对症状变化和青少年获得和利用BA所鼓励的技能的程度进行更精细和自然的评估，申请者将接受Erika Forbes博士(共同导师)的生态瞬时评估(EMA)培训，Erika Forbes博士是将生态瞬时评估用于抑郁和健康青少年的先驱。Garret Fitzmaurice博士(顾问)将提供增长曲线建模方面的统计咨询，以测试项目中提出的纵向心理社会(EMA)和神经(FMRI)假说。最后，拟议的培训计划将使应聘者大大加深他对青少年抑郁症的功能神经解剖学的理解，特别关注辅助奖赏处理和快感缺乏的神经回路(Pizzagalli博士和福布斯博士)。临床咨询和监督将通过与BA的主要权威Sona Dimidkin博士(顾问)和McLean医院行为健康部分计划主任THRöstur Björgvinsson(顾问)的会议获得。总之，拟议的研究和培训将为申请者提供坚实的fMRI和EMA基础，并可能产生关于与奖励相关的预处理预测因子和症状改善机制的重要发现。项目完成后，候选人将做好最佳准备，继续进行一项集神经、行为和心理社会研究方法于一体的创新研究计划，以回答这些重要问题。总而言之，这一奖项将使候选人转变为一名全面和独立的研究人员，拥有一系列补充和尖端的评估和神经调查工具，用于研究青年抑郁症。

 DESCRIPTION (provided by applicant): The prevalence of major depressive disorder (MDD) is relatively low in childhood (i.e., 1-3%), but increases substantially during adolescence. By the age of 18, approximately 15% of adolescents will have experienced at least one episode of MDD. A growing body of research implicates abnormalities in reward circuitry as playing a critical role in the development and maintenance of depressive symptoms in adolescents. Importantly, these reward-circuitry abnormalities have been linked to anhedonia (i.e., decreased pleasure or blunted reactivity to rewarding stimuli). Behavioral Activation (BA) represents a promising - and relatively simple to deliver - nonpharmacologic intervention for adolescent depression, which has been shown to be at least as effective as Cognitive Behavioral Therapy (CBT) with regards to symptom reduction and lowering the risk of relapse in adult samples. More recently, promising data have emerged from the application of BA to depressed adolescents. BA can be conceptualized as a treatment directly targeting anhedonia. More specifically, BA targets anhedonia through behavioral change strategies aimed at gradually increasing patients' exposure to and engagement with rewarding stimuli and positively reinforcing experiences. Given this treatment focus, BA may be particularly beneficial for adolescents struggling with relatively elevated levels of anhedonic symptoms. Accordingly, the present study will examine the role of anhedonia and reward functioning in predicting treatment response in BA. In addition, analyses will be conducted examining the reward-related neural and behavioral mechanisms underlying anhedonic symptom improvement in BA. To test hypotheses, this study integrates assessments of reward functioning from three units of analysis: 1) neural circuits (i.e., via a functional magnetic resonance imaging [fMRI] monetary reward task probing neural reward- circuitry functioning), 2) behavioral (i.e., with a probabilisti reward task [PRT] designed to objectively probe anhedonic behavior) and 3) self-report (i.e., Snaith-Hamilton Pleasure Scale [SHAPS] and Ecological Momentary Assessment [EMA]). In addition to the proposed research, the four-year K23 Award will allow the candidate to develop competency in three complementary areas. First, participants will undergo fMRI at pre- and post-treatment while completing a monetary reward task probing reward-circuitry functioning. Dr. Diego Pizzagalli (mentor), a leader in the use of fMRI to investigate the pathophysiology of depression and anhedonia, and Dr. Blaise Frederick (consultant), lead physicist at the McLean Imaging Center, will provide critical training in the acquisition, processing, and analysis of fMRI data. This training will allow the candidate to develop the skills necessary to integrate functiona neuroimaging into his depression treatment research program to more deeply probe the underlying neural mechanisms of symptom improvement. Individual mentorship and hands-on training will be supplemented by coursework in fMRI methodology, including 1) the Functional MRI Visiting Fellowship, an fMRI course offered through the Athinoula A. Martinos Center at the Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences & Technology (HST); 2) MATLAB for Medicine offered through MIT/HST; 3) SPM8 for Basic and Clinical Investigators at MIT; and 4) Structural and Functional Brain Connectivity via MRI and fMRI offered through the Martinos Center. Second, to obtain a more fine- grained and naturalistic assessment of symptom change and the extent to which adolescents acquire and utilize the skills encouraged in BA, the applicant will receive training in Ecological Momentary Assessment (EMA) from Dr. Erika Forbes (co-mentor), a pioneer in the use of EMA with depressed and healthy adolescents. Dr. Garret Fitzmaurice (consultant) will provide statistical consultation in Growth Curve Modeling to test the longitudinal psychosocial (EMA) and neural (fMRI) hypothesis proposed in the project. Finally, the proposed training plan would allow the candidate to substantially deepen his understanding of the functional neuroanatomy of adolescent depression, with a particular focus on the neural circuitry subserving reward processing and anhedonia (Drs. Pizzagalli & Forbes). Clinical consultation and supervision will be obtained through meetings with Drs. Sona Dimidjian (consultant), a leading authority in BA, and Thröstur Björgvinsson (consultant), Director of the Behavioral Health Partial Program at McLean Hospital. Collectively, the proposed research and training will provide the applicant with a strong foundation in fMRI and EMA, and may yield important findings regarding the reward-related pretreatment predictors and mechanisms of symptom improvement in anhedonic and depressed youth. Upon completion of the project, the candidate will be optimally prepared to pursue an innovative research program integrating neural, behavioral and psychosocial research methods to answer these important questions. In sum, this award would allow the candidate to transition into a well-rounded and independent researcher armed with an array of complementary and cutting-edge assessment and neuro-investigative tools for the study of depression in youth.