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

 描述（由申请人提供）：重度抑郁症（MDD）的患病率在儿童期相对较低（即，1-3%），但在青春期大幅增加。由 18岁时，约15%的青少年至少经历过一次MDD发作。越来越多的研究表明，奖励回路的异常在青少年抑郁症状的发展和维持中起着至关重要的作用。重要的是，这些奖励电路异常与快感缺乏有关（即，减少的快乐或对奖励刺激的迟钝反应）。行为激活（BA）代表了一种有前途的-并且相对简单的-青少年抑郁症的非药物干预，已被证明在症状减轻和降低成人样本复发风险方面至少与认知行为疗法（CBT）一样有效。最近，有希望的数据已经出现了从BA抑郁症青少年的应用。BA可以被概念化为直接针对快感缺乏的治疗。更具体地说，BA通过行为改变策略来靶向快感缺乏，这些策略旨在逐渐增加患者对奖励刺激和积极强化体验的接触和参与。考虑到这种治疗重点，BA可能特别有利于青少年与相对较高水平的快感缺失症状作斗争。因此，本研究将探讨快感缺乏和奖励功能在预测BA治疗反应中的作用。此外，将进行分析，检查奖励相关的神经和行为机制的基础上，在BA的快感缺乏症状的改善。为了验证假设，本研究从三个分析单元整合了对奖励功能的评估：1）神经回路（即，通过功能性磁共振成像[fMRI]货币奖励任务探测神经奖励-电路功能），2）行为（即，具有被设计为客观地探测快感缺失行为的概率奖励任务[PRT]）和3）自我报告（即，Snaith-Hamilton快乐量表[SHAPS]和生态瞬时评估[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功能性磁共振成像，同时完成一项探索奖励电路功能的金钱奖励任务。Diego Pizzagalli博士（导师）是使用fMRI研究抑郁症和快感缺乏症病理生理学的领导者，Blaise Frederick博士（顾问）是姆克林成像中心的首席物理学家，将提供fMRI采集，处理和分析方面的关键培训 数据该培训将使候选人能够发展将功能神经成像纳入其抑郁症治疗研究计划所需的技能，以更深入地探索症状改善的潜在神经机制。个人指导和实践培训将通过功能磁共振成像方法学课程进行补充，包括1）功能磁共振成像访问奖学金，通过Athinoula A提供的功能磁共振成像课程。Martinos Center at the Harvard-Massachusetts Institute of Technology（MIT）Division of Health Sciences & Technology（HST）; 2）MATLAB for Medicine provided through MIT/HST; 3）SPM 8 for Basic and Clinical Investigators at MIT; and 4）Structural and Functional Brain Connectivity via MRI and fMRI provided through the Martinos Center.其次，为了对症状变化以及青少年获得和利用BA鼓励的技能的程度进行更细致和自然的评估，申请人将接受Erika博士的生态瞬时评估（EMA）培训。福布斯（联合导师），他是对抑郁症和健康青少年使用EMA的先驱。Garret Fitzmaurice博士（顾问）将提供增长曲线建模的统计咨询，以测试该项目中提出的纵向心理社会（EMA）和神经（fMRI）假设。最后，拟议的培训计划将使候选人大大加深他对青少年抑郁症的功能性神经解剖学的理解，特别关注促进奖励处理和快感缺乏的神经回路（Pizzagalli和福布斯博士）。临床咨询和监督将通过与BA的主要权威索纳·迪米吉安博士（顾问）和姆克林医院行为健康部分项目主任Thröstur Björgvinsson（顾问）的会议获得。 总的来说，拟议的研究和培训将为申请人提供功能磁共振成像和EMA的坚实基础，并可能产生有关奖励相关的预处理预测因子和快感缺失和抑郁青年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，以追求创新的研究计划，整合神经，行为和心理社会研究方法，以回答这些重要问题。总之，该奖项将使候选人过渡到一个全面的和独立的研究人员配备了一系列的补充和尖端的评估和神经调查工具，用于青年抑郁症的研究。

 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.