Examination of Reward Processing in the Treatment of Adolescent Major Depression

描述(由申请人提供)：严重抑郁障碍(MDD)的流行率在青春期增加了5倍，到18岁时，大约20%的年轻人将经历抑郁发作。在15岁左右，MDD的性别差异开始显现，女孩报告的抑郁发作是男孩的两倍-这种差异一直持续到成年。这些事件与严重的短期和长期负面后果有关，尽管有这些令人震惊的流行病学数据，但青少年MDD的病理生理过程在很大程度上是未知的。在为期五年的K23导师患者导向研究职业发展奖中，申请者将从事一项创新的研究，考察奖励学习在青少年MDD中的作用，同时接受基本培训，这将显著扩展循证治疗和神经科学领域的专业知识。具体地说，该项目将研究抑郁女性青少年奖赏功能障碍的心理社会、行为和神经机制，以及这些机制的改善是否有助于心理治疗后症状的缓解。在这个新颖的项目中嵌入了明确的培训目标，将在Diego Pizzagalli博士(主要导师)和John Weisz博士(联合导师)的指导下实施。首先，在研究的初始阶段，抑郁和健康的女性青少年将参与脑电(EEG)实验，同时完成一项探索学习刺激-奖赏偶发事件的任务。Pizzagalli博士和Greg Hajcak博士(顾问)将提供收集、处理和分析事件相关电位(ERP)数据的关键培训，这将使应聘者开发与客观的、基于实验室的奖赏处理功能障碍评估相关的新研究技能。这种培训将通过参加由心理生理研究学会组织的事件相关电位(ERP)训练营来补充。其次，人际压力在加剧抑郁症状方面发挥着深远的作用，特别是在女性青少年中，因此，参与者将在收集功能磁共振成像(FMRI)数据的同时完成同行评估任务。Daniel Pine博士(顾问)将在获取和分析与奖励回路相关的数据方面提供关键指导，以更好地理解同伴拒绝和接受、奖励功能障碍和MDD之间的关系。为了补充这一培训，我还将报名参加阿蒂努拉·A·马蒂诺斯中心功能磁共振访问奖学金，这是一个为期5天的MR研究密集介绍。此外，为了更好地为分析功能磁共振数据做准备，我还将 注册SPM8基础和临床研究人员研讨会，这是一个由麻省理工学院提供的为期5天的强化研讨会。此外，我将完成哈佛医学院提供的神经生物学课程，以便为神经解剖学和认知神经科学奠定坚实的基础。最后，抑郁的女性青少年将完成为期16周的个人认知行为治疗，以调查治疗对行为和神经机制的影响，这些机制是奖励处理的基础。为了实现这一目标，申请者将分别从Hajcak博士和Pizzagalli博士那里学习ERP数据的时频分解和最先进的分布式源定位技术。此外，Weisz博士和THR？STUR BJ？rgvinsson博士(顾问)将为实施治疗研究提供专家指导，Garrett Fitzmaurice博士(顾问)将培训申请者使用先进的回归分析方法。为了补充Weisz博士、Bjürgvinsson博士和Pizzagalli博士的不足，我将参加由哈佛公共卫生学院提供的临床试验原理课程。本课程涉及临床试验的不同方面，包括研究设计、质量控制和生物统计学应用。总而言之，要解构有关MDD发病和复发的更核心问题，使用跨学科的方法是至关重要的。尤其是临床心理和情感方面的综合训练 神经科学有望极大地提高我们对MDD病因和治疗的理解。因此，为期五年的K23奖将在四个相辅相成的领域发展能力：(1)临床研究设计；(2)心理社会、行为和神经数据的统计建模；(3)与MDD相关的神经解剖学和认知神经科学；(4)神经成像技术，特别是高密度脑电和功能磁共振。重要的是，麦克莱恩医院是进行儿童和青少年研究的理想环境。临床和行为数据将在位于麦克莱恩校区的抑郁、焦虑和压力研究中心(CDASR)收集，该中心包括临床面试室和行为测试室，这些房间配备了双向对讲系统和用于行为观察的摄像机。神经成像扫描将在神经成像中心完成，该中心距离麦克莱恩校园内的CDASR只有很短的步行距离。扫描设施非常适合与儿童进行研究(例如，提供一台模拟的核磁共振扫描仪，为喜欢参加会议的父母提供候诊区)。在发生严重危机的情况下，McLean通过临床评估中心提供24小时临床支持，该中心专门负责稳定处于困境中的个人。总的来说，拟议的研究和培训将为申请者提供坚实的神经科学和临床试验基础，同时也显著促进我们对青少年MDD所涉及的神经认知机制的理解。

DESCRIPTION (provided by applicant): The prevalence of major depressive disorder (MDD) increases 5-fold during adolescence, and by the age of 18, approximately 20% of youth will experience a depressive episode. Around the age of 15, gender differences in MDD begin to emerge with girls reporting twice as many depressive episodes as compared to boys - a difference that persists throughout adulthood. These episodes are associated with profound short- and long-term negative consequences, and despite these alarming epidemiological data, the pathophysiological processes underlying MDD in adolescents are largely unknown. Throughout the five-year K23 Mentor Patient-Oriented Research Career Development Award, the applicant will pursue an innovative line of research examining the role of reward learning in adolescent MDD, and at the same time, receive essential training, which will significantly extend expertise in the domains of evidence-based treatments and neuroscience. Specifically, the project will examine psychosocial, behavioral, and neural mechanisms underpinning reward dysfunction in depressed female adolescents, and whether improvement in these mechanisms contributes to symptom attenuation following psychotherapy. Embedded within this novel project are clear training aims, which will be implemented with guidance from Dr. Diego Pizzagalli (primary mentor) and Dr. John Weisz (co-mentor). First, in the initial phase of the study, depressed and healthy female adolescents will participate in an electroencephalography (EEG) experiment while completing a task that probes learning of stimulus-reward contingencies. Dr. Pizzagalli and Dr. Greg Hajcak (consultant) will provide critical training for collecting, processing, and analyzing event-related potential (ERP) data, which will allow the candidate to develop new research skills linked to objective, laboratory-based assessments of reward processing dysfunction. Such training will be complemented by attendance of the Event-Related Potential (ERP) Boot Camp organized by the Society for Psychophysiological Research. Second, interpersonal stress plays a profound role in potentiating depressive symptoms, particularly among female adolescents, and thus, participants will complete a peer evaluation task while functional magnetic resonance imaging (fMRI) data are collected. Dr. Daniel Pine (consultant) will provide key mentorship regarding the acquisition and analysis of data associated with reward circuitry to better understand the relationship among peer rejection and acceptance, reward dysfunction, and MDD. To supplement this training I will also enroll in the Athinoula A. Martinos Center Functional MRI Visiting Fellowship, which is a 5-day intensive introduction to MR research. Moreover, to better prepare for the analysis of fMRI data, I will also register in the SPM8 seminar for Basic and Clinical Investigators, which is a 5-day intensive workshop offered through MIT. Further, I will complete a Neurobiology course offered through Harvard Medical School in order to develop a strong foundation regarding neuroanatomy and cognitive neuroscience. Last, depressed female adolescents will complete 16-weeks of individual cognitive behavioral therapy to investigate the treatment effects on behavioral and neural mechanisms that underlie reward processing. In pursuit of this goal, the applicant will learn time-frequency decomposition of ERP data and state-of-the-art distributed source localization techniques from Dr. Hajcak and Dr. Pizzagalli, respectively. Additionally, while Dr. Weisz and Dr. Thr¿stur Bj¿rgvinsson (consultant) will provide expert mentorship for implementing the treatment study, Dr. Garrett Fitzmaurice (consultant) will train the applicant in the use of advanced regression methods for analysis. To complement Drs. Weisz, Bj¿rgvinsson, and Pizzagalli, I will enroll in Principles of Clinical Trials, which is offered through the Harvar School of Public Health. The course addresses different aspects of clinical trials including study design, quality control, and biostatistical applications. In sum, to deconstruct more central questions regarding the onset and recurrence of MDD, it is essential to utilize an interdisciplinary approach. In particular, integrated training in clinical psychology and affective neuroscience is expected to dramatically improve our understanding of the etiology and treatment of MDD. Accordingly, the five-year K23 Award will develop competency in four complementary areas: (1) clinical research design; (2) statistical modeling of psychosocial, behavioral, and neural data; (3) neuroanatomy and cognitive neuroscience associated with MDD; and (4) neuroimaging techniques, specifically high-density EEG and fMRI. Importantly, McLean Hospital is an ideal environment to conduct research with children and adolescents. Clinical and behavioral data will be collected in the Center for Depression, Anxiety and Stress Research (CDASR), which is located on the McLean Campus, and includes clinical interview rooms and behavioral testing rooms that are equipped with a 2-way intercom system and a video camera for behavioral observations. Neuroimaging scans will be completed in the Neuroimaging Center located a brief walk from the CDASR on the McLean Campus. Scanning facilities are well suited to research with children (e.g., availability of a "mock" MRI scanner, waiting area for the parents who like to attend the session). In case of an acute crisis, McLean provides 24-hour clinical support through the Clinical Evaluation Center, which specializes in the stabilization of individuals in distress. Collectively, the research and training proposed will provide the applicant with a strong foundation in neuroscience and clinical trials, while also significantly advancing our understanding of neurocognitive mechanisms implicated in adolescent MDD.