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. Thrstur Bjrgvinsson (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, Bjrgvinsson, 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.
The prevalence of depression increases dramatically during adolescence, and it is associated with negative short- and long-term consequences. Despite alarming epidemiological data, the pathophysiology of depression is largely unknown. The goal of the project is to identify behavioral and neurobiological mechanisms underpinning depression in female adolescents, and moreover, to determine whether psychotherapy improves behavioral and neural functioning.
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