The Neurobiology of Adolescent Depression

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DESCRIPTION (provided by applicant): Rationale: Evidence suggests that the pathophysiology of MOD entails alterations of glia and neurons in specific brain regions such as the striatum (i.e., caudate and putamen) and subgenual prefrontal cortex (sgPFC). This application is to initiate an investigation of adolescent MOD through the study of brain neurochemistry using proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS allows the non-invasive in-vivo assessment of intra-cranial metabolite levels such as choline (Cho) and N-acetylaspartate (NAA), which reflect membrane break-down and neuronal viability respectively. Adolescent MOD is associated with serious short and long-term morbidity and mortality. Despite its public health importance, adolescent MOD has been subject to relatively little biological research. Goals: (1) To develop expertise in 1H-MRS through testing for specific neurochemical abnormalities in adolescent MOD. (2) Long-term plans are to become an independent investigator and integrate translational methods into pediatric mood disorder research. Training Plan: Includes training in: (1) MRS and analytic techniques in clinical research, (2) diagnostic and research methods relevant to mood disorders in youth, (3) biostatistics, (4) affective neuroscience, (5) ethics of clinical research, through: (1) didactic courses: MRS, neuroanatomy, biostatistics, neuroscience, and ethics; (2) mentoring; (3) consultation with multidisciplinary experts; (4) participation at scientific meetings; and (5) a research plan that complements career development activities. Research Plan: Specific aim will test hypotheses that adolescents with MOD have significantly lower NAA levels and significantly elevated Cho levels in the caudate and putamen, compared to healthy adolescents. Exploratory aim, will examine NAA and Cho levels in the sgPFC. Methods: Based on power analyses, subjects will consist of a) 30 adolescents, ages 13 through18, with parental MOD (for a relatively homogenous group of adolescent MOD), minimum 8 weeks' duration, CDRS-R scores>40, and onset at >13; b) 30 healthy comparisons without parental MOD, matched to MOD group for gender, age, handedness, and ethnicity; all at Tanner stages 4-5, and psychotropic naive. Neuroimaging will include 3 dimensional multivoxel 1H-MRS acquired at high (3T) magnetic field with high spatial resolution, <1 cm3 voxels focusing on caudate, putamen and sgPFC. Previous spectroscopy has had the limitation of using single voxels with low resolution. Significance: The proposed research will provide knowledge of the neurobiology of MOD during a developmental stage that is particularly vulnerable to neurodevelopmental perturbations. Such knowledge would ultimately improve early identification of MOD, and the development of novel treatments. If findings are promising, larger studies will follow to assess their relevance to MOD in general (familial and non-familial), the prediction of treatment response, and the diagnostic specificity of neurochemical abnormalities.