The Neurobiology of Adolescent Depression

描述（由申请人提供）：依据：证据表明，MOD的病理生理学需要特定脑区域（如纹状体）中神经胶质细胞和神经元的改变（即，尾状核和壳核）和膝下前额叶皮层（sgPFC）。本申请旨在通过使用质子磁共振波谱（1H-MRS）进行脑神经化学研究来启动青少年MOD的调查。1H-MRS允许对颅内代谢物水平进行非侵入性体内评估，例如胆碱（Cho）和N-乙酰天冬氨酸（NAA），其分别反映膜分解和神经元活力。青少年MOD与严重的短期和长期发病率和死亡率相关。尽管它的公共卫生的重要性，青少年MOD一直受到相对较少的生物学研究。目标：（1）通过检测青少年MOD中特定的神经化学异常来发展1H-MRS的专业知识。（2）长期计划是成为独立的研究者，并将翻译方法整合到儿科情绪障碍研究中。培训计划：包括以下方面的培训：（1）MRS和临床研究中的分析技术，（2）与青少年情绪障碍相关的诊断和研究方法，（3）生物统计学，（4）情感神经科学，（5）临床研究伦理学，通过：（1）教学课程：MRS，神经解剖学，生物统计学，神经科学和伦理学;（2）指导;（3）与多学科专家进行咨询;（4）参加科学会议;（5）制定一项与职业发展活动相辅相成的研究计划。研究计划：具体的目标将测试假设，青少年与MOD有显着降低NAA水平和显着升高的Cho水平在尾状核和壳核，与健康的青少年相比。探索性目的，将检查sgPFC中的NAA和Cho水平。研究方法：根据功效分析，受试者将包括a）30名青少年，年龄13至18岁，父母患有MOD（对于相对同质的青少年MOD组），最少8周的持续时间，CDRS-R评分>40，并且发作>13; B）30个没有父母MOD的健康比较，在性别、年龄、利手和种族方面与MOD组匹配;都是坦纳病4-5期，未接受过精神治疗神经成像将包括在高（3 T）磁场下以高空间分辨率采集的三维多体素1H-MRS，<1 cm 3的体素聚焦于尾状核、壳核和sgPFC。先前的光谱学具有使用具有低分辨率的单个体素的限制。重要性：拟议的研究将提供知识的神经生物学的MOD在发展阶段，特别是容易受到神经发育扰动。这些知识最终将改善MOD的早期识别和新治疗方法的开发。如果发现是有希望的，更大的研究将遵循，以评估其相关性MOD一般（家族性和非家族性），治疗反应的预测，和神经化学异常的诊断特异性。

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.