Glutamate Probes in Adolescent Depression

描述（由申请人提供）：本提案旨在获得K23指导患者导向研究职业发展奖，以完成所需的培训和研究经验，为候选人作为独立研究者的成功职业做好准备。候选人的长期目标是从事儿童和青少年精神病学的学术研究，专注于改善抑郁症患者的护理。这将通过增加对其病理生理学的理解来实现。抑郁症是儿童时期一种重要而常见的疾病，是一个重大的公共卫生问题，也是世界范围内导致残疾的主要原因。最近对成人抑郁症的基础科学和临床研究表明，谷氨酸是大脑的主要兴奋性神经递质，在抑郁症的神经化学基础中起作用。关于谷氨酸在青少年抑郁症中的作用的信息很少。质子磁共振波谱（1H-MRS）是一种非侵入性脑成像技术，可测量大脑中谷氨酸等化学物质的浓度。皮质内促进（ICF）是一种经颅磁刺激（TMS）神经生理测试，用于测量谷氨酸的功能。候选人建议使用1H-MRS和ICF在青少年抑郁症中进行谷氨酸浓度和功能的横断面研究[三组]受试者（尚未服用抗抑郁药物的抑郁症受试者，对抗抑郁药物有反应的抑郁症受试者和健康对照组）。抑郁症患者将在氟西汀标准临床治疗8周后重复这两项测试。这将验证以下假设：在青少年抑郁症患者中，皮质谷氨酸浓度下降而谷氨酸功能增加，氟西汀的成功治疗使这些差异正常化。这种创新的方法将促进对青少年抑郁症中谷氨酸神经传递的理解，为新的生物标志物的开发提供信息，并协助确定治疗靶点。这个项目是专门为联邦R01基金申请中抑郁青少年的后续纵向研究提供信息的。候选人先前有ICF测量的经验，但将受益于1H-MRS方法学和TMS神经生理学范式的额外培训。候选人和指导团队提出了一个职业发展计划，重点是1H-MRS神经成像，TMS神经生理学研究，临床和转化研究方法，[神经发育]和疾病研究的神经生物学。这个严格的计划包括密集的指导、梅奥诊所研究生院的课程和国际研讨会。关于出版物和拨款申请的明确基准将确保在奖励期间取得可观的生产力，并成功过渡到儿童和青少年精神病学的独立学术研究人员。

DESCRIPTION (provided by applicant): This proposal is for a K23 Mentored Patient-Oriented Research Career Development Award to complete training and research experience needed to prepare the candidate for a successful career as an independent investigator. The candidate's long-term goal is a career in academic child and adolescent psychiatry focused on research that improves the care of patients with depression. This will be accomplished through increased understanding of its pathophysiology. Depression is a significant and common illness during childhood, a major public health problem, and a leading causes of disability worldwide. Recent basic science and clinical research in adults with depression suggests that glutamate, the brain's primary excitatory neurotransmitter plays a role in the neurochemical basis of depression. There is little information about the functioning of glutamate in adolescents with depression. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive brain imaging technique that measures the concentrations of brain chemicals such as glutamate. Intracortical facilitation (ICF) is a transcranial magnetic stimulation (TMS) neurophysiological test which measures the functioning of glutamate. The candidate proposes to use 1H-MRS and ICF in a cross-sectional study of glutamate concentrations and functioning in adolescent depression [with three groups] of subjects (depressed subjects who have not yet taken an antidepressant medication, subjects who had depression that responded to an antidepressant, and healthy controls). [Depressed subjects will have these two measures repeated after eight weeks of standard clinical treatment with fluoxetine. This will test the hypotheses that cortical glutamate concentrations are decreased while glutamate functioning is increased in adolescents with depression and that successful treatment with fluoxetine normalizes these differences.] This innovative approach will advance understanding of glutamate neurotransmission in adolescent depression, inform the development of new biomarkers, and assist with the identification of treatment targets. This project is tailored to inform subsequent longitudinal studies of depressed adolescents for federal R01 grant applications. The candidate has prior experience with ICF measures but would benefit from additional training in 1H-MRS methodology and TMS neurophysiology paradigms. The candidate and mentoring team propose a career development plan focused on 1H-MRS neuroimaging, TMS neurophysiology studies, clinical and translational research methodologies, [neurodevelopment,] and the neurobiology of disease research. This rigorous plan includes intensive mentoring, courses through the Mayo Clinic Graduate School, and international seminars. Well defined benchmarks regarding publications and grant submissions will ensure substantial productivity during the award period and a successful transition to an independent academic researcher in child and adolescent psychiatry.