Changes in brain function during adolescence and risk for depression in girls

描述(由申请人提供)：抑郁症发病率增加和出现性别差异的发展时机表明，青春期是理解女性抑郁障碍发展的原因机制的关键时期。青春期神经发育可能在抑郁症的病因中发挥关键作用，但人们对青春期神经回路发育和抑郁症之间的联系知之甚少。作为对PA-09-108女性心理健康和性别/性别差异研究的回应，我们将确定情绪唤起刺激所涉及的神经回路的发育变化是否与女孩的青春期抑郁有关。将抑郁症状的发展轨迹映射到相关的神经系统将进一步加深我们对大脑功能成熟变化的理解，这些变化导致了与年龄相关的脆弱性。调查人员：基南博士、盖尔博士和福布斯博士是PI；他们两年前开始在抑郁症的神经科学方面进行合作。专门从事纵向建模的统计学家凯文·格里姆博士和女性心理健康专家艾莉森·希普韦尔博士是联合调查员。顾问是陈刚博士、罗纳德·达尔博士、康斯坦斯·哈曼博士和丹尼尔·派恩博士。创新：信息处理中的大脑行为扰动是临床神经科学研究的主要焦点。青春期神经回路的发育变化对于理解这一时期精神病理学的出现至关重要。然而，到目前为止，还没有研究被设计来检验这样的假设，即青春期情感和认知回路之间的功能联系的发展与抑郁症的发病有关，或者描述实际上赋予抑郁症发病风险的神经发育模式。方法：这项建议建立在最近完成的一项由NIMH资助的关于女孩抑郁前兆的研究基础上，在该研究中，9-14岁的抑郁症状和负性生活事件被记录下来。样本中有一半是根据表明患抑郁症风险较高的指标选择的。对于这个PA，我们建议对15-19岁的样本进行研究，并使用神经成像对抑郁和环境应激源进行年度评估，以及对情绪记忆和奖励处理进行年度评估。在情绪面孔和奖赏加工的记忆过程中，杏仁核-腹侧-外侧前额叶皮质(VLPFC)回路和纹状体-内侧前额叶(MPFC)回路之间的功能连接的发育模式将分别在四个时间点被捕捉，以及环境应激暴露。环境：这项提案涉及芝加哥大学、匹兹堡大学和加州大学戴维斯分校的多机构调查。对抑郁、压力暴露和脑功能的评估将在匹兹堡大学精神病学系和西方精神病学研究所和诊所的情绪障碍神经成像实验室进行，该实验室在大脑功能和儿童精神病理学研究方面得到国际认可。 公共卫生相关性：我们建议确定青春期大脑对情绪刺激的反应方式的发育变化是否可以告诉我们哪些女孩有患抑郁症的风险。青春期似乎是大脑中帮助调节情绪反应的回路发展的脆弱时期。通过从15岁到19岁进行一项纵向研究，我们将能够检查从青春期中期到后期大脑功能的个体差异，并测试发育成熟大脑回路的不同路径是否解释了患抑郁症风险的个体差异。

DESCRIPTION (provided by applicant): The developmental timing of the increase in the rate and the emergence of sex differences in depression points to adolescence as a critical period for understanding the causal mechanisms underlying the development of depressive disorders in females. Adolescent neural development is likely to play a key role in the etiology of depression, but little is known about the interface between the development of neural circuitry and depression across adolescence. In response to PA-09-108 Women's Mental Health and Sex/Gender Differences Research, we will determine if developmental changes in the neural circuitry engaged by emotionally evocative stimuli are related to adolescent depression in girls. Mapping developmental trajectories of depression symptoms onto relevant neural systems will further our understanding of the maturational changes in brain function that contribute to age-related vulnerability. Investigators: Drs. Keenan, Guyer and Forbes are the PIs; they began collaborating on the neuroscience of depression two years ago. Dr. Kevin Grimm, a statistician specializing in longitudinal modeling, and Dr. Alison Hipwell an expert in female mental health, are Co- Investigators. Consultants are Drs. Gang Chen, Ronald Dahl, Constance Hammen, and Daniel Pine. Innovation: Brain-behavior perturbations in information processing are a major focus of clinical neuroscience research. Developmental shifts in neural circuits during adolescence are critical to understanding the emergence of psychopathology during this period. No study to date, however, has been designed to test the hypothesis that development of the functional connections between affective and cognitive circuits during the adolescent period is related to depression-onset, or to characterize the patterns of neural development that in fact confer risk for depression onset. Approach: This proposal builds on a recently completed NIMH-funded study of precursors to depression in girls, in which depression symptoms and negative life events were documented from ages 9-14. Half of the sample was selected on measures indicative of high risk for developing depressive disorders. For this PA, we propose to study this sample from ages 15-19 years and to conduct annual assessments of depression and environmental stressors and annual assessments of emotional memory and reward processing using neuroimaging. Developmental patterns in functional connectivity between amygdala-ventral-lateral prefrontal cortex (vlPFC) circuitry and striatum-medial prefrontal cortex (mPFC) circuitry during memory for emotional faces and reward processing, respectively, will be captured across four time points, as will environmental stress exposure. Environment: This proposal involves a multi-institutional investigation at the Universities of Chicago, Pittsburgh, and California-Davis. Assessments of depression, stress exposure, and brain function will be conducted in the University of Pittsburgh's Department of Psychiatry and the Neuroimaging of Emotional Disorders Lab at Western Psychiatric Institute and Clinic, which is internationally recognized for research on brain functioning and child psychopathology. PUBLIC HEALTH RELEVANCE: We propose to determine if developmental changes in how the brain responds to emotional stimuli during adolescence can inform us regarding which girls are at risk for developing depressive disorders. Adolescence appears to be a time of vulnerability in terms of developing circuits in the brain that help regulate emotional responses. By conducting a longitudinal study from ages 15-19 we will be able to examine individual differences in brain functioning from mid to late adolescence and test whether different pathways to developing mature brain circuits explains individual differences in risk for depression.