Neural Substrates of Deprerssion Risk after Child Abuse

描述(由申请者提供)：这份K01申请的目标是用脑功能成像、情感神经科学和人类遗传学方面的专门研究培训来补充候选人之前在临床心理生物学方面的培训。培训计划包括正式的课程、教程和研究实践，这些将为在神经系统水平上研究压力和抑郁之间的关系以及这种关系的遗传调节提供必要的技能基础。多学科培训部分应用于特定的实验。这项研究计划直接建立在证据的基础上，即早期生活应激(ELS)可能通过诱导对额外压力的敏感化而增加成年后患抑郁症的风险。抑郁症的神经成像研究结果表明，皮质-边缘网络的功能变化不同，反映了风险、疾病和补偿机制的组合，尽管ELS相关的风险和韧性从未被研究过。这项拟议项目的主要目标是确定ELS中抑郁风险和韧性的神经标记物，相对于抑郁疾病的标记物。60名妇女将被招募到3组，包括20名对照组，20名从未抑郁的有儿童期性/身体虐待史的女性，以及20名被诊断为当前严重抑郁障碍(MOD)和儿童期性/身体虐待史的女性。将使用两种经过验证的激活探针，它们直接针对抑郁途径，并已显示出检测风险、弹性和疾病标记物的灵敏度，即(A)在悲伤情绪诱导期间的正电子发射断层扫描(PET)和(B)自我参照情绪处理的功能磁共振成像(FMRI)。方差分析将用于对比ELS中风险、弹性和MOD的神经标记物。将研究神经内分泌应激反应和遗传状态(5HTTLPR多态)对神经激活模式的独立贡献，并评估与ELS-MDD组状态的交互作用。这项研究将加深我们对ELS转化为抑郁症的神经机制的理解，并将促进在神经水平上深入了解ELS、遗传风险和神经内分泌状态之间的相互作用。这一K01奖项将为候选人提供不同学科的深度和广度，这对于考虑未来复杂精神障碍的多因素贡献者至关重要。

DESCRIPTION (provided by applicant): The goal of this K01 application is to complement the candidate's previous training in clinical psychobiology with specialized research training in functional brain imaging, affective neuroscience, and human genetics. The training plan includes formal coursework, tutorials and research practice that will provide foundation in skills necessary to study the relationship between stress and depression, as well as the genetic moderation of this relationship, at the neural systems level. The multidisciplinary training components are applied in a specific experiment. The research plan directly builds on evidence that early-life stress (ELS) increases risk for developing depressive disorders in adulthood, likely by inducing sensitization to additional stress. Findings from neuroimaging studies in depression suggest variable functional changes in cortical-limbic networks, reflecting a combination of risk, illness and compensatory mechanisms, though ELS-related risk and resilience have never been studied. It is the principal goal of the proposed project to identify neural markers of depression risk and resilience, relative to markers of depressive illness, in ELS. Sixty women will be recruited into 3 groups, including 20 controls, 20 never-depressed women with a history of childhood sexual/physical abuse, and 20 women with a diagnosis of current major depressive disorder (MOD) and a history of childhood sexual/physical abuse. Two well-validated activation probes that directly target depression pathways and have demonstrated sensitivity to detect risk, resilience and illness markers will be applied, i.e. (a) positron-emission tomography (PET) of cerebral blood flow during sad mood induction and (b) functional magnetic resonance imaging (fMRI) of self-referential emotional processing. Analysis of variance will be used to contrast neural markers of risk, resilience and MOD in ELS. The independent contributions of neuroendocrine stress response and genetic status (5HTTLPR polymorphism) to neural activation patterns will be studied and interactions with ELS-MDD group status will be evaluated. The study will enhance our understanding of the neural mechanisms, by which ELS is translated into depression and will promote insight into the interaction between ELS, genetic risk and neuroendocrine status at the neural level. This K01 award will provide the candidate with depth and breadth in distinct disciplines, which is critical for considering the multifactorial contributors to complex psychiatric disorders in the future.