Functional MRI Studies of Emotion in Depression and Rapid Antidepressant Response

描述（由申请人提供）：这个以患者为导向的指导职业发展奖（K23）的长期目标是支持候选人在功能神经影像学和情绪障碍实验治疗方面的职业发展。这将通过结构化的监督研究经验和正式的指导来完成，将重点放在以下培训领域：(1)临床研究方法，生物统计学和伦理学；(2)功能神经影像学方法学；(3)情感与认知神经科学。提出的研究策略的具体目标是表征治疗难治性抑郁症（TRD）患者体内情绪处理神经网络的功能，并确定这些网络中特定于快速抗抑郁反应的功能变化。传统的抗抑郁药物治疗产生治疗效果的速度很慢，20-30%的重度抑郁症患者未能获得足够的治疗反应（即经历TRD）。最近发现，麻醉剂氯胺酮（一种n -甲基- d-天冬氨酸（NMDA）谷氨酸受体拮抗剂）具有快速而强大的抗抑郁作用，这为检验有关速效治疗作用机制的假设提供了一个独特的机会。该研究将利用先进的认知神经科学技术和功能磁共振成像（fMRI）来研究支持情绪产生/调节的关键神经系统的具体功能贡献，包括前额叶皮层（PFC）、前扣带皮层（ACC）和相关的皮层下结构，在TRD和氯胺酮的快速抗抑郁反应中。TRD受试者将在基线（抑郁状态）进行功能磁共振成像，然后在单次静脉注射氯胺酮或对照治疗后24小时再次进行。fMRI策略将利用经过验证的负面情绪偏见（悲伤的面部表情）探针和情绪调节（认知重新评估）探针，具体地招募与抗抑郁作用机制有关的PFC/ACC结构。本研究将对TRD患者抑郁状态下情绪产生（如皮层下）和调节（如PFC/ACC）神经系统的作用以及这些系统的功能变化与氯胺酮引起的抑郁症状变化相关的特定假设进行测试。在K23奖励期间获得的技能和数据以及开发的研究方法将为候选人提供实现成为情绪障碍临床神经科学研究独立研究者的长期目标所需的工具。

DESCRIPTION (provided by applicant): The long-term objective of this Patient-Oriented Mentored Career Development Award (K23) is to support the career development of the candidate in functional neuroimaging and experimental therapeutics in mood disorders. This will be accomplished through a structured supervised research experience and formal instruction that will focus on the training areas of (1) Clinical Research Methodology, Biostatistics and Ethics; (2) Functional Neuroimaging Methodology; and (3) Affective and Cognitive Neuroscience. The specific objective of the proposed research strategy is to characterize the function of emotion-processing neural networks in vivo in patients with treatment-resistant depression (TRD), and to identify functional changes in these networks that are specific to rapid antidepressant response. Conventional antidepressant treatments are slow to result in therapeutic benefit, and 20-30% of patients with major depression fail to achieve an adequate therapeutic response (i.e., experience TRD). Recent findings of rapid and robust antidepressant effects of the anesthetic agent ketamine, a N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, present a unique opportunity to test hypotheses regarding the mechanisms of rapid-acting therapeutic action. The proposed research will utilize advanced cognitive neuroscience techniques and functional magnetic resonance imaging (fMRI) to investigate the specific functional contributions of key neural systems supporting emotion generation/regulation, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC) and associated subcortical structures, in TRD and rapid antidepressant response to ketamine. TRD subjects will undergo fMRI at baseline (in the depressed state) and then again 24 hours following a single IV infusion of ketamine or a control treatment. The fMRI strategy will utilize both a well-validated probe of negative emotion bias (sad facial expressions), and a probe of emotion regulation (cognitive reappraisal), which specifically recruits PFC/ACC structures implicated in mechanisms of antidepressant action. This research will test specific hypotheses regarding the role of emotion generation (e.g. subcortical) and regulation (e.g. PFC/ACC) neural systems in the depressed state in patients with TRD, and changes in the function of these systems associated with changes in depressive symptoms resulting from ketamine. The skills and data acquired and research methods developed during the K23 award period will provide the candidate with the tools required to achieve the long- term goal of becoming an independent investigator in clinical neuroscience research in mood disorders.