Functional MRI Studies of Emotion in Depression and Rapid Antidepressant Response

描述(由申请者提供)：这个以患者为导向的导师职业发展奖(K23)的长期目标是支持候选人在情绪障碍的功能神经成像和实验疗法方面的职业发展。这将通过结构化的监督研究经验和正式指导来实现，这些经验和正式指导将侧重于以下培训领域：(1)临床研究方法学、生物统计学和伦理学；(2)功能神经成像方法学；(3)情感和认知神经科学。提出的研究策略的具体目标是描述难治性抑郁症(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药物反应的功能变化。传统的抗抑郁药物治疗见效缓慢，20%-30%的重度抑郁症患者未能达到足够的治疗反应(即体验TRD)。最近发现的麻醉剂氯胺酮，一种N-甲基-D-天冬氨酸(NMDA)谷氨酸受体拮抗剂，快速而有力的抗抑郁作用，为检验关于快速作用治疗作用机制的假说提供了一个独特的机会。这项拟议的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，包括前额叶皮质(PFC)、前扣带回皮质(ACC)和相关的皮质下结构在TRD和氯胺酮快速抗抑郁反应中的特定功能贡献。TRD受试者将在基线(处于抑郁状态)时接受功能磁共振成像，然后在单次静脉输注氯胺酮或对照治疗后24小时再次进行功能磁共振成像。功能磁共振成像策略将利用一个经过充分验证的负面情绪偏见(悲伤的面部表情)探测，以及一个情绪调节探测(认知重新评估)，它专门招募与抗抑郁作用机制有关的PFC/ACC结构。这项研究将测试关于情绪产生(例如皮质下)和调节(例如PFC/ACC)神经系统在TRD患者抑郁状态中的作用的具体假设，以及与氯胺酮引起的抑郁症状变化相关的这些系统功能的变化。在K23获奖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所需的工具，以实现成为情绪障碍临床神经科学研究的独立研究员的长期目标。

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.