Functional MRI Studies of Emotion in Depression and Rapid Antidepressant Response

抑郁情绪和快速抗抑郁反应的功能 MRI 研究

• 批准号: 8165389
• 负责人: James Warren Murrough
• 金额: $ 17.6万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165389
• 关键词: Address; Affect; Amygdaloid structure; Anesthetics; Animals; Anterior; Antidepressive Agents; Area; Attenuated; Biological Neural Networks; Biometry; Brain; Chronic; Clinical; Clinical Research; Cognitive; Controlled Clinical Trials; Data; Depressed mood; Disease; Dose; Double-Blind Method; Down-Regulation; Emotional; Emotions; Ethics; Excitatory Amino Acid Antagonists; Face; Facial Expression; Functional Magnetic Resonance Imaging; Funding; Generations; Goals; Hour; Instruction; Intravenous infusion procedures; K-Series Research Career Programs; Ketamine; Knowledge; Major Depressive Disorder; Medial; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Midazolam; Mood Disorders; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Mental Health; Nature; Neurosciences Research; Parahippocampal Gyrus; Participant; Patients; Perception; Prefrontal Cortex; Process; Public Health; Randomized; Receptor Signaling; Recruitment Activity; Regulation; Relative (related person); Research; Research Methodology; Research Personnel; Research Project Grants; Resistance; Role; Structure; Support System; Symptoms; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Time; Training; active control; affective neuroscience; career development; cingulate cortex; cognitive neuroscience; cognitive system; depressive symptoms; effective therapy; emotion regulation; experience; imaging modality; improved; in vivo; neuroimaging; patient oriented; programs; relating to nervous system; research study; response; skills; tool; treatment trial

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. PUBLIC HEALTH RELEVANCE: Up to one-third of patients with major depression continue to suffer a high symptom burden despite an optimized treatment trial [e.g. they suffer treatment-resistant depression (TRD)], and symptom relief is slow even in patients who do respond. Therefore, rapidly acting, more effective treatments are urgently needed. The proposed research project aims to illuminate the functional brain mechanisms of rapid antidepressant response in patients with TRD, with the long-term goal of facilitating the identification of improved treatments for patients suffering from this disabling illness.

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情绪障碍的功能性神经影像学和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教学来完成，重点是（1）临床研究方法，生物统计学和伦理学的培训领域;（2）功能性神经影像学方法;和（3）情感和认知神经科学。拟议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反应的功能变化。常规的抗抑郁治疗产生治疗益处的速度较慢，并且20-30%的重度抑郁症患者未能实现足够的治疗反应（即，体验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）具有快速和稳健的抗抑郁作用，这为检验有关速效治疗作用机制的假设提供了独特的机会。拟议的研究将利用先进的认知神经科学技术和功能性磁共振成像（fMRI）来研究支持情绪产生/调节的关键神经系统（包括前额叶皮层（PFC），前扣带皮层（ACC）和相关的皮层下结构）在TRD和氯胺酮快速抗抑郁反应中的具体功能贡献。TRD受试者将在基线时（处于抑郁状态）接受fMRI，然后在单次IV输注氯胺酮或对照治疗后24小时再次接受fMRI。功能磁共振成像策略将利用一个经过充分验证的探针的负面情绪偏见（悲伤的面部表情），和一个探针的情绪调节（认知重新评价），专门招募PFC/ACC结构牵连的抗抑郁作用的机制。本研究将测试有关情绪产生（如皮层下）和调节（如PFC/ACC）神经系统在TRD患者抑郁状态中的作用的特定假设，以及这些系统功能的变化与氯胺酮引起的抑郁症状的变化相关。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心境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。 公共卫生相关性：尽管进行了优化的治疗试验，多达三分之一的重性抑郁症患者仍继续遭受高症状负担[例如，他们患有难治性抑郁症（TRD）]，即使在有反应的患者中，症状缓解也很缓慢。因此，迫切需要快速有效的治疗方法。拟议的研究项目旨在阐明TRD患者快速抗抑郁反应的功能性大脑机制，长期目标是促进为患有这种致残性疾病的患者确定更好的治疗方法。