Neural Circuit-Specific Mechanisms of Ketamine's Effect on Anhedonia and Anxiety in Depression Using Ultra-High Field 7-Tesla MRI

使用超高场 7 特斯拉 MRI 研究氯胺酮对抑郁症快感缺乏和焦虑影响的神经回路特异性机制

• 批准号: 10713827
• 负责人: Laurel Sophia Morris
• 金额: $ 76.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713827
• 关键词: Acute; Address; Adult; Aftercare; Anhedonia; Animals; Anterior; Anxiety; Area; Arousal; Behavior assessment; Behavioral; Brodmann' s area; Callithrix; Clinical assessments; Development; Diagnostic; Disease; Dose; Enrollment; Functional Magnetic Resonance Imaging; Functional disorder; Glutamates; Goals; Health; Hour; Human; Incentives; Individual; Intravenous; Intravenous infusion procedures; Ketamine; Knowledge; Laboratories; Magnetic Resonance Imaging; Major Depressive Disorder; Maps; Measurement; Measures; Mental Depression; Mental disorders; NMDA receptor antagonist; Participant; Patient Self-Report; Peripheral; Pharmaceutical Preparations; Placebos; Primates; Public Health; Randomized; Rest; Rewards; Role; Saline; Stimulus; Structure; Symptoms; Techniques; Therapeutic; Time; Work; analog; cingulate cortex; clinical heterogeneity; digital health; follow-up; hedonic; improved; neural; neural circuit; nonhuman primate; personalized medicine; response; reuptake; reward processing; translational neuroscience

Depression is a devastating public health problem, yet the pathophysiological mechanisms underlying distinct aspects of the disorder remain largely unknown. Convergent evidence from animal and human studies have strongly implicated functional perturbations in the subgenual anterior cingulate cortex (sgACC) in depression. However, it is not known how dysfunction within specific sub-circuits of this heterogenous structure map to specific depression-related symptom domains. This gap in knowledge concerning the pathophysiology of depression is a major impediment to the advancement of diagnostic and therapeutic approaches to this disabling disorder. To address this gap, we propose a rigorous translational neuroscience study to define the distinct circuit-specific mechanisms of anhedonia and anxiety in humans with depression, building upon work in non- human primates, and converging human evidence from our laboratories. In marmosets, selective over-activation of Brodmann Area 25 (BA25) within the sgACC via glutamate re-uptake inhibition causally leads to deficits in anticipatory arousal – an established analogue of anhedonia in humans. Critically, these behavioral deficits are selectively reversed by peripheral administration of the glutamate NMDA receptor antagonist ketamine. Pilot work from our laboratory show a remarkable degree of inter-species convergence, pointing towards conservation of a glutamate-sensitive sub-circuit within the sgACC/BA25 that controls hedonic responses to environmental stimuli. We show that the sgACC/BA25 is specifically overactive in response to positive (but not negative) incentives in individuals with major depressive disorder (MDD) compared to unaffected health control (HC) individuals. We also show that the magnitude of activation specifically within BA25 (but not more rostral prelimbic area 32 [PL32]) is positively associated with degree of self-reported anhedonia, as predicted by primate work. Finally, we show that a single intravenous infusion of ketamine specifically reverses overactivation of the BA25 to positive stimuli; the degree of reduction in BA25 following ketamine correlated with improved in self-reported anhedonia (but not anxiety), as predicted by primate work. The overall goal of the proposed work is to define the distinct circuit-specific mechanisms of anhedonia and anxiety in humans with depression. To complete Aim 1, we will enroll N=60 medication-free adults with MDD and N=60 HC adults. All individuals will undergo clinical and behavioral assessment of anhedonia, anxiety, and other depression-relevant domains and both resting-state and task-based acquisitions with a validated reward task using ultra-high-field 7-Tesla (7T) MRI. To complete Aim 2, the N=60 medication-free adults with MDD from Aim 1 will be randomized to either a single IV infusion of 0.5 mg/kg racemic ketamine (KET) or placebo (PBO, saline) and undergo repeated clinical and behavioral assessments and 7T MRI at 24 hours post treatment. To complete Aim 3, all MDD participants from Aim 2 will undergo follow up clinical and behavioral assessments and 7T MRI at 7 days post-treatment. Participants will complete mobile digital health measures over the 7-day follow up time, and for a total of 4 weeks from dosing.

抑郁症是一个破坏性的公共卫生问题，但具有不同的病理生理机制 该疾病的各个方面在很大程度上尚不清楚。来自动物和人类研究的收敛证据 在抑郁症中，强烈实现的功能扰动（SGACC）。 但是，尚不知道该异源结构映射的特定亚电路的功能障碍如何 特定与抑郁症相关的症状域。关于知识的差距 抑郁症是诊断和治疗方法发展的主要障碍 紊乱。为了解决这一差距，我们提出了一项严格的翻译神经科学研究，以定义独特的 抑郁症的人类抗议和动画的特定电路机制，在非 - 人类灵长类动物，并从我们的实验室收集人类证据。在果果中，选择性过度激活 SGACC内通过谷氨酸重新摄取抑制作用的Brodmann区域25（BA25）的因果关系会导致缺陷 预期的唤醒 - 一种在人类中既定的Anhedonia的类似物。至关重要的是，这些行为定义是 通过外周施用谷氨酸NMDA受体拮抗剂氯胺酮有选择地逆转。飞行员 我们实验室的工作表明种间间的融合，指向保护 SGACC/BA25中谷氨酸敏感的亚电路的控制 刺激。我们表明，SGACC/BA25在响应阳性（但不是负）方面特别活跃。 与未受影响的健康控制（HC）相比 个人。我们还表明，在BA25中，激活的幅度（但不超过前提 正如主要工作所预测的那样，区域32 [pl32]）与自我报告的抗抗反抗的程度呈正相关。 最后，我们表明，氯胺酮的单一静脉输注特异性反转BA25 积极刺激；氯胺酮与自我报告的改善相关后，BA25的降低程度 正如主要工作所预测的那样，Anhedonia（但不是焦虑）。拟议工作的总体目标是定义 抑郁症的人类的Anhedonia和动画的不同电路特异性机制。要完成AIM 1， 我们将招收n = 60种无药物的成年人和n = 60 HC成年人。所有人都将接受临床 以及对狂热，焦虑和其他与抑郁症的领域以及均休息状态的行为评估 以及使用超高场7-Tesla（7T）MRI的基于任务的收购，具有经过验证的奖励任务。完成 AIM 2，n = 60的无药物为AIM 1的成年人将随机分为单个IV输注 0.5毫克/千克的氯胺酮（KET）或安慰剂（PBO，盐水），并重复进行临床和行为 治疗后24小时评估和7T MRI。为了完成AIM 3，AIM 2的所有MDD参与者都将 在治疗后7天进行后续的临床和行为评估，并在7天后进行7T MRI。参与者会 在7天的随访时间内完成移动数字健康措施，并从给药后总共4周。