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

抑郁症是一个毁灭性的公共卫生问题，但其病理生理机制却截然不同 这种疾病的各个方面在很大程度上仍然未知。来自动物和人类研究的一致证据表明 抑郁症中膝下前扣带皮层（sgACC）的功能紊乱密切相关。 然而，尚不清楚这种异质结构的特定子电路内的功能障碍如何映射到 特定的抑郁症相关症状领域。关于病理生理学的知识差距 抑郁症是这种残疾的诊断和治疗方法进步的主要障碍 紊乱。为了解决这一差距，我们提出了一项严格的转化神经科学研究来定义不同的 抑郁症患者快感缺乏和焦虑的回路特异性机制，建立在非 人类灵长类动物，以及来自我们实验室的人类证据。在狨猴中，选择性过度激活 通过谷氨酸再摄取抑制，sgACC 内的 Brodmann 25 区 (BA25) 会导致 预期性唤醒——人类快感缺乏的一种既定类似物。至关重要的是，这些行为缺陷是 通过外周给予谷氨酸 NMDA 受体拮抗剂氯胺酮选择性逆转。飞行员 我们实验室的工作显示了物种间显着程度的趋同，指向保护 sgACC/BA25 内的谷氨酸敏感子电路控制对环境的享乐反应 刺激。我们发现 sgACC/BA25 对积极（但不是消极）的反应特别过度活跃 与未受影响的健康控制 (HC) 患者相比，重度抑郁症 (MDD) 患者的激励措施 个人。我们还表明，BA25 内的激活程度（但不是更多的吻侧前边缘区域） 正如灵长类动物研究所预测的那样，区域 32 [PL32]）与自我报告的快感缺失程度呈正相关。 最后，我们证明单次静脉注射氯胺酮可以特异性逆转 BA25 的过度激活 积极的刺激；氯胺酮后 BA25 的降低程度与自我报告的改善相关 正如灵长类动物研究所预测的，快感缺失（但不是焦虑）。拟议工作的总体目标是定义 抑郁症患者快感缺失和焦虑的独特回路特异性机制。为了完成目标 1， 我们将招募 N=60 名未接受药物治疗的 MDD 成人和 N=60 名 HC 成人。所有个人都将接受临床 快感缺乏、焦虑和其他抑郁相关领域以及静息状态的行为评估 以及基于任务的采集，并使用超高场 7-特斯拉 (7T) MRI 进行经过验证的奖励任务。完成 目标 2，目标 1 中的 N = 60 名患有 MDD 的无药物治疗成人将被随机分配到单次静脉输注 0.5 mg/kg 外消旋氯胺酮 (KET) 或安慰剂（PBO、生理盐水）并进行重复的临床和行为 治疗后 24 小时进行评估和 7T MRI。为了完成目标 3，目标 2 的所有 MDD 参与者将 在治疗后 7 天接受后续临床和行为评估以及 7T MRI。参与者将 在 7 天的随访时间内以及给药后总共 4 周内完成移动数字健康测量。

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.