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

抑郁症是一个破坏性的公共卫生问题，但其病理生理机制不同， 这种疾病的各个方面在很大程度上仍不为人所知。来自动物和人类研究的一致证据表明， 强烈暗示功能紊乱，在膝下前扣带皮层（sgACC）抑郁症。 然而，尚不清楚这种异质结构的特定子回路内的功能障碍如何映射到 特定抑郁症相关症状领域。这种知识的差距，有关的病理生理学， 抑郁症是一个主要的障碍，以进步的诊断和治疗方法， disorder.为了解决这一差距，我们提出了一个严格的翻译神经科学研究，以确定不同的 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，以及从我们实验室收集的人类证据。在绒猴中，选择性过度激活 通过谷氨酸再摄取抑制的sgACC内的Brodmann区域25（BA 25）的损伤导致 预期性唤起-人类快感缺乏症的一种已确立的类似物。重要的是，这些行为缺陷 通过外周给予谷氨酸NMDA受体拮抗剂氯胺酮选择性逆转。试点 我们实验室的工作表明，物种间的趋同程度非常显著， 在sgACC/BA 25内的谷氨酸敏感子回路，其控制对环境的享乐反应， 刺激。我们表明，sgACC/BA 25在对阳性（但不是阴性） 与未受影响的健康对照（HC）相比，重度抑郁症（MDD）患者的激励措施 个体我们还表明，BA 25内的激活幅度（但不是更吻侧前边缘系统）， 区域32 [PL 32]）与自我报告的快感缺乏程度正相关，如灵长类动物工作所预测的。 最后，我们发现单次静脉输注氯胺酮可以特异性逆转BA 25的过度激活， 氯胺酮后BA 25的降低程度与自我报告的 快感缺乏（但不是焦虑），正如灵长类动物的研究所预测的那样。拟议工作的总体目标是确定 抑郁症患者快感缺乏和焦虑的独特回路机制。为了完成目标1， 我们将入组N=60名无药物治疗的MDD成人和N=60名HC成人。所有人都将接受临床 以及快感缺乏、焦虑和其他抑郁相关领域的行为评估， 以及基于任务的采集，其中使用超高场7特斯拉（7 T）MRI进行验证的奖励任务。完成 目标2，N=60例来自目标1的无药物MDD成人将随机接受单次IV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研究 治疗后24小时进行评估和7 T MRI。为了完成目标3，目标2的所有MDD参与者将 在治疗后7天进行随访临床和行为评估以及7 T MRI。参与者将 在7天随访时间内完成移动的数字健康测量，并且从给药起总共持续4周。

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.