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，但其背后的病理生理机制 这种疾病的各个方面在很大程度上仍不清楚。来自动物和人类研究的一致证据表明 抑郁症患者的亚膝前扣带回皮质(SgACC)功能紊乱。 然而，目前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 与抑郁相关的特定症状领域。这一关于脑血管疾病病理生理学的知识缺口 抑郁症是发展这种残疾的诊断和治疗方法的主要障碍。 无序。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，以定义不同的 抑郁症患者快感缺失和焦虑的电路特异性机制，建立在非 人类灵长类动物，以及从我们的实验室收集的人类证据。在绒猴中，选择性过度激活 谷氨酸再摄取抑制导致sgACC内Brodmann区25(BA25)的缺失 预期性唤醒--人类快感缺乏症的一种公认的类比。关键的是，这些行为缺陷 外周给予谷氨酸NMDA受体拮抗剂氯胺酮选择性逆转。引航员 我们实验室的研究表明，物种间的趋同程度非常显著，指向保护 在sgACC/BA25中控制对环境的享乐反应的谷氨酸敏感子电路 刺激物。我们发现sgACC/BA25对积极(但不是消极)的反应是特别过度的。 重度抑郁障碍(MDD)患者与未受影响的健康对照(HC)的激励机制比较 个人。我们还表明，BA25内的激活程度(但不是更多的吻部初步 区域32[PL32])与自我报告的快感缺乏程度呈正相关，正如灵长类研究所预测的那样。 最后，我们证明，单次静脉输注氯胺酮可以特异性地逆转BA25的过度激活 对积极刺激；氯胺酮后BA25降低的程度与自我报告的改善相关 缺乏快感(但不是焦虑)，正如灵长类动物的研究预测的那样。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电路机制。为了完成目标1， 我们将招募N=60名患有MDD的无药物成人和N=60名HC成人。所有个人都将接受临床 以及对快感缺失、焦虑和其他与抑郁相关的领域以及休息状态的行为评估 以及基于任务的收购，使用超高场7-Tesla(7T)MRI提供经过验证的奖励任务。要完成 目标2，来自目标1的N=60名患有MDD的未服用药物的成年人将被随机分为两组，一组是单次静脉滴注 0.5 mg/kg外消旋氯胺酮(KET)或安慰剂(PBO，生理盐水)，反复进行临床和行为检查 治疗后24小时进行评估和7T磁共振检查。为了完成目标3，来自目标2的所有MDD参与者将 于治疗后第7天进行临床和行为评估及7T磁共振检查。参与者将 在7天的随访时间内完成移动数字健康测量，并从服药开始总共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.