Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition

项目摘要。 抑郁症被描述为神经可塑性受损的问题(例如，前额叶突触抑制)。 分子水平，认知灵活性降低，前额叶皮质(PFC)控制在神经认知水平。 静脉注射的氯胺酮表现出快速的抗抑郁作用，被认为可以通过快速逆转抑郁 增强分子神经可塑性；但令人惊讶的是，关于它对抑郁症患者的影响，人们知之甚少 神经认知处理。我们假设氯胺酮将迅速增加认知灵活性和PFC对 情感区域，允许僵化的、消极的认知偏向被迅速扭转。我们进一步期待这些 神经认知变化将为临床引入自动认知训练提供机会之窗 技术，这将巩固认知加工的适应性形式(具体地说，积极的内隐表征 自我)，而神经可塑性仍然很高。实例化第一次对大脑进行“启动”后的适应性处理形式 氯胺酮是一种潜在的协同治疗方法，可以延长单一氯胺酮的急性效应 超过其典型的3-7天的输液窗口，有效地培养快速和持久的抗抑郁效果。在……里面 这项研究，150名患者表现出目标档案(自我报告的认知灵活性障碍；消极的自我 陈述；和临床上升高的抑郁症状)将被随机接受单次输注氯胺酮 或精神活性对照(咪达唑仑)，并将完成旨在捕获拟议的神经认知的措施 “快速救援的签字。”这种方法将把氯胺酮抗抑郁机制的分子模型扩展到新的 认知域，揭示追踪快速缓解的神经认知状态。我们假设将会看到 认知灵活性和从PFC到显著网络区域的定向连接，并相应减少一 被认为是抑郁症的关键认知推动者的僵化的负面偏见：自我的负面表征 (“抑郁自我图式”)--一种对氯胺酮的快速影响表现出初步敏感性的认知模式 我们之前的研究。在完全析因(2x2)设计中，患者随后将被随机地接受基于计算机的简短的 输液后“机会之窗”期间的认知训练方案，旨在隐含地逆转消极自我-- 在他们的位置上灌输积极的自我表征，或者是同一训练的虚假变体。患者会 敏锐地随访1个月以上(自然随访6个月)，以评估积极的认知训练是否 增强和/或延长氯胺酮对抑郁症和对神经认知的影响的持久性 如释重负。在用氯胺酮启动大脑可塑性后，我们预计训练积极的自我表征将提供 极其高效、低成本、便携、非侵入性、安全且高度支持传播的扩展策略 氯胺酮的快速抗抑郁作用。这项研究将为神经认知提供新的、综合的信息 中间体在氯胺酮的分子和情绪效应之间架起了桥梁，并将是协同作用的首次尝试 将氯胺酮与认知训练干预相结合，以开发和扩大氯胺酮的快速效应。

Project Summary. Depression has been described as a problem of impaired neuroplasticity (e.g., prefrontal synaptic depression) at the molecular level, and decreased cognitive flexibility and prefrontal cortex (PFC) control at the neurocognitive level. Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing molecular neuroplasticity; but surprisingly little is known regarding its effects on depressed patients' neurocognitive processing. We posit that ketamine will rapidly increase cognitive flexibility and the PFC's influence on affective regions, allowing for rigid, negative biases in cognition to be rapidly reversed. We further expect these neurocognitive changes will provide a clinical window of opportunity in which to introduce automated cognitive training techniques, which will consolidate adaptive forms of cognitive processing (specifically, positive implicit representations of self) while neuroplasticity remains high. Instantiating adaptive forms of processing after first `priming' the brain with ketamine represents a potentially synergistic treatment approach that could extend the acute effects of a single ketamine infusion beyond its typical 3-7 day window, efficiently fostering antidepressant effects that are both rapid and enduring. In this study, 150 patients exhibiting a target profile (self-reported impairments in cognitive flexibility; negative self- representations; and clinically elevated depression symptoms) will be randomized to receive a single infusion of ketamine or a psychoactive control (midazolam) and will complete measures designed to capture a proposed neurocognitive `signature of rapid relief.' This approach will extend molecular models of ketamine's antidepressant mechanisms to novel cognitive domains, revealing the neurocognitive state that tracks with rapid relief. We hypothesize to see increases in cognitive flexibility and directed connectivity from PFC to salience network regions, and corresponding decreases in one of the rigid, negative biases posited to be a key cognitive promoter of depression: negative representations of self (“depressive self-schemas”)—a cognitive pattern that has shown preliminary sensitivity to ketamine's rapid influence in our previous studies. In a fully factorial (2x2) design, patients will then be randomized to receive a brief computer-based cognitive training protocol during the post-infusion “window of opportunity,” designed to implicitly reverse negative self- representations, instilling positive self-representations in their place, or a sham variant of the same training. Patients will be followed over 1 month acutely (with 6-month naturalistic follow-up) to assess whether active cognitive training enhances and/or extends the durability of ketamine's effects on depression and on the neurocognitive `signature of rapid relief.' After priming brain plasticity with ketamine, we expect that training positive self-representations will provide an exceedingly efficient, low-cost, portable, non-invasive, safe, and highly dissemination-ready strategy for extending ketamine's rapid antidepressant effects. This study will provide novel, integrative information on neurocognitive intermediaries bridging ketamine's molecular and mood effects, and will represent the first attempt to synergistically combine ketamine with a cognitive training intervention in order to exploit and extend ketamine's rapid effects.