Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition

测试针对抑郁神经认知的基于神经可塑性的协同干预措施

• 批准号: 9796295
• 负责人: Rebecca Price
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796295
• 关键词: Acute; Affective; Antidepressive Agents; Brain; Clinical; Cognition; Cognitive; Computers; E-learning; Educational Intervention; Exhibits; Fostering; Impairment; Infusion procedures; Intervention; Intravenous; Ketamine; Lead; Learning; Measures; Mental Depression; Midazolam; Molecular; Moods; Neurocognition; Neurocognitive; Neuronal Plasticity; Patient Self-Report; Patients; Pattern; Prefrontal Cortex; Property; Protocols documentation; Randomized; Testing; Training; Training Technics; Variant; Work; antidepressant effect; base; cognitive change; cognitive training; cost; depressed patient; depressive symptoms; design; flexibility; follow-up; molecular modeling; novel; portability; promoter; relating to nervous system; synaptic depression; uptake

Project Summary - no change from original proposal 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.

项目摘要-与原提案相比没有变化 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，认知灵活性和前额叶皮层（PFC）控制在神经认知水平下降。 静脉注射氯胺酮，它显示出快速的抗抑郁特性，被认为是通过快速逆转抑郁症， 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， 神经认知加工我们认为氯胺酮将迅速增加认知灵活性和PFC的影响， 情感区域，允许认知中的刚性，负面偏见被迅速逆转。我们进一步预计， 神经认知的变化将为引入自动认知训练提供临床机会 技术，这将巩固自适应形式的认知处理（具体来说，积极的隐式表征 而神经可塑性仍然很高。在第一次“启动”大脑后， 氯胺酮代表了一种潜在的协同治疗方法， 输注超过其典型的3-7天窗口，有效地促进快速和持久的抗抑郁作用。在 这项研究，150名患者表现出目标概况（自我报告的认知灵活性障碍;消极的自我， 和临床上升高的抑郁症状）将随机接受氯胺酮单次输注 或精神活性对照（咪达唑仑），并将完成旨在捕获拟议神经认知功能障碍的措施。 “快速缓解的标志”这种方法将扩展氯胺酮抗抑郁机制的分子模型， 认知领域，揭示了神经认知状态，跟踪与快速救济。我们假设， 认知灵活性和直接连接从PFC到显着网络区域，并相应地减少一个 僵化的消极偏见被认为是抑郁症的一个关键认知促进因素：自我的消极表征 （“抑郁的自我图式”）-一种认知模式，已显示出初步的敏感性氯胺酮的快速影响， 我们以前的研究。在完全析因（2x2）设计中，患者将随机接受简短的基于计算机的 在输注后“机会之窗”期间的认知训练方案，旨在隐式地逆转消极的自我， 代表，灌输积极的自我陈述，或者是同样训练的假变种。患者将 进行1个月以上的急性随访（6个月的自然主义随访），以评估主动认知训练是否 增强和/或延长氯胺酮对抑郁症和对神经认知的快速反应特征的作用的持久性 救济”。在用氯胺酮启动大脑可塑性后，我们希望训练积极的自我表征将提供一个更好的方法。 非常高效，低成本，便携式，非侵入性，安全，高度传播准备的战略， 克他命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， 中间桥梁氯胺酮的分子和情绪的影响，并将代表第一次尝试协同 联合收割机氯胺酮与认知训练干预，以开发和扩展氯胺酮的快速效果。