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 - 原始提案没有更改 在 分子水平，改善了在神经认知水平上的认知灵活性和前额叶皮层（PFC）控制。 静脉注射氯胺酮显示出快速抗抑郁的特性，可通过快速逆转抑郁症 增强分子神经塑性；但令人惊讶的是，它对抑郁症患者的影响知之甚少 神经认知处理。我们肯定氯胺酮将迅速提高认知灵活性，PFC对 情感区域，允许认知中僵化的负面偏见迅速逆转。我们进一步期望这些 神经认知的变化将提供临床机会窗口，以引入自动认知训练 技术将巩固认知处理的适应性形式（特别是积极的隐式表示 自我），而神经可塑性仍然很高。首先“启动”大脑后，实例化适应性的处理形式 氯胺酮代表了一种潜在的协同治疗方法，可以扩展单个氯胺酮的急性作用 超出其典型的3-7天窗口的输液，有效地促进了既快速又持久的抗抑郁作用。在 这项研究，有150名患者表现出目标特征（认知灵活性的自我报告障碍；负自我负面障碍； 表示；和临床上升高的抑郁症状）将被随机分配以接收氯胺酮单一输注 或精神活性控制（咪达唑仑），并将完成旨在捕获提出的神经认知的措施 “快速缓解的签名”。这种方法将将氯胺酮的抗抑郁机制的分子模型扩展到新颖 认知领域，揭示了快速缓解的神经认知状态。我们假设看到增加 认知灵活性和从PFC到显着网络区域的连接性，并相应地下降。 在刚性的僵化偏见中，被固定为抑郁症的关键认知促进者：自我的负面表示 （“抑郁型自我检查”） - 一种认知模式，表明对氯胺酮在 我们以前的研究。在完全阶乘（2x2）的设计中，将随机分配患者以接收基于计算机的简短 在灌注后“机会之窗”期间的认知训练方案，旨在隐式逆转负面自我 表示，灌输积极的自我代表，或者是同一培训的假变体。患者会 急性1个月（有6个月的自然主义随访），以评估是否有效认知训练 增强和/或扩展氯胺酮对抑郁症和神经认知'快速签名的影响的耐用性 救济。’用氯胺酮启动大脑可塑性后，我们希望训练积极的自我体现将提供 非常高效，低成本，便携，无创，安全且高度传播的策略用于扩展 氯胺酮的快速抗抑郁作用。这项研究将提供有关神经认知的新颖，集成的信息 中介机构桥接氯胺酮的分子和情绪影响，这将代表首次协同尝试 将氯胺酮与认知训练干预措施相结合，以利用和扩展氯胺酮的快速影响。