Neuroplasticity-Based Computerized Cognitive Remediation (nCCR) for Treatment Resistant Late-Life Depression

基于神经可塑性的计算机认知疗法（nCCR）治疗难治性晚年抑郁症

• 批准号: 10612341
• 负责人: Sarah Shizuko Morimoto
• 金额: $ 146.91万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612341
• 关键词: Address; Adopted; Adoption; Affective; Animal Model; Animals; Anterior; Antidepressive Agents; Attention; Behavioral; Brain; California; Cerebrum; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Cognitive deficits; Cognitive remediation; Communities; Computational algorithm; Corpus striatum structure; Data; Data Analytics; Disease; Disease remission; Doctor of Philosophy; Dorsal; Dose; Double-Blind Method; Elderly; Emerging Technologies; Evidence based treatment; Future; Health Care Costs; Impaired cognition; Impairment; Internet; Intervention; Learning; Major Depressive Disorder; Measures; Mediating; Mediation; Medical; Mental Depression; Methodology; Methods; Modeling; Moods; Multicenter Trials; National Institute of Mental Health; Neurobiology; Neuronal Plasticity; Norepinephrine; Outcome; Parietal Lobe; Participant; Patients; Performance; Pharmaceutical Preparations; Prefrontal Cortex; Procedures; Process; Public Health; Randomized; Relapse; Research Domain Criteria; Resistance; Rewards; Risk; Sampling; Science; Selective Serotonin Reuptake Inhibitor; Semantics; Serotonin; Site; Structure; Suicide; System; Technology; Testing; Therapeutic; Training; Translating; Utah; Verbal Learning; Work; active control; affective neuroscience; aging brain; behavior measurement; cingulate cortex; cognitive control; cognitive neuroscience; cognitive training; computerized; confirmatory trial; cost effective; depressive symptoms; design; digital medicine; digital tool; disability; dosage; effectiveness trial; experience; flexibility; functional improvement; geriatric depression; geriatric major depression; high risk; improved; indexing; inhibitor; iterative design; model design; mortality; multisensory; novel; older patient; recruit; response; reuptake; suicidal; suicidal risk; symptomatic improvement; theories; therapy resistant; treatment as usual; treatment group

Abstract This proposal is submitted in response to RFA-MH-18-707 and NOT-MH-20-027, and aims to conduct a randomized, double-blind, controlled confirmatory efficacy trial of a novel, neuroplasticity-based computerized cognitive remediation (nCCR) intervention for treatment resistant late-life major depressive disorder (LLD). We developed nCCR to target cognitive control deficits (CCD), a behavioral expression of altered function of the Research Domain Criteria (RDoC)-defined, cognitive control network (CCN). This novel intervention is consistent with NIMH priorities to advance interventions informed by cognitive and affective neuroscience (strategy 3.1) that can be disseminated to the community (strategy 3.3). In LLD, deficits in cognitive control functions (CCD) are common, and disabling. We and others have documented that specific CCD, and their underlying brain network abnormalities, are associated with poor response to antidepressants, relapse, and increased risk for suicide. These deficits are mediated by the CCN, a frontoparietal circuit that comprises the dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, and posterior parietal cortex, as well as projections to the ventromedial prefrontal cortex and subcortical structures, including the striatum. The theory guiding neuroplasticity-based cognitive interventions is that network abnormalities associated with negative disease-specific clinical outcomes can be altered through the induction of neuroplasticity (even in the aging brain), resulting in enhanced functioning of the target network, and symptomatic improvements. The methodology we employed is founded in basic animal science of induction of plasticity in the aging brain, and it is translated into computer algorithms that deliver (1) increasingly challenging; (2) dynamic difficulty adjusted; (3) attention demanding; and (4) immediately rewarding cognitive training designed to activate CCD associated with poor clinical outcomes. We recently tested nCCR in three preliminary clinical trials. Our preliminary data indicate that nCCR will likely engage our proposed target, CCD. Further, nCCR appears to have more robust mood effects in participants who have pronounced CCD, while SSRI/SNRI- treated patients are two times less likely to benefit. We designed nCCR to be: short (4-week dose), efficacious, mobile (available via web), cost-effective (does not require an MD/PhD), with the potential for wide distribution, easy adoptability, and extensibility to address this urgent, unmet therapeutic need in LLD. For these patients there is currently no treatment that adequately addresses both mood and cognitive impairment. The data produced by this proposal will allow us to study the relationship between CCD and changes in mood, and compare these effects to a control condition in LLD participants who have failed first-line treatments. Further, we propose a two-site, sufficiently powered trial to study our technology-facilitated parameters, as well as implementation procedures in two large medical systems, which have great potential to inform future interventions of this type and support scalability of mobile nCCR into “usual care” settings.

抽象的 该提案是为了回应 RFA-MH-18-707 和 NOT-MH-20-027 而提交的，旨在开展 一项基于神经可塑性的新型计算机化随机、双盲、对照验证性疗效试验 认知补救（nCCR）干预治疗难治性晚年重度抑郁症（LLD）。我们 开发了 nCCR 以针对认知控制缺陷（CCD），这是大脑功能改变的行为表现 研究领域标准 (RDoC) 定义的认知控制网络 (CCN)。这种新颖的干预措施是 与 NIMH 的优先事项一致，以推进基于认知和情感神经科学的干预措施 （策略 3.1）可以传播到社区（策略 3.3）。在LLD中，认知控制缺陷 功能（CCD）很常见，而且很禁用。我们和其他人已经记录了特定的 CCD 及其 潜在的大脑网络异常与抗抑郁药反应不佳、复发和抑郁症有关 自杀风险增加。这些缺陷是由 CCN 介导的，CCN 是一个额顶叶回路，包括 背外侧前额叶皮层、背侧前扣带皮层和后顶叶皮层，以及 投射到腹内侧前额皮质和皮质下结构，包括纹状体。 指导基于神经可塑性的认知干预的理论是，网络异常与 具有负面疾病特异性的临床结果可以通过诱导神经可塑性来改变（即使在 老化的大脑），从而增强目标网络的功能，并改善症状。这 我们采用的方法是建立在诱导衰老大脑可塑性的基础动物科学基础上的，并且 它被转化为计算机算法，可以实现 (1) 越来越具有挑战性； (2)动态难度调整； (3) 需要集中注意力； (4) 旨在激活 CCD 相关的立即奖励认知训练 临床结果不佳。我们最近在三项初步临床试验中测试了 nCCR。 我们的初步数据表明，nCCR 可能会攻击我们提出的目标 CCD。进一步地，nCCR 似乎对患有明显 CCD 的参与者有更强烈的情绪影响，而 SSRI/SNRI- 接受治疗的患者受益的可能性要低两倍。我们将 nCCR 设计为：短（4 周剂量）、有效、 移动（通过网络提供）、具有成本效益（不需要医学博士/博士学位）、具有广泛传播的潜力， 易于采用和可扩展，以满足 LLD 中这一紧迫的、未满足的治疗需求。对于这些患者 目前还没有一种治疗方法可以充分解决情绪和认知障碍。数据 该提案产生的结果将使我们能够研究 CCD 与情绪变化之间的关系，并且 将这些效果与一线治疗失败的 LLD 参与者的对照条件进行比较。更远， 我们建议进行一个两个站点、动力充足的试验来研究我们的技术促进参数，以及 两个大型医疗系统的实施程序，具有为未来提供信息的巨大潜力 此类干预措施并支持移动 nCCR 可扩展至“常规护理”环境。