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

摘要 本提案是针对RFA-MH-18-707和NOT-MH-20-027提交的，旨在进行 一种基于神经可塑性的新型计算机化随机、双盲、对照确证疗效试验 认知补救(NCCR)干预治疗难治性晚年严重抑郁障碍(LLD)。我们 开发NCCR以针对认知控制缺陷(CCD)，这是一种改变的功能的行为表达 研究领域标准(RDoC)-定义的认知控制网络(CCN)。这一新颖的干预是 与NIMH的优先事项保持一致，以促进认知和情感神经科学提供的干预 (战略3.1)，可向社区传播(战略3.3)。在LLD中，认知控制缺陷 功能(电荷耦合器件)是常见的，并被禁用。我们和其他人已经记录了特定的ccd，以及他们的 潜在的大脑网络异常，与抗抑郁药反应差、复发和 自杀风险增加。这些缺陷是由CCN介导的，CCN是一个额顶环路，包括 背外侧前额叶皮质、背侧前扣带回皮质、后顶叶皮质以及 投射到腹内侧前额叶皮质和皮质下结构，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 阴性的特定疾病的临床结果可以通过诱导神经可塑性改变(即使在 大脑老化)，导致靶网络功能增强，症状改善。这个 我们使用的方法是建立在诱导衰老大脑可塑性的基础动物科学中，并且 它被翻译成计算机算法，提供(1)日益具有挑战性的；(2)动态调整的难度； (3)注意力要求高；以及(4)立即奖励旨在激活与ccd相关的认知训练 临床结果不佳。我们最近在三个初步临床试验中测试了NCCR。 我们的初步数据显示，NCCR可能会与我们提议的目标--电荷耦合器件交战。此外，NCCR 在发音为CD的参与者中，SSRI/SNRI似乎具有更强的情绪影响 接受治疗的患者受益的可能性要低两倍。我们设计的NCCR是：短(4周剂量)，有效， 移动(可通过网络获得)，经济实惠(不需要MD/PHD)，具有广泛分发的潜力， 易于采用和扩展，以满足LLD这一迫切的、未得到满足的治疗需求。对于这些患者来说 目前还没有能充分解决情绪和认知障碍的治疗方法。数据 这项建议将使我们能够研究认知障碍与情绪变化的关系，以及 将这些影响与一线治疗失败的LLD参与者的控制条件进行比较。此外， 我们提出了一个两个站点的、足够强大的试验来研究我们的技术促进的参数，以及 在两个大型医疗系统中的实施程序，这对未来具有很大的潜力 这类干预措施支持将移动NCCR扩展到“日常护理”环境中。

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.