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

摘要 本提案是根据RFA-MH-18-707和NOT-MH-20-027提交的，旨在进行 一项新的基于神经可塑性的计算机化 认知补救（nCCR）干预治疗难治性晚期抑郁症（LLD）。我们 开发了nCCR，以针对认知控制缺陷（CCD），这是一种行为表达， 研究领域标准（RDoC）定义的认知控制网络（CCN）。这种新的干预是 与NIMH的优先事项一致，以促进认知和情感神经科学的干预措施 （战略3.1）可以向社区传播（战略3.3）。在LLD中，认知控制缺陷 功能（CCD）是常见的，禁用。我们和其他人已经记录了特定的CCD， 潜在的脑网络异常，与抗抑郁药反应不良，复发， 增加自杀的风险。这些缺陷是由CCN介导的，CCN是一种额顶叶回路， 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， 具有阴性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。的 我们采用的方法学是建立在基础动物科学的诱导可塑性在老化的大脑， 它被翻译成计算机算法，提供（1）越来越具有挑战性;（2）动态难度调整; (3)注意力要求;（4）立即奖励旨在激活CCD相关的认知训练 临床效果不佳。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可能会参与我们提出的目标，CCD。此外，nCCR 似乎有更强大的情绪影响的参与者有明显的CCD，而SSRI/SNRI- 接受治疗的患者获益的可能性要低两倍。我们将nCCR设计为：短（4周剂量），有效， 移动的（通过网络提供），成本效益高（不需要MD/PhD），具有广泛分布的潜力， 易于采用和可扩展性，以解决LLD中这一迫切的、未满足的治疗需求。对于这些患者 目前还没有充分解决情绪和认知障碍的治疗方法。数据 这一建议产生的结果将使我们能够研究CCD与情绪变化之间的关系， 将这些影响与一线治疗失败的LLD参与者的对照条件进行比较。此外，本发明还 我们提出了一个两个地点，足够的动力试验，以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，具有很大的潜力， 这种类型的干预和支持移动的nCCR到“常规护理”设置的可扩展性。

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.