Optimization of Neurophysiologic Biomarkers for Rehabilitation Interventions in Veterans with Chronic Psychosis

为响应RX-22-017，本职业发展奖(CDA-2)提供了一项指导性研究 和职业生涯早期精神病学家的培训计划，致力于促进退伍军人的健康和福祉 并成为一名独立的RR&D调查员。这项应用开发了一种新的生物标志物，与 皮质功能在退伍军人精神分裂症“精确康复”试验中的应用 尽管临床神经科学取得了进步，但目前还没有有效的治疗认知障碍的方法 SZ的损害；这种损害是导致SZ和SZ退伍军人严重残疾的主要因素 限制了他们的功能、独立性和生活质量。使用特定的药物可获得适度的临床益处 康复干预，例如，有针对性的认知训练(TCT)，但这种治疗是时间和 资源密集，治疗反应不完整且多变。预测性生物标记物可能有助于 前瞻性确定最有可能从TCT和其他康复干预中受益的患者， 但缺乏这样的生物标记物 限制了这些治疗的有效性。 最近，一个大脑皮层兴奋和抑制指数(“E/I平衡”)被提出作为 促进认知干预的翻译生物标记物。从概念上讲，E/I平衡反映了综合活动 大脑皮层中特定类型的细胞。E/I平衡的异常被认为与 与SZ相关的认知、知觉和社交障碍的病理生理学。在Molina等人中。(2020)， 我们首次报道了SZ患者E/I平衡异常的活体证据；这些脑电 (EEG)异常被皮质兴奋性的亲认知调节剂短暂地“正常化”。这 研究提供证据表明，E/I平衡可能指示支持认知康复的神经机制； 可以想象，这样的测量可以作为促进认知干预的预测性生物标记物。这 应用程序采取了开发E/I Balance作为大规模应用程序的预测工具所需的步骤 支持认知干预的SZ退伍军人的前瞻性康复试验。 为了开发这一潜在的康复试验生物标记物，这项申请将建立 E/I平衡在一个资深临床队列中的可靠性和内部一致性。过去的研究评估了E/I平衡 在药物操作的背景下，使用带有复杂感官刺激的脑电“便利时段”；这 应用程序评估E/I，无药物挑战，在感觉刺激和休息条件下。这个 E/I平衡与认知和功能的关系也将被评估。通过优化实验 测量E/I平衡的条件，这种应用将增加这个生物标记物被 能够区分不同对象之间的差异--这是将“合适的老兵”与 未来精准医学试验中的“正确干预”。作为“概念证明”，此应用程序将确定 “优化的”E/I测量是否可以预测患有SZ的退伍军人对TCT的急性前认知反应。 这份CDA-2由两个“阶段”构成。80名退伍军人将接受严格的临床、认知和 功能评估。阶段1(心理测量优化；目标1和2)将描述E/I测量的特征 在退伍军人中，在有和没有感觉刺激的情况下获得的。然后，将对实验条件进行优化 基于概化理论的E/I内部一致性和重测信度研究优化的范例将 转入第二阶段(可行性研究；目标3)。CDA-2有3个具体目标： 目标1.确定优化心理测量特性的实验条件(即，对 检测E/I平衡的个体差异)。 目的2.描述E/I平衡与康复相关结果的关系。 目的3.评价优化的E/I平衡方法预测听觉学习的灵敏度 在急性暴露于有利于认知的挑战(1小时的定向认知训练)之后。

In response to RX-22-017, this Career Development Award-2 (CDA-2) provides a mentored research and training program for an early career psychiatrist, committed to advancing Veteran’s health and wellbeing and to becoming an independent RR&D Investigator. This application develops a novel biomarker linked to cortical function for applications in “precision rehabilitation” trials for Veterans with schizophrenia (SZ). Despite advances in clinical neuroscience, there are no effective treatments for the cognitive impairment in SZ; this impairment is a primary contributor to significant disability for Veterans with SZ and limits their function, independence, and quality of life. Modest clinical benefits can be achieved with specific rehabilitative interventions, e.g., Targeted Cognitive Training (TCT), but such treatments are time- and resource-intensive, and treatment responses are incomplete and variable. Predictive biomarkers could aid in the prospective identification of patients most likely to benefit from TCT and other rehabilitative interventions, but the lack of such biomarkers has limited the effectiveness of these treatments. Recently, an index of cortical excitation and inhibition (“E/I balance”) has been proposed as a translational biomarker for pro-cognitive interventions. Conceptually, E/I balance reflects the integrated activity of specific cell types in the cerebral cortex. Abnormalities in E/I balance have been implicated in the pathophysiology of the cognitive, perceptual, and social impairment associated with SZ. In Molina et al. (2020), we reported the first in vivo evidence of abnormal E/I balance in SZ patients; these electroencephalographic (EEG) abnormalities were transiently ‘normalized’ by a pro-cognitive modulator of cortical excitability. This study provides evidence that E/I balance may index neural mechanisms that support cognitive rehabilitation; conceivably, such a measure might serve as a predictive biomarker for pro-cognitive interventions. This application takes the steps needed to develop E/I balance as a predictive tool for large-scale application in prospective rehabilitation trials of pro-cognitive interventions in Veterans with SZ. To develop this potential biomarker for rehabilitation trials, this application will establish both the reliability and internal consistency of E/I balance in a Veteran clinical cohort. Past studies assessed E/I balance in the context of drug manipulations, using an EEG “session of convenience” with complex sensory stimuli; this application assesses E/I without drug-challenge and under conditions of both sensory stimulation and rest. The relationship of E/I balance to cognition and function will also be assessed. By optimizing the experimental conditions for measuring E/I balance, this application will increase the likelihood that this biomarker will be capable of distinguishing differences between subjects—a prerequisite for matching the “right Veteran” to the “right intervention” in future precision medicine trials. As a “proof of concept”, this application will determine whether the “optimized” E/I measures predict an acute pro-cognitive response to TCT in Veterans with SZ. This CDA-2 is structured with 2 “phases”. Eighty Veterans will undergo rigorous clinical, cognitive, and functional assessments. Phase 1 (Psychometric Optimization; Aims 1 & 2) will characterize E/I measurements in Veterans, acquired with vs. without sensory stimulation. Experimental conditions will then be optimized for E/I internal consistency and test-retest reliability using Generalizability Theory. The optimized paradigms will be carried forward into Phase 2 (Feasibility Study; Aim 3). This CDA-2 has 3 specific aims: Aim 1. Identify the experimental conditions that optimize the psychometric properties (i.e., sensitivity to detect individual differences) of E/I balance. Aim 2. Characterize the relationships of E/I balance with rehabilitation-relevant outcomes. Aim 3. Evaluate the sensitivity of the optimized E/I balance measures for predicting auditory learning after acute exposure to a pro-cognitive challenge (1-h of Targeted Cognitive Training).