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

慢性精神病退伍军人康复干预的神经生理学生物标志物的优化

• 批准号: 10753415
• 负责人: JUAN MOLINA
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753415
• 关键词: Acute; Address; Antipsychotic Agents; Attention; Auditory; Biological Markers; Cerebral cortex; Chronic; Clinical; Clinical Trials Design; Cognition; Cognitive; Cognitive Therapy; Cognitive deficits; Cognitive remediation; Complex; Dedications; Disabled Persons; Dose; Educational workshop; Electroencephalography; Equilibrium; Exhibits; Exposure to; Feasibility Studies; Functional disorder; Future; Health; Healthcare Systems; Hour; Impaired cognition; Impairment; Independent Living; Individual Differences; Instruction; Intervention; K-Series Research Career Programs; Learning; Life; Link; Measurement; Measures; Medicine; Mentors; Mentorship; Modeling; Morbidity - disease rate; Neurobehavioral Manifestations; Neurosciences; Outcome; Pathogenesis; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phase; Physicians; Precision medicine trial; Property; Psychiatrist; Psychometrics; Psychoses; Quality of life; Recovery; Rehabilitation therapy; Reporting; Research; Research Personnel; Research Training; Resources; Rest; Schizophrenia; Scientist; Self Care; Self Management; Sensory; Services; Statistical Data Interpretation; Stimulus; Structure; Testing; Therapeutic; Time; Training; Training Programs; Treatment Effectiveness; Veterans; brain based; career; career development; cell type; clinical infrastructure; cognitive benefits; cognitive function; cognitive rehabilitation; cognitive training; cohort; computerized; design; disability; effective therapy; experience; functional improvement; functional status; improved; in vivo; indexing; mortality; neuromechanism; neurophysiology; novel; novel marker; pharmacologic; potential biomarker; prediction algorithm; predictive marker; predictive tools; prospective; psychiatric rehabilitation; psychosocial; recruit; response; schizophrenia spectrum disorder; sensory stimulus; social; standard of care; stem; symposium; theories; tool; treatment response; vigilance

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).

为了响应 RX-22-017，该职业发展奖 2 (CDA-2) 提供了一项指导性研究 针对早期职业恐慌的培训计划，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 研究者 该应用程序开发了一种与 相关的新型生物标记物。 皮质功能在精神分裂症退伍军人 (SZ) 的“精准康复”试验中的应用。 尽管临床神经科学取得了进步，但仍没有有效的治疗方法 SZ 损伤；这种损伤是导致患有 SZ 的退伍军人严重残疾的主要原因 限制了他们的功能、独立性和生活质量。 康复干预，例如有针对性的认知训练（TCT），但此类治疗需要时间和时间 资源密集型，治疗反应不完整且可变，预测性生物标志物可以提供帮助。 前瞻性识别最有可能受益于 TCT 和其他康复干预措施的患者， 但缺乏此类生物标志物 限制了这些治疗的有效性。 最近，皮质兴奋和抑制指数（“E/I 平衡”）被提出作为 从概念上讲，E/I 平衡反映了综合活动。 大脑皮层中特定细胞类型的 E/I 平衡异常与 与 SZ 相关的认知、知觉和社交障碍的病理生理学 In Molina et al. (2020)， 我们首次报告了这些 SZ 患者 E/I 平衡异常的体内证据； （脑电图）异常被皮质兴奋性的促认知调节剂暂时“正常化”。 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认知干预的预测生物标志物。 应用程序采取开发 E/I 平衡所需的步骤作为大规模应用的预测工具 对患有精神分裂症的退伍军人进行促认知干预的前瞻性康复试验。 为了开发这种用于康复试验的潜在生物标志物，该应用程序将建立 过去的研究评估了退伍军人临床队列中 E/I 平衡的可靠性和内部一致性。 在药物操纵的背景下，使用带有复杂感官刺激的脑电图“方便会话”； 应用程序在没有药物挑战的情况下，在感觉刺激和休息的条件下评估 E/I。 还将通过优化实验来评估 E/I 平衡与认知和功能的关系。 测量 E/I 平衡的条件，该应用将增加该生物标记物被 能够区分科目之间的差异——这是将“合适的退伍军人”与“合适的退伍军人”相匹配的先决条件 作为“概念验证”，该应用将确定未来精准医学试验中的“正确干预”。 “优化的”E/I 测量是否可以预测患有 SZ 的退伍军人对 TCT 的急性促认知反应。 CDA-2 分为两个“阶段”，八十名退伍军人将接受严格的临床、认知和治疗。 第 1 阶段（心理测量优化；目标 1 和 2）将表征 E/I 测量。 在退伍军人中，将针对有和没有感官刺激获得的实验条件进行优化。 使用通用性理论的 E/I 内部一致性和重测可靠性将得到优化。 进入第 2 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（即对心理测量的敏感性） 检测个体差异）的 E/I 平衡。 目标 2. 描述 E/I 平衡与康复相关结果的关系。 目标 3. 评估优化的 E/I 平衡测量对预测听觉学习的敏感性 急性暴露于促认知挑战（1 小时的定向认知训练）后。