Biomarker Validation to Improve Cognitive and Psychosocial Outcomes in Veterans with Chronic Psychosis

作为对RX-20-005的回应，本职业发展奖(CDA-1)将提供一项指导性研究 经验和培训计划的早期职业精神病学家，致力于照顾和福祉 退伍军人，发展成为一名退伍军人研究与开发调查员。认知障碍会导致严重的残疾 患有精神分裂症的退伍军人，限制了他们在社区独立运作和享受 最佳的生活质量。此应用程序旨在改善患有精神分裂症的退伍军人的功能结果 通过继续开发一种与皮质功能的机制模型相关联的有前景的生物标志物 精神分裂症患者。这一生物标志物最终将被用于预测对治疗干预的反应。 适用于退伍军人康复机构。 来自认知治疗的证据表明，精神分裂症患者可以经历 临床上有意义的认知功能改善；然而，相当一部分患者表现出 反应极少或无反应。生物标记物可以前瞻性地识别对药物最敏感的患者亚群 认知补救和其他有利于认知的干预措施的有益效果可以大大改善。 这些治疗方法的疗效。最近，从光谱特性中提取的一种新的生物标记物 脑电记录被认为是大脑皮层兴奋和抑制平衡的指标。 (“E/I平衡”)。我们报告(Molina等人，2020)，这项测量在患有 精神分裂症。我们还证明，这种E/I平衡生物标志物通过急性暴露于 NMDA受体调节剂美金刚，已被证明可以改善 精神分裂症患者。这些发现表明，这种新的生物标志物可以用来预测治疗 对美金刚的敏感性，以及可能的其他促进认知的干预措施。 虽然这些初步结果代表了一个令人信服的概念验证，但这个新的生物标记物还没有 准备在促进认知干预的前瞻性康复试验中大规模应用。首先，莫利纳 等人的研究。(2020)是唯一评估精神分裂症患者E/I生物标记物的研究；因此， 重复这一发现，并将其推广到患有精神分裂症的退伍军人身上，是至关重要的。其次，研究表明 还没有确定这种生物标志物的稳定性，也没有确定它是否适合作为一种重复的测量方法用于 前瞻性康复试验。第三，异常E/I平衡的认知和功能后果有 还没有确定。在两个具体目标中，CDA-1应用程序寻求通过以下方式解决这些问题 退伍军人精神分裂症患者(n=20)与非精神病退伍军人E/I平衡的测量 组(n=20)，来自VASDHS康复机构和门诊。所有参与者都将接受 在分开的两个测试日内进行全面的神经生理学、神经认知和功能评估 提前1-2周。第三，“培训目标”将使CDA-1候选人能够在关键领域发展专门知识 实验技术和分析策略，并发展必要的专业技能 在退伍军人管理局成功的职业发展。 总而言之，这款应用程序将对基于脑电的有前途的患者进行仔细的心理测量验证 生物标记物，并将表征其与认知和心理社会功能测量的关系 患有精神分裂症的退伍军人。因此，这一应用的一个重要产品将是一种新的生物标记物，它可以 用于促进认知疗法的前瞻性临床试验，以改善生活质量和功能 在资深患者群体中的结果。此外，这一CDA-1将使申请者能够追求强大的 培训计划，将为他的职业生涯做好准备，成为一名内科科学家和RR&D调查员，推进小说 患有严重精神疾病的退伍军人的治疗。

In response to RX-20-005, this Career Development Award-1 (CDA-1) will provide a mentored research experience and training program for an early career psychiatrist, committed to the care and wellbeing of Veterans, to develop as a VA RR&D Investigator. Cognitive impairment causes significant disability for Veterans with schizophrenia and limits their ability to function independently in the community and enjoy an optimal quality of life. This application aims to improve functional outcomes for Veterans with schizophrenia through the continued development of a promising biomarker linked to a mechanistic model of cortical function in schizophrenia. This biomarker will ultimately be used to predict the response to therapeutic interventions applied within VA rehabilitative settings. Evidence emerging from cognitive remediation suggests that schizophrenia patients can experience clinically meaningful improvement in cognitive functioning; however, a substantial portion of patients show minimal or no response. Biomarkers that could prospectively identify subgroups of patients most “sensitive” to the beneficial effects of cognitive remediation and other pro-cognitive interventions could substantially improve the efficacy of these treatments. Recently, a novel biomarker extracted from spectral properties of electroencephalographic recordings has been proposed as an index of cortical excitation and inhibition balance (“E/I balance”). We reported (Molina et al., 2020) that this measure was abnormal in patients with schizophrenia. We also demonstrated that this E/I balance biomarker was normalized by acute exposure to the NMDA receptor modulator, memantine, which has been shown to improve neurocognition in subgroups of schizophrenia patients. These findings suggest that this novel biomarker may be used to predict therapeutic sensitivity to memantine, and potentially other pro-cognitive interventions. While these preliminary results represent a compelling proof-of-concept, this novel biomarker is not yet ready for large-scale application in prospective rehabilitation trials of pro-cognitive interventions. First, Molina et al. (2020) is the only study to have assessed this E/I biomarker in schizophrenia patients; therefore, replication of this finding – and extending it to Veterans with schizophrenia - is essential. Second, studies have not yet established the stability of this biomarker, nor its suitability for use as a repeated measure in prospective rehabilitative trials. Third, the cognitive and functional consequences of abnormal E/I balance have not yet been determined. In two Specific Aims, this CDA-1 application seeks to address these issues by measuring E/I balance in Veterans with schizophrenia (n=20) and in a nonpsychiatric Veteran comparison group (n=20) recruited from VASDHS rehabilitation settings and outpatient clinics. All participants will undergo comprehensive neurophysiologic, neurocognitive and functional assessments during two test days separated by 1-2 weeks. A third, “Training Aim” will enable the CDA-1 candidate to develop expertise in critical experimental techniques and analytic strategies, and to develop the professional skills necessary for successful career advancement in the VA. In total, this application will conduct a careful psychometric validation of a promising EEG-based biomarker and will characterize its relationships to measures of cognitive and psychosocial functioning in Veterans with schizophrenia. Thus, an important “product” of this application will be a novel biomarker that can be utilized in prospective clinical trials for pro-cognitive therapeutics, to improve quality of life and functional outcomes in a Veteran patient population. Moreover, this CDA-1 will enable the applicant to pursue a robust training plan that will prepare him for a career as a physician-scientist and RR&D Investigator, advancing novel therapeutics for Veterans with severe mental illness.