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

作为对RX-20-005的回应，该职业发展奖-1（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科医生，致力于照顾和福祉的 退伍军人，发展为VA RR&D调查员。认知障碍导致严重残疾， 患有精神分裂症的退伍军人，限制了他们在社区中独立运作的能力， 最佳生活质量。该应用程序旨在改善退伍军人精神分裂症患者的功能结局 通过持续开发与皮质功能机制模型相关的有前途的生物标志物， 精神分裂症这种生物标志物最终将用于预测对治疗干预的反应 在VA康复环境中应用。 来自认知矫正的证据表明，精神分裂症患者可能会经历 认知功能的临床有意义的改善;然而，相当一部分患者表现出 很少或没有反应。生物标志物可以前瞻性地识别对以下药物最“敏感”的患者亚组： 认知补救和其他促认知干预的有益效果可以大大改善 这些治疗的效果。最近，一种新的生物标志物提取的光谱特性， 脑电记录已被提出作为皮质兴奋和抑制平衡的指标 （“E/I余额”）。我们报道了（Molina等人，2020年），这一措施是异常的患者， 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，已被证明可以改善亚组的神经认知， 精神分裂症患者这些发现表明，这种新的生物标志物可用于预测治疗效果。 对美金刚的敏感性，以及潜在的其他促认知干预。 虽然这些初步结果代表了一个令人信服的概念验证，但这种新的生物标志物还没有 准备大规模应用于前认知干预的前瞻性康复试验。首先，莫利纳 等人（2020）是唯一一项评估精神分裂症患者中E/I生物标志物的研究;因此， 复制这一发现--并将其扩展到患有精神分裂症的退伍军人--是至关重要的。第二，研究 尚未确定该生物标志物的稳定性，也未确定其作为重复测量的适用性， 前瞻性康复试验第三，E/I平衡异常的认知和功能后果具有 尚未确定在两个具体目标中，本CDA-1申请寻求通过以下方式解决这些问题： 测量退伍军人精神分裂症患者（n=20）和非精神病退伍军人的E/I平衡 组（n=20）从VASDHS康复机构和门诊招募。所有参与者将接受 在分开的两个测试日进行全面的神经生理学、神经认知和功能评估 1-2周。第三，“培训目标”将使CDA-1候选人能够发展关键领域的专业知识， 实验技术和分析策略，并发展必要的专业技能， 在退伍军人事务部的成功职业发展。 总之，该应用程序将对一个有前途的基于EEG的 生物标志物，并将表征其与认知和心理社会功能测量的关系， 有精神分裂症的退伍军人。因此，本申请的重要“产物”将是新的生物标志物，其可以 在前瞻性临床试验中用于促认知治疗，以改善生活质量和功能 退伍军人患者人群的结果。此外，该CDA-1将使申请人能够寻求一个强大的 培训计划，这将为他的职业生涯作为一个医生，科学家和RR&D研究员，推进小说 治疗患有严重精神疾病的退伍军人。

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.