Developing an ecologically valid virtual reality-EEG paradigm for biomarker assessment of procognitive treatment sensitivity in schizophrenia

项目摘要 经过几十年的促认知研究，深圳，FDA批准的促认知药物尚未确定。 然而，自下而上的有针对性的认知训练（TCT）被发现在改善认知和 SZ患者的功能结局。尽管如此，TCT是时间和劳动密集型的，昂贵的，并且只有 约有一半的患者受益。这强调了需要确定TCT的预测性生物标志物 灵敏度在最近的一份报告中，失配负波（MMN），一种基于脑电图（EEG）的测量， 早期听觉信息处理（EAIP）可预测治疗难治性SZ患者的TCT反应， 尽管它的能量不大为此，一个重要的问题是，能否增强EAIP的能力 “生物标志物”预测SZ患者TCT的认知和功能改善？ EAIP措施，MMN和听觉稳态反应（ASSR），大概是测量 在复杂的现实生活环境中的信息处理能力。在日常生活中，复杂的声音刺激 都是在被感知的环境中被处理的。然而，所有测量MMN和ASSR的方法， 利用孤立的声音片段（点击，音调），从任何环境背景中删除， 实验室测试椅这是可能的，脑电图测量产生使用上下文相关的自然声音 刺激可能是TCT敏感性的更好预测因素。然而，MMN和ASSR测量需要毫秒- 在结构化的测试会话中进行水平刺激控制-这在自然环境中不容易实现。 虚拟现实（VR）技术提供了自然的背景和严格的实验控制， 生成和评估EAIP的更多信息措施。 该应用程序朝着开发生态有效的基于VR的EEG范例迈出了关键一步 通过使用熟悉的VR中呈现的自然声音刺激（例如脚步声，千斤顶锤）来测量EAIP- 传递的上下文（例如，从点A步行到B、建筑工地）。VR-EEG任务将在 0-4个月期间与计算机科学系合作。效度、信度和生物标志物 将在健康受试者（HS）和SZ患者（N=40， HS：SZ= 20：20）。经过仔细筛选的合格研究受试者将完成 全面的神经认知和功能评估，实验室和基于VR的EEG任务， 在一项随机、顺序平衡、单一测试日的研究中，经过一小时的“声音扫描”TCT检查后。结果 将测试以下假设：1）基于VR的MMN和ASSR是EAIP赤字的可靠有效的衡量标准 SZ，2）基于VR的EEG测量将预测1小时TCT会话后的听觉感知学习， 3)基于VR的EEG测量将预测SZ的认知和功能状态。有证据表明， 这些基于VR的EAIP生物标志物的有效性将为未来VR-EEG引导的靶向研究提供基础。 前认知疗法

Project Summary After decades of procognitive research in SZ, an FDA approved procognitive drug is yet to be identified. However, a bottom-up targeted cognitive training (TCT) is found to be effective in improving cognition and functional outcome in SZ patients. Nonetheless, TCT is time and labor-intensive, expensive, and only beneficial to about half of the patients. This underscores the need to identify predictive biomarkers of TCT sensitivity. In a recent report, mismatch negativity (MMN), an electroencephalogram (EEG)- based measure of early auditory information processing (EAIP) predicted TCT response in treatment-refractory SZ patients, albeit, with modest power. To this end, an important question is, can we enhance the ability of EAIP “biomarkers” to predict cognitive and functional gains from TCT in SZ patients? EAIP measures, MMN and auditory steady state response (ASSR), are presumably measuring information processing capacity within complex, real-life environments. In everyday life, complex sound stimuli are processed in the context in which they are perceived. However, all methods to measure MMN and ASSR have utilized isolated sound fragments (clicks, tones), removed from any environmental context beyond a laboratory test chair. It is possible that EEG measures generated using contextually relevant naturalistic sound stimuli might be better predictors of TCT sensitivity. However, MMN and ASSR measures require millisecond- level stimulus control within a structured test session – that is not easily achieved in a naturalistic setting. Virtual reality (VR) technology provides both the naturalistic context and tight experimental control needed to generate and assess more informative measures of EAIP. This application takes the critical step toward developing an ecologically valid VR-based EEG paradigm to measure EAIP by using naturalistic sound stimuli (e.g. footsteps, jack hammer) presented in familiar VR- delivered contexts (e.g. walking from point A to B, construction site). The VR-EEG task will be developed in collaboration with the Computer Sciences Department during months 0-4. The validity, reliability and biomarker potential of the VR-based MMN and ASSR will be determined in healthy subjects (HS) and SZ patients (N=40, HS:SZ= 20:20) during project months 5-20. Carefully screened, eligible study participants will complete a comprehensive neurocognitive and functional assessment, laboratory- and VR- based EEG tasks before and after a one-hour “sound sweeps” TCT session in a randomized, order-balanced, single test day study. Findings will test the hypotheses that: 1) VR-based MMN and ASSR are reliable and valid measures of EAIP deficits in SZ, 2) the VR-based EEG measures will predict auditory perceptual learning after 1-hour of TCT session and 3) VR-based EEG measures will predict cognitive and functional state in SZ. Evidence suggesting ecological validity of these VR-based biomarkers of EAIP will provide basis for future VR-EEG guided studies of targeted procognitive therapeutics.