D-serine augmentation of neuroplasticity-based auditory learning in schizophrenia

项目摘要/摘要： 精神分裂症(Sz)患者在训练中表现出神经可塑性降低， 对早期听觉信息处理的要求越来越高。因为改进的听觉处理可以促进 在更接近日常功能的认知过程(言语记忆、执行能力)中获得 功能)，增强神经可塑性以更好地进行听觉处理是一种未得到满足的临床需求和 在纠正认知和整体功能之前，限速第一步。 近年来，N-甲基-D-天冬氨酸型谷氨酸受体(NMDAR)甘氨酸位点激动剂如D-天冬氨酸 丝氨酸越来越多地被证明有助于SZ和健康志愿者的神经可塑性，尤其是 当与认知补救相结合时。NMDAR激动剂似乎对 神经可塑性当以剂量依赖的方式以非每日间隔重复使用时，最佳剂量(80， 100或120 mg/kg)仍然是一个悬而未决的问题，D-丝氨酸+神经可塑性的组合能力也是一个悬而未决的问题 听觉学习能够产生持续的、功能上的改善。D-丝氨酸导致高度显著的，急性的 听觉神经可塑性和对NMDAR敏感的早期听觉加工测量的改善 不匹配负波(MMN)，在每周两次简短的、基于神经可塑性的疗程之前给予 听觉矫正计划。与阅读和工作记忆相关的可塑性改善 提示可塑性的改善是相关结果的功能预测。 其最终目标是通过增加D-来提高认知补救的效果和效率。 丝氨酸。首先，在R61期间，我将确认目标参与、可塑性变化和功能的关系 结果和D-丝氨酸治疗的最佳剂量。成功完成R61的定义如下 ≥中度急性效应大小改变与听觉可塑性、MMN和中度效应大小相关 在功能上相关的认知测量。在三年的R33期间，我将进行一项随机的安慰剂- D-丝氨酸的对照平行分组研究，评估D-丝氨酸+16次(1次)的持续效果 周)进行了基于神经可塑性的听觉修复。最成功的认知补救计划是 受限于长时间(30-50小时)的治疗方案。假设添加D-丝氨酸将提高 认知补救，R33的成功完成被定义为全球 治疗16小时后的认知功能。结果将不仅与Sz的听觉可塑性有关，而且还与 使用NMDAR药物加强跨神经认知障碍和领域的补救，使用ERP 监测简化认知补救计划的效果和好处，并将作为一项试点研究 确定是否有必要进行未来的决定性临床试验。

PROJECT SUMMARY/ABSTRACT: Schizophrenia (Sz) patients show reduced neuroplasticity during training on exercises that place implicit, increasing demands on early auditory information processing. As improved auditory processing can facilitate gains in those cognitive processes that are more proximal to daily functioning (verbal memory, executive functioning), enhancing neuroplasticity for better auditory processing represents an unmet clinical need and a rate-limiting first step prior to remediating cognition and overall function. Over recent years, N-methyl-D-aspartate-type glutamate receptor (NMDAR) glycine site agonists such as D- serine have increasingly been shown to facilitate neuroplasticity in both Sz and healthy volunteers, particularly when combined with cognitive remediation. NMDAR agonists appear to be maximally effective for neuroplasticity when used repeatedly at non-daily intervals in a dose dependent manner, the optimal dose (80, 100 or 120 mg/kg) remains an open question, as does the ability of combined D-serine + neuroplasticity-based auditory learning to produce sustained, functional improvement. D-serine leads to highly significant, acute improvement in both auditory neuroplasticity and the NMDAR sensitive early auditory processing measure mismatch negativity (MMN) when given prior to two 1x weekly sessions of a brief, neuroplasticity-based auditory remediation program. Plasticity improvements correlated with reading and working memory suggesting plasticity improvements are predictive of functionally of relevant outcomes. The ultimate goal of this is to enhance efficacy and efficiency of cognitive remediation by augmenting with D- serine. First, during the R61, I will confirm target engagement, relationships of plasticity changes and functional outcomes and the optimal dose of D-serine treatment. Successful completion of the R61 is defined by ≥moderate acute effect size change in auditory plasticity, MMN and a moderate effect size correlation with functionally relevant cognitive measures. During the three-year R33, I will conduct a randomized, placebo- controlled, parallel group study of D-serine, assessing the sustained effects of D-serine + 16 sessions (1x week) of neuroplasticity-based auditory remediation. Most successful, cognitive remediation programs are limited by lengthy (30-50 hrs) treatment regimens. Hypothesizing that adding D-serine will increase efficiency of cognitive remediation, successful completion of the R33 is defined as significant improvement in global cognition after 16 hours of treatment. Results will be relevant not only to auditory plasticity in Sz, but also to use of NMDAR drugs to augment remediation across neurocognitive disorders and domains, use of ERP to monitor effects and benefits of an abbreviated cognitive remediation program, and will serve as a pilot study to determine whether future, definitive clinical trials are warranted.