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

项目总结/摘要： 精神分裂症（Sz）患者在进行内隐运动训练时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 在那些更接近日常功能的认知过程中获得（言语记忆，执行记忆）， 功能），增强神经可塑性以改善听觉处理代表了未满足的临床需求， 在补救认知和整体功能之前的限速第一步。 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- 越来越多的研究表明，丝氨酸促进Sz和健康志愿者的神经可塑性， 与认知矫正相结合NMDAR激动剂似乎对以下患者最有效： 神经可塑性当以剂量依赖性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+基于神经可塑性的联合治疗的能力也是如此。 听觉学习产生持续的、功能性的改善。D-丝氨酸导致高度显著的急性 听觉神经可塑性和NMDAR敏感的早期听觉处理测量的改善 在每周两次基于神经可塑性的简短治疗前给予失匹配负波（MMN） 听觉矫正计划可塑性改善与阅读和工作记忆相关 这表明可塑性的改善可以预测相关结果的功能。 其最终目标是通过增加D- 丝氨酸首先，在R61期间，我将确认目标接合，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的定义为： 听觉可塑性、MMN的≥中度急性效应量变化和与 功能相关的认知测量。在三年的R33中，我将进行一个随机的安慰剂- D-丝氨酸的对照、平行组研究，评估D-丝氨酸+ 16次治疗的持续效应（1x 神经可塑性的听觉补救。大多数成功的认知补救计划是 受到长时间（30-50小时）治疗方案的限制。假设添加D-丝氨酸将增加 认知补救，成功完成R33被定义为全球的显著改善 治疗16小时后的认知。结果不仅与Sz的听觉可塑性有关，而且与 使用NMDAR药物加强神经认知障碍和领域的补救，使用ERP 监测简短的认知补救计划的效果和益处，并将作为试点研究， 确定未来是否有必要进行明确的临床试验。

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.