Augmentation of Cognitive Training in Children with TBI with D-Cycloserine

摘要 这项机械性的概念验证研究检验了这样一种假设 N-甲基-D-天冬氨酸受体(NMDAR)在儿童中重度感染后的功能 创伤性脑损伤(TBI)合并D-环丝氨酸(DC)将增加神经激活，并且当 与认知训练结合使用将增强认知训练的效果 工作记忆(WM)。研究参与者将是完成我们目前资助的 颅脑损伤后1年内神经认知功能恢复的研究在这种双盲、平行、 安慰剂对照研究患有中、重度脑外伤的儿童将被随机分为 两个治疗手臂。两个治疗组都将接受为期六周的认知训练 在以前的研究中显示的计算机培训计划，以改善WM。参赛者将收到分布式控制系统 或者在认知训练之外再服用安慰剂。在基线上，两个治疗部门的参与者都将 在服用第一剂药物之前和之后进行功能磁共振成像，以检验这一假设 Dcs增加了神经的激活。这种药理学MRI范例可能是一个生物标志物 丹参对认知功能影响的机制。在基线中 WM和执行功能的神经心理测验评价及父母的评分 他们的孩子的工作记忆和执行功能将被管理，以提供评估的基础 泛化。在六周的培训之后，同样的评估将是 重新进行管理，只有一项fMRI评估例外，以确定儿童是否 在经过训练的WM测试中，使用集散控制系统处理后的测试效果更好，具有更强的泛化能力 而不是孩子们服用安慰剂。在终止治疗三个月后 儿童将完成一次认知训练，并将在未训练的儿童身上进行重新测试 WM和EF及其家长将完成问卷调查，以评估 维持训练。这项研究将收集初步数据，以支持确定 开发药物的新靶点(NMDAR介导的神经可塑性) 神经认知恢复和该靶点的生物标记物(药物学fMRI)。

Abstract This mechanistic, proof of concept study tests the hypothesis that augmentation of suppressed N-Methyl-D-aspartate Receptor (NMDAR) function following pediatric moderate/severe traumatic brain injury (TBI) with D-cycloserine (DCS) will increase neural activation, and when used in conjunction with cognitive training will enhance the effect of cognitive training on working memory (WM). Study participants will be children who completed our currently funded study of neurocognitive recovery during the first year post-TBI. In this double blind, parallel, placebo controlled study children with moderate and severe TBI will be randomized to one of two treatment arms. Both treatment arms will receive six weeks of cognitive training from a computer training program shown in prior studies to improve WM. Participants will receive DCS or a placebo in addition to cognitive training. At baseline participants in both treatment arms will undergo fMRI before and after administration of the first dose of drug to test the hypothesis that DCS increases neural activation. This pharmacological MRI paradigm may be a biomarker for the mechanism for the therapeutic effects of DCS on cognitive function. In the baseline evaluation neuropsychological tests of WM and executive functioning and parent's ratings of their child's WM and executive functioning will be administered to provide a basis for assessing generalization. After six weeks of training, the same battery of evaluations will be readministered, with the exception on only one fMRI evaluation, to determine whether children treated with DCS improved more on the trained WM tests and showed greater generalization than children receiving placebo. After treatment has been terminated for three months the children will complete one session of cognitive training and will be retested on the non-trained measures of WM and EF and their parents will complete questionnaires to assess the maintenance of training. This study will collect preliminary data to support attempts to identify a new target (NMDAR mediated neural plasticity) for developing drugs that enhance neurocognitive recovery and a biomarker (pharmocological fMRI) for that target.