Brain plasticity underlying acquisition of new organizational skills in children

项目摘要 响应RFA-MH-16-406的这一阶段性创新应用寻求对初始(R61)2年期的支持 用于里程碑驱动的特定神经干预目标测试阶段 针对组织技能缺陷的小学三至五年级儿童的治疗 神经发育障碍背景下的组织技能。达到我们建议的里程碑将 触发额外三年的支持(R33阶段)，以确认更大样本中的目标参与度 随机分配干预与等待名单控制条件，以评估目标之间的关系 参与和功能结果的变化。组织技能障碍是导致学校失败的原因之一 以及不良的长期结果，并发生在多种神经发育障碍中。他们是 药物或大多数现有的行为疗法都不能充分解决这个问题。组织技能培训 (OST)在先前的对照试验中取得了强劲、持久的改善。为了进一步发展这一点 干预，我们试图确定有效干预所涉及的神经靶点。我们的试点数据和 理论考虑支持最重要的假设，即内在功能连接(IFC) 在背侧前扣带回(DACC)和前腹纹状体(Avs)之间是一种可治疗的 目标。因此，在最初的R61阶段，我们建议估计与干预相关的影响大小 至少22名同时获得高质量成像和临床数据的儿童的dACC-AVS IFC减少 改良OST前后(OST-m)。如果我们达到我们提出的里程碑，dACC-AVS的减少 国际金融公司将超过特定的影响规模，并在 随着组织技能的提高，我们将进入R33阶段。在R33阶段，我们将扩展 这项研究旨在获得至少86名随机接受OST-M干预的儿童，或者等待谁将接受干预 提供完整的高质量介入前和介入后/等待名单成像和临床数据。对于这两个阶段，我们 将获得最先进的磁共振成像(MRI)数据，主要关注静息状态 功能核磁共振。我们在R33阶段的具体目标是确认随机分组中的目标参与度 OST-m组与等待名单组；检查神经元靶点变化与 在组织技能和学术熟练程度方面的临床改进；以及确定 通过单独检查基线临床措施以及与 全脑体素静息状态指数。证据支持dACC-AVS IFC作为可修改的 神经靶点将支持未来的研究，以进一步增强认知/行为的有效性 对儿童的干预。重要的是，即使是否定的结果也将是关于OST“剂量”的信息 达到实质性效果所必需的。脑成像的不确定结果仍将为贝叶斯先验提供信息 未来对组织技能损伤及其改善的神经基础的研究。

Project Summary This phased innovation application in response to RFA-MH-16-406 seeks support for an initial (R61) 2-year phase for milestone-driven testing of a specific neural target of intervention by a novel modification of a treatment targeting organizational skills in children in 3rd to 5th grades of elementary school who have deficient organizational skills in the context of neurodevelopmental disorders. Attaining our proposed milestones would trigger support for three additional years (R33 phase) to confirm target engagement in a larger sample with random assignment to intervention vs. wait-list control conditions, to assess the relationships between target engagement and changes in functional outcomes. Organizational skills impairments contribute to school failure and to poor long-term outcomes and occur across multiple neurodevelopmental disorders. They are insufficiently addressed by medications or most existing behavioral treatments. Organizational skills training (OST) has resulted in robust, enduring improvements in a prior controlled trial. To further develop this intervention, we seek to identify the neural targets engaged by effective intervention. Our pilot data and theoretical considerations support the overarching hypothesis that intrinsic functional connectivity (iFC) between dorsal anterior cingulate cortex (dACC) and anterior ventral striatum (aVS) represents a treatable target. Accordingly, in the initial R61 phase we propose to estimate the effect size of intervention-related decreases in dACC-aVS iFC in at least 22 children with high-quality imaging and clinical data obtained both before and after modified OST (OST-m). If we meet our proposed milestones that the decrease in dACC-aVS iFC will exceed a specific effect size and account for an appreciable proportion of the variance in the improvement in organizational skills, we would proceed to the R33 phase. In the R33 phase, we would expand the study to obtain at least 86 more children randomized to the OST-m intervention or to wait-list who will provide complete high quality pre- and post-intervention/waitlist imaging and clinical data. For both phases, we will obtain state-of-the-art magnetic resonance imaging (MRI) data with a primary focus on resting-state functional MRI. Our specific aims in the R33 phase are to confirm target engagement in the group randomized to OST-m vs. the waitlist group; to examine the relationship between changes in the neuronal target and clinical improvements in organizational skills and academic proficiency; and to identify moderators of improvement in organizational skills by examining baseline clinical measures alone and in combination with whole-brain voxel-wise resting-state indices. Evidence supporting the validity of dACC-aVS iFC as a modifiable neural target would then support future studies to further enhance the effectiveness of cognitive/behavioral interventions in children. Importantly, even negative results will be informative regarding the OST “dosage” required to attain substantial effects. Inconclusive results from brain imaging would still inform Bayesian priors for future studies of the neural substrates of organizational skills impairments and their amelioration.