Brain plasticity underlying acquisition of new organizational skills in children

项目摘要 响应RFA-MH-16-406的分阶段创新申请寻求初始（R61）2年的支持 阶段，用于通过新的修改对特定的神经干预目标进行里程碑驱动的测试， 针对缺乏组织技能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。实现我们提出的里程碑将 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， 随机分配干预与等待列表对照条件，以评估目标之间的关系 职能成果的参与和变化。组织能力受损导致学业失败 和不良的长期结果，并发生在多种神经发育障碍。他们是 药物或大多数现有的行为治疗都无法充分解决这一问题。组织技能培训 (OST)在先前的对照试验中取得了稳健、持久的改善。进一步发展这一 干预，我们寻求识别有效干预所涉及的神经目标。我们的试点数据和 理论上的考虑支持一个总体假设，即内在功能连接（iFC） 背侧前扣带皮层（dACC）和前腹侧纹状体（aVS）之间的差异是可治疗的 目标因此，在最初的R61阶段，我们建议估计干预相关的效应量。 在至少22名儿童中，dACC-aVS iFC降低，获得了高质量的成像和临床数据， 修改OST之前和之后（OST-m）。如果我们达到我们提出的里程碑， iFC将超过特定的效应量，并占方差的相当大的比例， 在组织技能的改善，我们将继续到R33阶段。在R33阶段，我们将扩大 这项研究至少获得了86名随机分配到OST-m干预或等待名单的儿童，他们将 提供完整的高质量干预前和干预后/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 功能性磁共振成像我们在R33阶段的具体目标是确认随机分组组中的目标参与 OST-m与等待组;检查神经元靶点的变化与 组织技能和学术能力的临床改善;并确定 通过单独检查基线临床指标以及与 全脑体素静息状态指数。证据支持dACC-aVS iFC作为可调 神经靶点将支持未来的研究，以进一步提高认知/行为的有效性， 对儿童的干预。重要的是，即使是阴性结果也将提供有关OST“剂量”的信息。 需要达到实质性的效果。脑成像的非决定性结果仍然会告知贝叶斯先验 为今后研究组织技能损伤的神经基础及其改善提供了依据。

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.