Prophylactic Multimodal Cognitive Intervention for Children with Medulloblastoma (Resubmission)

 描述（由申请人提供）：接受脑肿瘤放射治疗的儿童始终表现出与学业失败和生活质量下降相关的智力功能下降。髓母细胞瘤是儿童最常见的恶性脑肿瘤，目前的多模式治疗的存活率接近80%。随着幸存者人数的不断增加，改善长期认知结果的努力变得势在必行。该研究计划的主要目标是开发干预措施，减轻CNS导向疗法对儿童癌症幸存者生活质量的影响。虽然有效，但药理学和治疗师提供的干预措施受到医疗禁忌症和当地提供者的限制。最近的研究表明，注意力和工作记忆（WM;在线维护和操纵信息）的损伤可能是脑肿瘤幸存者智力下降的近端原因。基于计算机的工作记忆干预已经证明了对发展性和获得性注意力障碍患者的有效性。在注意力、WM和执行功能方面取得了改善，培训后持续数月受益。在WM训练前后进行的功能性神经成像（fMRI）表明支持大脑系统的神经可塑性。这种干预最近被证明是可行的和有效的儿童癌症幸存者与相关的大脑为基础的变化的证据。现在关键是要确定我们是否可以通过在迟发效应出现之前进行预防性干预来保护认知功能，并通过联合收割机干预来优化结果。对患有慢性病的儿童的新研究表明，有氧运动对认知有益。此外，动物模型揭示了损伤后与运动相关的恢复，并提示了潜在的脑机制（例如，新的神经细胞形成）。在拟议的研究中，我们将招募新诊断的髓母细胞瘤治疗的儿童接受一线治疗，其中包括放射治疗期间的随机运动试验。治疗后，我们将立即将患者随机分配到计算机化WM干预组或时间和注意力控制组（一般社会支持）。两组都将完成干预前后的认知测试和功能磁共振成像。研究目的包括：测试计算机化WM干预的有效性（具体目标1），比较计算机化WM干预与有氧运动干预联合施用的认知影响（具体目标2），以及使用fMRI检查与WM训练相关的神经可塑性（具体目标3）。假设：1.被随机分配到WM干预组的参与者相对于对照组将表现出较少的WM下降，其益处可推广到高阶认知技能，并且随着时间的推移可持续。接受有氧运动和WM干预的参与者将表现出比单独接受任何一种干预的参与者更好的认知结果，以及3.被随机分配到WM干预组的参与者将在WM训练后表现出大脑激活模式的有意义的变化。

 DESCRIPTION (provided by applicant): Children treated with radiation therapy for brain tumors consistently demonstrate a decline in intellectual functioning that is associated with academic failure and reduced quality of life. Medulloblastoma is the most common malignant brain tumor in children and survival rates approach 80% with current multimodal therapy. With a growing survivor population, efforts to improve long-term cognitive outcomes become imperative. A primary goal of this research program is development of interventions that mitigate the impact of CNS-directed therapies on the quality of life of childhood cancer survivors. While efficacious, pharmacological and therapist- delivered interventions are limited by medical contraindications and availability of local providers. Recent research suggests impairments in attention and working memory (WM; online maintenance and manipulation of information) may be proximal contributors to intellectual declines among brain tumor survivors. A computer- based WM intervention has demonstrated efficacy with individuals with developmental and acquired attention disorders. Improvements have been achieved on measures of attention, WM and executive functions with benefits persisting months after training. Functional neuroimaging (fMRI) conducted before and after WM training suggests neuroplasticity for supporting brain systems. This intervention has recently been shown to be feasible and efficacious for childhood cancer survivors with evidence for associated brain-based changes. It is now crucial to determine whether we can preserve cognitive function by intervening prophylactically, before the emergence of late effects, and combine interventions to optimize outcomes. New research with children with chronic disease indicates aerobic exercise offers cognitive benefits. Further, animal models reveal exercise- related recovery following injury and suggest underlying brain mechanisms (e.g., new nerve cell formation). In the proposed study, we will recruit children treated for newly diagnosed medulloblastoma on a front-line protocol that includes a randomized exercise trial during radiation therapy. Immediately following treatment, we will randomly assign patients to a computerized WM intervention or a time and attention control group (generic social support). Both groups will complete pre- and post-intervention cognitive testing and fMRI. Study aims include: testing the efficacy of a prophylactically administered computerized WM intervention (Specific Aim 1), comparing the cognitive impact of a computerized WM intervention administered in conjunction with an aerobic exercise intervention (Specific Aim 2), and using fMRI to examine neuroplasticity associated with WM training (Specific Aim 3). It is hypothesized that: 1. participants randomized to the WM intervention will demonstrate less WM decline relative to controls, with benefits that are generalizable to higher-order cognitive skills and sustainable over time, 2. participants receiving both aerobic exercise and WM interventions will demonstrate better cognitive outcomes than participants receiving either intervention alone, and 3. participants randomized to the WM intervention will demonstrate meaningful changes in brain activation patterns after WM training.