Candidate mechanisms for chemotherapy-induced neurocognitive deficits in pediatric solid non-CNS tumor patients

1.摘要 强化治疗性化疗与亚急性神经毒性相关，可对大脑产生不利影响 功能这些不利的治疗后遗症增加了对幸存者和家庭的重大终身影响， 并且可能给社会、医疗和教育系统带来可测量的成本。到目前为止， 研究表明，40-70%的儿童幸存者谁经历了中枢神经系统（CNS）化疗， 在注意力、工作记忆和信息处理速度方面表现出缺陷，这些缺陷被认为是由 治疗的神经毒性。非中枢神经系统实体瘤（NST）共占三分之一以上， 在儿童癌症诊断中，对NST中化疗的神经毒性作用知之甚少 幸存者这个项目的首要目标是研究化疗相关的神经毒性的影响 对奖励处理、认知控制和 儿童NST幸存者的工作记忆。为了实现我们的目标，我们的目标是招募30名儿童NTS幸存者 (e.g.,骨肉瘤、淋巴瘤、癌和神经母细胞瘤），年龄为6-17岁，30名年龄匹配 特别是发育中的儿童。本项目的具体目标将是检查组之间的差异 与奖赏反应相关的电生理、行为和计算生物标志物（Aim 目标1a）、奖励评估（目标1b）、认知控制（目标2a）和工作记忆（目标2b）。我们的总体 一种假说认为，NST的化疗改变了参与特定认知功能的神经活动和脑结构， 功能（奖励处理，认知控制，工作记忆），我们预测，我们的选择， 这些功能的神经认知指数将揭示异常神经和计算的独特模式， 与健康、年龄和性别匹配的对照组相比，我们认为，这些领域的多样性 研究，如参与多个神经系统，使我们能够解决基础，翻译，和应用 问题，包括大脑、计算和行为的交叉点。我们的长期目标是 以了解这种跨领域的研究模式是否有助于制定更有针对性和更有效的 儿童NST的化疗治疗，以及认知缺陷的善后护理。通过识别这种 神经认知表型，这项研究将有助于发展未来的研究和赠款战略，旨在 减少化疗的副作用以及针对特定认知障碍的治疗干预 这个人口的分布。

1. Abstract Intensive curative chemotherapy is associated with subacute neurotoxicity, which can adversely affect brain functioning. These adverse treatment sequelae add to the significant lifelong impact on survivors and families, and may entail a measurable cost to societal, medical, and educational systems. To date, converging evidence shows that 40–70% of childhood survivors who have gone through central nervous system (CNS) chemotherapy exhibit deficits in attention, working memory, and information processing speed, deficits believed to be caused by the neurotoxicity of the treatment. While non-CNS solid tumors (NST) collectively account for over one third of cancer diagnoses among children, little is known about the neurotoxic effects of chemotherapy in NST survivors. The overarching goal of this project is to examine the impact of chemotherapy-related neurotoxicity on well-established neural, cognitive, and computational indices of reward processing, cognitive control and working memory in pediatric NST survivors. To achieve our goal, we aim to recruit 30 survivors of childhood NTS (e.g., osteosarcomas, lymphomas, carcinomas, and neuroblastomas) aged 6–17 years old and 30 age-matched typically developing children. The specific aims of this project will be to examine group differences between electrophysiological, behavioral, and computational biomarkers associated with reward responsiveness (Aim 1a), reward valuation (Aim 1b), cognitive control (Aim 2a) and working memory (Aim 2b). Our overarching hypothesis is that chemotherapy for NST alters neural activity and brain structures involved in specific cognitive functions (reward processing, cognitive control, working memory), and we predict that our selected neurocognitive indices of these functions will reveal unique patterns of abnormal neural and computational processes compared to healthy, age- and sex-matched controls. We believe that the diversity in these areas of research, such as engaging multiple neural systems, enables us to address basic, translational, and applied questions, including those at the intersection of the brain, computation, and behavior. Our long-term goal will be to find out whether this cross-cutting research model will aid in the development of a more targeted and efficient chemotherapy treatments for pediatric NST, as well as aftercare for cognitive deficits. By identifying such neurocognitive phenotypes, this research will help develop future research and grant strategies aimed at reducing the adverse effects of chemotherapy as well as tailor therapeutic interventions for the specific cognitive profile of this population.