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

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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.