Brain cancer is a common type of childhood malignancy, and radiotherapy (RT) is a mainstay of treatment. RT is effective for tumor eradication, and survival rates are high. However, RT damages the brain and disrupts ongoing developmental processes, resulting in debilitating cognitive “late” effects that may take years to fully manifest. These late effects likely derive from a long-term decrement in cell proliferation, combined with a neural environment that is hostile to plasticity, both of which are induced by RT. Long-term suppression of cell proliferation deprives the brain of the raw materials needed for optimum cognitive performance (such as new neurons in the hippocampus and new glia in frontal cortex), while chronic inflammation and dearth of trophic substances (such as growth hormone) limit neuroplastic potential in existing circuitry. Potential treatments for cognitive late effects should address both of these conditions. Exercise represents one such potential treatment, since it has the capacity to enhance cell proliferation, as well as to promote a neural milieu permissive for plasticity. Here, we review the evidence that cognitive late effects can be traced to RT-induced suppression of cell proliferation and hostile environmental conditions, as well as emerging evidence that exercise may be effective as an independent or adjuvant therapy. 1. Introduction Brain tumors are the second most common form of childhood cancer, after acute lymphoblastic leukemia (ALL) [1]. Treatment for both brain tumors and ALL includes cranial RT. Given 5-year survival rates that approach 90% for children treated for ALL and 70% for those treated for brain tumors [2], there are currently a great many survivors of these cancers that suffer from the consequences of RT, including adverse physiological, psychological, and cognitive side effects that manifest both acutely and years later. These so called “late effects” result in lowered quality of life (QOL) [3] in survivors, for which there is at present no effective treatment. RT for pediatric cancer has long been acknowledged as a primary cause of neurological complications and neurocognitive decline [4–8]. Childhood RT is associated with a significant decrease in IQ scores [8–14], thought to result from deficits in core processing functions impaired by RT, including processing speed [15], attention [15–18], working memory, and other executive functions [7, 19]. In addition to cognitive impairments, adult survivors of childhood RT also experience elevated rates of emotional distress, such as anxiety and/or depression
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