Putative Effects of Extreme Physical Activity on the Brain and Cognitive FunctionDespite the positive effects of moderate physical activity on the brain, a number of studies have linked extreme exercise to disruption of cellular, metabolic, and hormonal processes and, in turn, to adverse neurological sequelae and cognitive dysfunction. Here, we review cellular mechanisms by which extreme physical activity might interfere with normal neuronal function, particularly those involved in learning and memory.Increased Reactive Oxygen Species and Cytokine ProductionThe brain comprises approximately 2% of adult human body weight and yet consumes approximately 20% of oxygen at rest (Allaman, 2013). The high rate of oxygen consumption, coupled with the low levels of anti-oxidant enzymes found in the brain, particularly during intense levels of physical activity, increases the vulnerability of the CNS to oxidative stress (Uttara et al., 2009). It has been shown that extreme levels of physical activity generate high levels of reactive oxygen species (ROS), leading to oxidative damage to DNA, RNA, proteins, and lipids (Aguiló et al., 2005). Tsakiris et al. (2006) demonstrated that prolonged forced swimming induced increased levels of ROS in rats (Tsakiris et al., 2006). It has been demonstrated that intense physical activity results in oxidative stress in rodents as shown by a significant increase in brain glutathione peroxidase (Hara et al., 1997) and lipid peroxidation (Somani and Husain, 1996). Moreover, Rosa et al. (2007) demonstrated young adult mice undergoing 10 days of intense and exhaustive running program exhibited a high index of brain oxidative stress and impaired memory as assessed by fear conditioning. Recapitulating these effects in humans, Aguiló et al. (2005) demonstrated that intense mountain exercise leads to the generation of oxidative stress and high levels of ROS. While vitamin E, an essential anti-oxidant, typically inhibits the production of ROS during lipid peroxidation, intense physical activity in humans leads to a significant increase in vitamin E turnover that weakens antioxidant defence (Mastaloudis et al., 2001). Thus, although moderate levels of physical activity can enhance the antioxidant defence mechanisms, extreme levels of physical activity can deplete anti-oxidant reserve (Mastaloudis et al., 2001), leading to adverse neurological effects (Gomez-Cabrera et al., 2008). Alternatively, cytokines may modulate the negative effects of extreme physical activity. IL-6 is directly released by muscles during physical activity and activates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland and increases cortisol levels (Mastorakos et al., 2005). Together, these studies suggest that extreme levels of physical activities may weaken the immune system either by reducing anti-oxidant defence or by altering cortisol levels.