Physical exercise and cognition: mechanisms of action and evaluation of the potential therapeutic value in traumatic brain injury

Physical exercise, an economical and easily accessible lifestyle intervention can improve cognitive function in healthy adults and is a potential long-term treatment option for those who have sustained traumatic brain injury (TBI). Following TBI, the cognitive squeal of impairment can persist for years or even decades. As such, the use of physical exercise as a therapeutic intervention may have benefits both within the neurorehabilitation hospital as well as in community-dwelling individuals later in life. Many animal models of the effect of exercise on cognitive recovery following TBI have been reported but translation of these result into clinical practice is poor and numerous parameters of exercise appear to have differential effects. Our understanding of which is limited. Assessing the feasibility of exercise within the sub-acute phase of moderate-to-severe TBI, characterizing the mechanistic underpinnings of how exercise modulates cognitive function and evaluating the impact of exercise in communitydwelling individuals with TBI will improve our understanding of the potential impact this intervention may have for cognitive recovery post-TBI. This thesis used multiple scientific study approaches (observational, systematic review, clinical and translational) to gain global insights into the potential use of physical exercise in cognitive recovery following TBI. Firstly, an extensive up-to-date systematic review of the extant literature on the role of exercise in cognitive recovery following TBI was performed (chapter 3). Secondly, the feasibility of adding an 8-week aerobic exercise program into the sub-acute phase of moderate-to-severe TBI, on top of standard multidisciplinary rehabilitation, including cognitive training, was assessed (chapter 4). Thirdly, a two by two within-subjects study design was performed to assess the effect of a single bout of light intensity aerobic exercise on multiple constructs of executive function and a mechanistic understanding of this effect was sought using transcranial magnetic stimulation (TMS) measures of short-term neuroplasticity and serum levels of insulin-like growth factor-1 (IGF-1) and cortisol (chapter 5). Lastly, the association between self-reported physical activity and perceived cognitive health was studied in a nested case control study from a larger cohort of participants enrolled in the Barcelona Brain Health Initiative (chapter 6). In chapter 3, results from the systematic review revealed that very few (6) studies had assessed the effect of aerobic exercise on cognitive recovery post-TBI and numerous issues with this type of research pose challenges to studying the effect of exercise on cognitive recovery in the sub-acute phase of moderate-to-severe TBI. Consequently, the study in chapter 4 was designed and performed. Results from this chapter reported the feasibility of including 8-weeks of 1- hour sessions of aerobic exercise into the sub-acute rehabilitation from moderate-to-severe TBI on top of standard rehabilitation that includes cognitive training. Poor correlations between heart rate reserve (HRR) and perceived exertion were seen however and only 2 individuals exercise within target heart rate zones of 50-70% HRR. The apparent inability of individuals with moderate-to-severe TBI to exercise at the higher intensities (50-70% heart rate reserve (HRR)) lead to the study design of chapter 5. This chapter found that whilst light aerobic exercise modulates intracortical facilitation and multi-tasking performance in healthy adults, exercise-mediated changes in spatial working memory and intracortical inhibition were seen in individuals with mild TBI. No changes in IGF-1 were seen at any time point in either group. Lastly, chapter 6 demonstrated that being physically active, compared to being insufficiently active, was associated with an increased odds of reporting good global health in those with and without a history of TBI. Additionally, in those with a history of TBI, this physical activity classification was associated with an increased odds of reporting good cognitive health also. The study of the therapeutic benefit of aerobic exercise in the recovery of cognitive function post-TBI is in its infancy yet there is a growing body of evidence supporting its feasibility and potential efficacy. Whilst the optimal parameters of exercise are under debate, its use at different time points post-injury appear to be pragmatic and potentially beneficial. The efficacy of its therapeutic use in the sub-acute phase of injury should be studied yet methodological issues need to be overcome. The underlying biological mechanisms of its effect appear complex but highlight the window of opportunity for the optimization of different parameters. Finally, its efficacy across the lifespan following a TBI appears pragmatic yet how to improve adherence to a physically active lifestyle is an important issue in need of study