The effects of exercise on brain health and cognitive performance: a comprehensive review of current evidence

Presented as a pre-print exclusively for XZQT.IT.

A thesis presented to the Faculty of University of Toronto in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Neuroscience

by Serban Croitoru

Toronto, Ontario September 19th, 2024

This thesis provides a comprehensive overview of the current evidence regarding the effects of exercise on brain health and cognitive performance through a systematic review of randomised controlled trials, observational studies, and meta-analyses. The objective is to synthesise the findings on how various types and intensities of exercise impact neurological functioning across the lifespan. The review covers studies examining the effects of aerobic exercise, resistance training, and combined interventions on a range of cognitive domains including attention, memory, processing speed, and executive function, as well as on neuroimaging measures of brain structure and function. The findings indicate that regular exercise, particularly aerobic exercise, is associated with improved cognitive performance in healthy adults, with the strongest effects observed for executive functions. Exercise also appears to be neuroprotective, reducing the risk of age-related cognitive decline and neurodegenerative diseases like Alzheimer's. Potential neurobiological mechanisms are discussed, including enhanced neuroplasticity, cerebral blood flow, and upregulation of neurotrophic factors. Methodological limitations and gaps in the current literature are identified, with recommendations made for future research directions. This review provides a strong argument for the promotion of regular exercise as a cost-effective, accessible intervention to optimize brain health and functioning across the lifespan.

The relationship between physical exercise and cognitive functioning has been a topic of increasing scientific interest over the past few decades. As the global population ages and the prevalence of age-related cognitive decline and dementia rises, there is an urgent need to identify effective strategies to maintain brain health throughout the lifespan. Exercise has emerged as a promising non-pharmacological intervention, with a growing body of evidence suggesting that regular physical activity can have profound benefits for cognitive performance and neurological functioning.

Early observational studies provided initial support for the cognitive benefits of exercise. Subsequent cross-sectional studies demonstrated that higher levels of physical fitness were associated with better performance on a range of cognitive tasks, particularly those involving executive control processes like working memory, cognitive flexibility, and inhibition.

To better establish causality, researchers turned to randomized controlled trials (RCTs) of exercise interventions. A seminal study by Colcombe et al. (2004) found that a 6-month aerobic exercise program in older adults led to significant improvements in executive function and increased brain volume in prefrontal and temporal regions compared to a stretching control group. Subsequent RCTs have largely corroborated these findings, demonstrating beneficial effects of aerobic exercise on various domains of cognitive function, especially executive functions and memory.

While much of the initial research focused on aerobic exercise, more recent studies have explored the cognitive impacts of other exercise modalities like resistance training. Combination training protocols involving both aerobic and resistance exercises have also shown promise, although the relative contributions of each component are not yet clear.

In addition to behavioral measures of cognitive performance, neuroimaging studies have provided insights into the neurobiological mechanisms through which exercise may benefit the brain. These findings suggest that exercise may promote neurogenesis and synaptic plasticity in brain regions critical for learning and memory. Exercise has also been associated with increased cerebral blood flow, enhanced white matter integrity, and upregulation of neurotrophic factors like brain-derived neurotrophic factor (BDNF) that support neuronal survival and differentiation.

Despite the accumulating evidence for exercise as a cognitive enhancer, there are still many open questions and limitations in the current literature. The optimal dose, type, and timing of exercise to maximize cognitive benefits remains unclear. Most studies to date have been conducted in older adults, with fewer investigations of exercise effects in childhood, adolescence, and midlife. The potential to use exercise as an adjunctive treatment for neurological and psychiatric conditions is also an active area of research requiring further study.

A substantial body of evidence has accumulated over the past two decades regarding the cognitive benefits of aerobic exercise. Randomized controlled trials have consistently demonstrated that aerobic exercise training programs can improve performance on a range of cognitive tasks in healthy older adults.

The strongest effects have been observed for executive functions, a set of higher-order cognitive processes that include working memory, cognitive flexibility, and inhibitory control.

Subsequent studies have replicated and extended these findings, showing aerobic exercise-induced enhancements in executive functions across a range of tasks and populations.

Aerobic exercise has also been associated with improvements in memory function, particularly spatial and episodic memory. Meta-analyses have confirmed positive effects of aerobic exercise on various domains of memory, although the effect sizes tend to be smaller than those observed for executive functions.

While the majority of studies have been conducted in older adults, there is growing evidence that aerobic exercise can benefit cognitive function across the lifespan. The cognitive benefits of aerobic exercise appear to extend beyond healthy populations. Studies have shown that aerobic exercise can improve cognitive function in individuals with mild cognitive impairment, Alzheimer's disease, Parkinson's disease, and schizophrenia, among other neurological and psychiatric conditions. However, the effect sizes tend to be more modest in clinical populations, and further research is needed to establish the feasibility and efficacy of exercise as an adjunctive treatment for cognitive impairment.

While the cognitive benefits of aerobic exercise have been more extensively studied, a growing body of evidence suggests that resistance training (e.g., weightlifting, bodyweight exercises) can also positively impact brain health and cognitive performance.

Several randomized controlled trials have demonstrated that resistance training can improve various domains of cognitive function, particularly in older adults. Meta-analytic reviews have provided further support for the cognitive benefits of resistance training. The effect sizes were comparable to those typically reported for aerobic exercise interventions.

Potential mechanisms underlying the cognitive benefits of resistance training include increased insulin-like growth factor 1 (IGF-1), which has neurotrophic and neuroprotective properties, as well as enhanced cerebral blood flow and cortical activation. Resistance training may also indirectly benefit cognitive function by improving sleep quality, reducing inflammation, and enhancing psychological well-being.

Despite these promising findings, the literature on resistance training and cognitive function is still relatively nascent compared to the aerobic exercise literature. More research is needed to determine the optimal dosing and programming of resistance training for cognitive benefits, as well as to explore potential synergistic effects of combined resistance and aerobic training. Investigating the cognitive impacts of resistance training in younger populations and clinical groups is also an important avenue for future study.

Neuroimaging and neurophysiological studies have begun to elucidate the neurobiological mechanisms through which exercise may benefit cognitive function. While the precise pathways are not yet fully understood, several key themes have emerged from the current evidence.

One prominent hypothesis is that exercise promotes neuroplasticity, the brain's ability to adapt and reorganize in response to experience. Both animal and human studies have demonstrated that aerobic exercise can stimulate the growth of new neurons (neurogenesis) in the hippocampus, a brain region critical for learning and memory. Exercise also appears to enhance synaptic plasticity by increasing dendritic spine density and promoting long-term potentiation, the strengthening of neural connections that underlies memory formation.

Exercise-induced increases in neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), are thought to play a key role in these neuroplastic processes. BDNF is a protein that supports the survival, growth, and differentiation of neurons and is highly expressed in brain regions involved in learning and memory, such as the hippocampus. Both acute and chronic exercise have been shown to increase BDNF levels in the brain, and these increases are associated with improvements in cognitive performance.

Exercise also has profound effects on cerebral blood flow and brain metabolism. Aerobic exercise acutely increases blood flow to the brain, delivering oxygen and nutrients to support neuronal function. Chronic exercise training has been associated with increased capillary density and angiogenesis in the brain, which may help to preserve cognitive function by enhancing cerebral perfusion and reducing the risk of ischemic damage. Exercise-induced alterations in brain metabolism, such as increased lactate uptake and enhanced mitochondrial function, may also contribute to improved cognitive performance.

Finally, exercise may benefit cognitive function by modulating neurotransmitter systems in the brain. For example, acute exercise has been shown to increase the release of norepinephrine, dopamine, and serotonin, neurotransmitters that play key roles in attention, memory, and mood. Regular exercise may also enhance the efficiency of these neurotransmitter systems by upregulating receptor sensitivity and promoting synaptic remodeling.

While these neurobiological mechanisms provide a compelling framework for understanding the cognitive benefits of exercise, much more research is needed to fully map the complex pathways linking physical activity to brain health. Integrating advanced neuroimaging techniques, neurophysiological measures, and -omics approaches will be critical for developing a systems-level understanding of how exercise shapes the structure and function of the brain across the lifespan.

The evidence reviewed in this thesis has important implications for public health and clinical practice. Given the robust and wide-ranging cognitive benefits of exercise, particularly aerobic exercise, there is a strong rationale for promoting regular physical activity as a lifestyle intervention to support brain health across the lifespan.

From a public health perspective, finding ways to increase population-level engagement in exercise could yield substantial benefits for cognitive health and help to reduce the burden of age-related cognitive decline and dementia. This may require multi-level strategies, such as implementing physical activity programs in schools and workplaces, designing built environments that encourage active transport and recreation, and developing targeted public education campaigns. Policymakers and healthcare systems should prioritize efforts to make exercise accessible, affordable, and culturally appropriate for diverse communities.

In clinical settings, exercise should be routinely incorporated into preventive care and treatment plans for maintaining and enhancing cognitive function. Clinicians can play a key role in assessing patients' physical activity levels, providing individualized exercise prescriptions, and offering resources and referrals to support long-term behavior change. Integrating exercise interventions into the management of neurological and psychiatric conditions characterized by cognitive impairment is a promising approach that warrants further investigation.

Despite the substantial progress that has been made in understanding the relationship between exercise and cognitive function, there are still many important avenues for future research. Some key priorities include dose-response studies, investigations of multimodal interventions, large-scale prospective cohort studies, mechanistic studies, translational research, exploration of emerging exercise modalities, and investigations of genetic and epigenetic factors in exercise responses.

By addressing these research gaps and translating findings into practice and policy, the power of exercise can be harnessed to optimize brain health and cognitive performance across the lifespan. In doing so, not only can individual quality of life be enhanced, but more resilient and productive societies can be built in the face of an aging global population.

The evidence reviewed in this thesis provides a compelling case for the cognitive benefits of regular physical exercise, particularly aerobic exercise. From children to older adults, in healthy and clinical populations, exercise appears to enhance brain structure and function in ways that translate into meaningful improvements in cognitive performance.

While the precise neurobiological mechanisms are still being mapped, exercise-induced neuroplasticity, neurotrophic factor production, cerebrovascular adaptations, and neurotransmitter modulation likely play key roles. By integrating insights across levels of analysis, from molecular to behavioral, a systems-level understanding of how physical activity shapes the brain is beginning to develop.

The public health implications of this evidence are profound. In a world facing an epidemic of sedentary behavior and an aging population, exercise represents an accessible, cost-effective, and scalable intervention to support cognitive health. Governments, healthcare systems, schools, workplaces, and communities all have a role to play in promoting exercise as a core component of a brain-healthy lifestyle.

At the same time, there is still much work to be done to fully harness the potential of exercise as a cognitive enhancer and neuroprotective agent. Future research must focus on optimizing exercise prescriptions, exploring synergies with other lifestyle interventions, and developing personalized approaches informed by individual biology and preferences. Translating this evidence into sustainable, real-world interventions that can reach diverse populations is an urgent priority.

In conclusion, the current evidence strongly supports the brain-boosting power of physical exercise. By engaging in regular aerobic and resistance training activities, individuals across the lifespan can enhance their cognitive abilities, protect against age-related decline, and promote overall brain health. The challenge now is to apply this knowledge to develop effective policies, practices, and programs that make exercise accessible and achievable for all.

As the ancient Greek philosopher Plato famously observed, "In order for man to succeed in life, God provided him with two means, education and physical activity. Not separately, one for the soul and the other for the body, but for the two together. With these means, man can attain perfection." The insights from modern neuroscience suggest that Plato's intuition was prescient - the link between a healthy mind and a healthy body is indeed powerful and inextricable.

In pursuing a more active society, there is an opportunity to not only enhance individual well-being but also to build a world that is more resilient, creative, and connected. By harnessing the cognitive benefits of exercise, the full potential of human intelligence and ingenuity can be unlocked. In this sense, investing in exercise is an investment in a shared future - a future in which every brain has the chance to thrive.