A growing body of evidence supports the influence of exercise in vitality and function of the central nervous system (CNS) and promoting resistance against neurological disorders. According to these studies, exercise has the extraordinary capacity to enhance mental health, and current efforts are being devoted to use this capacity to reduce cognitive decay in aging and psychiatric disorders.
Exciting new evidence indicates that some of the influences of exercise in the brain can reach the genome with the potential to promote epigenetic modifications.
The understanding of the mechanisms by which exercise affects cognitive abilities has been nourished from several fronts. In particular, exercise has demonstrated an extraordinary aptitude to influence molecular pathways involved with synaptic function underlying learning and memory. Given the intrinsic relationship between exercise and energy metabolism, it is not that surprising that modulation of energy-related molecular systems seems a pivotal mechanism by which exercise affects synaptic plasticity and cognition. These findings harmonize with an emerging line of studies showing that the metabolism of energy at the cellular level is closely associated with regulation of synaptic plasticity and neuronal excitability. The story that is being unfolded is that proper energy metabolism involving the mitochondria is crucial for supporting neuronal signaling events through the plasma membrane. Within this territory, molecular systems such as those involving brain-derived neurotrophic factor (BDNF), which are at the interface of metabolism and synaptic plasticity, can play a crucial role on exercise-induced cognitive enhancement.
The brain has a remarkable capacity for modifying its structure and function according to the influences of the environment and experience. Physical activity has played one of the most vital roles during biological adaptation and survival of the species through thousands of years, in a process in which the modern brain was developed. During these events, exploration, defense, foraging as well as cognitive skills were tightly integrated to motor operations for survival. Thus, the hippocampus, a structure that has a fundamental role in memory processing is one of the main brain regions influenced by physical activity. In addition, development of brain regions that warrant energy efficiency such as the hypothalamus likely evolved with centers that control cognitive abilities, and this has introduced the concept of the “metabolic brain.” These adaptations enabled enough energy saving to support the development of a larger and more complex brain having the capacity to walk upright; all of these features obviously require coordination with cognitive strategies centered in successful survival.
With recent innovations in neuroimaging, the physical activity-human cognition literature has pursued exercise-induced changes in networks involving the prefrontal cortex and associated cognitive processes. Studies in the hippocampus stand to more directly bridge the gap between the human and animal models. Recent studies have bridged this gap by imaging the hippocampus in older humans and examined differences in the volume of this structure and related cognitive performance as a function of aerobic fitness.
Specifically, Erickson et al. investigated 165 cognitively healthy older adults between 59 to 81 years had their cardiorespiratory fitness assessed via a maximal graded exercise test, and their hippocampal volume measured using functional magnetic resonance imaging (fMRI) during performance on a spatial memory task. Findings indicated that higher fitness was associated with larger bilateral hippocampal volume, and greater fitness and hippocampal volume were associated with better spatial memory performance. In addition, hippocampal volume partially mediated the association between fitness and spatial memory performance. Given that the hippocampus demonstrates disproportionately lager degradation during aging, these findings suggest that aerobic fitness may be an effective means for preventing age-related cortical decay and cognitive impairment.
Another particularly compelling study investigated the role of exercise on neurogenesis in the hippocampus using both human and mouse models. Specifically, two magnetic resonance imaging (MRI) studies were conducted, with the first study imaging cerebral blood volume in the hippocampal formation of exercising mice. The findings revealed that exercise selectively upregulated cerebral blood volume in the dentate gyrus, which is the only region of the hippocampus that has been observed to support adult neurogenesis; and further, these increases were found to correlate with measures of neurogenesis collected post mortem. In their second study, cerebral blood volume was measured in adult humans (mean age = 33 years) following 12 weeks of aerobic exercise training. Similar to the mouse model, exercise selectively influenced the dentate gyrus, with cerebral blood volume changes correlating with cardiorespiratory fitness changes.
Kramer and colleagues examined the effects of aerobic fitness training on older adults using a randomized control design. That is, 124 older adults between the ages of 60 and 75 years were randomly assigned to either a 6-month intervention of walking (i.e., aerobic training) or flexibility (i.e., nonaerobic) training. Results indicated that the walking group, but not the flexibility group, improved their performance (i.e., shorter RT) across a series of tasks that tapped different aspects of cognitive control, indicating that physical activity is beneficial to cognitive performance during aging.
Cognitive control refers to a subset of goal-directed, self-regulatory operations involved in the selection, scheduling, and coordination of computational processes underlying perception, memory, and action. Core cognitive processes collectively termed “cognitive control” or “executive control” include; inhibition, working memory, and cognitive flexibility. Inhibition (or inhibitory control) refers to the ability to override a strong internal or external pull to appropriately act within the demands imposed by the environment. Working memory refers to the ability to mentally represent information, manipulate stored information, and act upon it. Finally, cognitive flexibility refers to the ability to quickly and flexibly switch perspectives, focus attention, and to adapt behavior for the purposes of goal directed action.
Colcombe and Kramer performed a meta-analysis to examine the relationship between aerobic training and cognition in older adults between 55 and 80 years of age using data from 18 randomized exercise interventions that included control groups. Results showed that exercise training increased cognitive performance by half a standard deviation (which is considered to be a moderate effect) when compared to the pretest and the control group. Further, the most robust behavioral change following the intervention was observed for tasks requiring greater amounts of cognitive control compared to other cognitive tasks requiring smaller amounts of cognitive control. Their findings suggested that aerobic training is associated with general benefits in cognition that are selectively and disproportionately larger for tasks or task components requiring greater amounts of cognitive control. A second recent meta-analysis corroborated Colcombe and Kramer’s findings, in that aerobic exercise was related to attention, processing speed, memory, and cognitive control. It should be noted, however, that smaller effects were observed in some studies included in the meta-analyses. Accordingly, Hillman et al. examined the relationship between self-reported physical activity and inhibition (one aspect of cognitive control) using a modified flanker task in 241 individuals between 15 and 71 years of age. Results indicated that increases in the amount of physical activity was related to decreases in response speed across conditions of the flanker task requiring variable amounts of inhibition, suggesting a generalized relationship between physical activity and response speed. In addition, physical activity was related to better accuracy for both congruent and incongruent trials in older adults, while no such relationship was observed for younger adults. Interestingly, this relationship was disproportionately larger for trials requiring greater amounts of inhibition in the older adults, suggesting that physical activity has both a general and selective association with task performance.
Other data with school age children has corroborated the findings in adults and extended them to developing populations. Specifically, Sibley and Etnier conducted a meta-analysis and found a positive relationship between physical activity and cognitive function in school age children (age 4–18 years), suggesting that physical activity may be related to cognition during development. Examination of the findings revealed that physical activity participation was related to cognitive performance along eight measurement categories (i.e., perceptual skills, intelligent quotient, achievement, verbal tests, mathematics tests, memory, developmental level/academic readiness, and other), with results indicating a beneficial relationship of physical activity on all cognitive categories, with the exception of memory. Although this effect was found for all age groups, it was stronger for children in the 4 to 7 and 11 to 13 year groupings, compared to the 8 to 10 and 14 to 18 year groupings.
Cross-sectional research has also supported the association between fitness and cognition during preadolescent development.
One additionally interesting aspect of research is the translation of these physical activity and fitness effects on cognition to ecologically valid settings. School-age children provide an excellent means by which to examine this relationship in the real world, as performance on fitness tests and academic achievement tests are routinely assessed as part of school curriculum. A growing literature base is beginning to develop on this topic, with the available data indicating that fitness has either a positive relationship or no relationship to scholastic measures of cognition. Regardless, the data suggest that time spent engaged in physical activities is beneficial as it does not detract from scholastic performance, and can in fact improve overall health and function.
With advancements in neuroimaging techniques, the understanding of the effects of aerobic fitness on brain structure and function has rapidly advanced over the last decade. In particular, a series of studies have been conducted on older humans to better understand the relation of aerobic fitness to brain and cognition. Normal aging results in the loss of brain tissue, with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices. As such, cognitive functions subserved by these brain regions (such as those involved in cognitive control and memory) are expected to decay more dramatically than other aspects of cognition. Specifically, age-related decreases in gray matter volume have been associated with decrements in a variety of cognitive control processes.
Decreases in gray matter volume may result from several factors including loss in the number of neurons, neuronal shrinkage, reduction in dendritic arborization, and alterations in glia. Further, decreases in white matter (brain tissue composed primarily of myelinated nerve fibers) volume, which represent changes in connectivity between neurons, also occur as a result of aging. Loss of white matter volume further relates to performance decrements on a host of cognitive tasks and may result from the demyelination of axons, reducing the rapid and effective conduction of electrical signals through the nervous system.
Scientists have speculated that an active lifestyle may serve to spare age-related loss in regions of the brain that support top-down cognitive control. Interestingly, related research has posited similar benefits of exercise to cognition and brain health in a variety of special populations afflicted with various diseases including dementia, Alzheimer’s disease, and schizophrenia.
Colcombe and his colleagues examined the relation of aerobic fitness to gray and white matter tissue loss using high resolution MRI in 55 healthy older adults between 55 to 79 years of age. They observed robust age-related decreases in tissue density in frontal, temporal, and parietal structures using voxel-based morphometry, a technique used to assess brain volume. Interestingly, substantial reductions in the amount of tissue loss in these structures were observed as a function of aerobic fitness (as measured via a cardiorespiratory stress test to assess maximal oxygen consumption). Given that the brain structures most affected by aging also demonstrated the greatest fitness-related sparing, these initial findings provide a biological basis for aerobic fitness-related benefits to brain health during aging.
Colcombe et al. conducted a second study to examine the effect of aerobic fitness training on brain structure using a randomized control design with 59 sedentary healthy adults between 60 to 79 years of age. Approximately half the participants received a 6-month aerobic exercise (i.e., walking) intervention and the other half received a stretching and toning intervention. Twenty younger adults were also included to assess changes in brain structure over the course of a 6-month period, but did not participate in an exercise intervention. Results indicated that brain volume increased for both gray and white matter in adults who participated in the aerobic fitness training. However, no such findings were observed for those older adults in the nonaerobic training group or for the younger adult comprising the control group. Specifically, those assigned to the aerobic training group demonstrated increases in gray matter in the frontal lobes, including the dorsal anterior cingulate cortex (ACC), supplementary motor area, middle frontal gyrus, dorsolateral region of the right inferior frontal gyrus, and the left superior temporal lobe. White matter volume changes were also evidenced for the aerobic fitness group with increases in white matter tracts within the anterior third of the corpus callosum. These areas are important for cognition, as they have been implicated in top-down control of attention and memory processes. Importantly, these findings suggest that aerobic training not only spares age-related loss of brain structures but also may in fact enhance the structural health of specific brain areas.
Aerobic fitness training has also been observed to induce changes in patterns of functional activation using fMRI, such that it is possible to image activity in the brain while an individual is performing a task. This approach involves inferring changes in neuronal activity from alteration in blood flow or metabolic activity in the brain. Colcombe and his colleagues examined the relation of aerobic fitness to brain and cognition across two studies with older adults. In the first study, 41 participants (mean age ~66 years) were divided into higher and lower fitness groups based on their performance on a car-diorespiratory stress test. In the second study, 29 participants (age range = 58–77 years) were recruited and randomly assigned to either a fitness-training (i.e., walking) or a control (i.e., stretching and toning) group. In both studies, participants were given a modified flanker task requiring variable amounts of inhibitory control. Results indicated that fitness (study 1) and fitness-training (study 2) was related to greater activation in the middle frontal gyrus and superior parietal cortex, regions involved in attentional control and inhibitory functioning. The authors concluded that increased recruitment of relevant brain regions for higher fit individuals may reflect an increase in the ability of the frontal attentional networks to bias task-related activation in the parietal cortex. In addition, they observed reduced activation in the rostral ACC in higher fit and aerobically trained older adults compared to their sedentary and untrained counterparts, respectively, indicating decreased behavioral conflict is related to increases in aerobic fitness (33). Importantly, these changes in patterns of activation were related to significant and substantial improvements in performance on the flanker task.
Functional connectivity using fMRI affords researchers a measure of temporal coherence between spatially remote regions of the brain. Although the default mode network (i.e., a large network including the posterior cingulate cortex, frontal medial cortex, and bilateral hippocampal and parahippocampal cortices) has been most widely studied relative to aerobic fitness, other large-scale networks including the frontal executive and fronto-parietal networks have also received attention. Such studies have demonstrated interesting effects of aerobic fitness on frontal, temporal, and parietal brain regions, as well as a network involving the hippocampus and ACC, during rest. These results suggest that increased functional connectivity is related to better cognitive control and memory in older adults. Such an approach is promising, as it provides new insight into the role of aerobic fitness on brain function during aging.
The findings across the human neuroimaging studies indicate that increases in aerobic fitness, derived from physical activity participation, is related to improvements in the integrity of brain structure and function, and may underlie improvements in cognition across tasks requiring top-down cognitive control.
Although neuroimaging (i.e., MRI and fMRI) has been valuable in understanding aspects of the physical activity-cognition relationship due to the relatively high spatial resolution provided by these measures, information about the impact of fitness on neuronal activity has provided additional insight into the temporal magnitude for the effects of physical activity on cognition.
Neural activity in the cerebral cortex and subcortical regions produces electrical potentials at the level of the scalp, and the electroencephalogram (EEG) can be recorded as a time series of the fluctuating voltages. That is, EEG activity is a recording of the difference in electrical potentials between various locations on the scalp. When electrodes are placed on the scalp, the EEG reflects activity of large populations of neurons firing in synchrony. Further, the dipoles from the individual neurons must be spatially aligned perpendicular to the scalp to be detected. Thus, EEG measurement is most likely to result from cortical pyramidal cells, which are aligned perpendicular to the cortex surface.
The recorded neuroelectric activity can be decomposed along the basic dimensions of frequency and amplitude. The amplitude of EEG is measured in microvolts (μV) and is indicative of the relative size of the neuroelectric signal. Research on the temporal dynamics of the neuroelectric system has further focused on a class of EEG activity, known as event-related brain potentials (ERPs), which have been found to be particularly susceptible to physical activity and cardiorespiratory fitness. ERPs refer to a class of EEG activity that occurs in response to, or in preparation for, a stimulus or response. This neuroelectric activity is indicative of the synchronous activity of large populations of neurons, and may be classified as either exogenous (i.e., obligatory responses dependent upon the physical properties of the eliciting stimulus) or endogenous (i.e., higher order cognitive processes that often require active participation from the subject, but are independent of the physical properties of the stimulus environment).
Recent ERP investigations have complemented the neuroimaging studies described above. Specifically, one ERP component following error commission is the ERN or Ne, which is a negative-going component observed in a response-locked averages of incorrect responses. It is maximal over fronto-central recording sites (i.e., FCz) and has been localized to the dorsal ACC using dipole localization techniques, fMRI, and magneto-encephalography. Though the ERN is generally believed to reflect a cognitive learning mechanism used to correct an individual’s responses during subsequent environmental interaction, the specific functional significance of the ERN remains unresolved.
With regard to the relation of physical activity and fitness to the ERN component, several studies have been conducted in child and adult populations. Specifically, Themanson, Hillman, and Curtin assessed the relationship between self-reported physical activity, ERN amplitude, and posterror task performance in older (60–71 years) and younger (18–21 years) adults during a task requiring variable amounts of cognitive control (i.e., task switching). Physical activity was assessed using the Yale Physical Activity Survey, and participants were instructed to respond as quickly as possible on each trial. The results indicated that older adults exhibited greater slowing of RT during task conditions requiring more extensive amounts of cognitive control and smaller ERN amplitude compared to younger adults. When physical activity was considered, decreases in ERN amplitude and greater response slowing following errors was found for older and younger physically active participants, relative to their sedentary counterparts. Given that posterror response slowing is a behavioral indicator of increased recruitment and implementation of additional top-down control to improve behavioral performance on subsequent environmental interactions, the findings suggest increased top-down control among physically active individuals during tasks requiring action monitoring. This increase in control not only improves behavioral performance, but also decreases the conflict-related activation of action-monitoring processes, resulting in a more efficient neuroelectric profile, and increases behavioral adjustments used to correct behavior after error commission.
A second study examining the influence of cardiorespiratory fitness on action monitoring was conducted using two groups of young adults (mean age = 20.4 years) that exhibited large differences in their respective fitness levels. Neuroelectric (i.e., ERN) and behavioral (i.e., posterror slowing) indices of action monitoring were acquired during the completion of a flanker task requiring variable amounts of inhibitory control. Similar to the initial study, participants were instructed to respond as quickly as possible. Findings demonstrated a relationship between fitness level and indices of action monitoring, with the higher fit group exhibiting smaller ERN amplitude than the lower fit group. These data corroborate the initial study and suggest that increases in aerobic fitness are associated with reduced activation of the neuroelectric index associated with action monitoring during error responses. Further, greater posterror response slowing was found for higher fit, relative to lower fit, individuals, suggesting an increase in both neural and behavioral posterror adjustments in top-down control.
Recent evidence derived from young adults (18–25 years) has indicated that increased fitness may not only relate to more efficiency in action monitoring processes during rapid responding but also greater flexibility in the allocation of these processes during tasks requiring variable response strategies.
Taken together, the findings of these investigations indicate that higher cardiorespiratory fitness is associated with greater flexibility in the allocation of action monitoring resources to meet desired outcomes. This titration of neuroelectric activation to meet task demands appears functional to the successful evaluation of action monitoring processes following error commission. Given that both superior task performance and alterations in task performance as a function of task demands were associated with greater levels of fitness, the data suggest that fitness may serve to enhance top-down control of processes to support the regulation of behavior. Accordingly, convergent evidence has emerged from multiple investigations to suggest that fitness is beneficial to the ACC and the neural network subserving top-down control of action monitoring processes.
Genetic studies in humans reveal that variations in the BDNF ( = brain-derived neurotrophic factor) genotype can have profound effects on cognitive function. The Val66Met BDNF polymorphism is a common single nucleotide polymorphism, consisting of a nonconservative amino acid substitution of valine to methionine at codon 66 in the human BDNF gene (Val66Met). This BDNF polymorphism has been implicated in abnormal hippocampal function and memory processing, as well as with abnormal cerebral cortical morphology and function. In particular, the polymorphism in the cerebral cortex has been associated with reduced activity-dependent release of BDNF and abnormalities of the cortex to respond to short-term motor stimulation. Evidence thus far indicates that the Val66Met polymorphism in BDNF play significant roles in structural and functional plasticity in mood disorders such as schizophrenia, elevated risk of depression, and even on the capacity of the brain for cognitive recovery after TBI. The overall evidence with regards to the Val66Met BDNF polymorphism in humans emphasizes the crucial role that BDNF plays on maintaining brain structure and function, as variations in the BDNF genotype appears to increase risk for various cognitive and mood disorders.
One of the most fundamental biological necessities is to conserve energy, which appears to contrast with the soaring energy demands of the brain. Although the brain mass is only 2% of that of the body, the metabolic demands of the brain accounts for 20% of the total energy consumed. The nervous system seems to have developed the ability to efficiently use energy by keeping tight control of body resources. In particular, exercise appears to play an action on the brain by coordinating peripheral events with higher order function using metabolic signals. These ideas have received experimental evidence by the use of multiple protein analysis, which has shown at the molecular level the association between metabolic processes and synaptic plasticity during exercise.
Studies in humans have shown that exercise during pregnancy maintains the aerobic fitness of the mother, reduces pregnancy-associated discomforts, and can improve placental and fetal growth. Based on studies that the placenta may be a source of neurotrophic factors for the developing fetus, it is possible that neurotrophic factors produced by the mother may permeate the placenta to influence the fetus.
Specific regions in the adult mammalian brain such as the olfactory bulb and hippocampal formation have the extraordinary capacity to produce new neurons in a process also known as neurogenesis. Abundant research in the last decade has shown that exercise is one of the strongest promoters of neurogenesis in the brain of adult rodents and humans, and this has introduced the possibility that proliferating neurons could contribute to the cognitive enhancement observed with exercise.
Epigenetic mechanisms allow for lasting modifications in the genome with important functional consequences, and exciting new evidence indicates that they may be involved in control of cognitive function and emotions. Chromatin refers to the complex of histones (proteins) and DNA that is tightly wound up in the nucleus and this conformation can regulate the expression of genes. When chromatin is tightly wound up, it is expressionally silent, while open chromatin tends to be more functional, that is, conducive for gene expression. Epigenetic mechanisms play an important role in the silencing of genes, primarily through DNA methylation and deacetylation of histones. Epigenetic mechanisms involving postreplication modifications of DNA and nuclear proteins have been shown to modulate BDNF gene. An exercise regimen known for its capacity to elevate hippocampal levels of BDNF mRNA and protein, and enhance learning and memory, has recently been shown to promote remodeling of chromatin containing the BDNF gene.
Results are consistent with the notion that exercise influences epigenetic mechanisms to promote stable elevations in BDNF gene expression, which may have important implications for regulation of synaptic plasticity and behavior. Furthermore, a new line of studies indicates that the pathobiology of several brain disorders may reside in epigenetic modifications in the genome.
Exercise and BDNF have been associated with reducing depression and promoting cognitive enhancement. This implies the fascinating possibility that epigenetic regulation of the BDNF gene can be a biological mechanism by which exercise can promote mental health (i.e., reduce depression) and resistance to neurological disorders. These studies showing the influence of exercise on the epigenome open new avenues and therapeutic prospects in the wage against neurological and psychiatric disorders. The original concept of epigenetics implies the idea that modifications in DNA expression and function can contribute to inheritance of information. Although this principle has not been fully demonstrated in mammals, exercise remains as a crucial candidate for promoting stable heritable biological adaptations.
New evidence indicates that exercise and dietary factors play complementary actions during the control of energy homeostasis and synaptic plasticity with important implications for the modulation of cognitive abilities.
Studies have defined the roles of the hypothalamus and hippocampus to integrate the effects of diet and exercise for the regulations of brain plasticity and cognitive function. Flavonoids generally abundant in vegetables and fruits have been shown to interact with exercise. The combination of a flavonoid enriched diet and exercise increased the expression of genes that have a positive effect on neuronal plasticity while decreased the expression of genes involved with deleterious functions such as inflammation and cell death. Exercise has also proven to be effective in reducing the effects of unhealthy diets. For example, studies have shown that a diet high in saturated fat and sucrose reduces the levels of BDNF-related synaptic plasticity and cognitive function, while the concurrent exposure to exercise compensated for the effects of the diet. The results of these studies are significant to define the potential of healthy diets and exercise to be used to overcome neurological disorders affecting cognitive abilities.
The broad action of exercise is significant to support fundamental aspects of the maintenance and function of neurons. The integrity of the plasma membrane is critical for neuronal signaling, and the lack of continuous maintenance may exacerbate the effects of various neurological disorders.
Abundant evidence supports the role of exercise enhancing cognitive function in young subjects and reducing cognitive decay in aging. Studies performed in humans indicate that exercise has the potential to reduce the risk for various neurological diseases including Alzheimer, Huntington’s and Parkinson’s, up to the point to attenuate functional decline after the onset of neurodegeneration. Exercise has also been shown to improve quality of life in individuals with Alzheimer’s disease, in terms of improving cognitive, mood, and physical functions on the daily living. Clinical intervention studies in individuals with Parkinson’s disease demonstrate that aerobic training improves movement initiation and aerobic capacity, and improves activities of daily living. Exercise is therapeutic and protective in depression, and its effects are proportional to the amount of exercise. Randomized and crossover clinical trials demonstrate the efficacy of aerobic or resistance training exercise (2–4 months) as a treatment for depression in both young and older individuals. Although exercise seems to have both preventative and therapeutic effects on the course of depression, the underlying mechanisms are poorly understood. Other proposed mechanisms include exercise-driven changes in the hypothalamic-pituitary-adrenal axis that regulates the stress response. In addition to this, the immune system seems to play a critical role in influence of exercise on the body and brain. A recent study shows that exercise appears to enhance protective mechanisms in the aging brain by promoting homeostasis following an induced immune challenge. It appears that aging produces cognitive vulnerability to peripheral immune challenge by displaying an exaggerated brain proinflammatory response, which may interfere with BDNF function and learning. These studies suggest an important role of the immune system in mediating exercise induced brain plasticity. The interaction of exercise and the immune system may be an important factor in the control of brain plasticity and disease. In addition, based on the encouraging results of epidemiological studies indicating that exercise may reduce the risk for genetic predisposition for dementia, interventional studies are necessary in this fertile area of research. A positive outcome in this prospect is supported by the results of new animal studies indicating that exercise has the capacity to influence epigenetic mechanisms that modulate cognitive abilities at the molecular level.
(Source: “The Influence of Exercise on Cognitive Abilities”, by Fernando Gomez-Pinilla and Charles Hillman)
Research-Selection for NovoScriptorium: Maximus E. Niles