Physical exercise and memory

It’s known that regular physical exercise have a lot of benefits:

• reduces the risk of heart and cardiovascular disease
• reduces the risk for type 2 diabetes and metabolic syndrome
• helps to control weight and to prevent osteoporosis and depression
• improves mood and mental health
• boosts the immune system.

Now we try to understand how exercise affects and benefits the brain. The latin quotation "mens sana in corpore sano" reveals that this relationship between mind and body had been known since antiquity. Recent studies try to explain how aerobic exercise has a positive influence on memory. In this regard it has been proved that exercise training increases size of hippocampus and improves memory and that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the hippocampal dentate gyrus.

Regular exercise increases brain volume in young and elderly

Research on animals has indicated that physical exercise is related to increased cell proliferation and survival in the hippocampus and consequently greater hippocampal-dependent learning and memory. Several studies have been performed with the aim to explain the link between fitness, hippocampal volume, and memory. One of these employed, after taking a sample of preadolescent children, magnetic resonance imaging to investigate whether higher- and lower-fit 9- and 10-year-old children showed differences in hippocampal volume and if the differences were related to performance on an item and relational memory task. Higher-fit children showed greater bilateral hippocampal volumes and superior relational memory task performance compared to lower-fit children. Furthermore, bilateral hippocampal volume was found to mediate the relationship between fitness level and relational memory. The findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.

Source:
A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children

The discussion about a possible relationship between physical exercise and motor skills with cognitive development in children was extended to other studies that examined the relationship of aerobic fitness and motor skills with spatial working memory and attention in preschool children; they claim that in young children, higher baseline aerobic fitness and motor skills were related to a better spatial working memory and/or attention at baseline.

Source:
Relationship of aerobic fitness and motor skills with memory and attention in preschoolers (Ballabeina): A cross-sectional and longitudinal study

Recent evidence extends this relationship to elderly humans by suggesting that high aerobic activity levels in older adults are associated with increased hippocampal volume and superior memory performance. It’s has been shown that the hippocampus decreases in late adulthood, leading to impaired memory and increased risk for dementia. So deterioration of the hippocampus occurs in elderly individuals with and without dementia and individual variation exists in the level and frequency of hippocampal decay. Determining the factors that influence this individual variation may help promote lifestyle changes that prevent such deterioration from taking place. Aerobic fitness and exercise are effective at preventing cortical decay and cognitive impairment in older adults and epidemiological studies suggest that physical activity can reduce the risk for developing dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion. A research shows, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training effectively increased hippocampal volume by 2%, reversing age-related loss in volume and suggesting that fitness protects against volume loss. These findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

Source:
Exercise training increases size of hippocampus and improves memory

Another study confirms that individuals with higher levels of aerobic fitness displayes greater volume of the hippocampus and better spatial memory performance than individuals with lower fitness levels and it assesses that hippocampal volume mediates the relationship between fitness and spatial memory. The analysis was conducted on brain scans of 165 older adults aged between 59 and 81 years; through the use of magnetic resonance researchers have developed a volumetric analysis of the left and right hippocampal areas of subjects, which were later tested on the orientation space. The study reveals a significant association between physical activity of participants and their memory skills. Higher fitness levels were associated with larger left and right hippocampi after controlling for age, sex, and years of education, and larger hippocampi and higher fitness levels were correlated with better spatial memory performance. Also in this case the results clearly indicate that higher levels of aerobic fitness are associated with increased hippocampal volume in older humans, which translates to better memory function.

Source:
Aerobic Fitness is Associated With Hippocampal Volume in Elderly Humans

Physical exercise can protect against dementia

This effect of increasing size of hippocampus is particularly evident in the anterior hippocampus, where stem cells, responsible for adult neurogenesis, reside. This is a particularly important discovery for Alzheimer's patients or those suffering from dementia. So at this point the question is if aerobic exercise can really protect against dementia. The cognitive decline and brain atrophy is associated with normal aging and dementia-causing conditions like Alzheimer's disease , Lewy body disease, and vascular dementia. Recently, moderate exercise and improved fitness have been shown to increase cognition in cognitively normal older persons as well as in individuals who complain of memory difficulty. It has long been known that exercise may have many health benefits and among all these beneficts is possible that exercise helps to protect against the three most common dementia pathologies. In an AD (Alzheimer's disease) transgenic mouse model, environmental enrichment, including an exercise wheel, decreased amyloid Aβ brain deposits. So environmental modulation can rescue the impaired phenotype of the Alzheimer's brain and that induction of brain plasticity may represent therapeutic and preventive avenues in AD. In the rodent Parkinson disease (PD) models, exercise was protective against motor but not cognitive tasks and improved the density of blood vessels and mRNA vascular endothelial growth factor (VEGF) activity in the nigra. Clinically, patients with PD improve their physical performance and activities of daily living through exercise. But that did not address cognitive improvement. Lastly, there is good evidence that exercise may be protective against stroke and VaD (vascular dementia). Furthermore, epidemiological studies on exercise show protective effects on cognition. Exercise may prevent cognition and slow cognitive decline and is associated with decreased incident dementia.

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Can aerobic exercise protect against dementia?

Physical activity stimulates growth factors and induces a BDNF-mediated mechanism that promotes neoplasticity

Exercise is a potent stimulator of cell proliferation in the adult dentate gyrus and stimulates the growth factors, essential for neuronal development. Hippocampal neurogenesis in the adult mammalian brain is modulated by various signals like growth factors, hormones, neuropeptides, and neurotransmitters. One of the growth factors that exercise affects is the brain-derived neurotrophic factor (BDNF) that has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors.
In fact, physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor-regulated mechanism. Some scientists asked a group of sedentary male college students to take part in a memory test followed by strenuous exercise. First, the young men watched a rapid-fire lineup of photos with the faces and names of strangers. After a break, they tried to recall the names they had just seen as the photos again. Afterward, half of the students rode a stationary bicycle, at an increasingly strenuous pace, until they were exhausted. The others sat quietly for 30 minutes. Then both groups do the brain test again. In particular, the exercised volunteers performed significantly better on the memory test than they had on their first try, while the volunteers who had rested did not improve. Moreover, blood samples taken throughout the experiment offered a biological explanation for the boost in memory among the exercisers. Immediately after the strenuous activity, the people who rode the bicycle had significantly higher levels of a protein known as BDNF. The men at rest showed no comparable change in BDNF levels. Increases in fitness, cognitive function and serum BDNF response assess that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans.

Source:
Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males

Therefore, exercise has been shown to impact brain plasticity and function by involving the action of brain-derived neurotrophic factor (BDNF); however, mechanisms involved are poorly understood. Two types of BDNF coexist in the brain, the precursor (proBDNF) and its mature product (mBDNF), which preferentially bind specific receptors and have distinct functions. A study demonstrates that 7 days of voluntary exercise increased both pro and mature BDNF in the rat hippocampus. Exercise also increased the activity of tissue-type plasminogen activator (tPA), a serine proteinase shown to facilitate proBDNF cleavage into mBDNF. The blockade of tPA activity reduced the exercise effects on proBDNF and mBDNF. The tPA blocking also inhibited the activation of TrkB receptor, and the TrkB signaling downstream effectors phospho-ERK, phospho-Akt, and phospho-CaMKII. The blocking of tPA also counteracted the effects of exercise on the plasticity markers phospho-synapsin I and growth-associated protein 43 (GAP-43). The cascade of biochemical processes ignited in the memory center of the brain culminates in increased production of BDNF molecules. These results indicate that the effects of exercise on hippocampal plasticity are dependent on BDNF processing and subsequent TrkB signaling, with important implications for neuronal function.

Source:
Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing

Another animal study describes how mild-intensity physical exercise represents a successful strategy to increase spatial learning and memory and hippocampal plasticity in aging rats. A mild-intensity exercise program increased muscle oxygen consumption by soleus and heart in aging rats and the observed cognitive-enhancing properties of short bouts of exercise were accompanied by the activation of serine/threonine protein kinase (AKT) and cAMP response element binding (CREB) pro-survival signaling that culminates in the marked increase on the brain-derived neurotrophic factor (BDNF) mRNA expression and BDNF protein levels on the hippocampus of aging rats. Thus the memory center of the brain of the rats that were allowed to run showed in addition to the increased BDNF also a new population of precursor molecules that presumably would soon develop into fully functioning BDNF molecules. Therefore short bouts of exercise represent a vital behavioral strategy to improve cognition and synaptic plasticity in aging rats which should be considered in additional studies addressing the effects of physical exercise in aging subjects.

Source:
Short bouts of mild-intensity physical exercise improve spatial learning and memory in aging rats: Involvement of hippocampal plasticity via AKT, CREB and BDNF signaling

One of the most inspiring recent experiment involves aging human pilots. Scientists at Stanford University School of Medicine asked 144 experienced pilots ages 40 to 65 to operate a cockpit simulator three separate times over the course of two years. For all of the pilots, performance declined somewhat as the years passed. A similar decline with age is common in all of us.
But in this case, the decline was especially striking among one particular group of men. These aging pilots carried a common genetic variation that is believed to reduce BDNF activity in their brains. The men with a genetic tendency toward lower BDNF levels seemed to lose their ability to perform complicated tasks at almost double the rate of the men without the variation.
The question of whether strenuous exercise could show such declines by raising BDNF levels, thereby salvaging our ability to perform skilled manual tasks well past middle age.
So many studies have shown that exercise increases levels of BDNF. While other growth factors and body chemicals are “upregulated” by exercise, the one factor that shows the fastest, most consistent and greatest response is BDNF. It seems to be key to maintaining not just memory but skilled task performance.
In people who have the variant and less BDNF activity, exercise is probably even more important but for everyone, the evidence is very, very strong that physical activity will increase BDNF levels and improve cognitive health.

Source:
BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals

Exercise and immune system

Research is uncovering a link between moderate and regular exercise and a strong immune system. Everyone knows that practicing regular physical activity is a cure for general health, because it decreases the incidence of cardiovascular diseases, metabolic diseases, osteoporosis and improves mood.
Habitual exercise is associated with a reduced frequency of infection compared with a sedentary state. However, prolonged strenuous activity causes a temporary depression of various aspects of immunity, such as lymphocyte proliferation, antibody production, neutrophil respiratory burst, monocyte antigen presentation. This disregulation lasts from 3 to 24 hours after exercise, and depends on the intensity and duration of the activity. Prolonged training, at least 1 week, results in immunity disfunction. Although athletes are not clinically immune deficient, it is possible that the consequences of changes in immune parameters may compromise resistance to common infection, such as upper respiratory tract infection (URTI). Nonetheless, this may be the price to pay as the anti-inflammatory effects of exercise mediated through cytokines and down regulation of toll-like receptor expression are likely mediators of many of the long-term health benefits of regular exercise.
Many clinical physical stressors (e.g. surgery, trauma, burn, sepsis) induce a pattern of hormonal and immunological responses that have similarities to that of exercise.

Regular moderate exercise boosts immunity

Moderate exercise has been linked to positive immune system response and a temporary boost in the production of macrophages.
Recent studies have shown that during sport immune cells circulate through the body more quickly and are better able to kill bacteria and viruses.
This relationship between exercise and susceptibility to infection and health has been modeled in the “J”-shaped curve. This model suggests that both sedentary lifestyle and prolonged, excessive activity enhance the probability to catch infection, in contrast with a regular physical activity.

According to professor Nieman, Dr. PH., of Apalachian State University, when moderate exercise is repeated on a near-daily basis there is cumulative effect that leads to a long-term immune response. His researches showed that those who walk at 70-75 % of their VO2 max 40 minutes per day had half as many sick fays due to colds or sore throats as those who don’t exercise.

Too much exercise can decrease immunity

There is evidence that too much intense and disregulated exercise can lead to immune deficiency and can increase the probability to catch UTRI. Many studies have reported that various immune cell functions are momentarily impaired following acute bouts of prolonged, continuous heavy exercise; athletes engaged in intensive training appear to be more susceptible to minor infections. According to some surveys, the incidence of flu and cold, generally URTI, are more common in athletes than in general population, and may lasting longer. This is important information for those who train at high levels, are elite athletes and compete. It is generally recognized that infection can result in a drop in performance.

The body, during long, high-intensity activity (marathon, triathlon, swimming, cycling) produces certain hormones that temporarily lower immunity. The circulating numbers and functional capacities of leukocytes may be decreased by repeated intense sports.
Adrenaline and cortisol, the stress hormones, raise blood pressure and cholesterol levels, and depress immune system. This effect have been linked to the increased susceptibility to infection in endurance athletes after extreme exercise. Consequently, excessive exercise is interpreted as a condition of stress by our organism, and the general pattern of hormonal and immunological responses is similar to that of trauma, infection, psychological stress, sepsis, etc.
Nevertheless, falls in concentration of glucose and glutamine can contribute to immunodepression. Also, during exercise, there is an increase production of reactive oxygen species (ROS), and some immune cell functions can be impaired. A raise in gut wall permeability may also allow increased entry of bacterial endotoxins into circulation, particularly during prolonged exercise in the heat. Hence the cause of augmented incidence of infection in people who practice excessive activity is multifactioral, due to a variety of stressors.

Acute effects of exercise on immune function

An acute bout of physical activity is accompanied by responses that are similar in many induced by infection, sepsis, trauma: there is a substantial increase in the number of circulating leukocytes, related to the intensity and duration of exercise. Increasing of cytokines, such as TNF-alpha, macrophage inflammatory protein-1, IL-1beta, IL-6,IL-10,IL-1receptor a; and acute phase protein: CRP.
The large increase of plasma IL-6 is due to the releasing of this from contracting muscle fibers and the damage caused by the disrupting of those during exercise, which lead to a local inflammation. Muscle-derived IL-6 is in part responsible for the raising of cortisol in the plasma during prolonged exercise. The stimulation may be due to an effect of IL-6 on hypothalamus, stimulating the release of CRH, which stimulate the release of ACTH from the anterior pituitary gland.
IL-6 has also a role in the production of anti-inflammatory cytokines IL-1ra and IL-10.
Some studies suggest also that endotoxin derived from gut, when crosses mucosa and enters into circulation, triggers a cascade involving TNF-alpha, IL-1beta and IL-6. This can be obtained by the raising of permeability of the gut wall and by the overcoming of the filtering capacity of the liver.
In accordance with elevations of circulating IL-6, IL-10 strenuous exercise decreases the percentage of type 1 T cells in the circulation, whereas the percentage of type 2 T cells does not change. Both epinephrine and cortisol suppress Th1 cells, while IL-6 stimulates Th2 cells. As type 1 T cells promote cell-mediated immunity, giving protection against above all viruses, exercise can decrease virus protection and this can explain why athletes are more susceptible to URTI.
However, it is very important to stress the shift towards type 2 T cells, because by producing IL-4,IL-5,IL-13 and IL-10, they are very useful to suppress the inflammation ability of the immune system, and so the tissue damage. Thus elevated IL-6 during exercise could be one of the mechanisms by which regular exercise provides defense against inflammatory diseases.

Figure 2- Possible mechanisms by which exercise increases susceptibility to infection but reduces inflammation and risk of developing chronic disease.

During exercise neutrophil count augments , but show a diminished responsiveness to stimulation by LPS after exercise. Acute activity, also, increases NK cells count, which decreases after the performance. Then, it has been shown a diminishing in proliferative response of lymphocytes to mitogens and a decreasing in the expression of an early marker in response to stimulation with mitogen (CD69).
In conclusion, acute strenuous exercise increases lots of immune parameters and leads to leukocytosis, but after this there is an “open window” in the immunity (3-72 hours), in which a lot of immune functions are decreased: leukocytopenia, moderate neutrophilia, diminished NK cells, diminished IgA, decreased fagocytosis, and if there’s no recovery and rest, this may be debilitate for the health. The immune system suffers immediately after the practicing of the sport, and so a prolonged effort can lead to immune deficiency .

During Exercise and After Exercise

It is possible to propose a model exercise-induced neuroimmune interection that can little explain the change in the immune system during activity, after activity, and highlights differences between regular and moderate exercise and prolonged and strenuous effort.
Epinephrine and to a lesser extent norepinephrine contribute to the acute effects on lymphocyte subpopulations as well as NK and LAK cell activities. The increase in catecholamines and
growth hormone mediates the acute effects on neutrophils, whereas cortisol exerts its effects within a time lag of at least 2 hours and contributes to the maintenance of lymphopenia and neutrocytosis after prolonged exercise. Also testosterone and estrogen may also contribute to the acute exercise-associated reduction in lymphocyte proliferative and NK cell activities. The role of beta-endorphin is not clear, but the evidence suggests that beta-endorphin
does not contribute to the immediate recruitment of NK cells into the circulation but may play a mechanistic role in chronic or prolonged exercise conditions. Although the classical stress hormones do not seem to be responsible for the exercise-associated increase in cytokines, sex steroid hormones can modulate cytokine effects with exercise.
Moreover, the concentration of insulin slightly decreased in response to exercise, but this decline does not appear to have a mechanistic role. The immediate
leukocytosis during exercise is attributable to elevated catecholamine levels, and the delayed neutrophilia is due to elevated cortisol levels.

Chronic effects of exercise training on immune function

Some studies indicate that leukocyte function, neutrophil and monocyte burst, T-lymphocyte CD4+/CD8+ ratio, mitogen-stimulated lymphocyte proliferation and antibody synthesis are increase in training load, but after this period, there’s a reduction in all the functions. Thus several aspects of innate and adaptive immunity are suppressed. However, exercise-induced immune dysfunction does not put athletes in danger of serious illness, but could be sufficient to increase the risk of picking up common infections such as flu, cold, sore throats, and general URTI.
Several longitudinal studies have monitored immune system in cyclists, swimmers, football players over the competitive season. They have showed that incidence of URTI was increased during intense training. Whereas, after moderate exercise the immune system generally returns to normal within few hours, and does not affect health and susceptibility to infection. However consistent, regular practice seems to make these changes a bit more-lasting.

Can exercise-induced immune depression be prevented?

Some trials (Pedersen’group in Copenaghen) indicate that supplementation with anti-oxidants, such as vitamin C and E can diminished the leukopenia and immune dysfunction after prolonged exercise. The mechanism seems to be related with the reduction of IL-6 and cortisol response.
Consumption of carbohydrates before and during trainings also leads to a decrease in hormones stress level. However reducing the power of IL-6 and cortisol with supplementation can lead to a reduce anti-inflammatory benefit and can limit the adaption to training, and so maybe the performance.

In summary, moderate exercise can improve the immune system, even if after this there’s a slightly temporary depression of immune function, depending on the intensity and duration of the exercise. Post-exercise immune function depression is most pronounced when the activity is continuous, prolonged, of high intensity, such as an agonistic activity. Periods of intensified training can result in longer lasting immune dysfunction. This is demonstrated by major incidences of URTI in elite athletes. This is obviously a concern because of the potential impact of an infection in performance. It is not a really concern for general population, as exercises have benefit in preventing chronic and inflammatory diseases. However, it should be avoid excessive efforts, and for example this important in compulsive behavior in some people like anorexic people, who suffers of alimentary problems and try to compensate with exaggerated physically activity.

BIBLIOGRAPHY

Immune function in sport and exercise February 2007
exercise and immunity April 2011
Chronic exercise training effects on immune function July 2000
exercise and the immune system: Regulation,integration and adaptation july 2000
risk of upper respiratory tract infection in athletes december 1997
exercise and immune function february 1999
effects of exercise on lymphocytes and cytokines /34/4/246.abstract march 2000