11 The Effects of Exercise on Stress

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The implications of physical exercise can be seen at a molecular and behavioural level; it induces neural changes, contributing to cell proliferation and neural plasticity which enhances different cognitive functions of the brain. Brain derived neurotrophic factor (BDNF) plays an important role in synaptic potentiation, gene transcription, and survival and enhancement of neuronal resilience.[1] BDNF is transported to synapses where it plays a role in increasing neuronal size, dendritic branching and spine number, neurotrophin levels, synaptic density, and neurogenesis in the rodent hippocampus [1]. Increased BDNF levels and neurogenesis has been consistently linked with enhanced performance on various cognitive tasks (i.e. spatial memory). In addition to its important role in promoting neurogenesis, many studies have linked exercise with an enhanced immune and cardiovascular system by maximizing and improving the efficiency of the pathways involved. The positive effects of physical exercise has also been implicated in reducing the symptoms of many neurological and psychiatric disorders like depression, obesity and even Attention Deficit Hyperactive Disorder (ADHD). Physical exercise affects many different pathways and biological systems that ultimately seeks to counteract the effects of stress at a cellular and behaviour level.

1 Exercise and Neurogenesis

1.1 Exercise on the Brain

Figure 1
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Transport of BDNF to synapses following exercise [1]

Neurogenesis is the process in which new neurons are formed from neural stem and progenitor cells, a process that is highly active during pre-natal development. There are two regions in the brain where neurogenesis predominantly occurs following birth: the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. The hippocampus plays an important role in learning, memory and emotion [2]. Areas in the hippocampus where a notable increase in BDNF mRNA levels were observed include the dentate gyrus, hilus and CA3 region within days of exercise in rat models and lasting for several weeks [3]. Brain-derived neurotrophic factor (BDNF) is a secreted protein which acts on neurons of the central nervous system and the peripheral nervous system. BDNF is a neurotrophic factor that supports neurogenesis and the survival of existing neurons, involved in synaptic potentiation, gene transcription, and neuronal resilience. Synthesized in the endoplasm reticulum, BDNF makes its way to the synapse where it binds to its TrkB receptor presynaptically to modify transmitter release and also acts post-synaptically to modify post-synaptic sensitivity (fig 1) [1]. This neurotrophic factor is implicated in increasing neuronal size, dendritic branching, spine number and neutrophin levels in the rodent hippocampus [1]). Following exercise, the rat hippocampus show an increase in mRNA and protein levels of BDNF (fig 2) which shows the potential that exercise has to maintain neuronal survival and enhance neurogenesis [1]. Running activity in mice has also been shown to increase levels of BDNF mRNA in the lumbar spinal cord [5], cerebellum [3] and caudal 1/3rd of the cerebral cortex [5]. Physical exercise also results in an increase in synaptic proteins, insulin-like growth factors and plays a role in the glutamate system which all play a significant role in neurogenesis and neural plasticity[4].

Figure 2
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BDNF mRNA and protein levels increase in the mouse hippocampus (CA1-CA3, hilus, DG)
after 7 days of volunteer wheel running (a) compared to sendentary (SED) mice (b).
There is a correlation between the distance of wheel running and BDNF levels (d).[1]

1.2 The Relationship Between Stress and Exercise

Moderate routine exercise has been shown to antagonize the effects of stress on the brain and body. Prolonged exposure to stress can have an impact on neuronal health; regions of the brain, such as the hippocampus, are especially vulnerable to high levels of corticosteroids [6]. Neurons are more susceptible to morphological changes, including atrophy of their dendrites and an overall reduction in the spine count which negatively contributes to brain plasticity [7][8][9].

Exercise has the potential to counteract the negative effects of stress. Exercise-induced rat models showed an increase in BDNF levels in the presence of low and moderate levels of stress (injection of 30 and 40 mg/kg of corticosterone) but BDNF levels decreased after a high injection of corticosterone (50 mg/kg)[10]. Yau et al (2011) demonstrated that stress-induced runners had higher levels of BDNF (relative to controls) but that exercise can act to mediate stress and promote neurogenesis but is ineffective under high levels of stress (fig. 3). One of the added benefits of exercise is that it is a strategy readily available to everyone—there are no costs associated with exercise and does not have the negative side effects that drugs and other forms of medical treatment has[10].

Figure 3
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BDNF levels increased in stress-induced mice subjected to exercise
but only up to a certain point [10].

Figure 4
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Exercise results in an increase in hippocampal volume
of the anterior and posterior hippocampus [14].

As individuals age, the hippocampus starts to deteriorate resulting in memory impairment. Older adults without dementia show an annual decrease in hippocampal volume by 1-2%[11][13]. Exercise has been shown to counteract these effects by promoting cell proliferation and survival in the hippocampus and enhancing learning and memory in rats. Erickson et al. (2011) studied the effects of exercise in improving spatial memory and hippocampal size in adults[14]. Adults were either subjected to moderate-intensity aerobic exercise 3 days a week or placed in the control group (which consisted of participating in stretching and toning exercises) for one year. Through the use of magnetic resonance imaging, an increase in hippocampal volume was observed for the exercise group compared to the controls who displayed an overall decline in hippocampal volume (fig 4). Specifically, the anterior hippocampus (which includes the dentate gyrus, subiculum, CA1 area) showed an increase in volume with aerobic exercise; the anterior hippocampus plays a role in spatial memory and is subject to more age-related atrophy[11][12]. An increase in hippocampal volume following 1 year of moderate-intensity exercise saw a direct improvement in memory performance (fig 4). These results seems to support that the anterior hippocampus is especially vulnerable to structural changes as an individual changes and that moderate-intensity aerobic exercise plays a role in not only preventinghippocampal volume loss but also acts to promote cell proliferation. In addition to an increased hippocampal volume, exercise leads to increased BDNF levels which contributes to enhanced learning and memory. Erickson et al. (2011) showed that there was a positive association between serum BDNF levels and right hippocampal volume which suggests that an increase in BDNF levels from aerobic exercise is selective to changes in the anterior hippocampus volume[14].

1.3 Neurogenesis Independent of Exercise

Figure 5
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In the presence of environmental enrichment (and absence of exercise), rats showed
an increase in NGF compared to sedentary mice [15].

Birch et al (2012) studied the role of environmental enrichment in the absence of exercise on the role of neurogenesis, nerve growth factor (NGF) and synaptogenesis[15]. They reported that environmental enrichment (independent of exercise) can be used a cognitive enhancer for neuroplasticity in the brain. Rats placed in an enriched environment in the absence of exercise for 3 and 6 weeks showed improved recognition memory where the latter group also displayed improved spatial and working memory (fig 5).

The rats enriched for 6 weeks showed an increase in NGF concentration and significant changes in the dentate gyrus including increased subgranular progenitor cell survival, increased expression of synaptophysin and synapsin I. This suggests that environmental enrichment, independent of exercise, can play a significant role in cognitive enhancement which means that that there are many other activities that an individual can participate in to achieve similar neuronal and physiological benefits of exercise [15]. However, further research is needed to determine if these cognitively enhancing activities can also play a significant role in decreasing stress. One subtle difference between cognitive enrichment activities and exercise is that exercise doesn’t really require the direct involvement of the brain, but emphasizes the use of the body rather than the brain and this might be a significant factor in contributing to its positive role in decreasing stress levels.

1.4 Cessation of Voluntary Exercise

A study by Nishijima et al (2013) studied the impact on hippocampal neurogenesis in mice following the cessation of wheel-running (fig. 6) [2]. Their results suggest that an interruption in wheel running acted as a risk factor for impairing hippocampal neurogenesis and increases anxiety in mice. Although the total volume of the dentate gyrus (fig 7A) did not differ significantly, the number of BrdU+ cells in physically active mice was higher than the mice with no exercise or in the mice with a cessation of physical exercise (fig. 7B). This study shows that although exercise can act to enhance cell survival, promote cognitive function and mediate depressive symptoms, these effects can be reversible following a cessation of exercise[2].

Figure 6
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Procedure: 3 groups of mice subjected to varying exercise regimens
(NoExercise, Ex, Ex-NoEx groups) [2]

Figure 7
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DG volume remained consistent but BrdU+ cells is lower in mice subjected
to voluntary exercise and subsequently removed from an exercise regime (Ex-NoEx)
than exercising mice (Ex) [2]

2 The Systemic Effects of Exercise

2.1 The Cardiovascular System

Figure 8: Molecular Structure of C-reactive protein[36]
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In addition to promoting neurogenesis and enhancing cognition, exercise is also linked to an enhanced immune and cardiovascular system and improving overall health. A study involving 439 overweight and obese postmenopausal women were subjected to either a 1-year caloric restriction diet, aerobic exercise, combined diet and exercise, or control groups[16]. There was a notable decrease in inflammatory biomarkers (including hs-CRP, IL-6, neutrophil count) in the diet and diet+exercise groups relative to the control group. Increased serum levels of high sensitivity C-reactive protein (hs-CRP) was found to have an association with obesity and low cardiopulmonary fitness. Hs-CRP is an inflammatory biomarker that is synthesized by the liver and is released in response to chemicals released by macrophage and fat cell activation. Specifically, there was a 40% reduction in hs-CRP in the diet and diet+exercise groups which has positive implications in reducing risk of cancer in postmenopausal women, including breast and endometrial cancers [16]. In addition, high levels of CRP has been found to be associated with an increased risk of type II diabetes, hypertension and cardiovascular disease[17][18]. These results seem to contribute to the idea that modifications in one’s lifestyle with the implementation of an exercise regimen can have a positive outcome in the physiology and perception of individuals which can effectively dampen the stress response.

2.2 The Immune System

Exercise has an anti-inflammatory effect by reducing the release of inflammatory markers that act to depress the immune system. Exercise is consistently associated with lower levels of CRP levels (6-35%) [19], which aids in reducing the body's stress response by dampening the inflammation. A systematic review investigating the role of exercise in mediating the immune response concluded that although long-term training has anti-inflammatory effects, short-term exercise produces an inflammatory response [20].

Obesity contributes to stress in many ways: it affects the immune system modulation, strains the HPA axis and damages an individual’s self-perception. Exercise is one of many effective intervention techniques, including diet change, which can modulate the consequences of Obesity. A study involving the implementation of a short-term exercise and diet (high-fat, low-fibre) intervention program on 21 obese youth observed significant reductions in pro-inflammatory cytokines and metabolic risk factors (i.e. IL-6, IL-8, TNFalpha, PAI-1, resistin, amylin and leptin) as well as a small reductions in body weight and BMI. An increase in exercise (and diet) is correlated with a reduction in inflammation, resulting in a more efficient and healthy immune system[21].


3 Exercise as a Treatment for Stress Related Disorders

In addition, many studies seem to support the idea that exercise can be used as a co-treatment in dampening the symptoms associated with stress-related neurological disorders. Dr. John J. Ratey, author of "Spark", speaks about the benefits of exercise and the potential for exercise to be used as a treatment for stress-related disorders. In this video, he elaborates on how crucial it is to implement and enforce a routine regimen involving physical exercise[38]

Video 1
Dr. John J. Ratey describes the importance of participating in a regular exercise regimen[38].

3.1 Depression

Depression is a mood disorder that is characterized by frequent and chronic negative thoughts and sense of well-being; there has been a lot of research conducting the role of exercise as a possible treatment for Depression. Endorphins are opioid peptides that are endogenously released by the pituitary gland and hypothalamus during physical exercise, pain, excitement, love and has its effects in producing analgesia and a feeling of well being[22]. Exercise results in an increase in endorphins which acts as a natural pain reliever and antidepressant and is known to be involved in mediating emotional states [23]. Patients diagnosed with unipolar Depression of mild to moderate severity underwent rehabilitative exercise; the data suggests that an increase in endorphin levels resulted in a significant decrease in subjects' Depression rating scale (HDRS) two weeks after the start of therapy [23]. There are many studies that seem to have conflicting conclusions on the role of exercise in reducing depressive symptoms. A study investigating the role of aerobic exercise on individuals with mild to moderate major depressive disorder (MDD) showed that exercise can be used as a form of treatment but it's effectiveness is dependent on the level and dose of exercise [24] and the severity of the disorder. A meta-analysis conducted by Josefsson et al. (2012) show that Depression has an antidepressant effect compared to control conditions, albeit the degree of anti-depressant effects vary across studies [25].

Although the exact mechanism by which endorphins alleviate Depression and anxiety is uncertain, the "endorphins hypothesis" (also referred to as the "runner's high") suggests that the release of endogenous opioid peptides reduces pain, resulting in analgesia and euphoria which acts to reduce anxiety and Depression. Using positron emission tomography methods, one study looking at long distance athletes showed that endorphins are released by exercise which does improve mood states[26].

Although there are studies that show that exercise has an anti-depressive effect, conflicting evidence also exists that support that exercise acts to increase anxiety in rodents. Fuss et al (2010) showed that although neurogenesis is increased in mice performing wheel running, it also increased anxiety in various tests of anxiety (open field, elevated O-maze, and dark-light box)[27]. Irradiation of running-induced hippocampal neurogenesis hinders the development of anxiety in mice which supports that there is a positive correlation between neurogenesis (induced by exercise) and anxiety. Important to note is that although irradiation hindered running-induced neurogenesis, BDNF levels still increased irrespective of irradiation. Although this study showed a positive correlation between neurogenesis and anxiety, it's also important to consider that changes in the brain could have occurred following irradiation which may have indirectly had an impact on neurogenesis resulting in more anxiety-like symptoms observed in the mice[27].

One must consider many variables when determining whether or not exercise does have an effect on reducing depressive symptoms such as the duration, intensity and type of exercise. Furthermore, more controlled measures must be put in place when carrying out experimental studies in order to better understand the role of exercise on reducing depressive symptoms [2].

3.2 Post-Traumatic Stress Disorder (PTSD)

Post traumatic stress disorder (PTSD) is a psychiatric disorder that results in a failure to recover from a traumatic experience. Hendriksen et al. (2010) investigated the role of exercise as a possible treatment intervention for rat models induced with PTSD-like symptoms [28]. Rats were placed in a light/dark box where they were given 10 shocks (6 second duration each) to induce the PTSD-like symptoms. The therapeutic effect of exercise and environmental enrichment as a form of treatment to reduce PTSD symptoms in the rats was studied. Rats exposed to environmental enrichment, including exercise, recovered faster than those animals that were treated with imipramine or escitalopram (common antidepressants used for the treatment for PTSD). Hendriksen et al.(2010) have postulated that one explanation for their findings was that enhanced cell proliferation is involved in treatment involving environmental enrichment which contributes to a faster recovery following trauma[28].

3.3 Attention Deficit Hyperactivity Disorder (ADHD)

Attention Deficit Hyperactivity Disorder (ADHD) is a neurological disorder that shows a lot of similarities to the effects of prolonged stress on the individual, such as Depression[29], anxiety [29], and difficulty sleeping [30]. Pontifex et al (2013) implemented an exercise regimen in ADHD children to study the effect of a 20-minute bout of aerobic exercise on ADHD children on lessening the core symptoms of ADHD and in improving cognition (see fig 9 for procedure) [31].

Figure 9
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The general procedure used by Pontifex et al (2013) for their experiment
[procedural diagram formatted by Sivaniya Subramaniapillai
for ease of comprehension] [31]

Figure 10: Exercise as a treatment model for ADHD
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Exercise led to an overall improvement in cognition in both control and ADHD groups
(respective to their counterpart groups)[31]

Following the bout of aerobic exercise (or seated reading for the control group), subjects completed the Eriksen Flanker test to assess attention followed by reading, spelling and arithmetic tests to measure academic performance [fig 10C]. Electroencephalography (EEG) methods were used to measure P3 [fig. 10E]and error-related negativity (ERN) [fig 10F] amplitudes as a means of measuring brain activity while subjects completed these cognitive tasks. ADHD and control groups showed overall improvements in the test of inhibitory control, allocation of attentional resources, stimulus classification and processing speed. These findings suggest that insufficient task activation may contribute to the visible presentation of the symptoms in children with ADHD. In addition, this study contributes to the idea that exercise can be used to complement medication to reduce the ADHD symptoms and possibly even reduce the dosage of prescribed medication following prolonged physical exercise and environment enrichment [31]. Physical exercise contributes to cell proliferation and neural plasticity with greater positive consequences seen in early childhood [32] which attests to the notion that exercise can have an optimal effect on children if a strict regime is implemented at an earlier age.

4 Disadvantages of Excessive Exercise

Figure 11: Excessive Exercise
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Excessive exercise can lead to without proper rest can result in activation of macrophages
that results in an inflammatory response, involving the CNS, liver, and immune system[35].

Although regular exercise has beneficial effects in improving the cardiovascular system, there is evidence that suggests that excessive or extreme forms of exercise can induce ventricular arrhythmia[33]. It is postulated that intense physical exercise puts a strain on the right ventricle which may lead to minor cell damage. Individuals who continuously participate in these high endurance activities will continue to put a strain on their right ventricle which will result to continuous straining and cell death on the right ventricle leading to chronic remodeling of the heart and ultimately, resulting in right ventricular cardiomyopathy (even in the absence of any genetic predispositions).This research suggests that although exercise has many beneficial effects, there is a limit to the intensity that the body can handle [33].

Chronic intense exercise in the absence of proper rest can put a strain on various organs and tissues of the body that will ultimately lead to dysfunction and possibly even death [33]. Besides abnormalities in heart structure and function, excessive exercise can have implications in straining and damaging overworked muscles due to overexertion (rhabdomyolysis) and can ultimately lead to kidney failure [34]. Therefore, excessive exercise has the potential to stress and strain the body if appropriate measures are not taken. Dr. James O'Keefe, a clinical cardiologist from Saint Luke's Mid America Heart Institute in Kansas City, Missouri, describes the risks of excessive exercise and emphasizes the importance of participating in moderate physical exercise.

Video 2
The harms of excessive exercise, as explained by Dr. James O'Keefe[39].

"Physical exercise, though not a drug, possesses many traits of a powerful pharmacologic agent. A routine of daily physical activity can be highly effective for prevention and treatment of many diseases, including coronary heart disease, hypertension, heart failure, and obesity.

However, as with any pharmacologic agent, a safe upper dose limit potentially exists, beyond which the adverse effects of physical exercise, such as musculoskeletal trauma and cardiovascular stress, may outweigh its benefits." -Dr. James O'Keefe [39]

Moderate routine exercise can lead to a healthier lifestyle, with exercising individuals living up to 7 years longer than sedentary individuals [39]. However, excessive, high endurance exercise can be detrimental to one's health by affecting the cardiovascular system and leading to many other systemic effects. Exercise in moderation, which includes walking or jogging for a brief period of time (30-60 minutes) is a great way to improve one's health and can lead to positive health outcomes [39]. Humans are just not designed for excessive exercise because it stresses the body without providing proper time to recuperate and can ultimately lead to a decreased longevity.

Figure 12
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The consequences of high endurance exercise on the heart. BNP = B-type natriuretic peptide;
CK-MB = creatine kinase MB;
LV = left ventricle; RA = right atrium; RV = right ventricle;
SCD = sudden cardiac death[40].

Figure 13: Arrhythmogenic right ventricular cardiomyopathy (ARVC)
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Individual who died suddenly due to ARVC: increased fat deposition in the
outer walls of the right ventricle and left ventricular posterolateral walls. [37].

Evidently, moderate levels of continuous physical exercise has a positive effect on an individual's health, affecting various areas of the system at chemical, cellular and structural levels. These changes can be seen at a behavioural level as exercise improves cognition, attention and promotes an overall healthy lifestyle. Appropriate levels of exercise can reduce the stress response and can even be used as a co-treatment in addition to medication to dampen the symptoms observed in neurological and psychiatric disorders. In addition to exercise, other intervention techniques can be used to mediate the stress response such as listening to music, participating in mindfulness practices, or even having a proper sleep regimen. Therefore, exercise should ideally be used in conjunction with other methods and interventions that promote cognitive enhancement in order to achieve homeostatic balance.

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