Neurobiological effects of physical exercise

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Neurobiological effects of
physical exercise
Exercise therapy – medical intervention
Image of a woman running
A woman engaging in aerobic exercise
ICD-9-CM 93.19
MeSH D005081
LOINC 73986-2
eMedicine 324583

The neurobiological effects of physical exercise are numerous and involve a wide range of interrelated effects on brain structure, brain function, and cognition.[1][2][3][4] A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent improvements in certain cognitive functions, healthy alterations in gene expression in the brain, and beneficial forms of neuroplasticity and behavioral plasticity; some of these long-term effects include: increased neuron growth, increased neurological activity (e.g., c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory.[1][2][3][4][5][6][7][8][9] The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.[1][10][11]

People who regularly perform aerobic exercise (e.g., running, jogging, brisk walking, swimming, and cycling) have greater scores on neuropsychological function and performance tests that measure certain cognitive functions, such as attentional control, inhibitory control, cognitive flexibility, working memory updating and capacity, and information processing speed.[1][5][7][9] Aerobic exercise is also a potent antidepressant and euphoriant;[12][13][14][15] as a result, consistent exercise produces general improvements in mood and self-esteem.[16][17]

Regular aerobic exercise improves symptoms associated with a variety of central nervous system disorders and may be used as an adjunct therapy for these disorders. There is clear evidence of exercise treatment efficacy for major depressive disorder[10][14][18][19] and attention deficit hyperactivity disorder.[20] A large body of preclinical evidence and emerging clinical evidence supports the use of exercise therapy for treating and preventing the development of drug addictions.[21][22][23][24] Reviews of clinical evidence also support the use of exercise as an adjunct therapy for certain neurodegenerative disorders, particularly Alzheimer’s disease[25][26][27] and Parkinson's disease.[28][29][30][31] Regular exercise is also associated with a lower risk of developing neurodegenerative disorders.[29][32] Regular exercise has also been proposed as an adjunct therapy for brain cancers.[33]

Long-term effects[edit]


Neuroplasticity is the process by which neurons adapt to a disturbance over time, and most often occurs in response to repeated exposure to stimuli.[34] Aerobic exercise increases the production of neurotrophic factors[note 1] (e.g., BDNF, IGF-1, VEGF, and GDNF) which mediate improvements in cognitive functions and various forms of memory by promoting blood vessel formation in the brain, adult neurogenesis,[note 2] and other forms of neuroplasticity.[2][5][16][36][37] Consistent aerobic exercise over a period of several months induces clinically significant improvements in executive functions and increased gray matter volume in multiple brain regions, particularly those which give rise to executive functions.[1][5][6][7][9] The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex, caudate nucleus, and hippocampus;[1][5][6][8] less significant increases in gray matter volume occur in the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens.[5][6][8] The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the dopamine and norepinephrine systems that give rise to cognitive control.[6][38] Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory.[6][8][17][39] Higher physical fitness scores, as measured by VO2 max, are associated with better executive function, faster processing speed, and greater volume of the hippocampus, caudate nucleus, and nucleus accumbens.[1][6] Long-term aerobic exercise is also associated with persistent beneficial epigenetic changes that result in improved stress coping, improved cognitive function, and increased neuronal activity (c-Fos and BDNF signaling).[4][40]

BDNF signaling[edit]

One of the most significant effects of exercise on the brain is the increased synthesis and expression of BDNF, a neuropeptide hormone, in the brain and periphery, resulting in increased signaling through its tyrosine kinase receptor, tropomyosin receptor kinase B (TrkB).[4][41][42] Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain.[36] Exercise-induced increases in brain BDNF signaling are associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory.[4][8][16][41] Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair.[5][41] Engaging in moderate-high intensity aerobic exercise such as running, swimming, and cycling increases BDNF biosynthesis through myokine signaling, resulting in up to a threefold increase in blood plasma and brain BDNF levels;[4][41][42] exercise intensity is positively correlated with the magnitude of increased BDNF biosynthesis and expression.[4][41][42] A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well.[16]

IGF-1 signaling[edit]

IGF-1 is a peptide that mediates some of the effects of growth hormone and acts through the IGF-1 receptor to control tissue growth and remodeling.[43] In the brain, IGF-1 functions as a neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal survival.[41][44][45] Physical activity is associated with increased levels of IGF-1 in blood serum, which is known to contribute to neuroplasticity in the brain due to its capacity to cross the blood–brain barrier and blood–cerebrospinal fluid barrier;[5][41][43][44] consequently, one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis, while a second review characterized it as a factor which links "body fitness" with "brain fitness".[43][44] The amount of IGF-1 released into blood plasma during exercise is positively correlated with exercise intensity and duration.[46]

VEGF signaling[edit]

VEGF is a neurotrophic and angiogenic (i.e., blood vessel growth promoting) signaling protein that binds to two receptor tyrosine kinases, VEGFR1 and VEGFR2, which are expressed in neurons and glial cells in the brain.[45] Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons.[45] Like BDNF and IGF-1, aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which subsequently crosses the blood–brain barrier and promotes neurogenesis and blood vessel formation the central nervous system.[36][37][47] Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.[5][37][47]

GDNF signaling[edit]

Structural growth[edit]

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter volume in brain regions associated with memory processing, cognitive control, motor function, and reward;[1][5][6][8] the most prominent gains in gray matter volume are seen in the prefrontal cortex, caudate nucleus, and hippocampus, which support cognitive control and memory processing, among other cognitive functions.[1][6][8][9] Moreover, the left and right halves of the prefrontal cortex, which is divided by the medial longitudinal fissure, appear to become more interconnected in response to consistent aerobic exercise.[7] Three reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that regularly engage in medium intensity exercise for several months.[1][6][48] Other regions of the brain that demonstrate moderate or less significant gains in gray matter volume during neuroimaging include the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens.[5][6][8][49]

Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood.[5][6][8] Sedentary adults over age 55 show a 1–2% decline in hippocampal volume annually.[8][50] A neuroimaging study with a sample of 120 adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one-year period.[8][50] Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline.[50] In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function.[5][8] Aerobic exercise has also been shown to induce growth in the white matter tracts in the anterior corpus callosum, which normally shrink with age.[5][48]

The various functions of the brain structures that show exercise-induced increases in gray matter volume include:

Cognitive control and memory[edit]

Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, exercise has been shown to improve numerous aspects of cognitive control and memory function.[5][7][9][57][58] In particular, consistent aerobic exercise has been shown to improve attentional control,[note 3] attention span, information processing speed, cognitive flexibility (e.g., task switching), inhibitory control,[note 4] working memory updating and capacity,[note 5] declarative memory,[note 6] and spatial memory.[5][6][7][9][57][58] Individuals who have a sedentary lifestyle tend to have impaired cognitive control relative to other more physically active non-exercisers.[9][57] A reciprocal relationship between exercise and cognitive control has also been noted: improvements in control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.[9] A systematic review of studies conducted on children suggests that some of the exercise-induced improvements in executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional control) only improve following consistent exercise on a regular basis.[58]

Short-term effects[edit]

Psychological stress and cortisol[edit]

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors.[60][61][62] Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis).[60][61][62] Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control;[37][61][62] however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has neurotoxic effects in the human brain.[37][57][62] For example, chronic psychological stress decreases BDNF expression which has detrimental effects on hippocampal volume and can lead to depression.[37][60]

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner;[61] however, it does not result in long-term increases in cortisol production since this exercise-induced effect on cortisol is a response to transient negative energy balance.[note 7][61] Individuals who have recently exercised exhibit improvements in stress coping behaviors.[4][40][37] Aerobic exercise increases physical fitness and lowers neuroendocrine (i.e., HPA axis) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated heart rate response).[37][63] Exercise also reverses stress-induced decreases in BDNF expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.[37][60][63] Physical exercise also releases neurotransmitters like endorphins, which ease the negative feelings that come with depression.[64]


Continuous exercise can produce short-term euphoria, an affective state associated with feelings of profound contentment, elation, and well-being, which is colloquially known as a "runner's high" in distance running or a "rower's high" in rowing.[12][13][65][66] Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically phenethylamine (a stimulant), β-endorphin (an opioid), and anandamide (a cannabinoid).[67][68][69][70][71]

Neurotransmitters, neuromodulators, and neuropeptides[edit]


β-Phenylethylamine, commonly referred to as phenethylamine, is a potent human trace amine and neuromodulator which functions as endogenous amphetamine.[note 8][72][73] Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary β-phenylacetic acid, the primary metabolite of phenethylamine.[67][68][69] Two reviews noted a study where the mean 24 hour urinary β-phenylacetic acid concentration following just 30 minutes of intense exercise rose 77% above its base level;[67][68][69] the reviews suggest that phenethylamine synthesis sharply increases during physical exercise during which it is rapidly metabolized due to its short half-life of roughly 30 seconds.[67][68][69][74] In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase at approximately the same rate at which dopamine is produced.[74]

In light of this observation, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both phenethylamine and amphetamine are potent euphoriants.[67][68][69]


β-Endorphins (contracted from "endogenous morphine") are endogenous opioid neuropeptides that bind to μ-opioid receptors, in turn producing euphoria and pain relief.[70] A meta-analytic review found that exercise significantly increases the secretion of β-endorphins and that this secretion is correlated with improved mood states.[70] β-endorphins have also been found to improve sleep.[75] Moderate intensity exercise produces the greatest increase in β-endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in β-endorphin synthesis.[70]

A review on β-endorphins and exercise noted that an individual's mood improves for the remainder of the day following physical exercise and that one's mood is positively correlated with overall daily physical activity level.[70] Exercise-induced improvements in mood occur in sedentary individuals, recreational exercisers, and marathoner runners, but recreational athletes and marathon runners experience more pronounced mood-lifting effects from exercising.[70]


Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors.[71] It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~70–80% maximum heart rate).[71] Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the blood–brain barrier and act within the central nervous system.[71] Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis.[65][71]

In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running.[76][non-primary source needed]

Monoamine neurotransmitters[edit]


Glutamate, one of the most common neurochemicals in the brain, is an excitatory neurotransmitter involved in many aspects of brain function, including learning and memory.[77] Exercise normalizes the cotransmission of glutamate and dopamine in the nucleus accumbens.[21] A review of the effects of exercise on neurocardiac function in preclinical models noted that exercise-induced neuroplasticity of the rostral ventrolateral medulla (RVLM) has an inhibitory effect on glutamatergic neurotransmission, in turn reducing sympathetic activity;[78] the review hypothesized that this neuroplasticity in the RVLM is a mechanism by which regular exercise prevents inactivity-related cardiovascular disease.[78]

Effects in children[edit]

Sibley and Etnier (2003) performed a meta-analysis that looked at the relationship between physical activity and cognitive performance in children.[79] They reported a beneficial relationship in the categories of perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests, developmental level/academic readiness and other, with the exception of memory, that was found to be unrelated to physical activity.[79] The correlation was strongest for the age ranges of 4–7 and 11–13 years.[79] On the other hand, Chaddock and colleagues (2011) found results that contrasted Sibley and Etnier's meta-analysis. In their study, the hypothesis was that lower-fit children would perform poorly in executive control of memory and have smaller hippocampal volumes compared to higher-fit children.[80] Instead of physical activity being unrelated to memory in children between 4 and 18 years of age, it may be that preadolescents of higher fitness have larger hippocampal volumes, than preadolescents of lower fitness. According to a previous study done by Chaddock and colleagues (Chaddock et al. 2010), a larger hippocampal volume would result in better executive control of memory.[81] They concluded that hippocampal volume was positively associated with performance on relational memory tasks.[81] Their findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.[81] In Best’s (2010) meta-analysis of the effect of activity on children’s executive function, there are two distinct experimental designs used to assess aerobic exercise on cognition. The first is chronic exercise, in which children are randomly assigned to a schedule of aerobic exercise over several weeks and later assessed at the end.[82] The second is acute exercise, which examines the immediate changes in cognitive functioning after each session.[82] The results of both suggest that aerobic exercise may briefly aid children’s executive function and also influence more lasting improvements to executive function.[82] Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is.[83] This area of study has been a focus for education boards that make decisions on whether physical education should be implemented in the school curriculum, how much time should be dedicated to physical education, and its impact on other academic subjects.[79]

Animal studies have also shown that exercise can impact brain development early on in life. Mice that had access to running wheels and other such exercise equipment had better neuronal growth in the neural systems involved in learning and memory.[83] Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function.[83] Some investigations have linked low levels of aerobic fitness in children with impaired executive function in older adults, but there is mounting evidence it may also be associated with a lack of selective attention, response inhibition, and interference control.[80]

Effects on central nervous system disorders[edit]


Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, psychostimulant addiction in particular.[21][22][23][24] Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity.[21][22] One review noted that exercise may prevent the development of drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[24] Moreover, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).[21][22] Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction.[21][23] As of July 2015, more clinical research is still needed to understand the mechanisms and confirm the efficacy of exercise in drug addiction treatment and prevention.[24]

Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
ΔFosB expression in
nucleus accumbens D1-type MSNs
Behavioral plasticity
Escalation of intake Yes Yes Yes [22]
Yes Not applicable Yes Yes Attenuated Attenuated [22]
conditioned place preference
Reinstatement of drug-seeking behavior [22]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [22]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [22]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [22]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [22]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [22]
Dendritic spine density in
the nucleus accumbens

Attention deficit hyperactivity disorder[edit]

ADHD is a neuropsychiatric disorder that involves deficits in certain aspects of cognitive control, particularly attentional control and inhibitory control.[51] Regular physical exercise, particularly aerobic exercise, is an effective adjunct treatment for ADHD, although the best type and intensity is not currently known.[20][84] However, studies have found that even just a half hour of moderate exercise per day improves concentration and mood. The biology behind exercise's effect on concentration is that exercise increases one's levels of dopamine, serotonin, and norepinephrine, all which are neurotransmitters that aid in attention.[85] In non-randomized trials, physical exercise has been shown to result in better behavior and motor abilities without causing any side effects in ADHD populations.[20][84]

Major depressive disorder[edit]

A number of medical reviews have indicated that exercise has a marked and persistent antidepressant effect in humans,[5][14][15][18][86][87] an effect believed to be mediated through enhanced BDNF signaling in the brain.[8][18] Several systematic reviews have analyzed the potential for physical exercise in the treatment of depressive disorders. The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is more effective than a control intervention and comparable to psychological or antidepressant drug therapies.[86] Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that that physical exercise is effective as an adjunct treatment (i.e., treatments that are used together) with antidepressant medication;[18] the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression and mental illness in general.[14][15] One systematic review noted that yoga may be effective in alleviating symptoms of prenatal depression.[88] Another review asserted that evidence from clinical trials supports the efficacy of physical exercise as a treatment for depression over a 2–4 month period.[5]

A 2015 review of clinical evidence and medical guideline for the treatment of depression with exercise noted that the available evidence on the effectiveness of exercise therapy for depression suffers from some limitations;[19] nonetheless, it stated that there is clear evidence of efficacy for reducing symptoms of depression.[19] The review also noted that patient characteristics, the type of depressive disorder, and the nature of the exercise program all affect the antidepressant properties of exercise therapy.[19] A July 2016 meta-analysis concluded that physical exercise improves overall quality of life in individuals with depression relative to controls.[10]

Brain cancers[edit]

Neurodegenerative disorders[edit]

Alzheimer's disease[edit]

Alzheimer's Disease is a cortical neurodegenerative disorder and the most prevalent form of dementia, representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive function, behavioral abnormalities, and a reduced capacity to perform basic activities of daily life.[26][27] Two meta-analytic systematic reviews of randomized controlled trials with durations of 3–12 months have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's disease.[26][27] The reviews found beneficial effects of physical exercise on cognitive function, the rate of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's disease.[26][27] One review suggested that, based upon transgenic mouse models, the cognitive effects of exercise on Alzheimer's disease may result from a reduction in the quantity of amyloid plaque.[26][89]

The Caerphilly Prospective study followed 2,375 male subjects over 30 years and examined the association between healthy lifestyles and dementia, among other factors.[90] Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment.[90][91] A subsequent systematic review of longitudinal studies also found higher levels of physical activity to be associated with a reduction in the risk of dementia and cognitive decline;[32] this review further asserted that increased physical activity appears to be causally related with these reduced risks.[32]

Parkinson's disease[edit]

Parkinson's disease (PD) is a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait.[92]

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way.[93] A few studies reported seeing an improvement in brain health and cognitive function due to exercise.[93] One particular study by Kramer and colleagues (1999) found that aerobic training improved executive control processes supported by frontal and prefrontal regions of the brain.[94] These regions are responsible for the cognitive deficits in PD patients, however there was speculation that the difference in the neurochemical environment in the frontal lobes of PD patients may inhibit the benefit of aerobic exercise.[95] Nocera and colleagues (2010) performed a case study based on this literature where they gave participants with early-to mid-staged PD, and the control group cognitive/language assessments with exercise regimens. Individuals performed 20 minutes of aerobic exercise three times a week for 8 weeks on a stationary exercise cycle. It was found that aerobic exercise improved several measures of cognitive function,[95] providing evidence that such exercise regimens may be beneficial to patients with PD.

Huntington's disease[edit]

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder leading to a decline in motor skills, chorea, subcortical dementia, and other psychiatric symptoms.[96]

Physical therapy can be sought to help improve the motor impairments of the disease. The conclusions about the effects of exercise on cognitive function in HD patients have varied across the literature. Pang and colleagues (2006) studied R6/1 transgenic mice models of HD, with results that showed exercise delayed the onset of symptoms and slowed cognitive decline.[96] On the other hand, another study by Kohl and colleagues (2007) used the R6/2 transgenic mouse model of HDstrain to see if physical activity could stimulate hippocampal neurogenesis from neural stem cells.[97] Their study found that physical exercise did stimulate cell proliferation and survival in normal healthy mice, but did not enhance hippocampal neurogenesis in the transgenic mice.[97] They speculated that this result may be due to an effect the mutated Huntingtin gene, and by extension the mutated Huntingtin protein, has on the mechanisms needed for successful hippocampal neurogenesis in HD patients.[97]

See also[edit]


  1. ^ Neurotrophic factors are peptides or other small proteins that promote the growth, survival, and differentiation of neurons by binding to and activating their associated tyrosine kinases.[35]
  2. ^ Adult neurogenesis is the postnatal (after-birth) growth of new neurons, a beneficial form of neuroplasticity.[34]
  3. ^ Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,[38] such as in the cocktail party effect.
  4. ^ Inhibitory control is the process of altering one's learned behavioral responses, sometimes called "prepotent responses", in a way that makes it easier to complete a particular goal.[51][59] Inhibitory control allows individuals to control their impulses and habits when necessary or desired,[51][57][59] e.g., to overcome procrastination.
  5. ^ Working memory is the form of memory used by an individual at any given moment for active information processing,[38] such as when reading or writing an encyclopedia article. Working memory has a limited capacity and functions as an information buffer, analogous to a computer's data buffer, that permits the manipulation of information for comprehension, decision-making, and guidance of behavior.[51]
  6. ^ Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and events.[54]
  7. ^ In healthy individuals, this energy deficit resolves simply from eating and drinking a sufficient amount of food and beverage after exercising.
  8. ^ In other words, phenethylamine and amphetamine have roughly identical effects on the central nervous system.


  1. ^ a b c d e f g h i j Erickson KI, Hillman CH, Kramer AF (August 2015). "Physical activity, brain, and cognition". Current Opinion in Behavioral Sciences 4: 27–32. doi:10.1016/j.cobeha.2015.01.005. Research in children finds that higher fit and more active preadolescent children show greater hippocampal and basal ganglia volume, greater white matter integrity, elevated and more efficient patterns of brain activity, and superior cognitive performance and scholastic achievement. Higher fit and more physically active older adults show greater hippocampal, prefrontal cortex, and basal ganglia volume, greater functional brain connectivity, greater white matter integrity, more efficient brain activity, and superior executive and memory function. ...
    Cognitive performance: Cross-sectional, observational, and randomized clinical trials of PA in late adulthood have demonstrated that engaging in PA may preserve and/or enhance cognitive function even in cognitively impaired individuals (e.g., [18]). Summaries of these studies can now be found in several meta-analyses, most of which confirm that PA positively influences cognitive function in late adulthood with small to moderate sized effects [19]. In a meta-analysis of 18 randomized PA trials, engaging in moderate intensity PA resulted in enhanced cognitive function across all cognitive domains examined, but with the largest effect sizes for indices of executive function [20]. Meta-analyses of longitudinal observational studies have also confirmed that self-reported engagement in PA is associated with nearly a 40% reduced risk of experiencing cognitive decline over several years [21]. These, and other studies, make a convincing argument that both continuing to engage in, and starting to engage in, PA in late adulthood may have a profound effect on maintaining cognitive health, improving function, and reducing the risk of developing cognitive impairment.
    Brain structure: There have been now more than 30 published studies of PA or fitness on brain structure in older adults (>60 years) with the majority showing positive associations (see [22]). Such effects are important since increasing age is associated with brain atrophy and loss of volume, which precedes and predicts conversion to dementia. Higher aerobic fitness levels have been associated with larger gray matter volumes in older adults in several areas including the frontal cortex [23,24], hippocampus [25,26], and caudate nucleus [27]. Longitudinal observational studies have also shown that greater amounts of PA are associated with larger gray matter volumes in these regions, and greater volume is, in turn, associated with a reduced risk of cognitive impairment [28]. These cross-sectional and observational results in older adults are further supported by clinical trials that have shown that six-months to one-year of regular PA is associated with an increase in both frontal cortex [29••,30] and hippocampal volume ... These effects on gray matter volume are accompanied by differences found in white matter integrity. For example, several studies have reported that higher cardiorespiratory fitness levels and PA are associated with greater white matter integrity along several tracts linking frontal and subcortical areas [34–36] and that greater changes in fitness after an intervention was associated with an increase in white matter integrity [37]. In sum, there is now convincing evidence that PA and fitness influence brain structure, characterized by both gray matter volume and white matter integrity, in late adulthood.
  2. ^ a b c Paillard T, Rolland Y, de Souto Barreto P (July 2015). "Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review". J Clin Neurol 11 (3): 212–219. doi:10.3988/jcn.2015.11.3.212. PMC 4507374. PMID 26174783. Aerobic physical exercise (PE) activates the release of neurotrophic factors and promotes angiogenesis, thereby facilitating neurogenesis and synaptogenesis, which in turn improve memory and cognitive functions. ... Exercise limits the alteration in dopaminergic neurons in the substantia nigra and contributes to optimal functioning of the basal ganglia involved in motor commands and control by adaptive mechanisms involving dopamine and glutamate neurotransmission. 
  3. ^ a b McKee AC, Daneshvar DH, Alvarez VE, Stein TD (January 2014). "The neuropathology of sport". Acta Neuropathol. 127 (1): 29–51. doi:10.1007/s00401-013-1230-6. PMC 4255282. PMID 24366527. The benefits of regular exercise, physical fitness and sports participation on cardiovascular and brain health are undeniable ... Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration. 
  4. ^ a b c d e f g h Denham J, Marques FZ, O'Brien BJ, Charchar FJ (February 2014). "Exercise: putting action into our epigenome". Sports Med 44 (2): 189–209. doi:10.1007/s40279-013-0114-1. PMID 24163284. Aerobic physical exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in modulating chromatin remodelers [21, 79–82]. ... These results were the first to demonstrate that acute and relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications observed due to chronic running training have also been associated with improved learning and stress-coping strategies, epigenetic changes and increased c-Fos-positive neurons ... Nonetheless, these studies demonstrate the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos). ... The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent [164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and neuronal development and recovery via aerobic exercise. 
  5. ^ a b c d e f g h i j k l m n o p q r Gomez-Pinilla F, Hillman C (January 2013). "The influence of exercise on cognitive abilities". Compr Physiol 3 (1): 403–428. doi:10.1002/cphy.c110063. PMC 3951958. PMID 23720292. A second recent meta-analysis (162) corroborated Colcombe and Kramer’s (30) findings, in that aerobic exercise was related to attention, processing speed, memory, and cognitive control. ... Normal aging results in the loss of brain tissue (31), with markedly larger tissue loss evidenced in the frontal, temporal, and parietal cortices (16, 58, 149). 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 (158). 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 ... aerobic fitness relates to larger hippocampal volume (23) and better relational memory performance (24), during preadolescent childhood. ... 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 (32). 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 (32). ... In addition, aerobic fitness has been shown to promote better functioning of brain, especially in neural networks involved in cognitive control of inhibition and attention (33). ... In addition to BDNF, the actions of IGF-1 and vascular endothelial growth factor (VEGF) (54) are considered essential for the angiogenic and neurogenic effects of exercise in the brain. ... 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. ... exercise seems to have both preventative and therapeutic effects on the course of depression 
  6. ^ a b c d e f g h i j k l m n Erickson KI, Leckie RL, Weinstein AM (September 2014). "Physical activity, fitness, and gray matter volume". Neurobiol. Aging. 35 Suppl 2: S20–528. doi:10.1016/j.neurobiolaging.2014.03.034. PMC 4094356. PMID 24952993. Retrieved 9 December 2014. We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus. ... Meta-analyses (Colcombe and Kramer, 2003; Smith et al., 2010) suggest that the effects of exercise on the brain might not be uniform across all regions and that some brain areas, specifically those areas supporting executive functions, might be more influenced by participation in exercise than areas not as critically involved in executive functions. ... The effects appear to be general in the sense that many different cognitive domains are improved after several months of aerobic exercise, but specific in the sense that executive functions are improved more than other cognitive domains. ... physical activity and exercise may reduce the risk for AD (Barnes and Yaffe, 2011; Podewils et al., 2005; Sofi et al., 2011) ... Erickson et al. (2010) reported that greater amounts of physical activity were associated with greater gray matter volume 9-years later in the prefrontal cortex, anterior cingulate, parietal cortex, cerebellum, and hippocampus. ... higher fitness levels (VO2max) were associated with larger hippocampal volumes, better executive function, and faster processing speed. ... Verstynen et al. (2012) examined the association between cardiorespiratory fitness levels (VO2max) and the size of the basal ganglia ... Verstynen et al. (2012) found that higher fitness levels were associated with greater volume of the caudate nucleus and nucleus accumbens, and in turn, greater volumes were associated with better performance on a task-switching paradigm. ... That is, higher physical activity levels mitigated the detrimental effects of lifetime stress on the size of the hippocampus. ... The few randomized interventions published thus far have found results highly overlapping with the cross-sectional studies and suggest that the prefrontal cortex and hippocampus remain pliable in late life and that moderate intensity exercise for 6 months–1 year is sufficient for changing the size of these areas. 
  7. ^ a b c d e f Guiney H, Machado L (February 2013). "Benefits of regular aerobic exercise for executive functioning in healthy populations". Psychon Bull Rev 20 (1): 73–86. doi:10.3758/s13423-012-0345-4. PMID 23229442. Executive functions are strategic in nature and depend on higher-order cognitive processes that underpin planning, sustained attention, selective attention, resistance to interference, volitional inhibition, working memory, and mental flexibility ... Data to date from studies of aging provide strong evidence of exercise-linked benefits related to task switching, selective attention, inhibition of prepotent responses, and working memory capacity; furthermore, cross-sectional fitness data suggest that working memory updating could potentially benefit as well. In young adults, working memory updating is the main executive function shown to benefit from regular exercise, but cross-sectional data further suggest that task-switching and post-error performance may also benefit. In children, working memory capacity has been shown to benefit, and cross-sectional data suggest potential benefits for selective attention and inhibitory control. ... Support for the idea that higher levels of aerobic activity may be associated with superior brain structure has been gained through cross-sectional studies in older adults and children (for a recent review, see Voss, Nagamatsu, et al., 2011). ... only those in the aerobic exercise group exhibited improved connectivity between the left and right prefrontal cortices, two areas that are crucial to the effective functioning of the fronto-executive network. ... Together, these studies provide evidence that regular aerobic exercise benefits control over responses during selective attention in older adults. ... aerobic fitness is a good predictor of performance on tasks that rely relatively heavily on inhibitory control over prepotent responses (e.g., Colcombe et al., 2004, Study 1; Prakash et al., 2011) and also that regular aerobic exercise improves performance on such tasks ... Overall, the results from the span and Sternberg tasks suggest that regular exercise can also confer benefits for the volume of information that children and older adults can hold in mind at one time. 
  8. ^ a b c d e f g h i j k l m n Erickson KI, Miller DL, Roecklein KA (2012). "The aging hippocampus: interactions between exercise, depression, and BDNF". Neuroscientist 18 (1): 82–97. doi:10.1177/1073858410397054. PMC 3575139. PMID 21531985. Late adulthood is associated with increased hippocampal atrophy and dysfunction.  ... However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. ... For example, longitudinal studies have reported between 1% and 2% annual hippocampal atrophy in adults older than 55 years without dementia ... Over a nine-year period, greater amounts of physical activity in the form of walking are associated with greater gray matter volume in several regions including prefrontal, temporal, and hippocampal areas. ... The prefrontal cortex and hippocampus deteriorate in late adulthood, preceding and leading to deficits in executive and memory function. We examined in this review the evidence that age-related changes in BDNF might at least partially explain hippocampal atrophy and increased risk for memory impairment. We can conclude that 1) decreases in BDNF protein expression are associated with poorer hippocampal function and increased rates of geriatric depression and AD. ... 3) Aerobic exercise enhances executive and memory function and reduces hippocampal atrophy in late adulthood, and this may be partially mediated through a BDNF pathway. 
  9. ^ a b c d e f g h Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP (2014). "Cognitive control in the self-regulation of physical activity and sedentary behavior". Front Hum Neurosci 8: 747. doi:10.3389/fnhum.2014.00747. PMC 4179677. PMID 25324754. Recent theory (e.g., Temporal Self-Regulation Theory; Hall and Fong, 2007, 2010, 2013) and evidence suggest that the relation between physical activity and cognitive control is reciprocal (Daly et al., 2013). Most research has focused on the beneficial effects of regular physical activity on executive functions-the set of neural processes that define cognitive control. Considerable evidence shows that regular physical activity is associated with enhanced cognitive functions, including attention, processing speed, task switching, inhibition of prepotent responses and declarative memory (for reviews see Colcombe and Kramer, 2003; Smith et al., 2010; Guiney and Machado, 2013; McAuley et al., 2013). Recent research demonstrates a dose-response relationship between fitness and spatial memory (Erickson et al., 2011) ... The effects of physical activity on cognitive control appear to be underpinned by a variety of brain processes including: increased hippocampal volume, increased gray matter density in the prefrontal cortex (PFC), upregulation of neurotrophins and greater microvascular density ... Together, this research suggests that an improvement in control processes, such as attention and inhibition or interference control, is associated with an improvement in self-regulation of physical activity. ... Hoang et al. (2013) found that young adults who initially exhibited low levels of physical activity and remained relatively inactive for 25 years had nearly twofold greater odds of impaired executive function compared with those who exhibited higher activity levels; very-low physical activity patterns were associated with even more pronounced declines in executive functioning. … sedentary behavior indirectly led to poor executive function through depressive symptoms (Vance et al., 2005). … sedentary individuals display less capacity to quickly and accurately switch between tasks. 
  10. ^ a b c Schuch FB, Vancampfort D, Rosenbaum S, Richards J, Ward PB, Stubbs B (July 2016). "Exercise improves physical and psychological quality of life in people with depression: A meta-analysis including the evaluation of control group response". Psychiatry Res. 241: 47–54. doi:10.1016/j.psychres.2016.04.054. PMID 27155287. Exercise has established efficacy as an antidepressant in people with depression. ... Exercise significantly improved physical and psychological domains and overall QoL. ... The lack of improvement among control groups reinforces the role of exercise as a treatment for depression with benefits to QoL. 
  11. ^ Pratali L, Mastorci F, Vitiello N, Sironi A, Gastaldelli A, Gemignani A (November 2014). "Motor Activity in Aging: An Integrated Approach for Better Quality of Life". Int. Sch. Res. Notices 2014: 257248. doi:10.1155/2014/257248. PMID 27351018. Research investigating the effects of exercise on older adults has primarily focused on brain structural and functional changes with relation to cognitive improvement. In particular, several cross-sectional and intervention studies have shown a positive association between physical activity and cognition in older persons [86] and an inverse correlation with cognitive decline and dementia [87]. Older adults enrolled in a 6-month aerobic fitness intervention increased brain volume in both gray matter (anterior cingulate cortex, supplementary motor area, posterior middle frontal gyrus, and left superior temporal lobe) and white matter (anterior third of corpus callosum) [88]. In addition, Colcombe and colleagues showed that older adults with higher cardiovascular fitness levels are better at activating attentional resources, including decreased activation of the anterior cingulated cortex. One of the possible mechanisms by which physical activity may benefit cognition is that physical activity maintains brain plasticity, increases brain volume, stimulates neurogenesis and synaptogenesis, and increases neurotrophic factors in different areas of the brain, possibly providing reserve against later cognitive decline and dementia [89, 90]. 
  12. ^ a b Cunha GS, Ribeiro JL, Oliveira AR (June 2008). "[Levels of beta-endorphin in response to exercise and overtraining]". Arq Bras Endocrinol Metabol (in Portuguese) 52 (4): 589–598. PMID 18604371. Interestingly, some symptoms of OT are related to beta-endorphin (beta-end(1-31)) effects. Some of its effects, such as analgesia, increasing lactate tolerance, and exercise-induced euphoria, are important for training. 
  13. ^ a b Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR (2008). "The runner's high: opioidergic mechanisms in the human brain". Cereb. Cortex 18 (11): 2523–2531. doi:10.1093/cercor/bhn013. PMID 18296435. The runner's high describes a euphoric state resulting from long-distance running. 
  14. ^ a b c d Josefsson T, Lindwall M, Archer T (2014). "Physical exercise intervention in depressive disorders: meta-analysis and systematic review". Scand J Med Sci Sports 24 (2): 259–272. doi:10.1111/sms.12050. PMID 23362828. Physical activity has also become increasingly and firmly associated with improvements in mental health and psychological well-being (Mutrie, 2000; Landers & Arent, 2007). In particular, exercise is believed to be effective in preventing depression and also to significantly reduce depressive symptoms in clinical as well as in nonclinical populations (O’Neal et al., 2000; Landers & Arent, 2007). Several correlational studies show that exercise is negatively related to depressive symptoms (e.g., Galper et al., 2006; Hassmén et al., 2000). Moreover, a considerably large number of intervention studies have by now investigated the effect of various exercise programs on depression and the vast majority of them indicate that exercise significantly reduces depression (e.g., Blumenthal et al., 2007; Martinsen et al., 1985; Singh et al., 1997). ... To date, it is not possible to determine exactly how effective exercise is in reducing depression symptoms in clinical and nonclinical depressed populations, respectively. However, the results from the present meta-analysis as well as from seven earlier meta-analyses (North et al., 1990; Craft & Landers, 1998; Lawlor & Hopker, 2001; Stathopoulou et al., 2006; Mead et al., 2009; Rethorst et al., 2009; Krogh et al., 2011) indicate that exercise has a moderate to large antidepressant effect. Some meta-analytic results (e.g., Rethorst et al., 2009) suggest that exercise may be even more efficacious for clinically depressed people. ... In short, our final conclusion is that exercise may well be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program. 
  15. ^ a b c Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB (2014). "Physical activity interventions for people with mental illness: a systematic review and meta-analysis". J Clin Psychiatry 75 (9): 964–974. doi:10.4088/JCP.13r08765. PMID 24813261. This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness. The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders). ... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined. ...
    Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects. Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review.
  16. ^ a b c d Szuhany KL, Bugatti M, Otto MW (October 2014). "A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor". J Psychiatr Res 60C: 56–64. doi:10.1016/j.jpsychires.2014.10.003. PMC 4314337. PMID 25455510. Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). ... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans 
  17. ^ a b Lees C, Hopkins J (2013). "Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials". Prev Chronic Dis 10: E174. doi:10.5888/pcd10.130010. PMC 3809922. PMID 24157077. This omission is relevant, given the evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis, angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship between aerobic fitness, hippocampal volume, and memory has been found (12,13). ... Mental health outcomes included reduced depression and increased self-esteem, although no change was found in anxiety levels (18). ... This systematic review of the literature found that [aerobic physical activity (APA)] is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic performance (24).  ... The actual aerobic-based activity does not appear to be a major factor; interventions used many different types of APA and found similar associations. In positive association studies, intensity of the aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between studies; however, even as little as 45 minutes per week appeared to have a benefit. 
  18. ^ a b c d Mura G, Moro MF, Patten SB, Carta MG (2014). "Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review". CNS Spectr 19 (6): 496–508. doi:10.1017/S1092852913000953. PMID 24589012. Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants. ...
    This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.41,51,73,92,93 Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies.
  19. ^ a b c d Ranjbar E, Memari AH, Hafizi S, Shayestehfar M, Mirfazeli FS, Eshghi MA (June 2015). "Depression and Exercise: A Clinical Review and Management Guideline". Asian J. Sports Med. 6 (2): e24055. doi:10.5812/asjsm.6(2)2015.24055. PMC 4592762. PMID 26448838. Keeping in mind that exercise shows no medication side effects such as withdrawal symptoms (20), weight gain, dry mouth or insomnia (21), but shows potential health benefits such as weight reduction, it is highly recommended to use exercise as an adjunctive treatment for depression (22). New findings confirm that exercise can be recommended as a first-line treatment for mild to moderate depression; as an adjunct to medications (23); as an alternative to cognitive behavioral therapy (11); and in preventing depression in clinical as well as healthy populations (24-26). ... Although recent findings have shown that exercise can decrease depressive symptoms, there are still many questions and limitations to wider application of exercise in depression. For instance, there are deficiencies in methodological planning such as uncontrolled nonrandomized trials, small sample sizes, inadequate allocation concealment, lack of intention-to-treat analyses, non-blinded outcome assessments, and inclusion of subjects without clinical diagnosis that limit the interpretability of research outcomes (53).
    Box 1: Patients with Depression Who May Particularly Benefit From Exercise Programs
    Box 2: Depressive Disorders Other Than Major Depression That May Benefit From Exercise Programs
    Box 3: The Characteristics of an Exercise Program that will Maximize the Anti-depressive Properties
  20. ^ a b c Kamp CF, Sperlich B, Holmberg HC (July 2014). "Exercise reduces the symptoms of attention-deficit/hyperactivity disorder and improves social behaviour, motor skills, strength and neuropsychological parameters". Acta Paediatr. 103 (7): 709–14. doi:10.1111/apa.12628. PMID 24612421. Retrieved 14 March 2015. The present review summarises the impact of exercise interventions (1–10 weeks in duration with at least two sessions each week) on parameters related to ADHD in 7-to 13-year-old children. We may conclude that all different types of exercise (here yoga, active games with and without the involvement of balls, walking and athletic training) attenuate the characteristic symptoms of ADHD and improve social behaviour, motor skills, strength and neuropsychological parameters without any undesirable side effects. Available reports do not reveal which type, intensity, duration and frequency of exercise is most effective in this respect and future research focusing on this question with randomised and controlled long-term interventions is warranted. 
  21. ^ a b c d e f Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439. [exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. ... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes. 
  22. ^ a b c d e f g h i j k l m n o p q Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). 
  23. ^ a b c Linke SE, Ussher M (2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am J Drug Alcohol Abuse 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMID 25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects. 
  24. ^ a b c d Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in drug addiction and response to exercise intervention: From human to animal studies". Front. Neuroendocrinol. doi:10.1016/j.yfrne.2015.07.001. PMID 26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation. ... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed. 
  25. ^ a b Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S (April 2015). "Exercise programs for people with dementia". Cochrane Database Syst Rev 4: CD006489. doi:10.1002/14651858.CD006489.pub4. PMID 25874613. 
  26. ^ a b c d e Farina N, Rusted J, Tabet N (January 2014). "The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review". Int Psychogeriatr 26 (1): 9–18. doi:10.1017/S1041610213001385. PMID 23962667. Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17). ... The most prevalent subtype of dementia is Alzheimer’s disease (AD), accounting for up to 65.0% of all dementia cases ... Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms by which exercise may act on cognition in AD. 
  27. ^ a b c d Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J (January 2014). "Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease". Am J Occup Ther 68 (1): 50–56. doi:10.5014/ajot.2014.009035. PMID 24367955. Alzheimer’s disease (AD) is a progressive neurological disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic activities of daily living [(ADLs)] ... All studies included people with AD who completed an exercise program consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise programs varied from 12 weeks to 12 months. ... Six studies involving 446 participants tested the effect of exercise on ADL performance ... exercise had a large and significant effect on ADL performance (z = 4.07, p < .0001; average effect size = 0.80). ... These positive effects were apparent with programs ranging in length from 12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011; Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003). ... No adverse effects of exercise on ADL performance were noted. ... The study with the largest effect size implemented a walking and aerobic program of only 30 min four times a week (Venturelli et al., 2011). 
  28. ^ a b Mattson MP (2014). "Interventions that improve body and brain bioenergetics for Parkinson's disease risk reduction and therapy". J Parkinsons Dis 4 (1): 1–13. doi:10.3233/JPD-130335. PMID 24473219. 
  29. ^ a b c Grazina R, Massano J (2013). "Physical exercise and Parkinson's disease: influence on symptoms, disease course and prevention". Rev Neurosci 24 (2): 139–152. doi:10.1515/revneuro-2012-0087. PMID 23492553. 
  30. ^ a b van der Kolk NM, King LA (September 2013). "Effects of exercise on mobility in people with Parkinson's disease". Mov. Disord. 28 (11): 1587–1596. doi:10.1002/mds.25658. PMID 24132847. 
  31. ^ a b Tomlinson CL, Patel S, Meek C, Herd CP, Clarke CE, Stowe R, et al. (September 2013). "Physiotherapy versus placebo or no intervention in Parkinson's disease". Cochrane Database Syst Rev 9: CD002817. doi:10.1002/14651858.CD002817.pub4. PMID 24018704. 
  32. ^ a b c Blondell SJ, Hammersley-Mather R, Veerman JL (May 2014). "Does physical activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies". BMC Public Health 14: 510. doi:10.1186/1471-2458-14-510. PMC 4064273. PMID 24885250. Longitudinal observational studies show an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A case can be made for a causal interpretation. Future research should use objective measures of physical activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised controlled trials will be conducted. ... On the whole the results do, however, lend support to the notion of a causal relationship between physical activity, cognitive decline and dementia, according to the established criteria for causal inference. 
  33. ^ a b Cormie P, Nowak AK, Chambers SK, Galvão DA, Newton RU (April 2015). "The potential role of exercise in neuro-oncology". Front. Oncol. 5: 85. doi:10.3389/fonc.2015.00085. PMC 4389372. PMID 25905043. 
  34. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, eds. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 5, 351. ISBN 9780071481274. The clinical actions of fluoxetine, like those of many neuropharmacologic agents, reflect drug-induced neural plasticity, which is the process by which neurons adapt over time in response to chronic disturbance. ... For example, evidence indicates that prolonged increases in cortisol may be damaging to hippocampal neurons and can suppress hippocampal neurogenesis (the generation of new neurons postnatally). 
  35. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 8:Atypical Neurotransmitters". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 199, 215. ISBN 9780071481274. Neurotrophic factors are polypeptides or small proteins that support the growth, differentiation, and survival of neurons. They produce their effects by activation of tyrosine kinases. 
  36. ^ a b c Tarumi T, Zhang R (January 2014). "Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise". Front Physiol 5: 6. doi:10.3389/fphys.2014.00006. PMC 3896879. PMID 24478719. Exercise-related improvements in brain function and structure may be conferred by the concurrent adaptations in vascular function and structure. Aerobic exercise increases the peripheral levels of growth factors (e.g., BDNF, IFG-1, and VEGF) which cross the blood-brain barrier (BBB) and stimulate neurogenesis and angiogenesis (Trejo et al., 2001; Lee et al., 2002; Fabel et al., 2003; Lopez-Lopez et al., 2004). 
  37. ^ a b c d e f g h i Silverman MN, Deuster PA (October 2014). "Biological mechanisms underlying the role of physical fitness in health and resilience". Interface Focus 4 (5): 20140040. doi:10.1098/rsfs.2014.0040. PMID 25285199. Physical fitness, achieved through regular exercise and/or spontaneous physical activity, can protect against the development of chronic stress- and inflammatory-related disease by optimizing physiological and neuroendocrine stress responsivity, promoting an anti-inflammatory state, and enhancing neuroplasticity and growth factor expression. stress responsive systems are adaptive when activated and terminated in a timely manner, prolonged (or insufficient) activation of these systems can cause a variety of maladaptive responses. ... For example, Rimelle et al. [123] documented significantly lower cortisol and heart rate responses to psychosocial stress (Trier social stress test) in trained men compared with untrained men. Moreover, significantly greater calmness and better mood, and a trend towards lower state anxiety, were noted in these trained men during the stress protocol. ... Whereas hippocampal and/or serum/plasma BDNF levels are downregulated by chronic psychosocial stress and inflammation [138,180,201], central and peripheral BDNF levels can be upregulated by acute exercise [33,198,202,203]. ... Exercise-induced increases in brain monoamines (norepinephrine and serotonin) may also contribute to increased expression of hippocampal BDNF [194]. In addition, other growth factors—insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor—have been shown to play an important role in BDNF-induced effects on neuroplasticity [33,172,190,192], as well as exerting neuroprotective effects of their own [33,214,215], thereby contributing to the beneficial effects of exercise on brain health. Like BDNF, increases in circulating IGF-1 levels in response to acute exercise are only transient and possibly time-dependent as it relates to chronic training (i.e. increases seen after 12 weeks of training) [216]. ... Whereas reduced HPA axis reactivity to a given stressor has repeatedly been reported in physically fit individuals, the finding of reduced sympathetic reactivity is less consistent. 
  38. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157. ISBN 9780071481274. Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. ... 
  39. ^ Carvalho A, Rea IM, Parimon T, Cusack BJ (2014). "Physical activity and cognitive function in individuals over 60 years of age: a systematic review". Clin Interv Aging 9: 661–682. doi:10.2147/CIA.S55520. PMC 3990369. PMID 24748784. 
  40. ^ a b Ehlert T, Simon P, Moser DA (February 2013). "Epigenetics in sports". Sports Med 43 (2): 93–110. doi:10.1007/s40279-012-0012-y. PMID 23329609. Alterations in epigenetic modification patterns have been demonstrated to be dependent on exercise and growth hormone (GH), insulin-like growth factor 1 (IGF-1), and steroid administration. ... the authors observed improved stress coping in exercised subjects. Investigating the dentate gyrus, a brain region which is involved in learning and coping with stressful and traumatic events, they could show that this effect is mediated by increased phosphorylation of serine 10 combined with H3K14 acetylation, which is associated with local opening of condensed chromatin. Consequently, they found increased immediate early gene expression as shown for c-FOS (FBJ murine osteosarcoma viral oncogene homologue). 
  41. ^ a b c d e f g Phillips C, Baktir MA, Srivatsan M, Salehi A (2014). "Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling". Front Cell Neurosci 8: 170. doi:10.3389/fncel.2014.00170. PMC 4064707. PMID 24999318. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. ... Studies have demonstrated the intensity of exercise training is positively correlated with BDNF plasma levels in young, healthy individuals (Ferris et al., 2007). Resistance exercise has also been shown to elevate serum BDNF levels in young individuals (Yarrow et al., 2010). Moreover, it has been shown that moderate levels of physical activity in people with AD significantly increased plasma levels of BDNF (Coelho et al., 2014). ... In humans, it has been shown that 4 h of rowing activity leads to increased levels of plasma BDNF from the internal jugular (an indicator of central release from the brain) and radial artery (an indicator of peripheral release; Rasmussen et al., 2009). Seifert et al. (2010) reported that basal release of BDNF increases following 3 months endurance training in young and healthy individuals, as measured from the jugular vein. These trends are augmented by rodent studies showing that endurance training leads to increased synthesis of BDNF in the hippocampal formation (Neeper et al., 1995, 1996). ... Both BDNF and IGF-1 play a significant role in cognition and motor function in humans. ... Multiple large-scale studies in humans have shown that serum levels of IGF-1 are correlated with fitness and as well as body mass indices (Poehlman and Copeland, 1990). Furthermore, animal studies have shown that exercise in rats is associated with increased amounts of IGF-1 in the CSF. 
  42. ^ a b c Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J (November 2014). "Organ-Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans". Physiology (Bethesda) 29 (6): 421–436. doi:10.1152/physiol.00067.2013. PMID 25362636. The Effects of Acute Exercise
    Studies in humans and animals have shown that brain blood flow remains largely unchanged in response to acute exercise[,] ... does not increase with increasing exercise intensity[, and] ... increased metabolic demands of active brain parts are mostly met by redistributing oxygen supply, although changes in oxygen extraction may also contribute. During exercise, blood flow is directed to the areas controlling locomotor, vestibular, cardiorespiratory, and visual functions (8, 91), facilitated by direct communication of neurons and vascular cells (94, 134). ... with increasing exercise intensity, brain glucose uptake decreases (75) as the uptake and utilization of lactate is enhanced (65, 139, 182). Regional differences in brain glucose uptake are also evident, which is furthermore influenced by the level of physical fitness. Thus the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex during exercise is significantly more pronounced in subjects with higher exercise capacity (75) ...
    The Effects of Long-Term Exercise Training
    [A] physically active lifestyle has been shown to lead to higher cognitive performance and delayed or prevented neurological conditions in humans (71, 101, 143, 191). ... The production of brain-derived neurotrophic factor (BDNF), a key protein regulating maintenance and growth of neurons, is known to be stimulated by acute exercise (145), which may contribute to learning and memory. BDNF is released from brain already at rest but increases two- to threefold during exercise, which contributes 70–80% of circulating BDNF (145).
  43. ^ a b c Torres-Aleman I (2010). "Toward a comprehensive neurobiology of IGF-I". Dev Neurobiol 70 (5): 384–96. doi:10.1002/dneu.20778. PMID 20186710. However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I ... An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness 
  44. ^ a b c Aberg D (2010). "Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis". Endocr Dev 17: 63–76. doi:10.1159/000262529. PMID 19955757. The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. ... Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain.  ... GH and IGF-1 have been shown to affect a multitude of mechanisms, including neurogenesis, oligodendrogenesis, angiogenesis, glutamate receptor activation, cholinergic system, dopaminergic reward system, monoamine abundance, dendritic arborization, astrocyte communication via connexin 43, and opioid receptor abundance ... IGF-1 also reaches the brain via both the capillary bed BBB and via the blood-CSF barrier. It appears that IGF-1 uptake is mediated by a specific carrier both in the capillary bed BBB [40] and in the blood-CSF barrier [41, 42]. Moreover, IGF-1 transport across the BBB can be either increased, such as by exercise [43] ... Thus, although not fully characterized, there appear to be mechanisms for transport of both GH and IGF-1 across the BBB. ... Interestingly, exercise is a factor known to enhance cell genesis in the brain, and it appears that IGF-1 is a key mediator of the effect of exercise in terms of cell genesis in the adult brain [52, 53]. ... IGF-1 treatment enhances neurogenesis [52, 53, 55], oligodendrogenesis [56, 58] and angiogenesis [59]. ... As physical exercise has positive effects in many diseases as well as in normal health, it is of interest that circulating IGF-1 as been shown to be one of the mediators of enhanced neurogenesis in the hippocampus. 
  45. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, eds. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 221, 412. ISBN 9780071481274. BDNF, CNTF, insulin-like growth factor-1 (IGF-1), and VEGF have been proven to support motor neuron survival in vitro and in vivo. ... VEGF exerts its effects through two receptor tyrosine kinases, VEGFR1 (also known as flt-1) and VEGFR2 (or flk-1). VEGF and its receptors are expressed in neurons and glia, and this expression is highly up-regulated by hypoxia. The neurotrophic properties of VEGF were first identified when mutations in the VEGF promoter of mice resulted in ALS-like symptoms. Subsequently, VEGF was found to rescue hypoxia-induced motor neuron death both in vivo and in vitro. Recently, a polymorphism in the VEGF promoter sequence was identified in a subset of ALS patients. It is thought that low VEGF levels may underlie motor neuron degeneration in at least one group of patients, but measurement of VEGF in ALS patients has proven difficult. VEGF may also be important for response to stroke and other forms of neural injury. ... One of the prototypical triggers for apoptosis, at least in vitro, is the withdrawal of neurotrophic factors. Neurotrophic factor receptors, such as the TrkA receptor for NGF or the IGF-I receptor for insulin-like growth factor, activate prosurvival signaling cascades 
  46. ^ Gatti R, De Palo EF, Antonelli G, Spinella P (July 2012). "IGF-I/IGFBP system: metabolism outline and physical exercise". J. Endocrinol. Invest. 35 (7): 699–707. doi:10.3275/8456. PMID 22714057. Copeland et al. (90) studied the effect of a moderate-intensity exercise and a high-intensity equal duration intervalled exercise in healthy males. IGF-I and IGFBP-3 increased during both exercise trials, but only the IGFBP-3 area under curve was significantly greater during high-intensity exercise than resting control session. ... Decreased IGF-I and increased IGFBP-1 levels, observed by Rarick et al. (100) after mild aerobic training, might be an adaptive physiological response to prevent hypoglycemia following insulin-sensitizing training. In fact the decrease of circulating IGF-I during short-term training seems to be reflective of favorable neuromuscular anabolic adaptation and is a normal adaptive response to increased physical activity. The potential for exercise-induced increases in circulating IGF-I seems to require longer training duration (100). 
  47. ^ a b Bouchard J, Villeda SA (2015). "Aging and brain rejuvenation as systemic events". J. Neurochem. 132 (1): 5–19. doi:10.1111/jnc.12969. PMC 4301186. PMID 25327899. The beneficial effects of exercise extend beyond peripheral tissues to also include the brain. ... Because of the blood–brain barrier, it was traditionally thought that the beneficial effects of exercise on the CNS were not orchestrated through systemic changes in the periphery. However, recent studies suggest that the effects of exercise are, in part, mediated by changes in the systemic environment. Investigations looking at magnetic resonance imaging (MRI) measurements of cerebral blood volume in the hippocampus have demonstrated that exercise selectively increased the cerebral blood volume of the dentate gyrus, correlating with post-mortem increase in neurogenesis (Pereira et al. 2007). From a molecular perspective, elevated systemic levels of circulating growth factors such as vascular endothelial growth factor and insulin-like growth factor 1 (IGF-1) in blood elicited by increased exercise have been shown to mediate, in part, enhancements in neurogenesis (Trejo et al. 2001; Fabel et al. 2003). Coincidently, circulating levels of IGF-1 decrease with age and the restoration to levels resembling a younger systemic environment up-regulate neurogenesis and improve learning and memory (Lichtenwalner et al. 2001; Darnaudery et al. 2006). 
  48. ^ a b Valkanova V, Eguia Rodriguez R, Ebmeier KP (June 2014). "Mind over matter—what do we know about neuroplasticity in adults?". Int Psychogeriatr 26 (6): 891–909. doi:10.1017/S1041610213002482. PMID 24382194. Control group: Active
    Intervention: Aerobic exercise
    [Increased GMV in:] Lobes (dorsal anterior cingulate cortex, supplementary motor area, middle frontal gyrus bilaterally); R inferior frontal gyrus, middle frontal gyrus and L superior temporal lobe; increase in the volume of anterior white matter tracts ... ↑GMV anterior hippocampus
  49. ^ Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A (July 2011). "Physical activity and memory functions: an interventional study". Neurobiol. Aging 32 (7): 1304–19. doi:10.1016/j.neurobiolaging.2009.08.001. PMID 19716631. 
  50. ^ a b c Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF (February 2011). "Exercise training increases size of hippocampus and improves memory". Proc. Natl. Acad. Sci. U.S.A. 108 (7): 3017–3022. doi:10.1073/pnas.1015950108. PMC 3041121. PMID 21282661. 
  51. ^ a b c d e f g h Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 313–321. ISBN 9780071481274.  • Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.
     • Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...
    These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called “top-down” control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...
    In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.
  52. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 315. ISBN 9780071481274. However, damage to the prefrontal cortex has a significant deleterious effect on social behavior, decision making, and adaptive responding to the changing circumstances of life. ... Several subregions of the prefrontal cortex have been implicated in partly distinct aspects of cognitive control, although these distinctions remain somewhat vaguely defined. The anterior cingulate cortex is involved in processes that require correct decision-making, as seen in conflict resolution (eg, the Stroop test, see in Chapter 16), or cortical inhibition (eg, stopping one task and switching to another). The medial prefrontal cortex is involved in supervisory attentional functions (eg, action-outcome rules) and behavioral flexibility (the ability to switch strategies). The dorsolateral prefrontal cortex, the last brain area to undergo myelination during development in late adolescence, is implicated in matching sensory inputs with planned motor responses. The ventromedial prefrontal cortex seems to regulate social cognition, including empathy. The orbitofrontal cortex is involved in social decision making and in representing the valuations assigned to different experiences. 
  53. ^ Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, eds. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147, 266, 376. ISBN 9780071481274. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. Thus, acting in diverse terminal fields, dopamine confers motivational salience (“wanting”) on the reward itself or associated cues (nucleus accumbens shell region) ... Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward. ... The NAc and VTA are central components of the circuitry underlying reward and memory of reward. ... The NAc is involved in learning associated with reinforcement ... The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc. 
  54. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY, eds. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 148, 324–328, 438. ISBN 9780071481274. [dopamine] helps consolidate multiple forms of memory (amygdala and hippocampus) ... the specific crucial structures underlying the ability to store declarative memories are the hippocampus, the subicular complex, and the entorhinal cortex ... These findings strongly suggest that LTP in the hippocampus is required for at least some forms of learning and memory known to be dependent on this brain region. ... Evidence that the caudate nucleus and putamen influence stimulus-response learning comes from lesion studies in rodents and primates and from neuroimaging studies in humans and from studies of human disease. In Parkinson disease, the dopaminergic innervation of the caudate and putamen is severely compromised by the death of dopamine neurons in the substantia nigra pars compacta (Chapter 17). Patients with Parkinson disease have normal declarative memory ... However, they have marked impairments of stimulus-response learning. Patients with Parkinson disease or other basal ganglia disorders such as Huntington disease (in which caudate neurons themselves are damaged) have deficits in other procedural learning tasks, such as the acquisition of new motor programs. ... Huntington disease is associated with degenerative changes that are most apparent in the caudate nucleus and putamen. 
  55. ^ Grimaldi G, Argyropoulos GP, Bastian A, Cortes M, Davis NJ, Edwards DJ, Ferrucci R, Fregni F, Galea JM, Hamada M, Manto M, Miall RC, Morales-Quezada L, Pope PA, Priori A, Rothwell J, Tomlinson SP, Celnik P (2014). "Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease". Neuroscientist. doi:10.1177/1073858414559409. PMID 25406224. 
  56. ^ Sereno MI, Huang RS (2014). "Multisensory maps in parietal cortex". Curr. Opin. Neurobiol. 24 (1): 39–46. doi:10.1016/j.conb.2013.08.014. PMC 3969294. PMID 24492077. 
  57. ^ a b c d e Diamond A (2013). "Executive functions". Annu Rev Psychol 64: 135–168. doi:10.1146/annurev-psych-113011-143750. PMC 4084861. PMID 23020641. Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking “outside the box,” seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). ... EFs and prefrontal cortex are the first to suffer, and suffer disproportionately, if something is not right in your life. They suffer first, and most, if you are stressed (Arnsten 1998, Liston et al. 2009, Oaten & Cheng 2005), sad (Hirt et al. 2008, von Hecker & Meiser 2005), lonely (Baumeister et al. 2002, Cacioppo & Patrick 2008, Campbell et al. 2006, Tun et al. 2012), sleep deprived (Barnes et al. 2012, Huang et al. 2007), or not physically fit (Best 2010, Chaddock et al. 2011, Hillman et al. 2008). Any of these can cause you to appear to have a disorder of EFs, such as ADHD, when you do not. You can see the deleterious effects of stress, sadness, loneliness, and lack of physical health or fitness at the physiological and neuroanatomical level in prefrontal cortex and at the behavioral level in worse EFs (poorer reasoning and problem solving, forgetting things, and impaired ability to exercise discipline and self-control). ...
    EFs can be improved (Diamond & Lee 2011, Klingberg 2010). ... At any age across the life cycle EFs can be improved, including in the elderly and in infants. There has been much work with excellent results on improving EFs in the elderly by improving physical fitness (Erickson & Kramer 2009, Voss et al. 2011) ... Inhibitory control (one of the core EFs) involves being able to control one’s attention, behavior, thoughts, and/or emotions to override a strong internal predisposition or external lure, and instead do what’s more appropriate or needed. Without inhibitory control we would be at the mercy of impulses, old habits of thought or action (conditioned responses), and/or stimuli in the environment that pull us this way or that. Thus, inhibitory control makes it possible for us to change and for us to choose how we react and how we behave rather than being unthinking creatures of habit. It doesn’t make it easy. Indeed, we usually are creatures of habit and our behavior is under the control of environmental stimuli far more than we usually realize, but having the ability to exercise inhibitory control creates the possibility of change and choice.
  58. ^ a b c Janssen M, Toussaint HM, van Mechelen W, Verhagen EA (2014). "Effects of acute bouts of physical activity on children's attention: a systematic review of the literature". Springerplus 3: 410. doi:10.1186/2193-1801-3-410. PMC 4132441. PMID 25133092. There is weak evidence for the effect of acute bouts of physical activity on attention. ... Fortunately, the literature-base on the acute effect of PA on the underlying cognitive processes of academic performance is growing. Hillman et al. (2011) found in their review a positive effect of acute PA on brain health and cognition in children, but concluded it was complicated to compare the different studies due to the different outcome measures (e.g. memory, response time and accuracy, attention, and comprehension). Therefore, this review focuses on the sole outcome measure ‘attention’ as a mediator for cognition and achievement. 
  59. ^ a b Ilieva IP, Hook CJ, Farah MJ (2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J Cogn Neurosci: 1–21. doi:10.1162/jocn_a_00776. PMID 25591060. 
  60. ^ a b c d Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 14: Mood and Emotion". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 350–359. ISBN 9780071481274. The excessive release of stress hormones, such as cortisol, which occurs in many individuals with mood disorders, may result from hyperfunctioning of the PVN of the hypothalamus, hyperfunctioning of the amygdala (which activates the PVN), or hypofunctioning of the hippocampus (which exerts a potent inhibitory influence on the PVN). ... Chronic stress decreases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, which in turn may contribute to the atrophy of CA3 neurons and their increased vulnerability to a variety of neuronal insults. Chronic elevation of glucocorticoid levels is also known to decrease the survival of these neurons. Such activity may increase the dendritic arborizations and survival of the neurons, or help repair or protect the neurons from further damage. ... Stress and glucocorticoids inhibit, and a wide variety of antidepressant drugs, exercise, and enriched environments activate hippocampal neurogenesis. 
  61. ^ a b c d e Fuqua JS, Rogol AD (July 2013). "Neuroendocrine alterations in the exercising human: implications for energy homeostasis". Metab. Clin. Exp. 62 (7): 911–921. doi:10.1016/j.metabol.2013.01.016. PMID 23415825. Cortisol has wide-ranging effects, including alterations of carbohydrate, protein, and lipid metabolism; catabolic effects on skin, muscle, connective tissue, and bone; immunomodulatory effects; blood pressure and circulatory system regulation; and effects on mood and central nervous system function. In the short term, activation of the HPA axis in response to stress is adaptive. However, long-term stress promoting chronic exposure of tissues to high cortisol concentrations becomes maladaptive. ... Exercise, particularly sustained aerobic activity, is a potent stimulus of cortisol secretion. The circulating concentrations of cortisol are directly proportional to the intensity of exercise as measured by oxygen uptake. As is the case for the GH/IGF-1 and HPG axes, the HPA axis also receives many other inputs, including the light/dark cycle, feeding schedules, immune regulation, and many neurotransmitters that mediate the effects of exercise and physical and psychic stress [52]. ... The HPA is activated by stress, whether physical (exercise) or psychological. ... Thus, a negative net energy balance leads to activation of the HPA axis and the circulating concomitants of the catabolic state in an attempt to keep core processes functional, realizing that the stress of exercise has no effect on cortisol and circulating metabolic substrates beyond the impact of the exercise energy expenditure on energy availability [60]. Thuma et al. [61] had already made the important observation that the reported differences in cortisol levels pre- and post-exercise depended on whether this difference was measured from a single pre-test level or from the physiologic circadian baseline as determined in an independent session in the resting state. By this analytical technique, these investigators showed that increasing energy expenditure led to significant cortisol release. This release was apparent if they subtracted the physiologic circadian baseline from the post-exercise value. 
  62. ^ a b c d Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K (January 2015). "Hormones as "difference makers" in cognitive and socioemotional aging processes". Front Psychol 5: 1595. doi:10.3389/fpsyg.2014.01595. PMC 4302708. PMID 25657633. It is known that chronically elevated levels of the stress hormone cortisol exert neurotoxic effects on the aging brain with negative impacts on cognition and socioemotional functioning. ... Cortisol is a steroid hormone released by the HPA axis in response to challenging situations. As the primary effector of the biological stress response in humans, it is implicated in a diverse array of physiologic, metabolic, immunologic, and psychological processes directed toward successful coping (Sapolsky et al., 2000; Kassel and Herrlich, 2007). Cortisol receptors are well-represented in limbic structures involved in affective response (i.e., hippocampus, hypothalamus, amygdala) and in regions central to executive function such as the prefrontal cortex and anterior cingulate cortex (Dedovic et al., 2009; Joëls and Baram, 2009). As a result, the effects of cortisol extend beyond the stress and threat response system to impact mood, attention, and memory (Lupien and McEwen, 1997; Sapolsky et al., 2000; de Kloet et al., 2005). ... In contrast, evidence indicated positive associations between cortisol levels that were acutely elevated by stress or hydrocortisone administration and inhibitory control (Schlosser et al., 2013) as well as spatial learning (Meyer et al., 2013). Regarding cortisol’s effect on memory, the evidence is currently mixed (Schwabe et al., 2012; van Ast et al., 2013). ... There also is evidence that effects of cortisol on cognition vary in a dose-dependent fashion. In particular, there is evidence of cognitive improvements under conditions of moderate, time-limited cortisol elevation but evidence of cognitive impairments when cortisol concentrations are persistent or excessively high (Lupien et al., 1999; Abercrombie et al., 2003; Hupbach and Fieman, 2012; Schilling et al., 2013; Moriarty et al., 2014). 
  63. ^ a b Zschucke E, Gaudlitz K, Ströhle A (January 2013). "Exercise and physical activity in mental disorders: clinical and experimental evidence". J Prev Med Public Health. 46 Suppl 1: S12–521. doi:10.3961/jpmph.2013.46.S.S12. PMC 3567313. PMID 23412549. In psychiatric patients, different mechanisms of action for PA and EX have been discussed: On a neurochemical and physiological level, a number of acute changes occur during and following bouts of EX, and several long-term adaptations are related to regular EX training. For instance, EX has been found to normalize reduced levels of brain-derived neurotrophic factor (BDNF) and therefore has neuroprotective or even neurotrophic effects [7–9]. Animal studies found EX-induced changes in different neurotransmitters such as serotonin and endorphins [10,11], which relate to mood, and positive effects of EX on stress reactivity (e.g., the hypothalamus-pituitary-adrenal axis [12,13]). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide have been reported [14]. Potential psychological mechanisms of action include learning and extinction, changes in body scheme and health attitudes/behaviors, social reinforcement, experience of mastery, shift of external to more internal locus of control, improved coping strategies, or simple distraction [15,16]. 
  64. ^ "Depression and anxiety: Exercise eases symptoms - Mayo Clinic". Retrieved 2016-04-18. 
  65. ^ a b Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A (2012). "Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'". J. Exp. Biol. 215 (Pt 8): 1331–1336. doi:10.1242/jeb.063677. PMID 22442371. Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. ... Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks 
  66. ^ Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI (2010). "Rowers' high: behavioural synchrony is correlated with elevated pain thresholds". Biol. Lett. 6 (1): 106–108. doi:10.1098/rsbl.2009.0670. PMC 2817271. PMID 19755532. 
  67. ^ a b c d e Szabo A, Billett E, Turner J (2001). "Phenylethylamine, a possible link to the antidepressant effects of exercise?". Br J Sports Med 35 (5): 342–343. doi:10.1136/bjsm.35.5.342. PMC 1724404. PMID 11579070. The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after exercise. ... These results show substantial increases in urinary phenylacetic acid levels 24 hours after moderate to high intensity aerobic exercise. As phenylacetic acid reflects phenylethylamine levels3 , and the latter has antidepressant effects, the antidepressant effects of exercise appear to be linked to increased phenylethylamine concentrations. Furthermore, considering the structural and pharmacological analogy between amphetamines and phenylethylamine, it is conceivable that phenylethylamine plays a role in the commonly reported "runners high" thought to be linked to cerebral β-endorphin activity. The substantial increase in phenylacetic acid excretion in this study implies that phenylethylamine levels are affected by exercise. ... A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid levels in healthy regularly exercising men. The findings may be linked to the antidepressant effects of exercise. 
  68. ^ a b c d e Lindemann L, Hoener MC (2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/ PMID 15860375. The pharmacology of TAs might also contribute to a molecular understanding of the well-recognized antidepressant effect of physical exercise [51]. In addition to the various beneficial effects for brain function mainly attributed to an upregulation of peptide growth factors [52,53], exercise induces a rapidly enhanced excretion of the main β-PEA metabolite β-phenylacetic acid (b-PAA) by on average 77%, compared with resting control subjects [54], which mirrors increased β-PEA synthesis in view of its limited endogenous pool half-life of ~30 s [18,55]. 
  69. ^ a b c d e Berry MD (2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials 2 (1): 3–19. doi:10.2174/157488707779318107. PMID 18473983. It has also been suggested that the antidepressant effects of exercise are due to an exercise-induced elevation of PE [151]. 
  70. ^ a b c d e f Dinas PC, Koutedakis Y, Flouris AD (2011). "Effects of exercise and physical activity on depression". Ir J Med Sci 180 (2): 319–325. doi:10.1007/s11845-010-0633-9. PMID 21076975. According to the 'endorphins hypothesis', exercise augments the secretion of endogenous opioid peptides in the brain, reducing pain and causing general euphoria. ... Based upon a large effect size, the results confirmed the endorphins hypothesis demonstrating that exercise leads to an increased secretion of endorphins which, in turn, improved mood states.
    β-Endorphin, an endogenous μ-opioid receptor selective ligand, has received much attention in the literature linking endorphins and depression or mood states. ... exercise of sufficient intensity and duration can increase circulating β-endorphin levels. ... Moreover, a recent study demonstrated that exercise and physical activity increased β-endorphin levels in plasma with positive effects on mood. Interestingly, the researchers reported that, independently of sex and age, dynamic anaerobic exercises increased β-endorphin, while resistance and aerobic exercises seem to only have small effects on β-endorphins. ... The results showed that mood tends to be higher in a day an individual exercises as well as that daily activity and exercise overall are strongly linked with mood states. In line with these findings, a recent study showed that exercise significantly improved mood states in non-exercises, recreational exercisers, as well as marathon runners. More importantly, the effects of exercise on mood were twofold in recreational exercisers and marathon runners.
  71. ^ a b c d e Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M (2014). "Physical activity and the endocannabinoid system: an overview". Cell. Mol. Life Sci. 71 (14): 2681–2698. doi:10.1007/s00018-014-1575-6. PMID 24526057. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. ... the evidence that PA induces some of the psychotropic effects elicited by the Cannabis sativa active ingredient Δ9-tetrahydrocannabinol (Δ9-THC, Fig. 1), like bliss, euphoria, and peacefulness, strengthened the hypothesis that endocannabinoids (eCBs) might mediate, at least in part, the central and peripheral effects of exercise [14]. ... To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in 2003 by Sparling and coworkers [63], who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of AEA ... A dependence of the increase of AEA concentration on exercise intensity has also been documented. Plasma levels of AEA significantly increased upon 30 min of moderate exercise (heart rate of 72 and 83 %), but not at lower and significantly higher exercise intensities, where the age-adjusted maximal heart rate was 44 and 92 %, respectively ... Several experimental data support the hypothesis that ECS might, at least in part, explain PA effects on brain functions, because: (1) CB1 is the most abundant GPCR in the brain participating in neuronal plasticity [18]; (2) eCBs are involved in several brain responses that greatly overlap with the positive effects of exercise; (3) eCBs are able to cross the blood–brain barrier [95]; and (4) exercise increases eCB plasma levels [64–67]. 
  72. ^ "β-phenylethylamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015. 
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  74. ^ a b Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
    Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
  75. ^ "Physical Activity Reduces Stress | Anxiety and Depression Association of America, ADAA". Retrieved 2016-04-19. 
  76. ^ Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, and Gass P (2015). "A runner’s high depends on cannabinoid receptors in mice". PNAS 112 (42): 13105–13108. doi:10.1073/pnas.1514996112. PMID 26438875. Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner's high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models. 
  77. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 117–130. ISBN 9780071481274.  • The major excitatory neurotransmitter in the brain is glutamate; the major inhibitory neurotransmitter is GABA. ...
     • The most extensively studied form of synaptic plasticity is long-term potentiation (LTP) in the hippocampus, which is triggered by strong activation of NMDA receptors and the consequent large rise in postsynaptic calcium concentration.
     • Long-term depression (LTD), a long-lasting decrease in synaptic strength, also occurs at most excitatory and some inhibitory synapses in the brain. ... The bidirectional control of synaptic strength by LTP and LTD is believed to underlie some forms of learning and memory in the mammalian brain.
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  84. ^ a b Rommel AS, Halperin JM, Mill J, Asherson P, Kuntsi J (September 2013). "Protection from genetic diathesis in attention-deficit/hyperactivity disorder: possible complementary roles of exercise". J. Am. Acad. Child Adolesc. Psychiatry 52 (9): 900–10. doi:10.1016/j.jaac.2013.05.018. PMC 4257065. PMID 23972692. As exercise has been found to enhance neural growth and development, and improve cognitive and behavioural functioning in [healthy] individuals and animal studies, we reviewed the literature on the effects of exercise in children and adolescents with ADHD and animal models of ADHD behaviours.
    A limited number of undersized non-randomized, retrospective and cross-sectional studies have investigated the impact of exercise on ADHD and the emotional, behavioural and neuropsychological problems associated with the disorder. The findings from these studies provide some support for the notion that exercise has the potential to act as a protective factor for ADHD.  ... Although it remains unclear which role, if any, BDNF plays in the pathophysiology of ADHD, enhanced neural functioning has been suggested to be associated with the reduction of remission of ADHD symptoms.49,50,72 As exercise can elicit gene expression changes mediated by alterations in DNA methylation38, the possibility emerges that some of the positive effects of exercise could be caused by epigenetic mechanisms, which may set off a cascade of processes instigated by altered gene expression that could ultimately link to a change in brain function.
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