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
[edit on Wikidata]

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][10] 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][11][12]

In healthy adults, aerobic exercise has been shown to induce transient effects on cognition after a single exercise session and persistent effects on cognition following regular exercise over the course of several months.[1][10][13] 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, declarative memory, spatial memory, and information processing speed.[1][5][7][9][10][13] The transient effects of exercise on cognition include improvements in most executive functions (e.g., attention, working memory, cognitive flexibility, inhibitory control, problem solving, and decision making) and information processing speed for a period of up to 2 hours after exercising.[13]

Aerobic exercise induces short- and long-term effects on mood and emotional states by promoting positive affect, inhibiting negative affect, and decreasing the biological response to acute psychological stress.[13] Over the short-term, aerobic exercise functions as both an antidepressant and euphoriant,[14][15][16][17] whereas consistent exercise produces general improvements in mood and self-esteem.[18][19]

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 and attention deficit hyperactivity disorder.[11][16][20][21][22][23] 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.[24][25][26][27][28] Reviews of clinical evidence also support the use of exercise as an adjunct therapy for certain neurodegenerative disorders, particularly Alzheimer’s disease and Parkinson's disease.[29][30][31][32][33][34] Regular exercise is also associated with a lower risk of developing neurodegenerative disorders.[32][35] Regular exercise has also been proposed as an adjunct therapy for brain cancers.[36]

Long-term effects

Neuroplasticity

Neuroplasticity is the process by which neurons adapt to a disturbance over time, and most often occurs in response to repeated exposure to stimuli.[37] Aerobic exercise increases the production of neurotrophic factors[note 1] (e.g., BDNF, IGF-1, VEGF) 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][18][39][40] Consistent aerobic exercise over a period of several months induces clinically significant improvements in executive functions and increased gray matter volume in nearly all regions of the brain,[41] with the most marked increases occurring in brain regions that 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][42] Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory.[6][8][19][43] Higher physical fitness scores, as measured by VO2 max, are associated with better executive function, faster information processing speed, and greater gray matter 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][44]

BDNF signaling

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 receptor tyrosine kinase, tropomyosin receptor kinase B (TrkB).[4][45][46] Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain.[39] Exercise-induced increases in brain BDNF signaling are associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory.[4][8][18][45] Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair.[5][45] 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][45][46] exercise intensity is positively correlated with the magnitude of increased BDNF biosynthesis and expression.[4][45][46] A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well.[18]

IGF-1 signaling

IGF-1 is a peptide and neurotrophic factor that mediates some of the effects of growth hormone;[47] IGF-1 elicits its physiological effects by binding to a specific receptor tyrosine kinase, the IGF-1 receptor, to control tissue growth and remodeling.[47] In the brain, IGF-1 functions as a neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal survival.[45][48][49] 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][45][47][48] 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".[47][48] The amount of IGF-1 released into blood plasma during exercise is positively correlated with exercise intensity and duration.[50]

VEGF signaling

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.[49] Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons.[49] 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 in the central nervous system.[39][40][51] Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.[5][40][51]

Structural growth

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter volume in nearly all regions of the brain,[41] with more pronounced increases occurring in brain regions associated with memory processing, cognitive control, motor function, and reward;[1][5][6][8][41] 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, the hippocampus, and the cingulate cortex appear to become more functionally interconnected in response to consistent aerobic exercise.[1][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][52] 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][53]

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][54] 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][54] 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.[54] 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][52]

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

Long-term effects on cognition

Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, regular exercise over a period of several months has been shown to persistently improve numerous executive functions and several forms of memory.[5][7][9][61][62][63] In particular, consistent aerobic exercise has been shown to improve attentional control,[note 3] 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][10][61][62] In healthy young and middle-aged adults, the effect sizes of improvements in cognitive function are largest for indices of executive functions and small to moderate for aspects of memory and information processing speed.[1][10] It may be that in older adults, individuals benefit cognitively by taking part in both aerobic and resistance type exercise of at least moderate intensity.[65] Individuals who have a sedentary lifestyle tend to have impaired executive functions relative to other more physically active non-exercisers.[9][61] A reciprocal relationship between exercise and executive functions has also been noted: improvements in executive control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.[9]

Short-term effects

Short-term effects on cognition

In addition to the persistent effects of regular exercise over the course of several months on cognitive functions, acute exercise (i.e., a single bout of exercise) has been shown to transiently improve a number of cognitive functions.[13][66][67] Reviews and meta-analyses of research on the effects of acute exercise in healthy young and middle-aged adults on cognition have concluded that information processing speed and a number of executive functions – including attention, working memory, problem solving, cognitive flexibility, verbal fluency, decision making, and inhibitory control – all improve for a period of up to 2 hours post-exercise.[13][66][67] A systematic review of studies conducted on children also suggested 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.[62]

Psychological stress and cortisol

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors.[68][69][70] Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis).[68][69][70] Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control;[40][69][70] 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.[40][61][70] For example, chronic psychological stress decreases BDNF expression which has detrimental effects on hippocampal volume and can lead to depression.[40][68]

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner;[69] 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][69] Individuals who have recently exercised exhibit improvements in stress coping behaviors.[4][40][44] 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).[13][40][71] 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.[40][68][71]

Euphoria

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.[14][15][72][73] Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically phenethylamine (an endogenous psychostimulant), β-endorphin (an endogenous opioid), and anandamide (an endocannabinoid).[74][75][76][77][78]

Effects on neurochemicals

β-Phenylethylamine

β-Phenylethylamine, commonly referred to as phenethylamine, is a potent human trace amine and neuromodulator which functions as endogenous amphetamine.[note 8][79][80] 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.[74][75][76] Two reviews noted a study where the mean 24 hour urinary β-phenylacetic acid acid concentration following just 30 minutes of intense exercise rose 77% above its base level;[74][75][76] 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.[74][75][76][81] 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.[81]

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.[74][75][76]

β-Endorphin

β-Endorphin (contracted from "endogenous morphine") is an endogenous opioid neuropeptide that binds to μ-opioid receptors, in turn producing euphoria and pain relief.[77] A meta-analytic review found that exercise significantly increases the secretion of β-endorphin and that this secretion is correlated with improved mood states.[77] 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.[77]

A review on β-endorphin 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.[77] Exercise-induced improvements in mood occur in sedentary individuals, recreational exercisers, and marathon runners, but recreational athletes and marathon runners experience more pronounced mood-lifting effects from exercising.[77]

Anandamide

Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors.[78] 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).[78] 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.[78] 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.[72][78]

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.[82][non-primary source needed]

Monoamine neurotransmitters

Glutamate and GABA

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.[83] Based upon animal models, exercise appears to normalize the excessive levels of glutamate neurotransmission into the nucleus accumbens that occurs in drug addiction.[25] 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 this region, in turn reducing sympathetic activity;[84] the review hypothesized that this neuroplasticity in the RVLM is a mechanism by which regular exercise prevents inactivity-related cardiovascular disease.[84]

Acetylcholine

Effects in children

Sibley and Etnier (2003) performed a meta-analysis that looked at the relationship between physical activity and cognitive performance in children.[85] 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.[85] The correlation was strongest for the age ranges of 4–7 and 11–13 years.[85] 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.[86] 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.[87] They concluded that hippocampal volume was positively associated with performance on relational memory tasks.[87] Their findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain.[87] 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.[88] The second is acute exercise, which examines the immediate changes in cognitive functioning after each session.[88] The results of both suggest that aerobic exercise may briefly aid children’s executive function and also influence more lasting improvements to executive function.[88] Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is.[89] 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.[85]

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.[89] Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function.[89] 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.[86]

Effects on central nervous system disorders

Addiction

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.[24][25][26][27][28] 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.[25][26] 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.[28] 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).[25][26] Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction.[25][27] As of 2016, more clinical research is still needed to understand the mechanisms and confirm the efficacy of exercise in drug addiction treatment and prevention.[24][28]

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
(aerobic)
Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs
[26]
Behavioral plasticity
Escalation of intake Yes Yes Yes [26]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [26]
Psychostimulant
self-administration
[26]
Psychostimulant
conditioned place preference
[26]
Reinstatement of drug-seeking behavior [26]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[26]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [26]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [26]
Altered striatal opioid signaling No change or
μ-opioid receptors
μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [26]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [26]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [26]
Dendritic spine density in
the nucleus accumbens
[26]

Attention deficit hyperactivity disorder

Regular physical exercise, particularly aerobic exercise, is an effective add-on treatment for ADHD in children and adults, particularly when combined with stimulant medication (i.e., amphetamine or methylphenidate), although the best intensity and type of aerobic exercise for improving symptoms are not currently known.[22][23][90] In particular, the long-term effects of regular aerobic exercise in ADHD individuals include better behavior and motor abilities, improved executive functions (including attention, inhibitory control, and planning, among other cognitive domains), faster information processing speed, and better memory.[22][23][90] Parent-teacher ratings of behavioral and socio-emotional outcomes in response to regular aerobic exercise include: better overall function, reduced ADHD symptoms, better self-esteem, reduced levels of anxiety and depression, fewer somatic complaints, better academic and classroom behavior, and improved social behavior.[22] Exercising while on stimulant medication augments the effect of stimulant medication on executive function.[22] It is believed that these short-term effects of exercise are mediated by an increased abundance of synaptic dopamine and norepinephrine in the brain.[22]

Major depressive disorder

A number of medical reviews have indicated that exercise has a marked and persistent antidepressant effect in humans,[5][16][17][20][91][92] an effect believed to be mediated through enhanced BDNF signaling in the brain.[8][20] 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.[91] Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment (i.e., treatments that are used together) with antidepressant medication;[20] 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.[16][17] One systematic review noted that yoga may be effective in alleviating symptoms of prenatal depression.[93] 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 which included a 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;[21] nonetheless, it stated that there is clear evidence of efficacy for reducing symptoms of depression.[21] 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.[21] A meta-analysis from July 2016 concluded that physical exercise improves overall quality of life in individuals with depression relative to controls.[11]

Brain cancers

Neurodegenerative disorders

Alzheimer's disease

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.[29][30] 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.[29][30] 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.[29][30] 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.[29][94]

The Caerphilly Prospective study followed 2,375 male subjects over 30 years and examined the association between healthy lifestyles and dementia, among other factors.[95] Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment.[95][96] 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;[35] this review further asserted that increased physical activity appears to be causally related with these reduced risks.[35]

Parkinson's disease

Parkinson's disease (PD) is a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait.[97]

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way.[98] A few studies reported seeing an improvement in brain health and cognitive function due to exercise.[98] 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.[99] 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.[100] 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,[100] providing evidence that such exercise regimens may be beneficial to patients with PD.

See also

Notes

  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.[38]
  2. ^ Adult neurogenesis is the postnatal (after-birth) growth of new neurons, a beneficial form of neuroplasticity.[37]
  3. ^ Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention,[42] 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.[55][64] Inhibitory control allows individuals to control their impulses and habits when necessary or desired,[55][61][64] 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,[42] 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.[55]
  6. ^ Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and events.[58]
  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.

References

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  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 3575139Freely accessible. PMID 21531985. 
  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 4179677Freely accessible. PMID 25324754. 
  10. ^ a b c d e Cox EP, O'Dwyer N, Cook R, Vetter M, Cheng HL, Rooney K, O'Connor H (August 2016). "Relationship between physical activity and cognitive function in apparently healthy young to middle-aged adults: A systematic review". J. Sci. Med. Sport. 19 (8): 616–628. doi:10.1016/j.jsams.2015.09.003. PMID 26552574. A range of validated platforms assessed CF across three domains: executive function (12 studies), memory (four studies) and processing speed (seven studies). ... In studies of executive function, five found a significant ES in favour of higher PA, ranging from small to large. Although three of four studies in the memory domain reported a significant benefit of higher PA, there was only one significant ES, which favoured low PA. Only one study examining processing speed had a significant ES, favouring higher PA.
    CONCLUSIONS: A limited body of evidence supports a positive effect of PA on CF in young to middle-aged adults. Further research into this relationship at this age stage is warranted. ...
    Significant positive effects of PA on cognitive function were found in 12 of the 14 included manuscripts, the relationship being most consistent for executive function, intermediate for memory and weak for processing speed.
     
  11. ^ 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. 
  12. ^ 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. PMC 4897547Freely accessible. 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]. 
  13. ^ a b c d e f g h i j Basso JC, Suzuki WA (March 2017). "The Effects of Acute Exercise on Mood, Cognition, Neurophysiology, and Neurochemical Pathways: A Review". Brain Plasticity. 2 (2): 127–152. doi:10.3233/BPL-160040Freely accessible. Lay summaryCan A Single Exercise Session Benefit Your Brain? (12 June 2012). A large collection of research in humans has shown that a single bout of exercise alters behavior at the level of affective state and cognitive functioning in several key ways. In terms of affective state, acute exercise decreases negative affect, increases positive affect, and decreases the psychological and physiological response to acute stress [28]. These effects have been reported to persist for up to 24 hours after exercise cessation [28, 29, 53]. In terms of cognitive functioning, acute exercise primarily enhances executive functions dependent on the prefrontal cortex including attention, working memory, problem solving, cognitive flexibility, verbal fluency, decision making, and inhibitory control [9]. These positive changes have been demonstrated to occur with very low to very high exercise intensities [9], with effects lasting for up to two hours after the end of the exercise bout (Fig. 1A) [27]. Moreover, many of these neuropsychological assessments measure several aspects of behavior including both accuracy of performance and speed of processing. McMorris and Hale performed a meta-analysis examining the effects of acute exercise on both accuracy and speed of processing, revealing that speed significantly improved post-exercise, with minimal or no effect on accuracy [17]. These authors concluded that increasing task difficulty or complexity may help to augment the effect of acute exercise on accuracy. ... However, in a comprehensive meta-analysis, Chang and colleagues found that exercise intensities ranging from very light (<50% MHR) to very hard (>93% MHR) have all been reported to improve cognitive functioning [9]. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. ...
    Conclusion
    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.
     
  18. ^ 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 4314337Freely accessible. 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. 
  19. ^ 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 3809922Freely accessible. 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. 
  20. ^ 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. ...
    Conclusions
    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.
     
  21. ^ 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 4592762Freely accessible. 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
  22. ^ a b c d e f Den Heijer AE, Groen Y, Tucha L, Fuermaier AB, Koerts J, Lange KW, Thome J, Tucha O (July 2016). "Sweat it out? The effects of physical exercise on cognition and behavior in children and adults with ADHD: a systematic literature review". J. Neural. Transm. (Vienna). doi:10.1007/s00702-016-1593-7. PMID 27400928. 
  23. ^ 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. 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. 
  24. ^ a b c Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC 4745113Freely accessible. PMID 26903885. There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... However, a RTC study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon. [emphasis added] 
  25. ^ 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 3788047Freely accessible. PMID 23806439. 
  26. ^ 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 3139704Freely accessible. 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). 
  27. ^ 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. PMC 4831948Freely accessible. 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. 
  28. ^ 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. 40: 24–41. 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. 
  29. ^ 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. 
  30. ^ 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). 
  31. ^ 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. 
  32. ^ 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. 
  33. ^ 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. 
  34. ^ 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. 
  35. ^ 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 4064273Freely accessible. 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. 
  36. ^ 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 4389372Freely accessible. PMID 25905043. 
  37. ^ 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). 
  38. ^ 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. 
  39. ^ 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 3896879Freely accessible. 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). 
  40. ^ 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. PMC 4142018Freely accessible. PMID 25285199. 
  41. ^ a b c Batouli SH, Saba V (June 2017). "At least eighty percent of brain grey matter is modifiable by physical activity: A review study". Behavioural Brain Research. 332: 204–217. doi:10.1016/j.bbr.2017.06.002. PMID 28600001. The results of this study showed that a large network of brain areas, equal to 82% of the total grey matter volume, were associated with PA. This finding has important implications in utilizing PA as a mediator factor for educational purposes in children, rehabilitation applications in patients, improving the cognitive abilities of the human brain such as in learning or memory, and preventing age-related brain deteriorations. ... There is a significant association between the volume of the brain areas and their corresponding functions. Examples include the association of total and regional brain volumes (BV) with executive function and speed of processing, intelligence, working, verbal and spatial memory, and skill acquisition performance [27–29]. The connections between brain function and structure is due to the neural information processing being dependent on the size, arrangement, and configuration of the neurons, the number and type of the synaptic connections of the neurons, on the quality of their connection with distant neurons, and on the properties of non-neuronal cells such as glia [30]. ... This study showed that PA is positively associating with nearly all brain regions. 
  42. ^ 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. 
  43. ^ 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 3990369Freely accessible. PMID 24748784. 
  44. ^ 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). 
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  49. ^ 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. 
  50. ^ 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). 
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    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
     
  53. ^ 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. 
  54. ^ 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 3041121Freely accessible. PMID 21282661. 
  55. ^ a b c d e f g 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. 
  56. ^ 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. 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. 
  57. ^ 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. 
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  59. ^ 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. 22: 83–97. doi:10.1177/1073858414559409. PMC 4712385Freely accessible. PMID 25406224. 
  60. ^ 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 3969294Freely accessible. PMID 24492077. 
  61. ^ a b c d e Diamond A (2013). "Executive functions". Annu Rev Psychol. 64: 135–168. doi:10.1146/annurev-psych-113011-143750. PMC 4084861Freely accessible. PMID 23020641. 
  62. ^ 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 4132441Freely accessible. 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. 
  63. ^ Moreau D, Kirk IJ, Waldie, KE (2017). "High-intensity training enhances executive function in children in a randomized, placebo-controlled trial". eLife. 6:e25062. doi:10.7554/eLife.25062. PMID 28825973. 
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  65. ^ Northey, Joseph Michael; Cherbuin, Nicolas; Pumpa, Kate Louise; Smee, Disa Jane; Rattray, Ben (2017-03-30). "Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis". Br J Sports Med: bjsports–2016–096587. doi:10.1136/bjsports-2016-096587. ISSN 0306-3674. PMID 28438770. 
  66. ^ a b Basso JC, Shang A, Elman M, Karmouta R, Suzuki WA (November 2015). "Acute Exercise Improves Prefrontal Cortex but not Hippocampal Function in Healthy Adults". Journal of the International Neuropsychological Society : JINS. 21 (10): 791–801. doi:10.1017/S135561771500106X. PMID 26581791. 
  67. ^ a b McMorris T, Hale BJ (December 2012). "Differential effects of differing intensities of acute exercise on speed and accuracy of cognition: a meta-analytical investigation". Brain and Cognition. 80 (3): 338–351. doi:10.1016/j.bandc.2012.09.001. PMID 23064033. 
  68. ^ 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. 
  69. ^ 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. 
  70. ^ 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 4302708Freely accessible. PMID 25657633. 
  71. ^ 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 3567313Freely accessible. 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]. 
  72. ^ 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 
  73. ^ 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 2817271Freely accessible. PMID 19755532. 
  74. ^ 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 1724404Freely accessible. PMID 11579070. The 24 hour mean urinary concentration of phenylacetic acid was increased by 77% after 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. 
  75. ^ 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/j.tips.2005.03.007. 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]. 
  76. ^ 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]. 
  77. ^ 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. 
  78. ^ 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. 
  79. ^ "β-phenylethylamine: Biological activity". Guide to Pharmacology. The International Union of Basic and Clinical Pharmacology. Retrieved 10 February 2015. 
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  81. ^ 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 1.4.3.4) (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 ...
     
  82. ^ 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. PMC 4620874Freely accessible. PMID 26438875. 
  83. ^ 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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  90. ^ 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): 900–910. doi:10.1016/j.jaac.2013.05.018. PMC 4257065Freely accessible. 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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