neurobiological effects of physical exercise

Neuroplasticity is the process by which neurons adapt to a disturbance over time, and most often occurs in response to repeated exposure to stimuli.{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 5, 351 | edition = 2nd}} Aerobic exercise increases the production of neurotrophic factors{{#tag:ref|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.{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 199, 215 | chapter=Chapter 8:Atypical Neurotransmitters | edition = 2nd}}|group="note"}} (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,{{#tag:ref|Adult neurogenesis is the postnatal (after-birth) growth of new neurons, a beneficial form of neuroplasticity.|group="note"}} and other forms of neuroplasticity.{{cite journal |vauthors=Szuhany KL, Bugatti M, Otto MW |date=October 2014 |title=A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor |journal=J Psychiatr Res |volume=60C |pages=56–64 |doi=10.1016/j.jpsychires.2014.10.003 |pmc=4314337 |pmid=25455510}} 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,{{cite journal | vauthors = Batouli SH, Saba V | title = At least eighty percent of brain grey matter is modifiable by physical activity: A review study | journal = Behavioural Brain Research | volume = 332 | pages = 204–217 | date = June 2017 | pmid = 28600001 | doi = 10.1016/j.bbr.2017.06.002 | s2cid = 205895178}} with the most marked increases occurring in brain regions that give rise to executive functions. 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; less significant increases in gray matter volume occur in the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens. 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.{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147–148, 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin}} Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory.{{cite journal |vauthors=Lees C, Hopkins J |year=2013 |title=Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials |journal=Prev Chronic Dis |volume=10 |pages=E174 |doi=10.5888/pcd10.130010 |pmc=3809922 |pmid=24157077}}{{cite journal | vauthors = Carvalho A, Rea IM, Parimon T, Cusack BJ | title = Physical activity and cognitive function in individuals over 60 years of age: a systematic review | journal = Clin Interv Aging | volume = 9 | pages = 661–682 | year = 2014 | pmid = 24748784 | pmc = 3990369 | doi = 10.2147/CIA.S55520 | doi-access = free }} 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.

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter volume in nearly all regions of the brain, with more pronounced increases occurring in brain regions associated with memory processing, cognitive control, motor function, and reward; 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. 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. 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.{{cite journal | vauthors = Valkanova V, Eguia Rodriguez R, Ebmeier KP | title = Mind over matter—what do we know about neuroplasticity in adults? | journal = Int Psychogeriatr | volume = 26 | issue = 6 | pages = 891–909 | date = June 2014 | pmid = 24382194 | doi = 10.1017/S1041610213002482 | s2cid = 20765865| doi-access = free }} 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.{{cite journal |vauthors=Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, Völker K, Ho HV, Mooren F, Knecht S, Flöel A | title = Physical activity and memory functions: an interventional study | journal = Neurobiol. Aging | volume = 32 | issue = 7 | pages = 1304–19 |date=July 2011 | pmid = 19716631 | doi = 10.1016/j.neurobiolaging.2009.08.001 | s2cid = 22238883 }}

Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood. Sedentary adults over age 55 show a 1–2% decline in hippocampal volume annually. 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. 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.{{cite journal |vauthors=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 | title = Exercise training increases size of hippocampus and improves memory | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 7 | pages = 3017–3022 |date=February 2011 | pmid = 21282661 | pmc = 3041121 | doi = 10.1073/pnas.1015950108 | bibcode = 2011PNAS..108.3017E | doi-access = free }} In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function. Aerobic exercise has also been shown to induce growth in the white matter tracts in the anterior corpus callosum, which normally shrink with age.

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

• Caudate nucleus – responsible for stimulus-response learning and inhibitory control; implicated in Parkinson's disease and ADHD{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 148, 324–328, 438 | edition = 2nd}}
• Cerebellum – responsible for motor coordination and motor learning{{cite journal | vauthors = 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 | title = Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease | journal = Neuroscientist | volume = 22 | issue = 1| pages = 83–97 | year = 2014 | pmid = 25406224 | doi = 10.1177/1073858414559409 | pmc=4712385}}
• Hippocampus – responsible for storage and consolidation of declarative memory and spatial memory
• Nucleus accumbens – responsible for incentive salience ("wanting" or desire, the form of motivation associated with reward) and positive reinforcement; implicated in addiction{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 147, 266, 376 | edition = 2nd}}
• Parietal cortex – responsible for sensory perception, working memory, and attention{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 313–321 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control }}{{cite journal | vauthors = Sereno MI, Huang RS | title = Multisensory maps in parietal cortex | journal = Curr. Opin. Neurobiol. | volume = 24 | issue = 1 | pages = 39–46 | year = 2014 | pmid = 24492077 | pmc = 3969294 | doi = 10.1016/j.conb.2013.08.014 }}
• Prefrontal and anterior cingulate cortices – required for the cognitive control of behavior, particularly: working memory, attentional control, decision-making, cognitive flexibility, social cognition, and inhibitory control of behavior;{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | page = 315 | edition = 2nd | chapter = Chapter 13: Higher Cognitive Function and Behavioral Control}} implicated in attention deficit hyperactivity disorder (ADHD) and addiction

{{see also|Executive functions}}

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.{{cite journal |vauthors=Moreau D, Kirk IJ, Waldie, KE | title = High-intensity training enhances executive function in children in a randomized, placebo-controlled trial | journal = eLife | volume = 6:e25062 | year = 2017 | pmid = 28825973 | pmc = 5566451| doi = 10.7554/eLife.25062 | doi-access = free }} In particular, consistent aerobic exercise has been shown to improve attentional control,{{#tag:ref|Attentional control allows an individual to focus their attention on a specific source and ignore other stimuli that compete for one's attention, such as in the cocktail party effect. |group="note"}} information processing speed, cognitive flexibility (e.g., task switching), inhibitory control,{{#tag:ref| 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.{{cite journal | vauthors = Ilieva IP, Hook CJ, Farah MJ | title = Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis | journal = J Cogn Neurosci | volume = 27 | issue = 6| pages = 1–21 | year = 2015 | pmid = 25591060 | doi = 10.1162/jocn_a_00776| s2cid = 15788121 | url = https://repository.upenn.edu/neuroethics_pubs/130 }} Inhibitory control allows individuals to control their impulses and habits when necessary or desired, e.g., to overcome procrastination. |group="note"}} working memory updating and capacity,{{#tag:ref|Working memory is the form of memory used by an individual at any given moment for active information processing, 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.|group="note"}} declarative memory,{{#tag:ref|Declarative memory, also known as explicit memory, is the form of memory that pertains to facts and events.|group="note"}} and spatial memory.{{cite journal | vauthors = Janssen M, Toussaint HM, van Mechelen W, Verhagen EA | title = Effects of acute bouts of physical activity on children's attention: a systematic review of the literature | journal = SpringerPlus | volume = 3 | pages = 410 | year = 2014 | pmid = 25133092 | pmc = 4132441 | doi = 10.1186/2193-1801-3-410| doi-access = free }} 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. 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.{{cite journal | vauthors = Northey JM, Cherbuin N, Pumpa KL, Smee DJ, Rattray B | title = Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis | journal = British Journal of Sports Medicine | volume = 52 | issue = 3 | pages = 154–160 | date = February 2018 | pmid = 28438770 | doi = 10.1136/bjsports-2016-096587 | s2cid = 13553374 | doi-access = free }} Individuals who have a sedentary lifestyle tend to have impaired executive functions relative to other more physically active non-exercisers. 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.

{{Further|Myokine}}

{{expand section|with=an introduction about myokines and how this concept relates to BDNF, IGF-1, VEGF, and other neuroactive biomolecules that penetrate the blood–brain or blood–CSF barriers. General references:{{cite journal | vauthors = Delezie J, Handschin C | title = Endocrine Crosstalk Between Skeletal Muscle and the Brain | journal = Frontiers in Neurology | volume = 9 | pages = 698 | date = 24 August 2018 | pmid = 30197620 | pmc = 6117390 | doi = 10.3389/fneur.2018.00698 | doi-access = free }}{{cite journal | vauthors = Kim S, Choi JY, Moon S, Park DH, Kwak HB, Kang JH | title = Roles of myokines in exercise-induced improvement of neuropsychiatric function | journal = Pflügers Archiv | volume = 471 | issue = 3 | pages = 491–505 | date = March 2019 | pmid = 30627775 | doi = 10.1007/s00424-019-02253-8 | s2cid = 57765282 }}|date=March 2019|small=no}}

{{Further|Brain-derived neurotrophic factor}}

One of the most significant effects of exercise on the brain is increased synthesis and expression of BDNF, a neuropeptide and hormone, resulting in increased signaling through its receptor tyrosine kinase, tropomyosin receptor kinase B (TrkB).{{cite journal |vauthors=Phillips C, Baktir MA, Srivatsan M, Salehi A | title = Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling | journal = Front Cell Neurosci | volume = 8 | pages = 170 | year = 2014 | pmid = 24999318 | pmc = 4064707 | doi = 10.3389/fncel.2014.00170| doi-access = free }}{{cite journal |vauthors=Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J | title = Organ-Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans | journal = Physiology | volume = 29 | issue = 6 | pages = 421–436 | date = November 2014 | pmid = 25362636 | doi = 10.1152/physiol.00067.2013}} Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain. Exercise-induced increases in BDNF signaling are associated with improved cognitive function, improved mood, and improved memory. Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair. 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 BDNF levels; exercise intensity is positively correlated with the magnitude of increased BDNF biosynthesis and expression. A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well. This has important implications for exercise as a mechanism to reduce stress since stress is closely linked with decreased levels of BDNF in the hippocampus. In fact, studies suggest that BDNF contributes to the anxiety-reducing effects of antidepressants. The increase in BDNF levels caused by exercise helps reverse the stress-induced decrease in BDNF which mediates stress in the short term and buffers against stress-related diseases in the long term.{{cite journal | vauthors = Anderson E, Shivakumar G | title = Effects of exercise and physical activity on anxiety | journal = Frontiers in Psychiatry | volume = 4 | pages = 27 | year = 2013 | pmid = 23630504 | pmc = 3632802 | doi = 10.3389/fpsyt.2013.00027 | doi-access = free }}

{{Further|Insulin-like growth factor 1}}

{{abbr|IGF-1|Insulin-like growth factor 1}} is a peptide and neurotrophic factor that mediates some of the effects of growth hormone; IGF-1 elicits its physiological effects by binding to a specific receptor tyrosine kinase, the IGF-1 receptor, to control tissue growth and remodeling. In the brain, IGF-1 functions as a neurotrophic factor that, like {{abbr|BDNF|brain-derived neurotrophic factor}}, plays a significant role in cognition, neurogenesis, and neuronal survival.{{cite journal | vauthors = Aberg D | title = Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis | journal = Endocr Dev | volume = 17 | pages = 63–76 | year = 2010 | pmid = 19955757 | doi = 10.1159/000262529| series = Endocrine Development | isbn = 978-3-8055-9302-1 }}{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 221, 412 | edition = 2nd}} 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;{{cite journal | vauthors = Torres-Aleman I | title = Toward a comprehensive neurobiology of IGF-I | journal = Dev Neurobiol | volume = 70 | issue = 5 | pages = 384–96 | year = 2010 | pmid = 20186710 | doi = 10.1002/dneu.20778 | s2cid = 27947753| doi-access = free }} 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". The amount of IGF-1 released into blood plasma during exercise is positively correlated with exercise intensity and duration.{{cite journal | vauthors = Gatti R, De Palo EF, Antonelli G, Spinella P | title = IGF-I/IGFBP system: metabolism outline and physical exercise | journal = J. Endocrinol. Invest. | volume = 35 | issue = 7 | pages = 699–707 | date = July 2012 | pmid = 22714057 | doi = 10.3275/8456 | s2cid = 22974661}}

{{Further|Vascular endothelial growth factor}}

{{abbr|VEGF|Vascular endothelial growth factor}} 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. Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons. Like {{abbr|BDNF|brain-derived neurotrophic factor}} and {{abbr|IGF-1|Insulin-like growth factor 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.{{cite journal | vauthors = Tarumi T, Zhang R | title = Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise | journal = Front Physiol | volume = 5 | pages = 6 | date = January 2014 | pmid = 24478719 | pmc = 3896879 | doi = 10.3389/fphys.2014.00006| doi-access = free }}{{cite journal | vauthors = Bouchard J, Villeda SA | title = Aging and brain rejuvenation as systemic events | journal = J. Neurochem. | volume = 132 | issue = 1 | pages = 5–19 | year = 2015 | pmid = 25327899 | pmc = 4301186 | doi = 10.1111/jnc.12969}} Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.

{{see also|Executive functions}}

In addition to the persistent effects on cognition that result from several months of daily exercise, acute exercise (i.e., a single bout of exercise) has been shown to transiently improve a number of cognitive functions. Reviews and meta-analyses of research on the effects of acute exercise on cognition in healthy young and middle-aged adults 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.{{cite journal | vauthors = Basso JC, Shang A, Elman M, Karmouta R, Suzuki WA | title = Acute Exercise Improves Prefrontal Cortex but not Hippocampal Function in Healthy Adults | journal = Journal of the International Neuropsychological Society | volume = 21 | issue = 10 | pages = 791–801 | date = November 2015 | pmid = 26581791 | doi = 10.1017/S135561771500106X | doi-access = free }}{{cite journal | vauthors = McMorris T, Hale BJ | title = Differential effects of differing intensities of acute exercise on speed and accuracy of cognition: a meta-analytical investigation | journal = Brain and Cognition | volume = 80 | issue = 3 | pages = 338–351 | date = December 2012 | pmid = 23064033 | doi = 10.1016/j.bandc.2012.09.001 | s2cid = 8320775 }} 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. Other research has suggested immediate performative enhancements during exercise, such as exercise-concurrent improvements in processing speed and accuracy during both visual attention and working memory tasks.{{cite journal | vauthors = Dodwell G, Müller HJ, Töllner T | title = Electroencephalographic evidence for improved visual working memory performance during standing and exercise | journal = British Journal of Psychology | volume = 110 | issue = 2 | pages = 400–427 | date = May 2019 | pmid = 30311188 | doi = 10.1111/bjop.12352 | s2cid = 52960179 | doi-access = free }}{{Cite journal |last1=Dodwell |first1=Gordon |last2=Liesefeld |first2=Heinrich R. |last3=Conci |first3=Markus |last4=Müller |first4=Hermann J. |last5=Töllner |first5=Thomas |date=December 2021 |title=EEG evidence for enhanced attentional performance during moderate-intensity exercise |url=https://onlinelibrary.wiley.com/doi/10.1111/psyp.13923 |journal=Psychophysiology |language=en |volume=58 |issue=12 |pages=e13923 |doi=10.1111/psyp.13923 |pmid=34370887 |s2cid=236969156 |issn=0048-5772}}

{{Anchor|Euphoria}}

{{Main|Runner's high}}

Continuous exercise can produce a transient state of euphoria – an emotional state involving the experience of pleasure and 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.{{cite journal |vauthors=Cunha GS, Ribeiro JL, Oliveira AR |date=June 2008 |title=[Levels of beta-endorphin in response to exercise and overtraining] |journal=Arq Bras Endocrinol Metabol |language=pt |volume=52 |issue=4 |pages=589–598 |doi=10.1590/S0004-27302008000400004 |pmid=18604371 |doi-access=free|hdl=10183/40053 |hdl-access=free }}{{cite journal |vauthors=Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR |year=2008 |title=The runner's high: opioidergic mechanisms in the human brain |journal=Cereb. Cortex |volume=18 |issue=11 |pages=2523–2531 |doi=10.1093/cercor/bhn013 |pmid=18296435 |quote=The runner's high describes an euphoric state resulting from long-distance running. |doi-access=free}}{{cite journal | vauthors = Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A | title = Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high' | journal = J. Exp. Biol. | volume = 215 | issue = Pt 8 | pages = 1331–1336 | year = 2012 | pmid = 22442371 | doi = 10.1242/jeb.063677 | s2cid = 5129200| doi-access = free | bibcode = 2012JExpB.215.1331R }}{{cite journal | vauthors = Cohen EE, Ejsmond-Frey R, Knight N, Dunbar RI | title = Rowers' high: behavioural synchrony is correlated with elevated pain thresholds | journal = Biol. Lett. | volume = 6 | issue = 1 | pages = 106–108 | year = 2010 | pmid = 19755532 | pmc = 2817271 | doi = 10.1098/rsbl.2009.0670 }} Not everyone experiences this.{{Cite news |last=Friedman |first=Danielle |date=2024-07-30 |title=How to Optimize Your Workout to Boost Your Mood |url=https://www.nytimes.com/2024/07/30/well/move/exercise-boost-mood.html |access-date=2025-01-29 |work=The New York Times |language=en-US |issn=0362-4331}}

{{Catecholamine and trace amine biosynthesis|align=right}}

β-Phenylethylamine, commonly referred to as phenethylamine, is a human trace amine and potent catecholaminergic and glutamatergic neuromodulator that has similar psychostimulant and euphoriant effects and a similar chemical structure to amphetamine.{{cite journal | vauthors = Berry MD, Gainetdinov RR, Hoener MC, Shahid M | title = Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges | journal = Pharmacology & Therapeutics | volume = 180 | pages = 161–180 | date = December 2017 | pmid = 28723415 | doi = 10.1016/j.pharmthera.2017.07.002 | s2cid = 207366162| doi-access = free }} Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary {{nowrap|β-phenylacetic acid}}, the primary metabolite of phenethylamine.{{cite journal | vauthors = Szabo A, Billett E, Turner J | title = Phenylethylamine, a possible link to the antidepressant effects of exercise? | journal = Br J Sports Med | volume = 35 | issue = 5 | pages = 342–343 | year = 2001 | pmid = 11579070 | pmc = 1724404 | doi = 10.1136/bjsm.35.5.342}}{{cite journal | vauthors = Lindemann L, Hoener MC | title = A renaissance in trace amines inspired by a novel GPCR family | journal = Trends Pharmacol. Sci. | volume = 26 | issue = 5 | pages = 274–281 | year = 2005 | pmid = 15860375 | doi = 10.1016/j.tips.2005.03.007}}{{cite journal | vauthors = Berry MD | title = The potential of trace amines and their receptors for treating neurological and psychiatric diseases | journal = Rev Recent Clin Trials | volume = 2 | issue = 1 | pages = 3–19 | year = 2007 | pmid = 18473983 | doi = 10.2174/157488707779318107| citeseerx = 10.1.1.329.563 }} Two reviews noted a study where the average 24 hour urinary {{nowrap|β-phenylacetic acid}} concentration among participants following just 30 minutes of intense exercise increased by 77% relative to baseline concentrations in resting control subjects; the reviews suggest that phenethylamine synthesis sharply increases while an individual is exercising, during which time it is rapidly metabolized due to its short half-life of roughly 30 seconds. In a resting state, phenethylamine is synthesized in catecholamine neurons from {{nowrap|{{smallcaps all|L}}-phenylalanine}} by aromatic amino acid decarboxylase (AADC) at approximately the same rate at which dopamine is produced.{{cite journal | vauthors= Broadley KJ | title = The vascular effects of trace amines and amphetamines | journal = Pharmacol. Ther. | volume = 125 | issue = 3 | pages = 363–375 |date=March 2010 | pmid = 19948186 | doi = 10.1016/j.pharmthera.2009.11.005}}

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.

β-Endorphin (contracted from "endogenous morphine") is an endogenous opioid neuropeptide that binds to μ-opioid receptors, in turn producing euphoria and pain relief.{{cite journal | vauthors = Dinas PC, Koutedakis Y, Flouris AD | title = Effects of exercise and physical activity on depression | journal = Ir J Med Sci | volume = 180 | issue = 2 | pages = 319–325 | year = 2011 | pmid = 21076975 | doi = 10.1007/s11845-010-0633-9 | s2cid = 40951545}} A meta-analytic review found that exercise significantly increases the secretion of {{nowrap|β-endorphin}} and that this secretion is correlated with improved mood states. Moderate intensity exercise produces the greatest increase in {{nowrap|β-endorphin}} synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in {{nowrap|β-endorphin}} synthesis. A review on {{nowrap|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.

However, human studies showed that pharmacological blockade of endogenous endorphins does not inhibit a runner's high, while blockade of endocannabinoids may have such an effect.{{cite journal | vauthors = Siebers M, Biedermann SV, Bindila L, Lutz B, Fuss J | title = Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans | journal = Psychoneuroendocrinology | volume = 126 | pages = 105173 | date = April 2021 | pmid = 33582575 | doi = 10.1016/j.psyneuen.2021.105173| s2cid = 231858251 }}

Anandamide is an endogenous cannabinoid and retrograde neurotransmitter that binds to cannabinoid receptors (primarily CB₁), in turn producing euphoria.{{cite journal | vauthors = Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M | title = Physical activity and the endocannabinoid system: an overview | journal = Cell. Mol. Life Sci. | volume = 71 | issue = 14 | pages = 2681–2698 | year = 2014 | pmid = 24526057 | doi = 10.1007/s00018-014-1575-6 | s2cid = 14531019| pmc = 11113821 }} 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). 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. 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.

Image:HPA Axis Diagram (Brian M Sweis 2012).svg|alt=Diagram of the HPA axis]]

{{See also|Effects of stress on memory}}

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors. Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis).{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 350–359 | chapter = Chapter 14: Mood and Emotion | edition = 2nd}}{{cite journal | vauthors = Fuqua JS, Rogol AD | title = Neuroendocrine alterations in the exercising human: implications for energy homeostasis | journal = Metab. Clin. Exp. | volume = 62 | issue = 7 | pages = 911–921 | date = July 2013 | pmid = 23415825 | doi = 10.1016/j.metabol.2013.01.016}} Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control; 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.{{cite journal | vauthors = Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K | title = Hormones as 'difference makers' in cognitive and socioemotional aging processes | journal = Front Psychol | volume = 5 | pages = 1595 | date = January 2015 | pmid = 25657633 | pmc = 4302708 | doi = 10.3389/fpsyg.2014.01595| doi-access = free }} For example, chronic psychological stress decreases {{abbr|BDNF|brain-derived neurotrophic factor}} expression, which has detrimental effects on hippocampal volume and can lead to depression.

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner; 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.{{#tag:ref|In healthy individuals, this energy deficit resolves simply from eating and drinking a sufficient amount of food and beverage after exercising.|group="note"}} Aerobic exercise increases physical fitness and lowers neuroendocrine (i.e., {{abbr|HPA axis|hypothalamic–pituitary–adrenal axis}}) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated heart rate response).{{cite journal |vauthors=Zschucke E, Gaudlitz K, Ströhle A | title = Exercise and physical activity in mental disorders: clinical and experimental evidence | journal = J Prev Med Public Health | volume = 46 | pages = S12–521 | date = January 2013 | issue = Suppl 1 | pmid = 23412549 | pmc = 3567313 | doi = 10.3961/jpmph.2013.46.S.S12}} Exercise also reverses stress-induced decreases in {{abbr|BDNF|brain-derived neurotrophic factor}} expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.

{{expand section||date=June 2017}}

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.{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 117–130 | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids}} Based upon animal models, exercise appears to normalize the excessive levels of glutamate neurotransmission into the nucleus accumbens that occurs in drug addiction. 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;{{cite journal | vauthors = Mischel NA, Subramanian M, Dombrowski MD, Llewellyn-Smith IJ, Mueller PJ | title = (In)activity-related neuroplasticity in brainstem control of sympathetic outflow: unraveling underlying molecular, cellular, and anatomical mechanisms | journal = Am. J. Physiol. Heart Circ. Physiol. | volume = 309 | issue = 2 | pages = H235–43 | date = May 2015 | pmid = 25957223 | doi = 10.1152/ajpheart.00929.2014 | pmc=4504968}} the review hypothesized that this neuroplasticity in the RVLM is a mechanism by which regular exercise prevents inactivity-related cardiovascular disease.

Exerkines are putative "signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways".{{cite journal | vauthors = Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S, Febbraio MA, Galis ZS, Gao Y, Haus JM, Lanza IR, Lavie CJ, Lee CH, Lucia A, Moro C, Pandey A, Robbins JM, Stanford KI, Thackray AE, Villeda S, Watt MJ, Xia A, Zierath JR, Goodpaster BH, Snyder MP | display-authors = 3 | title = Exerkines in health, resilience and disease | journal = Nature Reviews. Endocrinology | volume = 18 | issue = 5 | pages = 273–289 | date = May 2022 | pmid = 35304603 | pmc = 9554896 | doi = 10.1038/s41574-022-00641-2 }}

{{more medical citations needed|section|date=February 2015}}

Engaging in active physical pursuits has demonstrated positive effects on the mental health of children and adolescents,{{Cite journal|display-authors=3 |last1=Strong |first1=William B. |last2=Malina |first2=Robert M. |last3=Blimkie |first3=Cameron J.R. |last4=Daniels |first4=Stephen R. |last5=Dishman |first5=Rodney K. |last6=Gutin |first6=Bernard |last7=Hergenroeder |first7=Albert C. |last8=Must |first8=Aviva |last9=Nixon |first9=Patricia A. |last10=Pivarnik |first10=James M. |last11=Rowland |first11=Thomas |last12=Trost |first12=Stewart |last13=Trudeau |first13=François |date=June 2005 |title=Evidence Based Physical Activity for School-age Youth |url=http://dx.doi.org/10.1016/j.jpeds.2005.01.055 |journal=The Journal of Pediatrics |volume=146 |issue=6 |pages=732–737 |doi=10.1016/j.jpeds.2005.01.055 |pmid=15973308 |issn=0022-3476}} enhances their academic performance,{{Cite journal |date=2002 |title=Physical activity levels among children aged 9-13 years: United States, 2002. |url=http://dx.doi.org/10.1037/e303072004-001 |access-date=2023-12-08 |website=PsycEXTRA Dataset|doi=10.1037/e303072004-001 }} boosts cognitive function,{{Cite journal |last1=Ebbeling |first1=Cara B |last2=Pawlak |first2=Dorota B |last3=Ludwig |first3=David S |date=August 2002 |title=Childhood obesity: public-health crisis, common sense cure |url=http://dx.doi.org/10.1016/s0140-6736(02)09678-2 |journal=The Lancet |volume=360 |issue=9331 |pages=473–482 |doi=10.1016/s0140-6736(02)09678-2 |pmid=12241736 |s2cid=6374501 |issn=0140-6736}} and diminishes the likelihood of obesity and cardiovascular diseases among this demographic.{{Cite book |last1=Ward |first1=Dianne Stanton |last2=Saunders |first2=Ruth P. |last3=Pate |first3=Russell R. |date=2007 |title=Physical Activity Interventions in Children and Adolescents |url=http://dx.doi.org/10.5040/9781492596868 |doi=10.5040/9781492596868|isbn=9781492596868 }} Establishing consistent exercise routines with regular frequency and duration is pivotal.{{Cite journal |last1=van Sluijs |first1=Esther M F |last2=McMinn |first2=Alison M |last3=Griffin |first3=Simon J |date=2007-09-20 |title=Effectiveness of interventions to promote physical activity in children and adolescents: systematic review of controlled trials |journal=BMJ |volume=335 |issue=7622 |pages=703 |doi=10.1136/bmj.39320.843947.be |pmid=17884863 |s2cid=5659723 |issn=0959-8138|doi-access=free |pmc=2001088 }}{{Cite journal |last1=Pate |first1=Russell R. |last2=Trost |first2=Stewart G. |last3=Mullis |first3=Rebecca |last4=Sallis |first4=James F. |last5=Wechsler |first5=Howell |last6=Brown |first6=David R. |date=August 2000 |title=Community Interventions to Promote Proper Nutrition and Physical Activity among Youth |url=http://dx.doi.org/10.1006/pmed.2000.0632 |journal=Preventive Medicine |volume=31 |issue=2 |pages=S138–S149 |doi=10.1006/pmed.2000.0632 |issn=0091-7435}}{{Cite journal |last1=Stone |first1=Elaine J |last2=McKenzie |first2=Thomas L |last3=Welk |first3=Gregory J |last4=Booth |first4=Michael L |date=November 1998 |title=Effects of physical activity interventions in youth |url=http://dx.doi.org/10.1016/s0749-3797(98)00082-8 |journal=American Journal of Preventive Medicine |volume=15 |issue=4 |pages=298–315 |doi=10.1016/s0749-3797(98)00082-8 |pmid=9838974 |issn=0749-3797}} Cultivating beneficial exercise habits and sustaining adequate physical activity may support the overall physical and mental well-being of young individuals. Therefore, identifying factors that either impede or encourage exercise behaviors could be a significant strategy in promoting the development of healthy exercise habits among children and adolescents.

A 2003 meta-analysis found a positive effect of exercise in children on perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests, and academic readiness.{{cite journal | vauthors = Sibley BA, Etnier JL |title=The Relationship between Physical Activity and Cognition in Children: A Meta-Analysis |journal=Pediatric Exercise Science |date=August 2003 |volume=15 |issue=3 |pages=243–256 |doi=10.1123/pes.15.3.243 |s2cid=56815489 }} The correlation was strongest for the age ranges of 4–7 and 11–13 years.

A 2010 meta-analysis of the effect of activity on children's executive function found that aerobic exercise may briefly aid children's executive function and also influence more lasting improvements to executive function.{{cite journal | vauthors = Best JR | title = Effects of Physical Activity on Children's Executive Function: Contributions of Experimental Research on Aerobic Exercise | journal = Developmental Review | volume = 30 | issue = 4 | pages = 331–551 | date = December 2010 | pmid = 21818169 | pmc = 3147174 | doi = 10.1016/j.dr.2010.08.001 }} Other studies suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is.{{cite journal | vauthors = Hillman CH, Erickson KI, Kramer AF | title = Be smart, exercise your heart: exercise effects on brain and cognition | journal = Nature Reviews. Neuroscience | volume = 9 | issue = 1 | pages = 58–65 | date = January 2008 | pmid = 18094706 | doi = 10.1038/nrn2298 | s2cid = 1204039 }} 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.

Another study found that sixth-graders who participated in vigorous physical activity at least three times a week had the highest scores compared to those who participated in moderate or no physical activity at all. Children who participated in vigorous physical activity scored three points higher, on average, on their academic test, which consisted of math, science, English, and world studies.{{cite journal | vauthors = Coe DP, Pivarnik JM, Womack CJ, Reeves MJ, Malina RM | title = Effect of physical education and activity levels on academic achievement in children | journal = Medicine and Science in Sports and Exercise | volume = 38 | issue = 8 | pages = 1515–1519 | date = August 2006 | pmid = 16888468 | doi = 10.1249/01.mss.0000227537.13175.1b | s2cid = 9676116 | doi-access = free }}

Neuroimaging studies indicate that exercise may influence changes in brain structure and function. Some investigations have linked low levels of aerobic fitness in children with impaired executive function when older as adults, but lack of selective attention, response inhibition, and interference control may also explain this outcome.{{cite journal | vauthors = Chaddock L, Hillman CH, Buck SM, Cohen NJ | title = Aerobic fitness and executive control of relational memory in preadolescent children | journal = Medicine and Science in Sports and Exercise | volume = 43 | issue = 2 | pages = 344–349 | date = February 2011 | pmid = 20508533 | doi = 10.1249/MSS.0b013e3181e9af48 | s2cid = 400283 | doi-access = free }}

{{See also|Central nervous system disorders}}

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, and psychostimulant addiction in particular. Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) may reduce drug addiction risk, which appears to occur through the reversal of drug-induced, addiction-related neuroplasticity. 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). Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction. {{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.

{{FOSB addiction table|Table title=Summary of addiction-related plasticity}}

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.{{cite journal | vauthors = Rommel AS, Halperin JM, Mill J, Asherson P, Kuntsi J | title = Protection from genetic diathesis in attention-deficit/hyperactivity disorder: possible complementary roles of exercise | journal = J. Am. Acad. Child Adolesc. Psychiatry | volume = 52 | issue = 9 | pages = 900–910 | date = September 2013 | pmid = 23972692 | pmc = 4257065 | doi = 10.1016/j.jaac.2013.05.018}} 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. 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. Exercising while on stimulant medication augments the effect of stimulant medication on executive function. It is believed that these short-term effects of exercise are mediated by an increased abundance of synaptic dopamine and norepinephrine in the brain.

Numerous systematic reviews and meta-analyses have indicated that exercise has a marked and persistent antidepressant effect in humans,{{Cite journal |vauthors=Noetel M, Sanders T, Gallardo-Gómez D, Taylor P, Del Pozo Cruz B, van den Hoek D, Smith JJ, Mahoney J, Spathis J, Moresi M, Pagano R, Pagano L, Vasconcellos R, Arnott H, Varley B, Parker P, Biddle S, Lonsdale C |date=2024-02-14 |title=Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials |journal=BMJ (Clinical Research Ed.) |volume=384 |pages=e075847 |doi=10.1136/bmj-2023-075847 |pmc=10870815 |pmid=38355154 |doi-access=free}}{{cite journal |vauthors=Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB |year=2014 |title=Physical activity interventions for people with mental illness: a systematic review and meta-analysis |journal=J Clin Psychiatry |volume=75 |issue=9 |pages=964–974 |doi=10.4088/JCP.13r08765 |pmid=24813261}} an effect believed to be mediated through enhanced {{abbr|BDNF|brain-derived neurotrophic factor}} signaling in the brain. Several systematic reviews have analyzed the potential for physical exercise in the treatment of depressive disorders. The 2013 Cochrane Collaboration review on {{no selflink|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.{{cite journal | vauthors = Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE | title = Exercise for depression | journal = Cochrane Database Syst. Rev. | volume = 2013 | issue = 9 | pages = CD004366 | date = September 2013 | pmid = 24026850 | doi = 10.1002/14651858.CD004366.pub6 | pmc = 9721454}} 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; 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. A 2016 meta-analysis concluded that physical exercise improves overall quality of life in individuals with depression relative to controls. One systematic review noted that yoga may be effective in alleviating symptoms of prenatal depression.{{cite journal | vauthors = Gong H, Ni C, Shen X, Wu T, Jiang C | title = Yoga for prenatal depression: a systematic review and meta-analysis | journal = BMC Psychiatry | volume = 15 | pages = 14 | date = February 2015 | pmid = 25652267 | pmc = 4323231 | doi = 10.1186/s12888-015-0393-1 | doi-access = free }} 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. These benefits have also been noted in old age, with a review conducted in 2019 finding that exercise is an effective treatment for clinically diagnosed depression in older adults.{{cite journal | vauthors= Miller KJ, Gonçalves-Bradley DC, Areerob P, Hennessy D, Mesagno C, Grace F | year = 2020 | title = Comparative effectiveness of three exercise types to treat clinical depression in older adults: A systematic review and network meta-analysis of randomised controlled trials | url = http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/172086| journal = Ageing Research Reviews | volume = 58 | pages = 100999 | pmid = 31837462 | doi = 10.1016/j.arr.2019.100999 | hdl = 1959.17/172086 | s2cid = 209179889 }}

A 2024 systematic review and network meta-analysis of 218 randomized controlled trials involving over 14,000 participants found that various forms of exercise, including walking or jogging, yoga, resistance training, and mixed aerobic activities, were associated with reductions in depressive symptoms. The review observed that the effects of exercise were comparable to those of psychotherapy and pharmacotherapy, with more intensive exercise yielding greater benefits. Resistance training was identified as particularly effective for younger individuals, while yoga appeared to be more beneficial for older adults. While confidence in the findings was limited by methodological concerns in the included studies, the review noted that exercise produced significant improvements in symptoms across a wide range of participants and treatment contexts.

Physical exercise plays a significant role in the prevention and management of stroke. It is well established that physical activity decrease the risk of ischemic stroke and intracerebral haemorrhage.{{cite journal | vauthors = O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, Czlonkowska A, Weimar C, Wang X, Yusuf S | display-authors = 6 | title = Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study | journal = Lancet | volume = 376 | issue = 9735 | pages = 112–123 | date = July 2010 | pmid = 20561675 | doi = 10.1016/s0140-6736(10)60834-3 | s2cid = 2753073 }}{{cite journal | vauthors = Lee CD, Folsom AR, Blair SN | title = Physical activity and stroke risk: a meta-analysis | journal = Stroke | volume = 34 | issue = 10 | pages = 2475–2481 | date = October 2003 | pmid = 14500932 | doi = 10.1161/01.STR.0000091843.02517.9D | s2cid = 2332015 | doi-access = free }}{{Cite journal |last1=Viktorisson |first1=Adam |last2=Palstam |first2=Annie |last3=Nyberg |first3=Fredrik |last4=Berg |first4=Christina |last5=Lissner |first5=Lauren |last6=Sunnerhagen |first6=Katharina S. |date=2024-05-29 |title=Domain-Specific Physical Activity and Stroke in Sweden |journal=JAMA Network Open |language=en |volume=7 |issue=5 |pages=e2413453 |doi=10.1001/jamanetworkopen.2024.13453 |pmid=38809556 |issn=2574-3805|pmc=11137634 }} Engaging in physical activity before experiencing a stroke has been found to have a positive impact on the severity and outcomes of stroke.{{cite journal | vauthors = Viktorisson A, Reinholdsson M, Danielsson A, Palstam A, Sunnerhagen KS | title = Pre-stroke physical activity in relation to post-stroke outcomes - linked to the International Classification of Functioning, Disability and Health (ICF): A scoping review | journal = Journal of Rehabilitation Medicine | volume = 54 | pages = jrm00251 | date = January 2022 | pmid = 34904691 | pmc = 8862654 | doi = 10.2340/jrm.v53.51 }} Exercise has the potential to increase the expression of VEGF, caveolin, and angiopoietin in the brain. These changes may promote angiogenesis and neovascularization that contribute to improved blood supply to the stroke affected areas of the brain.{{cite journal | vauthors = Ding YH, Luan XD, Li J, Rafols JA, Guthinkonda M, Diaz FG, Ding Y | title = Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke | journal = Current Neurovascular Research | volume = 1 | issue = 5 | pages = 411–420 | date = December 2004 | pmid = 16181089 | doi = 10.2174/1567202043361875 | s2cid = 22015361 }}{{cite journal | vauthors = Rezaei R, Nasoohi S, Haghparast A, Khodagholi F, Bigdeli MR, Nourshahi M | title = High intensity exercise preconditioning provides differential protection against brain injury following experimental stroke | journal = Life Sciences | volume = 207 | pages = 30–35 | date = August 2018 | pmid = 29522768 | doi = 10.1016/j.lfs.2018.03.007 | s2cid = 3812671 }}{{cite journal | vauthors = Gao Y, Zhao Y, Pan J, Yang L, Huang T, Feng X, Li C, Liang S, Zhou D, Liu C, Tu F, Tao C, Chen X | display-authors = 6 | title = Treadmill exercise promotes angiogenesis in the ischemic penumbra of rat brains through caveolin-1/VEGF signaling pathways | journal = Brain Research | volume = 1585 | pages = 83–90 | date = October 2014 | pmid = 25148708 | doi = 10.1016/j.brainres.2014.08.032 | s2cid = 25507984 }} Exercise may affect the activation of endothelial nitric oxide synthase (eNOS) and subsequent production of nitric oxide (NO).{{cite journal | vauthors = Endres M, Gertz K, Lindauer U, Katchanov J, Schultze J, Schröck H, Nickenig G, Kuschinsky W, Dirnagl U, Laufs U | display-authors = 6 | title = Mechanisms of stroke protection by physical activity | journal = Annals of Neurology | volume = 54 | issue = 5 | pages = 582–590 | date = November 2003 | pmid = 14595647 | doi = 10.1002/ana.10722 | s2cid = 28445967 }}{{cite journal | vauthors = Gertz K, Priller J, Kronenberg G, Fink KB, Winter B, Schröck H, Ji S, Milosevic M, Harms C, Böhm M, Dirnagl U, Laufs U, Endres M | display-authors = 6 | title = Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow | journal = Circulation Research | volume = 99 | issue = 10 | pages = 1132–1140 | date = November 2006 | pmid = 17038638 | doi = 10.1161/01.RES.0000250175.14861.77 | s2cid = 9063866 | doi-access = free }}{{cite journal | vauthors = Hafez S, Khan MB, Awad ME, Wagner JD, Hess DC | title = Short-Term Acute Exercise Preconditioning Reduces Neurovascular Injury After Stroke Through Induced eNOS Activation | journal = Translational Stroke Research | volume = 11 | issue = 4 | pages = 851–860 | date = August 2020 | pmid = 31858409 | doi = 10.1007/s12975-019-00767-y | s2cid = 255954922 }} The increase in NO production may lead to improved post-stroke cerebral blood flow, ensuring a sufficient oxygen and nutrient supply to the brain. Physical activity has been associated with increased expression and activation of hypoxia-inducible factor 1 alpha (HIF-1α), heat shock proteins, and brain-derived neurotrophic factor (BDNF).{{cite journal | vauthors = Sharp FR, Bernaudin M | title = HIF1 and oxygen sensing in the brain | journal = Nature Reviews. Neuroscience | volume = 5 | issue = 6 | pages = 437–448 | date = June 2004 | pmid = 15152194 | doi = 10.1038/nrn1408 | s2cid = 318020 }}{{cite journal | vauthors = Dornbos D, Ding Y | title = Mechanisms of neuronal damage and neuroprotection underlying ischemia/reperfusion injury after physical exercise | journal = Current Drug Targets | volume = 13 | issue = 2 | pages = 247–262 | date = February 2012 | pmid = 22204323 | doi = 10.2174/138945012799201658 }}{{cite journal | vauthors = Wang L, Deng W, Yuan Q, Yang H | title = Exercise preconditioning reduces ischemia reperfusion-induced focal cerebral infarct volume through up-regulating the expression of HIF-1α | journal = Pakistan Journal of Pharmaceutical Sciences | volume = 28 | issue = 2 Suppl | pages = 791–798 | date = March 2015 | pmid = 25796156 | url = https://pubmed.ncbi.nlm.nih.gov/25796156 }} These factors play crucial roles in promoting cellular survival, neuroprotection, and repair processes in the brain following a stroke. Exercise also inhibit glutamate and caspase activities, which are involved in neuronal death pathways.{{cite journal | vauthors = Jia J, Hu YS, Wu Y, Liu G, Yu HX, Zheng QP, Zhu DN, Xia CM, Cao ZJ | display-authors = 6 | title = Pre-ischemic treadmill training affects glutamate and gamma aminobutyric acid levels in the striatal dialysate of a rat model of cerebral ischemia | journal = Life Sciences | volume = 84 | issue = 15–16 | pages = 505–511 | date = April 2009 | pmid = 19302809 | doi = 10.1016/j.lfs.2009.01.015 }}{{cite journal | vauthors = Zhang F, Wu Y, Jia J, Hu YS | title = Pre-ischemic treadmill training induces tolerance to brain ischemia: involvement of glutamate and ERK1/2 | journal = Molecules | volume = 15 | issue = 8 | pages = 5246–5257 | date = August 2010 | pmid = 20714296 | pmc = 6257775 | doi = 10.3390/molecules15085246 | doi-access = free }}{{cite journal | vauthors = Yang X, He Z, Zhang Q, Wu Y, Hu Y, Wang X, Li M, Wu Z, Guo Z, Guo J, Jia J | display-authors = 6 | title = Pre-ischemic treadmill training for prevention of ischemic brain injury via regulation of glutamate and its transporter GLT-1 | journal = International Journal of Molecular Sciences | volume = 13 | issue = 8 | pages = 9447–9459 | date = 2012-07-26 | pmid = 22949807 | pmc = 3431805 | doi = 10.3390/ijms13089447 | doi-access = free }}{{cite journal | vauthors = Aboutaleb N, Shamsaei N, Khaksari M, Erfani S, Rajabi H, Nikbakht F | title = Pre-ischemic exercise reduces apoptosis in hippocampal CA3 cells after cerebral ischemia by modulation of the Bax/Bcl-2 proteins ratio and prevention of caspase-3 activation | journal = The Journal of Physiological Sciences | volume = 65 | issue = 5 | pages = 435–443 | date = September 2015 | pmid = 26012958 | doi = 10.1007/s12576-015-0382-7 | s2cid = 255606303 | doi-access = free | pmc = 10717499 }} Additionally, it may promote neurogenesis in the brain. These effects collectively contribute to the reduction of brain infarction and edema, leading to potential improvements in neurological and functional outcomes. The neuroprotective properties of physical activity in relation to haemorrhagic strokes are less studied. Pre-stroke physical activity has been associated with improved outcomes after intracerebral haemorrhages.{{cite journal | vauthors = Viktorisson A, Buvarp D, Reinholdsson M, Danielsson A, Palstam A, Stibrant Sunnerhagen K | title = Associations of Prestroke Physical Activity With Stroke Severity and Mortality After Intracerebral Hemorrhage Compared With Ischemic Stroke | journal = Neurology | volume = 99 | issue = 19 | pages = e2137–e2148 | date = November 2022 | pmid = 36344278 | pmc = 9651453 | doi = 10.1212/WNL.0000000000201097 }} Furthermore, physical activity may reduce the volume of intracerebral haemorrhages.{{cite journal | vauthors = Viktorisson A, Buvarp D, Danielsson A, Skoglund T, Sunnerhagen KS | title = Prestroke physical activity is associated with admission haematoma volume and the clinical outcome of intracerebral haemorrhage | journal = Stroke and Vascular Neurology | pages = 511–520 | date = May 2023 | volume = 8 | issue = 6 | pmid = 37137521 | doi = 10.1136/svn-2023-002316 | s2cid = 258464205 | doi-access = free | pmc = 10800276 }}{{cite journal | vauthors = Kinoshita K, Hamanaka G, Ohtomo R, Takase H, Chung KK, Lok J, Lo EH, Katsuki H, Arai K | display-authors = 6 | title = Mature Adult Mice With Exercise-Preconditioning Show Better Recovery After Intracerebral Hemorrhage | journal = Stroke | volume = 52 | issue = 5 | pages = 1861–1865 | date = May 2021 | pmid = 33840224 | pmc = 8085050 | doi = 10.1161/STROKEAHA.120.032201 }} Being physically active after stroke also enhance the functional recovery.{{cite journal | vauthors = McKevitt C, Fudge N, Redfern J, Sheldenkar A, Crichton S, Rudd AR, Forster A, Young J, Nazareth I, Silver LE, Rothwell PM, Wolfe CD | display-authors = 6 | title = Self-reported long-term needs after stroke | journal = Stroke | volume = 42 | issue = 5 | pages = 1398–1403 | date = May 2011 | pmid = 21441153 | doi = 10.1161/STROKEAHA.110.598839 | s2cid = 33967186 }}{{cite journal | vauthors = Buvarp D, Viktorisson A, Axelsson F, Lehto E, Lindgren L, Lundström E, Sunnerhagen KS | title = Physical Activity Trajectories and Functional Recovery After Acute Stroke Among Adults in Sweden | journal = JAMA Network Open | volume = 6 | issue = 5 | pages = e2310919 | date = May 2023 | pmid = 37126346 | pmc = 10152305 | doi = 10.1001/jamanetworkopen.2023.10919 }}{{cite journal | vauthors = Gunnes M, Indredavik B, Langhammer B, Lydersen S, Ihle-Hansen H, Dahl AE, Askim T | title = Associations Between Adherence to the Physical Activity and Exercise Program Applied in the LAST Study and Functional Recovery After Stroke | journal = Archives of Physical Medicine and Rehabilitation | volume = 100 | issue = 12 | pages = 2251–2259 | date = December 2019 | pmid = 31374191 | doi = 10.1016/j.apmr.2019.04.023 | hdl = 10642/8488 | s2cid = 199388335 | hdl-access = free }}

The American Academy of Neurology's January 2018 update of their clinical practice guideline for mild cognitive impairment states that clinicians should recommend regular exercise (two times per week) to individuals who have been diagnosed with this condition. This guidance is based upon a moderate amount of high-quality evidence which supports the efficacy of regular physical exercise (twice weekly over a 6-month period) for improving cognitive symptoms in individuals with mild cognitive impairment.

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. Two reviews found evidence for possible positive 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. A subsequent review found higher levels of physical activity may be associated with reduced risk of dementia and cognitive decline.

Parkinson's disease symptoms reflect various functional impairments and limitations, such as postural instability, gait disturbance, immobility, and frequent falls. Some evidence suggests that physical exercise may lower the risk of Parkinson's disease.{{cite journal |vauthors=Fang X, Han D, Cheng Q, Zhang P, Zhao C, Min J, Wang F |date=September 2018 |title=Association of Levels of Physical Activity With Risk of Parkinson Disease: A Systematic Review and Meta-analysis |journal=JAMA Network Open |volume=1 |issue=5 |pages=e182421 |doi=10.1001/jamanetworkopen.2018.2421 |pmc=6324511 |pmid=30646166}} A 2017 study found that strength and endurance training in people with Parkinson's disease had positive effects lasting for several weeks.{{Cite journal |last1=Mak |first1=Margaret K. |last2=Wong-Yu |first2=Irene S. |last3=Shen |first3=Xia |last4=Chung |first4=Chloe L. |date=November 2017 |title=Long-term effects of exercise and physical therapy in people with Parkinson disease |url=https://www.nature.com/articles/nrneurol.2017.128 |journal=Nature Reviews Neurology |language=en |volume=13 |issue=11 |pages=689–703 |doi=10.1038/nrneurol.2017.128 |pmid=29027544 |s2cid=29666456 |issn=1759-4766}} A 2023 Cochrane review on the effects of physical exercise in people with Parkinson's disease indicated that aquatic exercise might reduce severity of motor symptoms and improve quality of life.{{Cite journal|display-authors=3 |last1=Ernst |first1=Moritz |last2=Folkerts |first2=Ann-Kristin |last3=Gollan |first3=Romina |last4=Lieker |first4=Emma |last5=Caro-Valenzuela |first5=Julia |last6=Adams |first6=Anne |last7=Cryns |first7=Nora |last8=Monsef |first8=Ina |last9=Dresen |first9=Antje |last10=Roheger |first10=Mandy |last11=Eggers |first11=Carsten |last12=Skoetz |first12=Nicole |last13=Kalbe |first13=Elke |date=2023-01-05 |title=Physical exercise for people with Parkinson's disease: a systematic review and network meta-analysis|journal=The Cochrane Database of Systematic Reviews |volume=1 |issue=1 |pages=CD013856 |doi=10.1002/14651858.CD013856.pub2 |issn=1469-493X |pmc=9815433 |pmid=36602886}} Furthermore, endurance training, functional training, and multi-domain training (i.e., engaging in several types of exercise) may provide improvements.

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• Brain fitness
• Exercise is Medicine
• Exercise prescription
• Exercise therapy
• Memory improvement
• Neuroinflammation#Exercise
• Nootropic

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