Born to move: a review on the impact of physical exercise on brain health and the evidence from human controlled trials

Abstract

Background: Physical exercise has been found to impact neurophysiological and structural aspects of the human brain. However, most research has used animal models, which yields much confusion regarding the real effects of exercise on the human brain, as well as the underlying mechanisms. Objective: To present an update on the impact of physical exercise on brain health; and to review and analyze the evidence exclusively from human randomized controlled studies from the last six years. Methods: A search of the literature search was conducted using the MEDLINE (via PubMed), EMBASE, Web of Science and PsycINFO databases for all randomized controlled trials published between January 2014 and January 2020. Results: Twenty-four human controlled trials that observed the relationship between exercise and structural or neurochemical changes were reviewed. Conclusions: Even though this review found that physical exercise improves brain plasticity in humans, particularly through changes in brain-derived neurotrophic factor (BDNF), functional connectivity, basal ganglia and the hippocampus, many unanswered questions remain. Given the recent advances on this subject and its therapeutic potential for the general population, it is hoped that this review and future research correlating molecular, psychological and image data may help elucidate the mechanisms through which physical exercise improves brain health.

RESUMO

Introdução: Evidências das últimas décadas têm mostrado que o exercício físico impacta de forma significativa aspectos neurofisiológicos e estruturais do cérebro humano. No entanto, a maioria das pesquisas emprega modelos animais, o que gera confusão no que diz respeito aos efeitos reais do exercício no cérebro humano, assim como os mecanismos adjacentes. Objetivo: Apresentar uma atualização sobre o impacto do exercício no cérebro; revisar e analisar sistematicamente as evidências provenientes exclusivamente de estudos randomizados controlados em humanos, dos últimos seis anos. Métodos: Foi conduzida uma busca na literatura usando as bases de dados MEDLINE (via PubMed), EMBASE, Web of Science e PsycINFO, para todos os estudos randomizados e controlados publicados entre janeiro de 2014 e janeiro de 2020. Resultados: Foram revisados 24 estudos randomizados controlados em humanos, que observavam a relação entre exercício físico e alterações neuroquímicas e estruturais no cérebro. Conclusões: Ainda que esta revisão tenha observado que o exercício físico melhora a plasticidade cerebral em humanos, particularmente por meio de alterações no fator neurotrófico derivado do cérebro (BDNF), conectividade funcional, núcleos da base e hipocampo, muitas questões ainda precisam ser respondidas. Dados os avanços recentes nessa temática e seu potencial terapêutico para a população em geral, espera-se que este manuscrito e pesquisas futuras que correlacionem estudos moleculares e variáveis psicológicas e de imagem possam ajudar na elucidação dos mecanismos pelos quais o exercício físico melhora a saúde cerebral.

Keywords:

Physical Activity - Exercise - Brain - Mental Health - Review

Palavras-chave:

Atividade Física - Exercício Físico - Cérebro - Saúde Mental - Revisão

Authors’ contributions:

CFV: designed and implemented the study, designed the data extraction, carried out data analysis and wrote the manuscript with support from SL, HA and AB. EHMD: helped with data extraction and literature search. EHMD and MD gave support in the interpretation of the data. All authors read and approved the final version.

Publication History

Received: 06 May 2020

Accepted: 17 September 2020

Article published online:
04 July 2023

• References

• 1 Bramble DM, Lieberman DE. Endurance running and the evolution of Homo. Nature. 2004 Nov;432(7015):345-52. https://doi.org/10.1038/nature03052
• 2 Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr Physiol. 2012 Apr;2(2):1143-211. https://doi.org/10.1002/cphy.c110025
• 3 Duzel E, van Praag H, Sendtner M. Can physical exercise in old age improve memory and hippocampal function? Brain. 2016 Mar;139(Pt 3):662-73. https://doi.org/10.1093/brain/awv407
• 4 Mello MT, Boscolo RA, Esteves AM, Tufilk SO. Exercício físico e os aspectos psicobiológicos. Rev Bras Med Esporte. 2005 Jun;11(3):195-9. https://doi.org/10.1590/S1517-86922005000300010
• 5 Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006 Jan;26(1):3-11. https://doi.org/10.1523/JNEUROSCI.3648-05.2006
• 6 Forti LN, Van Roie E, Njemini R, Coudyzer W, Beyer I, Delecluse C, et al. Dose-and gender-specific effects of resistance training on circulating levels of brain derived neurotrophic factor (BDNF) in community-dwelling older adults. Exp Gerontol. 2015 Oct;70:144-9. https://doi.org/10.1016/j.exger.2015.08.004
• 7 Deslandes A, Moraes H, Ferreira C, Veiga H, Silveira H, Mouta R, et al. Exercise and mental health: many reasons to move. Neuropsychobiology. 2009 Aug;59(4):191-8. https://doi.org/10.1159/000223730
• 8 Kim B, Feldman EL. Insulin resistance as a key link for the increased risk of cognitive impairment in themetabolic syndrome. Exp Mol Med. 2015 Mar;47(3):e149. https://doi.org/10.1038/emm.2015.3
• 9 Maddock RJ, Casazza GA, Fernandez DH, Maddock MI. Acute modulation of cortical glutamate and GABA content by physical activity. J Neurosci. 2016 Feb;36(8):2449-57. https://doi.org/10.1523/JNEUROSCI.3455-15.2016
• 10 Church DD, Hoffman JR, Mangine GT, Jajtner AR, Townsend JR, Beyer KS, et al. Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise. J Appl Physiol (1985). 2016 Jul;121(1):123-8. https://doi.org/10.1152/japplphysiol.00233.2016
• 11 Vaughan S, Wallis M, Polit D, Steele M, Shum D, Morris N. The effects of multimodal exercise on cognitive and physical functioning and brain-derived neurotrophic factor in older women: a randomised controlled trial. Age Ageing. 2014 Sep;43(5):623-9. https://doi.org/10.1093/ageing/afu010
• 12 Wagner G, Herbsleb M, de la Cruz F, Schumann A, Brünner F, Schachtzabel C, et al. Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial. J Cereb Blood Flow Metab. 2015 Oct;35(10):1570-8. https://doi.org/10.1038/jcbfm.2015.125
• 13 Kleemeyer MM, Kühn S, Prindle J, Bodammer NC, Brechtel L, Garthe A, et al. Changes in fitness are associated with changes in hippocampal microstructure and hippocampal volume among older adults. Neuroimage. 2016 May;131:155-61. https://doi.org/10.1016/j.neuroimage.2015.11.026
• 14 Varma VR, Chuang YF, Harris GC, Tan EJ, Carlson MC. Low-intensity daily walking activity is associated with hippocampal volume in older adults. Hippocampus. 2015 May;25(5):605-15. https://doi.org/10.1002/hipo.22397
• 15 Kandola A, Hendrikse J, Lucassen PJ, Yücel M. Aerobic exercise as a tool to improve hippocampal plasticity and function in humans: practical implications for mental health treatment. Front Hum Neurosci. 2016 Jul;10:373. https://doi.org/10.3389/fnhum.2016.00373
• 16 Den Ouden L, Kandola A, Suo C, Hendrikse J, Costa R, Watt MJ, et al. The Influence of Aerobic Exercise on Hippocampal Integrity and Function: Preliminary Findings of a Multi-Modal Imaging Analysis. Brain Plast. 2018 Dec;4(2):211-6. https://doi.org/10.3233/BPL-170053
• 17 Kim YS, Shin SK, Hong SB, Kim HJ. The effects of strength exercise on hippocampus volume and functional fitness of older women. Exp Gerontol. 2017 Oct;97:22-8. https://doi.org/10.1016/j.exger.2017.07.007
• 18 Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006 Jan;144(2):73-81. https://doi.org/10.7326/0003-4819-144-2-200601170-00004
• 19 Diamond A. Effects of physical exercise on executive functions: going beyond simply moving to moving with thought. Ann Sports Med Res. 2015 Jan;2(1):1011. PMID: 26000340 PMCID: PMC4437637
• 20 Tsujii T, Komatsu K, Sakatani K. Acute effects of physical exercise on prefrontal cortex activity in older adults: a functional near-infrared spectroscopy study. In: Welch WJ, Palm F, Bruley DF, Harrison DK, editors. Oxygen Transport to Tissue XXXIV. Advances in Experimental Medicine and Biology. V. 765. New York, NY: Springer; 2012. https://doi.org/10.1007/978-1-4614-4989-8_41
• 21 Hashimoto N, Yokogawa M, Kojima H, Tanaka S, Nakagawa T. Effect of moderate exercise intensities on the cortical activity in young adults. J Phys Ther Sci. 2018 Oct;30(10):1257-61. https://doi.org/10.1589/jpts.30.1257
• 22 Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, et al. Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A. 2004 Mar;101(9):3316-21. https://doi.org/10.1073/pnas.0400266101
• 23 Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011 Feb;108(7):3017-22. https://doi.org/10.1073/pnas.1015950108
• 24 Wittfeld K, Jochem C, Dörr M, Schminke U, Gläser S, Bahls M, et al. Cardiorespiratory Fitness and Gray Matter Volume in the Temporal, Frontal, and Cerebellar Regions in the General Population. Mayo Clin Proc. 2020 Jan;95(1):44-56. https://doi.org/10.1016/j.mayocp.2019.05.030
• 25 Ruotsalainen I, Gorbach T, Perkola J, Renvall V, Syväoja HJ, Tammelin T, et al. Physical activity, aerobic fitness, and brain white matter: Their role for executive functions in adolescence. Dev Cogn Neurosci. 2020 Apr;42:100765. https://doi.org/10.1016/j.dcn.2020.100765
• 26 Best JR, Chiu BK, Liang Hsu C, Nagamatsu LS, Liu-Ambrose T. Long-Term effects of resistance exercise training on cognition and brain volume in older women: results from a randomized controlled trial. J Int Neuropsychol Soc. 2015 Nov;21(10):745-56. https://doi.org/10.1017/S1355617715000673
• 27 Demirakca T, Cardinale V, Dehn S, Ruf M, Ende G. The exercising brain: changes in functional connectivity induced by an integrated multimodal cognitive and whole-body coordination training. Neural Plast. 2015 Dec;2016:8240894. https://doi.org/10.1155/2016/8240894
• 28 Grégoire CA, Berryman N, St-Onge F, Vu T, Bosquet L, Arbour N, et al. Gross motor skills training leads to increased brain-derived neurotrophic factor levels in healthy older adults: a pilot study. Front Physiol. 2019 Apr;10:410. https://doi.org/10.3389/fphys.2019.00410
• 29 Hvid LG, Nielsen MKF, Simonsen C, Andersen M, Caserotti P. Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults - a randomized controlled trial. Exp Gerontol. 2017 Jul;93:29-35. https://doi.org/10.1016/j.exger.2017.03.019
• 30 Kim JH, Kim DY. Aquarobic exercises improve the serum blood irisin and brain-derived neurotrophic factor levels in elderly women. Exp Gerontol. 2018 Apr;104:60-5. https://doi.org/10.1016/j.exger.2018.01.024
• 31 Matura S, Fleckenstein J, Deichmann R, Engeroff T, Füzéki E, Hattingen E, et al. Effects of aerobic exercise on brain metabolism and grey matter volume in older adults: results of the randomised controlled SMART trial. Transl Psychiatry. 2017 Jul;7(7):e1172. https://doi.org/10.1038/tp.2017.135
• 32 Magon S, Donath L, Gaetano L, Thoeni A, Radue EW, Faude O, et al. Striatal functional connectivity changes following specific balance training in elderly people: MRI results of a randomized controlled pilot study. Gait Posture. 2016 Sep;49:334-9. https://doi.org/10.1016/j.gaitpost.2016.07.016
• 33 Marston KJ, Peiffer JJ, Rainey-Smith SR, Gordon N, Teo SY, Laws SM, et al. Resistance training enhances delayed memory in healthy middle-aged and older adults: A randomised controlled trial. J Sci Med Sport. 2019 Nov;22(11):1226-31. https://doi.org/10.1016/j.jsams.2019.06.013
• 34 Nagamatsu LS, Weinstein AM, Erickson KI, Fanning J, Awick EA, Kramer AF, et al. Exercise mode moderates the relationship between mobility and basal ganglia volume in healthy older adults. J Am Geriatr Soc. 2016 Jan;64(1):102-8. https://doi.org/10.1111/jgs.13882
• 35 Niemann C, Godde B, Staudinger UM, Voelcker-Rehage C. Exercise-induced changes in basal ganglia volume and cognition in older adults. Neuroscience. 2014 Dec;281:147-63. https://doi.org/10.1016/j.neuroscience.2014.09.033
• 36 Nocera J, Crosson B, Mammino K, McGregor KM. Changes in Cortical Activation Patterns in Language Areas following an Aerobic Exercise Intervention in Older Adults. Neural Plast. 2017;2017:6340302. https://doi.org/10.1155/2017/6340302
• 37 Oliveira AB, Ribeiro RT, Mello MT, Tufik S, Peres M. Anandamide Is related to clinical and cardiorespiratory benefits of aerobic exercise training in migraine patients: a randomized controlled clinical trial. Cannabis Cannabinoid Res. 2019 Dec;4(4):275-284. https://doi.org/10.1089/can.2018.0057
• 38 Suwabe K, Byun K, Hyodo K, Reagh ZM, Roberts JM, Matsushita A, et al. Rapid stimulation of human dentate gyrus function with acute mild exercise. Proc Proc Natl Acad Sci U S A. 2018 Oct;115(41):10487-92. https://doi.org/10.1073/pnas.1805668115
• 39 Tamura M, Nemoto K, Kawaguchi A, Kato M, Arai T, Kakuma T, et al. Long-term mild-intensity exercise regimen preserves prefrontal cortical volume against aging. Int J Geriatr Psychiatry. 2015 Jul;30(7):686-94. https://doi.org/10.1002/gps.4205
• 40 Rosano C, Guralnik J, Pahor M, Glynn NW, Newman AB, Ibrahim TS, et al. Hippocampal Response to a 24-Month Physical Activity Intervention in Sedentary Older Adults. Am J Geriatr Psychiatry. 2017 Mar;25(3):209-17. https://doi.org/10.1016/j.jagp.2016.11.007
• 41 Zschucke E, Renneberg B, Dimeo F, Wüstenberg T, Ströhle A. The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback. Psychoneuroendocrinology. 2015 Jan;51:414-25. https://doi.org/10.1016/j.psyneuen.2014.10.019
• 42 Szuhany KL, Bugatti M, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Res. 2015 Jan;60:56-64. https://doi.org/10.1016/j.jpsychires.2014.10.003
• 43 Ruscheweyh R, Willemer C, Krüger K, Duning T, Warnecke T, Sommer J, et al. Physical activity and memory functions: an interventional study. Neurobiol Aging. 2011 Jul;32(7):1304-19. https://doi.org/10.1016/j.neurobiolaging.2009.08.001
• 44 Knaepen K, Goekint M, Heyman ME, Meeusen R. Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects. Sports Med. 2010 Sep;40(9):765-801. https://doi.org/10.2165/11534530-20200166000-00000
• 45 Rosano C, Venkatraman VK, Guralnik J, Newman AB, Glynn NW, Launer L, et al. Psychomotor speed and functional brain MRI 2 years after completing a physical activity treatment. J Gerontol A Biol Sci Med Sci. 2010 Jun;65(6):639-47. https://doi.org/10.1093/gerona/glq038
• 46 Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A et al. High impact running improves learning. Neurobiol Learn Mem. 2007 May;87(4):597-609. https://doi.org/10.1016/j.nlm.2006.11.003
• 47 Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, Hart E, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009 Oct;94(10):1062-9. https://doi.org/10.1113/expphysiol.2009.048512
• 48 Tang SW, Chu E, Hui T, Helmeste D, Law C. Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects. Neurosci Lett. 2008 Jan;431(1):62-5. https://doi.org/10.1016/j.neulet.2007.11.019
• 49 Vedovelli K, Giacobbo BL, Corrêa MS, Wieck A, Argimon IIL, Bromberg E. Multimodal physical activity increases brain-derived neurotrophic factor levels and improves cognition in institutionalized older women. Geroscience. 2017 Aug;39(4):407-17. https://doi.org/10.1007/s11357-017-9987-5
• 50 Matias I, Gatta-Cherifi B, Tabarin A, Clark S, Leste-Lasserre T, Marsicano G, et al. Endocannabinoids measurement in human saliva as potential biomarker of obesity. PLoS One. 2012;7(7):e42399. https://doi.org/10.1371/journal.pone.0042399
• 51 Tantimonaco M, Ceci R, Sabatini S, Rossi A, Gasperi V, Maccarrone M. Physical activity and the endocannabinoid system: An overview. Cell Mol Life Sci. 2014 Jul;71(14):2681-98. https://doi.org/10.1007/s00018-014-1575-6
• 52 Gasperi V, Ceci R, Tantimonaco M, Talamonti E, Battista N, Parisi A, et al. The fatty acid amide hydrolase in lymphocytes from sedentary and active subjects. Med Sci Sports Exerc. 2014 Jan;46(1):24-32. https://doi.org/10.1249/MSS.0b013e3182a10ce6
• 53 Brellenthin AG, Crombie KM, Hillard CJ, Koltyn KF. Endocannabinoid and mood responses to exercise in adults with varying activity levels. Med Sci Sports Exerc. 2017 Aug;49(8):1688-96. https://doi.org/10.1249/MSS.20200166202001661276
• 54 Sparling P, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A. Exercise activates the endocannabinoid system. Neuroreport. 2003 Dec;14(17):2209-11. https://doi.org/10.1097/00001756-200312020-00015
• 55 Crosby KM, Bains JS. The intricate link between glucocorticoids and endocannabinoids at stress-relevant synapses in the hypothalamus. Neuroscience. 2012 Mar;204:31-7. https://doi.org/10.1016/j.neuroscience.2011.11.049
• 56 Antunes HKM, Leite GSF, Lee KS, Barreto AT, Dos Santos RVT, Souza HS, et al. Exercise deprivation increases negative mood in exercise-addicted subjects and modifies their biochemical markers. Physiol Behav. 2016 Mar;156:182-90. https://doi.org/10.1016/j.physbeh.2016.01.028
• 57 Basso JC, Suzuki WA. The effects of acute exercise on mood, cognition, neurophysiology and neurochemical pathways: a review. Brain Plast. 2017 Feb;2(2):127-52. https://doi.org/10.3233/BPL-160040
• 58 Dennis A, Thomas AG, Rawlings NB, Near J, Nichols TE, Clare S, et al. An ultra-high field magnetic resonance spectroscopy study of post exercise lactate, glutamate and glutamine change in the human brain. Front Physiol. 2015;6:351. https://doi.org/10.3389/fphys.2015.00351
• 59 Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 1994 Oct;91(22):10625-9. https://doi.org/10.1073/pnas.91.22.10625
• 60 Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003 Mar;14(2):125-30. https://doi.org/10.1111/1467-9280.t01-1-01430
• 61 Smith SM, Miller KL, Salimi-Khorshidi G, Webster M, Beckmann CF, Nichols TE, et al. Network modelling methods for FMRI. Neuroimage. 2011 Jan;54(2):875-91. https://doi.org/10.1016/j.neuroimage.2010.08.063
• 62 Heo S, Kramer AF. The Influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: results of a one-year exercise intervention [master's thesis]. Urbana-Campaign: University of Illinois; 2010.
• 63 Voss MW, Erickson KI, Prakash RS, Chaddock L, Malkowski E, Alves H, et al. Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition? Neuropsychologia. 2010 Apr;48(5):1394-406. https://doi.org/10.1016/j.neuropsychologia.2010.01.005
• 64 Thomas AG, Dennis A, Bandettini PA, Johansen-Berg H. The effects of aerobic activity on brain structure. Front Psychol. 2012 Mar;3:86. https://doi.org/10.3389/fpsyg.2012.00086
• 65 Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, et al. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009 Oct;19(10):1030-9. https://doi.org/10.1002/hipo.20547
• 66 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. Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U.S.A. 2011; 108:3017–3022.
• 67 Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010 Feb;67(2):133-43. https://doi.org/10.1001/archgenpsychiatry.2009.193
• 68 Gomes FGN, Fernandes J, Campos DV, Cassilhas RC, Viana GM, D'Almeida V, et al. The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids. Psychoneuroendocrinology. 2014 Dec;50:106-17. https://doi.org/10.1016/j.psyneuen.2014.08.009
• 69 Nokia MS, Lensu S, Ahtiainen JP, Johansson PP, Koch LG, Britton SL, et al. Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained. J Physiol. 2016 Apr;594(7):1855-73. https://doi.org/10.1113/JP271552
• 70 Kim YS, Shin SK, Hong SB, Kim HJ. The effects of strength exercise on hippocampus volume and functional fitness of older women. Exp Gerontol. 2017; 97:22-28. https://doi.org/10.1016/j.exger.2017.07.007
• 71 Puttemans V, Wenderoth N, Swinnen SP. Changes in brain activation during the acquisition of a multifrequency bimanual coordination task: from the cognitive stage to advanced levels of automaticity. J Neurosci. 2005 Apr;25(17):4270-8. https://doi.org/10.1523/JNEUROSCI.3866-04.2005
• 72 Steele CJ, Penhune VB. Specific increases within global decreases: a functional magnetic resonance imaging investigation of five days of motor sequence learning. J Neurosci. 2010 Jun;30(24):8332-41. https://doi.org/10.1523/JNEUROSCI.5569-09.2010
• 73 Taubert M, Villringer A, Ragert P. Learning-related gray and white matter changes in humans: an update. Neuroscientist. 2012 Aug;18(4):320-5. https://doi.org/10.1177/1073858411419048.
• 74 Verstynen TD, Lynch B, Miller DL, Voss MW, Prakash RS, Chaddock L, et al. Caudate nucleus volume mediates the link between cardiorespiratory fitness and cognitive flexibility in older adults. J Aging Res. 2012 Jul;2012:939285. https://doi.org/10.1155/2012/939285