Non-pharmacological Approaches to Cognitive Enhancement

  • Áine M. Kelly
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 228)


Pharmaceuticals and medical devices hold the promise of enhancing brain function, not only of those suffering from neurodevelopmental, neuropsychiatric or neurodegenerative illnesses, but also of healthy individuals. However, a number of lifestyle interventions are proven cognitive enhancers, improving attention, problem solving, reasoning, learning and memory or even mood. Several of these interventions, such as physical exercise, cognitive, mental and social stimulation, may be described as environmental enrichments of varying types. Use of these non-pharmacological cognitive enhancers circumvents some of the ethical considerations associated with pharmaceutical or technological cognitive enhancement, being low in cost, available to the general population and presenting low risk to health and well-being. In this chapter, there will be particular focus on the effects of exercise and enrichment on learning and memory and the evidence supporting their efficacy in humans and in animal models will be described.


Cognitive enhancement Physical activity Environmental enrichment Neurogenesis BDNF 


  1. Aimone JB, Wiles J, Gage FH (2006) Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 9:723–727PubMedGoogle Scholar
  2. Albeck DS, Sano K, Prewitt GE, Dalton L (2006) Mild forced treadmill exercise enhances spatial learning in the aged rat. Behav Brain Res 168:345–348PubMedGoogle Scholar
  3. American Time Use Study, U.S. Bureau of Labor Statistics (2013)
  4. Anstey KJ, Matters B, Brown AK, Lord SR (2000) Normative data on neuropsychological tests for very old adults living in retirement villages and hostels. Clin Neuropsychol 14:309–317PubMedGoogle Scholar
  5. Barnes DE, Santos-Modesitt W, Poelke G, Kramer AF, Castro C, Middleton LE, Yaffe K (2013a) The Mental Activity and eXercise (MAX) trial: a randomized controlled trial to enhance cognitive function in older adults. JAMA Intern Med 173:797–804PubMedGoogle Scholar
  6. Barnes JN, Taylor JL, Kluck BN, Johnson CP, Joyner MJ (2013b) Cerebrovascular reactivity is associated with maximal aerobic capacity in healthy older adults. J Appl Physiol (1985) 114:1383–1387Google Scholar
  7. Bechara RG, Kelly AM (2013) Exercise improves object recognition memory and induces BDNF expression and cell proliferation in cognitively enriched rats. Behav Brain Res 245:96–100PubMedGoogle Scholar
  8. Bechara RG, Lyne R, Kelly AM (2014) BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat. Behav Brain Res 275:297–306PubMedGoogle Scholar
  9. Bekinschtein P, Cammarota M, Medina JH (2014) BDNF and memory processing. Neuropharmacology 76:677–683PubMedGoogle Scholar
  10. Berchtold NC, Castello N, Cotman CW (2010) Exercise and time-dependent benefits to learning and memory. Neuroscience 167:588–597PubMedPubMedCentralGoogle Scholar
  11. Bindu B, Alladi PA, Mansooralikhan BM, Srikumar BN, Raju TR, Kutty BM (2007) Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions. Neuroscience 144:412–423PubMedGoogle Scholar
  12. Birch AM, Kelly AM (2013) Chronic intracerebroventricular infusion of nerve growth factor improves recognition memory in the rat. Neuropharmacology 75:255–261PubMedGoogle Scholar
  13. Birch AM, Mcgarry NB, Kelly AM (2013) Short-term environmental enrichment, in the absence of exercise, improves memory, and increases NGF concentration, early neuronal survival, and synaptogenesis in the dentate gyrus in a time-dependent manner. Hippocampus 23(6):437–450PubMedGoogle Scholar
  14. Bramham CR, Panja D (2014) BDNF regulation of synaptic structure, function, and plasticity. Neuropharmacology 76 Pt C:601–602PubMedGoogle Scholar
  15. Brenes JC, Padilla M, Fornaguera J (2009) A detailed analysis of open-field habituation and behavioral and neurochemical antidepressant-like effects in postweaning enriched rats. Behav Brain Res 197:125–137PubMedGoogle Scholar
  16. Brown J, Cooper-Kuhn CM, Kempermann G, van Praag H, Winkler J, Gage FH, Kuhn HG (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 17:2042–2046PubMedGoogle Scholar
  17. Cassilhas RC, Lee KS, Fernandes J, Oliveira MG, Tufik S, Meeusen R, de Mello MT (2012) Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience 202:309–317PubMedGoogle Scholar
  18. Castren E, Rantamaki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70:289–297PubMedGoogle Scholar
  19. Chang YK, Labban JD, Gapin JI, Etnier JL (2012) The effects of acute exercise on cognitive performance: a meta-analysis. Brain Res 1453:87–101PubMedGoogle Scholar
  20. Cho HC, Kim J, Kim S, Son YH, Lee N, Jung SH (2012) The concentrations of serum, plasma and platelet BDNF are all increased by treadmill VO(2)max performance in healthy college men. Neurosci Lett 519:78–83PubMedGoogle Scholar
  21. Cian C, Barraud PA, Melin B, Raphel C (2001) Effects of fluid ingestion on cognitive function after heat stress or exercise-induced dehydration. Int J Psychophysiol 42:243–251PubMedGoogle Scholar
  22. Clark PJ, Brzezinska WJ, Puchalski EK, Krone DA, Rhodes JS (2009) Functional analysis of neurovascular adaptations to exercise in the dentate gyrus of young adult mice associated with cognitive gain. Hippocampus 19:937–950PubMedPubMedCentralGoogle Scholar
  23. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, Mcauley E, Cohen NJ, Webb A, Jerome GJ, Marquez DX, Elavsky S (2004) Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U S A 101:3316–3321PubMedPubMedCentralGoogle Scholar
  24. Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR, Sejnowski TJ, Tuszynski MH (2009) NGF is essential for hippocampal plasticity and learning. J Neurosci 29:10883–10889PubMedPubMedCentralGoogle Scholar
  25. Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013) Exercise for depression. Cochrane Database Syst Rev 9, CD004366PubMedGoogle Scholar
  26. Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ (2010) Running enhances spatial pattern separation in mice. Proc Natl Acad Sci U S A 107:2367–2372PubMedPubMedCentralGoogle Scholar
  27. Crosnoe R, Leventhal T, Wirth RJ, Pierce KM, Pianta RC, NICHD Early Child Care Research Network (2010) Family socioeconomic status and consistent environmental stimulation in early childhood. Child Dev 81:972–987PubMedPubMedCentralGoogle Scholar
  28. Dickinson D, Tenhula W, Morris S, Brown C, Peer J, Spencer K, Li L, Gold JM, Bellack AS (2010) A randomized, controlled trial of computer-assisted cognitive remediation for schizophrenia. Am J Psychiatry 167:170–180PubMedGoogle Scholar
  29. Dietrich MO, Mantese CE, Porciuncula LO, Ghisleni G, Vinade L, Souza DO, Portela LV (2005) Exercise affects glutamate receptors in postsynaptic densities from cortical mice brain. Brain Res 1065:20–25PubMedGoogle Scholar
  30. Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F (2006) Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience 140:823–833PubMedGoogle Scholar
  31. Ding Q, Ying Z, Gomez-Pinilla F (2011) Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing. Neuroscience 192:773–780PubMedPubMedCentralGoogle Scholar
  32. Duman RS, Nakagawa S, Malberg J (2001) Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology 25:836–844PubMedGoogle Scholar
  33. Earhart GM (2013) Dynamic control of posture across locomotor tasks. Mov Disord 28:1501–1508PubMedPubMedCentralGoogle Scholar
  34. Ebersbach G, Ebersbach A, Gandor F, Wegner B, Wissel J, Kupsch A (2014) Impact of physical exercise on reaction time in patients with Parkinson’s disease-data from the Berlin BIG Study. Arch Phys Med Rehabil 95:996–999PubMedGoogle Scholar
  35. Ekstrand J, Hellsten J, Tingstrom A (2008) Environmental enrichment, exercise and corticosterone affect endothelial cell proliferation in adult rat hippocampus and prefrontal cortex. Neurosci Lett 442:203–207PubMedGoogle Scholar
  36. Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wojcicki TR, Mcauley E, Kramer AF (2009) Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 19:1030–1039PubMedPubMedCentralGoogle Scholar
  37. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, Mclaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, Mcauley E, Kramer AF (2010) Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci 30:5368–5375PubMedPubMedCentralGoogle Scholar
  38. 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 (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 108:3017–3022PubMedPubMedCentralGoogle Scholar
  39. Ernst C, Olson AK, Pinel JP, Lam RW, Christie BR (2006) Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? J Psychiatry Neurosci 31:84–92PubMedPubMedCentralGoogle Scholar
  40. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18:2803–2812PubMedGoogle Scholar
  41. Faherty CJ, Raviie Shepherd K, Herasimtschuk A, Smeyne RJ (2005) Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism. Brain Res Mol Brain Res 134:170–179PubMedGoogle Scholar
  42. Farina N, Rusted J, Tabet N (2014) The effect of exercise interventions on cognitive outcome in Alzheimer’s disease: a systematic review. Int Psychogeriatr 26:9–18PubMedGoogle Scholar
  43. Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience 124:71–79PubMedGoogle Scholar
  44. Ferrara N (2009) VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw 20:158–163PubMedGoogle Scholar
  45. Ferris LT, Williams JS, Shen CL (2007) The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function. Med Sci Sports Exerc 39:728–734PubMedGoogle Scholar
  46. Frazzitta G, Maestri R, Ghilardi MF, Riboldazzi G, Perini M, Bertotti G, Boveri N, Buttini S, Lombino FL, Uccellini D, Turla M, Pezzoli G, Comi C (2014) Intensive rehabilitation increases BDNF serum levels in parkinsonian patients: a randomized study. Neurorehabil Neural Repair 28:163–168PubMedGoogle Scholar
  47. Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J, Sun B, Tandon NN (2002) Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 87:728–734PubMedGoogle Scholar
  48. Gage FH, Temple S (2013) Neural stem cells: generating and regenerating the brain. Neuron 80:588–601PubMedGoogle Scholar
  49. Galani R, Berthel MC, Lazarus C, Majchrzak M, Barbelivien A, Kelche C, Cassel JC (2007) The behavioral effects of enriched housing are not altered by serotonin depletion but enrichment alters hippocampal neurochemistry. Neurobiol Learn Mem 88:1–10PubMedGoogle Scholar
  50. Garza AA, Ha TG, Garcia C, Chen MJ, Russo-Neustadt AA (2004) Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav 77:209–220PubMedGoogle Scholar
  51. Geda YE, Roberts RO, Knopman DS, Christianson TJ, Pankratz VS, Ivnik RJ, Boeve BF, Tangalos EG, Petersen RC, Rocca WA (2010) Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch Neurol 67:80–86PubMedPubMedCentralGoogle Scholar
  52. Gobbo OL, O’Mara SM (2004) Impact of enriched-environment housing on brain-derived neurotrophic factor and on cognitive performance after a transient global ischemia. Behav Brain Res 152:231–241PubMedGoogle Scholar
  53. Goekint M, Heyman E, Roelands B, Njemini R, Bautmans I, Mets T, Meeusen R (2008) No influence of noradrenaline manipulation on acute exercise-induced increase of brain-derived neurotrophic factor. Med Sci Sports Exerc 40:1990–1996PubMedGoogle Scholar
  54. Goekint M, Roelands B, De Pauw K, Knaepen K, Bos I, Meeusen R (2010) Does a period of detraining cause a decrease in serum brain-derived neurotrophic factor? Neurosci Lett 486:146–149PubMedGoogle Scholar
  55. Gold SM, Schulz KH, Hartmann S, Mladek M, Lang UE, Hellweg R, Reer R, Braumann KM, Heesen C (2003) Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. J Neuroimmunol 138:99–105PubMedGoogle Scholar
  56. Gomez-Pinilla F, Hillman C (2013) The influence of exercise on cognitive abilities. Compr Physiol 3:403–428PubMedPubMedCentralGoogle Scholar
  57. Gomez-Pinilla F, Vaynman S, Ying Z (2008) Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition. Eur J Neurosci 28:2278–2287PubMedPubMedCentralGoogle Scholar
  58. Grego F, Vallier JM, Collardeau M, Bermon S, Ferrari P, Candito M, Bayer P, Magnie MN, Brisswalter J (2004) Effects of long duration exercise on cognitive function, blood glucose, and counterregulatory hormones in male cyclists. Neurosci Lett 364:76–80PubMedGoogle Scholar
  59. Grego F, Vallier JM, Collardeau M, Rousseu C, Cremieux J, Brisswalter J (2005) Influence of exercise duration and hydration status on cognitive function during prolonged cycling exercise. Int J Sports Med 26:27–33PubMedGoogle Scholar
  60. Gregoire CA, Bonenfant D, Le Nguyen A, Aumont A, Fernandes KJ (2014) Untangling the influences of voluntary running, environmental complexity, social housing and stress on adult hippocampal neurogenesis. PLoS One 9:e86237PubMedPubMedCentralGoogle Scholar
  61. Griffin EW, Bechara RG, Birch AM, Kelly AM (2009) Exercise enhances hippocampal-dependent learning in the rat: evidence for a BDNF-related mechanism. Hippocampus 19:973–980PubMedGoogle Scholar
  62. Griffin EW, Mullally S, Foley C, Warmington SA, O’Mara SM, Kelly AM (2011) Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol Behav 104:934–941PubMedGoogle Scholar
  63. Harburger LL, Lambert TJ, Frick KM (2007a) Age-dependent effects of environmental enrichment on spatial reference memory in male mice. Behav Brain Res 185:43–48PubMedPubMedCentralGoogle Scholar
  64. Harburger LL, Nzerem CK, Frick KM (2007b) Single enrichment variables differentially reduce age-related memory decline in female mice. Behav Neurosci 121:679–688PubMedGoogle Scholar
  65. Heath GW, Parra DC, Sarmiento OL, Andersen LB, Owen N, Goenka S, Montes F, Brownson RC, Lancet Physical Activity Series Working Group (2012) Evidence-based intervention in physical activity: lessons from around the world. Lancet 380:272–281PubMedGoogle Scholar
  66. Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85:1694–1704PubMedGoogle Scholar
  67. Hindle JV, Petrelli A, Clare L, Kalbe E (2013) Nonpharmacological enhancement of cognitive function in Parkinson’s disease: a systematic review. Mov Disord 28:1034–1049PubMedGoogle Scholar
  68. Holwerda TJ, Deeg DJ, Beekman AT, van Tilburg TG, Stek ML, Jonker C, Schoevers RA (2014) Feelings of loneliness, but not social isolation, predict dementia onset: results from the Amsterdam Study of the Elderly (AMSTEL). J Neurol Neurosurg Psychiatry 85:135–142PubMedGoogle Scholar
  69. Hopkins ME, Bucci DJ (2010a) BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memory. Neurobiol Learn Mem 94:278–284PubMedPubMedCentralGoogle Scholar
  70. Hopkins ME, Bucci DJ (2010b) Interpreting the effects of exercise on fear conditioning: the influence of time of day. Behav Neurosci 124:868–872PubMedGoogle Scholar
  71. Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen HI (2006) Compulsive exercise acutely upregulates rat hippocampal brain-derived neurotrophic factor. J Neural Transm 113:803–811PubMedGoogle Scholar
  72. Isaacs KR, Anderson BJ, Alcantara AA, Black JE, Greenough WT (1992) Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. J Cereb Blood Flow Metab 12:110–119PubMedGoogle Scholar
  73. Jack CR Jr, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, Bernstein MA, Gunter JL, Pankratz VS, Aisen PS, Weiner MW, Petersen RC, Shaw LM, Trojanowski JQ, Knopman DS, Alzheimer’s Disease Neuroimaging Initiative (2010) Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain 133:3336–3348PubMedPubMedCentralGoogle Scholar
  74. Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362PubMedGoogle Scholar
  75. Keilhoff G, Fusar-Poli P, Becker A (2012) Effects of antipsychotics on dentate gyrus stem cell proliferation and survival in animal models: a critical update. Neural Plast 2012:832757PubMedPubMedCentralGoogle Scholar
  76. Kempermann G, Gage FH (1999) Experience-dependent regulation of adult hippocampal neurogenesis: effects of long-term stimulation and stimulus withdrawal. Hippocampus 9:321–332PubMedGoogle Scholar
  77. Kennard JA, Woodruff-Pak DS (2012) A comparison of low- and high-impact forced exercise: effects of training paradigm on learning and memory. Physiol Behav 106:423–427PubMedPubMedCentralGoogle Scholar
  78. Kerr AL, Steuer EL, Pochtarev V, Swain RA (2010) Angiogenesis but not neurogenesis is critical for normal learning and memory acquisition. Neuroscience 171:214–226PubMedGoogle Scholar
  79. Kobilo T, Liu QR, Gandhi K, Mughal M, Shaham Y, van Praag H (2011) Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learn Mem 18:605–609PubMedPubMedCentralGoogle Scholar
  80. Kramer AF, Erickson KI (2007a) Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends Cogn Sci 11:342–348PubMedGoogle Scholar
  81. Kramer AF, Erickson KI (2007b) Effects of physical activity on cognition, well-being, and brain: human interventions. Alzheimers Dement 3:S45–S51PubMedGoogle Scholar
  82. Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G (2006) Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging 27:1505–1513PubMedGoogle Scholar
  83. Kumar A, Rani A, Tchigranova O, Lee WH, Foster TC (2012) Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology. Neurobiol Aging 33(828):e1–e17Google Scholar
  84. Lambourne K, Tomporowski P (2010) The effect of exercise-induced arousal on cognitive task performance: a meta-regression analysis. Brain Res 1341:12–24PubMedGoogle Scholar
  85. Larson EB, Wang L, Bowen JD, Mccormick WC, Teri L, Crane P, Kukull W (2006) Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 144:73–81PubMedGoogle Scholar
  86. Laurin D, Verreault R, Lindsay J, Macpherson K, Rockwood K (2001) Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol 58:498–504PubMedGoogle Scholar
  87. Laursen TM, Munk-Olsen T, Vestergaard M (2012) Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry 25:83–88PubMedGoogle Scholar
  88. Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP (2008) Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 300:1027–1037PubMedGoogle Scholar
  89. Laviola G, Hannan AJ, Macri S, Solinas M, Jaber M (2008) Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis 31:159–168PubMedGoogle Scholar
  90. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33:569–579PubMedPubMedCentralGoogle Scholar
  91. Leasure JL, Jones M (2008) Forced and voluntary exercise differentially affect brain and behavior. Neuroscience 156:456–465PubMedGoogle Scholar
  92. Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical Activity Series Working Group (2012) Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 380:219–229PubMedPubMedCentralGoogle Scholar
  93. Lessmann V (1998) Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol 31:667–674PubMedGoogle Scholar
  94. Lista I, Sorrentino G (2010) Biological mechanisms of physical activity in preventing cognitive decline. Cell Mol Neurobiol 30:493–503PubMedGoogle Scholar
  95. Mahncke HW, Connor BB, Appelman J, Ahsanuzddin ON, Hardy JL, Wood RA, Joyce NM, Boniske T, Atkins SM, Merzenich MM (2006) Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study. Proc Natl Acad Sci U S A 103:12523–12528PubMedPubMedCentralGoogle Scholar
  96. Mammen G, Faulkner G (2013) Physical activity and the prevention of depression: a systematic review of prospective studies. Am J Prev Med 45:649–657PubMedGoogle Scholar
  97. Mandolesi L, De Bartolo P, Foti F, Gelfo F, Federico F, Leggio MG, Petrosini L (2008) Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion. J Alzheimers Dis 15:11–28PubMedGoogle Scholar
  98. Marais L, Stein DJ, Daniels WM (2009) Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats. Metab Brain Dis 24:587–597PubMedGoogle Scholar
  99. Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, Akerstrom T, Yfanti C, Broholm C, Mortensen OH, Penkowa M, Hojman P, Zankari A, Watt MJ, Bruunsgaard H, Pedersen BK, Febbraio MA (2009) Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 52:1409–1418PubMedGoogle Scholar
  100. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702PubMedPubMedCentralGoogle Scholar
  101. Molteni R, Ying Z, Gomez-Pinilla F (2002) Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray. Eur J Neurosci 16:1107–1116PubMedGoogle Scholar
  102. Mora F, Segovia G, del Arco A (2007) Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev 55:78–88PubMedGoogle Scholar
  103. Naismith SL, Mowszowski L, Diamond K, Lewis SJ (2013) Improving memory in Parkinson’s disease: a healthy brain ageing cognitive training program. Mov Disord 28:1097–1103PubMedGoogle Scholar
  104. Nakahashi T, Fujimura H, Altar CA, Li J, Kambayashi J, Tandon NN, Sun B (2000) Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett 470:113–117PubMedGoogle Scholar
  105. Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW (1996) Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res 726:49–56PubMedGoogle Scholar
  106. Nithianantharajah J, Hannan AJ (2009) The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders. Prog Neurobiol 89:369–382PubMedGoogle Scholar
  107. Nithianantharajah J, Hannan AJ (2011) Mechanisms mediating brain and cognitive reserve: experience-dependent neuroprotection and functional compensation in animal models of neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry 35:331–339PubMedGoogle Scholar
  108. Nouchi R, Taki Y, Takeuchi H, Hashizume H, Akitsuki Y, Shigemune Y, Sekiguchi A, Kotozaki Y, Tsukiura T, Yomogida Y, Kawashima R (2012) Brain training game improves executive functions and processing speed in the elderly: a randomized controlled trial. PLoS One 7:e29676PubMedPubMedCentralGoogle Scholar
  109. O’Callaghan RM, Ohle R, Kelly AM (2007) The effects of forced exercise on hippocampal plasticity in the rat: a comparison of LTP, spatial- and non-spatial learning. Behav Brain Res 176:362–366PubMedGoogle Scholar
  110. O’Callaghan RM, Griffin EW, Kelly AM (2009) Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampus. Hippocampus 19:1019–1029PubMedGoogle Scholar
  111. Oertel-Knochel V, Mehler P, Thiel C, Steinbrecher K, Malchow B, Tesky V, Ademmer K, Prvulovic D, Banzer W, Zopf Y, Schmitt A, Hänsel F (2014) Effects of aerobic exercise on cognitive performance and individual psychopathology in depressive and schizophrenia patients. Eur Arch Psychiatry Clin Neurosci 264(7):589–604PubMedGoogle Scholar
  112. Olafsdottir S, Berg C, Eiben G, Lanfer A, Reisch L, Ahrens W, Kourides Y, Molnar D, Moreno LA, Siani A, Veidebaum T, Lissner L (2014) Young children’s screen activities, sweet drink consumption and anthropometry: results from a prospective European study. Eur J Clin Nutr 68:223–228PubMedGoogle Scholar
  113. Olson AK, Eadie BD, Ernst C, Christie BR (2006) Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16:250–260PubMedGoogle Scholar
  114. Ota KT, Duman RS (2013) Environmental and pharmacological modulations of cellular plasticity: role in the pathophysiology and treatment of depression. Neurobiol Dis 57:28–37PubMedGoogle Scholar
  115. Ozbulut O, Genc A, Bagcioglu E, Coskun KS, Acar T, Alkoc OA, Karabacak H, Sener U, Ucok K (2013) Evaluation of physical fitness parameters in patients with schizophrenia. Psychiatry Res 210:806–811PubMedGoogle Scholar
  116. Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, Kierer A, Muller S, Oest M, Meyer T, Backens M, Schneider-Axmann T, Thornton AE, Honer WG, Falkai P (2010) Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry 67:133–143PubMedGoogle Scholar
  117. Pang TY, Hannan AJ (2013) Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity. Neuropharmacology 64:515–528PubMedGoogle Scholar
  118. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA (2007) An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 104:5638–5643PubMedPubMedCentralGoogle Scholar
  119. Petzinger GM, Fisher BE, Mcewen S, Beeler JA, Walsh JP, Jakowec MW (2013) Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol 12:716–726PubMedPubMedCentralGoogle Scholar
  120. Pontifex MB, Hillman CH, Fernhall B, Thompson KM, Valentini TA (2009) The effect of acute aerobic and resistance exercise on working memory. Med Sci Sports Exerc 41:927–934PubMedGoogle Scholar
  121. Pothakos K, Kurz MJ, Lau YS (2009) Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson’s disease with severe neurodegeneration. BMC Neurosci 10:6PubMedPubMedCentralGoogle Scholar
  122. Querido JS, Sheel AW (2007) Regulation of cerebral blood flow during exercise. Sports Med 37:765–782PubMedGoogle Scholar
  123. Quirie A, Hervieu M, Garnier P, Demougeot C, Mossiat C, Bertrand N, Martin A, Marie C, Prigent-Tessier A (2012) Comparative effect of treadmill exercise on mature BDNF production in control versus stroke rats. PLoS One 7:e44218PubMedPubMedCentralGoogle Scholar
  124. Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, Hart E, Secher NH, Pedersen BK, Pilegaard H (2009) Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol 94:1062–1069PubMedGoogle Scholar
  125. Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A, Dahle C, Gerstorf D, Acker JD (2005) Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15:1676–1689PubMedGoogle Scholar
  126. Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP (2006) Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11:514–522PubMedGoogle Scholar
  127. Robert PH, Berr C, Volteau M, Bertogliati-Fileau C, Benoit M, Guerin O, Sarazin M, Legrain S, Dubois B, PréAL Study Group (2008) Importance of lack of interest in patients with mild cognitive impairment. Am J Geriatr Psychiatry 16:770–776PubMedGoogle Scholar
  128. Rojas Vega S, Struder HK, Vera Wahrmann B, Schmidt A, Bloch W, Hollmann W (2006) Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans. Brain Res 1121:59–65PubMedGoogle Scholar
  129. Rosenzweig MR, Bennett EL (1996) Psychobiology of plasticity: effects of training and experience on brain and behavior. Behav Brain Res 78:57–65PubMedGoogle Scholar
  130. Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M (2005) Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol 4:705–711PubMedGoogle Scholar
  131. Russo-Neustadt AA, Chen MJ (2005) Brain-derived neurotrophic factor and antidepressant activity. Curr Pharm Des 11:1495–1510PubMedGoogle Scholar
  132. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP (2001) Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav Brain Res 120:87–95PubMedGoogle Scholar
  133. Schiffer T, Schulte S, Hollmann W, Bloch W, Struder HK (2009) Effects of strength and endurance training on brain-derived neurotrophic factor and insulin-like growth factor 1 in humans. Horm Metab Res 41:250–254PubMedGoogle Scholar
  134. Schmidt-Kassow M, Deusser M, Thiel C, Otterbein S, Montag C, Reuter M, Banzer W, Kaiser J (2013) Physical exercise during encoding improves vocabulary learning in young female adults: a neuroendocrinological study. PLoS One 8:e64172PubMedPubMedCentralGoogle Scholar
  135. Schmiedek F, Lovden M, Lindenberger U (2010) Hundred days of cognitive training enhance broad cognitive abilities in adulthood: findings from the COGITO study. Front Aging Neurosci 2:27PubMedPubMedCentralGoogle Scholar
  136. Seifert T, Brassard P, Wissenberg M, Rasmussen P, Nordby P, Stallknecht B, Adser H, Jakobsen AH, Pilegaard H, Nielsen HB, Secher NH (2010) Endurance training enhances BDNF release from the human brain. Am J Physiol Regul Integr Comp Physiol 298:R372–R377PubMedGoogle Scholar
  137. Shankar A, Hamer M, McMunn A, Steptoe A (2013) Social isolation and loneliness: relationships with cognitive function during 4 years of follow-up in the English longitudinal study of ageing. Psychosom Med 75:161–170PubMedGoogle Scholar
  138. Sharma HS, Cervos-Navarro J, Dey PK (1991) Increased blood-brain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats. Neurosci Res 10:211–221PubMedGoogle Scholar
  139. Sigwalt AR, Budde H, Helmich I, Glaser V, Ghisoni K, Lanza S, Cadore EL, Lhullier FL, de Bem AF, Hohl A, de Matos FJ, de Oliveira PA, Prediger RD, Guglielmo LG, Latini A (2011) Molecular aspects involved in swimming exercise training reducing anhedonia in a rat model of depression. Neuroscience 192:661–674PubMedGoogle Scholar
  140. Smith GE, Housen P, Yaffe K, Ruff R, Kennison RF, Mahncke HW, Zelinski EM (2009) A cognitive training program based on principles of brain plasticity: results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) study. J Am Geriatr Soc 57:594–603PubMedPubMedCentralGoogle Scholar
  141. Song MR, Lee YS, Baek JD, Miller M (2012) Physical activity status in adults with depression in the National Health and Nutrition Examination Survey, 2005–2006. Public Health Nurs 29:208–217PubMedGoogle Scholar
  142. Soya H, Nakamura T, Deocaris CC, Kimpara A, Iimura M, Fujikawa T, Chang H, Mcewen BS, Nishijima T (2007) BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 358:961–967PubMedGoogle Scholar
  143. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Bostrom E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisen J (2013) Dynamics of hippocampal neurogenesis in adult humans. Cell 153:1219–1227PubMedPubMedCentralGoogle Scholar
  144. Speisman RB, Kumar A, Rani A, Pastoriza JM, Severance JE, Foster TC, Ormerod BK (2013) Environmental enrichment restores neurogenesis and rapid acquisition in aged rats. Neurobiol Aging 34:263–274PubMedPubMedCentralGoogle Scholar
  145. Stranahan AM, Khalil D, Gould E (2007) Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus 17:1017–1022PubMedPubMedCentralGoogle Scholar
  146. Swain RA, Harris AB, Wiener EC, Dutka MV, Morris HD, Theien BE, Konda S, Engberg K, Lauterbur PC, Greenough WT (2003) Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 117:1037–1046PubMedGoogle Scholar
  147. Takahashi H, Sassa T, Shibuya T, Kato M, Koeda M, Murai T, Matsuura M, Asai K, Suhara T, Okubo Y (2012) Effects of sports participation on psychiatric symptoms and brain activations during sports observation in schizophrenia. Transl Psychiatry 2:e96PubMedPubMedCentralGoogle Scholar
  148. Tang SW, Chu E, Hui T, Helmeste D, Law C (2008) Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects. Neurosci Lett 431:62–65PubMedGoogle Scholar
  149. Tang K, Xia FC, Wagner PD, Breen EC (2010) Exercise-induced VEGF transcriptional activation in brain, lung and skeletal muscle. Respir Physiol Neurobiol 170:16–22PubMedPubMedCentralGoogle Scholar
  150. Tardif S, Simard M (2011) Cognitive stimulation programs in healthy elderly: a review. Int J Alzheimers Dis 2011:378934PubMedPubMedCentralGoogle Scholar
  151. Tomporowski PD (2003) Effects of acute bouts of exercise on cognition. Acta Psychol (Amst) 112:297–324Google Scholar
  152. Tomporowski PD, Lambourne K, Okumura MS (2011) Physical activity interventions and children’s mental function: an introduction and overview. Prev Med 52(Suppl 1):S3–S9PubMedPubMedCentralGoogle Scholar
  153. Toscano-Silva M, da Silva Gomes S, Scorza FA, Bonvent JJ, Cavalheiro EA, Arida RM (2010) Hippocampal mossy fiber sprouting induced by forced and voluntary physical exercise. Physiol Behav 101:302–308PubMedGoogle Scholar
  154. Trejo JL, Llorens-Martin MV, Torres-Aleman I (2008) The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 37:402–411PubMedGoogle Scholar
  155. Tuon T, Valvassori SS, Lopes-Borges J, Luciano T, Trom CB, Silva LA, Quevedo J, Souza CT, Lira FS, Pinho RA (2012) Physical training exerts neuroprotective effects in the regulation of neurochemical factors in an animal model of Parkinson’s disease. Neuroscience 227:305–312PubMedGoogle Scholar
  156. Uc EY, Doerschug KC, Magnotta V, Dawson JD, Thomsen TR, Kline JN, Rizzo M, Newman SR, Mehta S, Grabowski TJ, Bruss J, Blanchette DR, Anderson SW, Voss MW, Kramer AF, Darling WG (2014) Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting. Neurology 83(5):413–425PubMedGoogle Scholar
  157. Valero J, Espana J, Parra-Damas A, Martin E, Rodriguez-Alvarez J, Saura CA (2011) Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APP(Sw, Ind) transgenic mice. PLoS One 6:e16832PubMedPubMedCentralGoogle Scholar
  158. Van der Borght K, Kobor-Nyakas DE, Klauke K, Eggen BJ, Nyakas C, Van der Zee EA, Meerlo P (2009) Physical exercise leads to rapid adaptations in hippocampal vasculature: temporal dynamics and relationship to cell proliferation and neurogenesis. Hippocampus 19:928–936PubMedGoogle Scholar
  159. van Praag H (2009) Exercise and the brain: something to chew on. Trends Neurosci 32:283–290PubMedPubMedCentralGoogle Scholar
  160. van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999a) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 96:13427–13431PubMedPubMedCentralGoogle Scholar
  161. van Praag H, Kempermann G, Gage FH (1999b) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270PubMedGoogle Scholar
  162. van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191–198PubMedGoogle Scholar
  163. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034PubMedGoogle Scholar
  164. van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685PubMedPubMedCentralGoogle Scholar
  165. Vancampfort D, Probst M, De Hert M, Soundy A, Stubbs B, Stroobants M, De Herdt A (2014) Neurobiological effects of physical exercise in schizophrenia: a systematic review. Disabil Rehabil 36(21):1749–1754PubMedGoogle Scholar
  166. Vaynman S, Gomez-Pinilla F (2006) Revenge of the “sit”: how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 84:699–715PubMedGoogle Scholar
  167. Vaynman S, Ying Z, Gomez-Pinilla F (2004a) Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res 76:356–362PubMedGoogle Scholar
  168. Vaynman S, Ying Z, Gomez-Pinilla F (2004b) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590PubMedGoogle Scholar
  169. Verghese J, Lipton RB, Katz MJ, Hall CB, Derby CA, Kuslansky G, Ambrose AF, Sliwinski M, Buschke H (2003) Leisure activities and the risk of dementia in the elderly. N Engl J Med 348:2508–2516PubMedGoogle Scholar
  170. Voss MW, Vivar C, Kramer AF, van Praag H (2013) Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci 17:525–544PubMedGoogle Scholar
  171. Watson P, Black KE, Clark SC, Maughan RJ (2006) Exercise in the heat: effect of fluid ingestion on blood-brain barrier permeability. Med Sci Sports Exerc 38:2118–2124PubMedGoogle Scholar
  172. Wilson RS, Barnes LL, de Leon Mendes CF, Aggarwal NT, Schneider JS, Bach J, Pilat J, Beckett LA, Arnold SE, Evans DA, Bennett DA (2002a) Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology 59:364–370PubMedGoogle Scholar
  173. Wilson RS, Bennett DA, Bienias JL, Aggarwal NT, de Leon Mendes CF, Morris MC, Schneider JA, Evans DA (2002b) Cognitive activity and incident AD in a population-based sample of older persons. Neurology 59:1910–1914PubMedGoogle Scholar
  174. Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA (2002c) Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA 287:742–748PubMedGoogle Scholar
  175. Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A, Krueger K, Fromme A, Korsukewitz C, Floel A, Knecht S (2007) High impact running improves learning. Neurobiol Learn Mem 87:597–609PubMedGoogle Scholar
  176. Wolf SA, Melnik A, Kempermann G (2011) Physical exercise increases adult neurogenesis and telomerase activity, and improves behavioral deficits in a mouse model of schizophrenia. Brain Behav Immun 25:971–980PubMedGoogle Scholar
  177. Wu CW, Chang YT, Yu L, Chen HI, Jen CJ, Wu SY, Lo CP, Kuo YM (2008) Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J Appl Physiol (1985) 105:1585–1594Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Physiology, School of Medicine, Level 2, Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland
  2. 2.Trinity College Institute of NeuroscienceTrinity College DublinDublin 2Ireland
  3. 3.Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland

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