The hippocampus is particularly vulnerable to the neurotoxic effects of obesity, diabetes mellitus, hypertension, hypoxic brain injury, obstructive sleep apnoea, bipolar disorder, clinical depression and head trauma. Patients with these conditions often have smaller hippocampi and experience a greater degree of cognitive decline than individuals without these comorbidities. Moreover, hippocampal atrophy is an established indicator for conversion from the normal ageing process to developing mild cognitive impairment and dementia. As such, an important aim is to ascertain which modifiable factors can have a positive effect on the size of the hippocampus throughout life. Observational studies and preliminary clinical trials have raised the possibility that physical exercise, cognitive stimulation and treatment of general medical conditions can reverse age-related atrophy in the hippocampus, or even expand its size. An emerging concept—the dynamic polygon hypothesis—suggests that treatment of modifiable risk factors can increase the volume or prevent atrophy of the hippocampus. According to this hypothesis, a multidisciplinary approach, which involves strategies to both reduce neurotoxicity and increase neurogenesis, is likely to be successful in delaying the onset of cognitive impairment with ageing. Further research on the constellation of interventions that could be most effective is needed before recommendations can be made for implementing preventive and therapeutic strategies.
Atrophy in the hippocampus is a key factor in the process of age-related memory loss and dementia, and might not be solely attributable to Alzheimer disease pathology
Automated MRI measurements of brain size assist in detecting reductions or expansions in hippocampal volume, which can occur with ageing, some medical conditions or neurodegeneration
Vascular risk factors, such as obesity, diabetes mellitus and obstructive sleep apnoea, are associated with a reduction in hippocampal size and early development of cognitive impairment
Elevated levels of inflammatory markers and cortisol, and dynamic changes in the levels of several enzymes and transcription factors, have been implicated in hippocampal atrophy
Cognitive stimulation, physical exercise and treatment of vascular risk factors seem to result in measurable increases in hippocampal volume, in addition to improvements in memory
Improved understanding of the modifiable factors that cause changes in hippocampal volume throughout life will assist in the development of clinical trials aimed at preventing age-related cognitive impairment
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schuff, N. et al. Age-related metabolite changes and volume loss in the hippocampus by magnetic resonance spectroscopy and imaging. Neurobiol. Aging 20, 279–285 (1999).
Driscoll, I. et al. Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. Neurology 72, 1906–1913 (2009).
Driscoll, I. et al. The aging hippocampus: cognitive, biochemical and structural findings. Cereb. Cortex 13, 1344–1351 (2003).
Scheltens, P., Fox, N., Barkhof, F. & De Carli, C. Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion. Lancet Neurol. 1, 13–21 (2002).
Mueller, S. G. et al. Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease. Hum. Brain Mapp. 31, 1339–1347 (2010).
Vemuri, P. et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. Neurology 73, 294–301 (2009).
Henneman, W. J. et al. Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology 72, 999–1007 (2009).
McDonald, C. R. et al. Regional rates of neocortical atrophy from normal aging to early Alzheimer disease. Neurology 73, 457–465 (2009).
Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010).
Jack, C. R. Jr et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 132, 1355–1365 (2009).
Kril, J. J., Hodges, J. & Halliday, G. Relationship between hippocampal volume and CA1 neuron loss in brains of humans with and without Alzheimer's disease. Neurosci. Lett. 361, 9–12 (2004).
Jagust, W. J. et al. Neuropathological basis of magnetic resonance images in aging and dementia. Ann. Neurol. 63, 72–80 (2008).
Nelson, P. T., Braak, H. & Markesbery, W. R. Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J. Neuropathol. Exp. Neurol. 68, 1–14 (2009).
Frisoni, G. B. et al. In vivo mapping of amyloid toxicity in Alzheimer disease. Neurology 72, 1504–1511 (2009).
Tam, C. W., Burton, E. J., McKeith, I. G., Burn, D. J. & O'Brien, J. T. Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies. Neurology 64, 861–865 (2005).
Burton, E. J. et al. Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain 132, 195–203 (2009).
van de Pol, L. A. et al. Hippocampal atrophy on MRI in frontotemporal lobar degeneration and Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 77, 439–442 (2006).
Zarow, C., Sitzer, T. E. & Chui, H. C. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr. Neurol. Neurosci. Rep. 8, 363–370 (2008).
Papadopoulos, D. et al. Substantial archaeocortical atrophy and neuronal loss in multiple sclerosis. Brain Pathol. 19, 238–253 (2009).
Bonilha, L. et al. Asymmetrical extra-hippocampal grey matter loss related to hippocampal atrophy in patients with medial temporal lobe epilepsy. J. Neurol. Neurosurg. Psychiatry 78, 286–294 (2007).
Cendes, F. Progressive hippocampal and extrahippocampal atrophy in drug resistant epilepsy. Curr. Opin. Neurol. 18, 173–177 (2005).
Erten-Lyons, D. et al. Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology 72, 354–360 (2009).
de Leon, M. J. et al. The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation. AJNR Am. J. Neuroradiol. 14, 897–906 (1993).
Scheltens, P. et al. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates. J. Neurol. Neurosurg. Psychiatry 55, 967–972 (1992).
Jack, C. R. Jr et al. Temporal lobe seizures: lateralization with MR volume measurements of the hippocampal formation. Radiology 175, 423–429 (1990).
Jack, C. R. Jr et al. Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults. Radiology 172, 549–554 (1989).
Jack, C. R. Jr, Petersen, R. C., O'Brien, P. C. & Tangalos, E. G. MR-based hippocampal volumetry in the diagnosis of Alzheimer's disease. Neurology 42, 183–188 (1992).
Jack, C. R. Jr et al. Magnetic resonance image-based hippocampal volumetry: correlation with outcome after temporal lobectomy. Ann. Neurol. 31, 138–146 (1992).
Fischl, B. et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341–355 (2002).
Dale, A. M., Fischl, B. & Sereno, M. I. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9, 179–194 (1999).
Barnes, J. et al. A comparison of methods for the automated calculation of volumes and atrophy rates in the hippocampus. Neuroimage 40, 1655–1671 (2008).
Whitwell, J. L., Crum, W. R., Watt, H. C. & Fox, N. C. Normalization of cerebral volumes by use of intracranial volume: implications for longitudinal quantitative MR imaging. AJNR Am. J. Neuroradiol. 22, 1483–1489 (2001).
Jack, C. R. Jr et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology 49, 786–794 (1997).
Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).
Du, A. T. et al. Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiol. Aging 27, 733–740 (2006).
Du, A. T. et al. Effects of subcortical ischemic vascular dementia and AD on entorhinal cortex and hippocampus. Neurology 58, 1635–1641 (2002).
Zarow, C. et al. Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia. Ann. Neurol. 57, 896–903 (2005).
Scher, A. I. et al. Hippocampal morphometry in population-based incident Alzheimer's disease and vascular dementia: the HAAS. J. Neurol. Neurosurg. Psychiatry 82, 373–376 (2011).
Kril, J. J., Patel, S., Harding, A. J. & Halliday, G. M. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J. Neurol. Neurosurg. Psychiatry 72, 747–751 (2002).
Fotuhi, M., Hachinski, V. & Whitehouse, P. J. Changing perspectives regarding late-life dementia. Nat. Rev. Neurol. 5, 649–658 (2009).
Menteer, J., Macey, P. M., Woo, M. A., Panigrahy, A. & Harper, R. M. Central nervous system changes in pediatric heart failure: a volumetric study. Pediatr. Cardiol. 31, 969–976 (2010).
Whitmer, R. A. et al. Central obesity and increased risk of dementia more than three decades later. Neurology 71, 1057–1064 (2008).
Yaffe, K. et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292, 2237–2242 (2004).
Raji, C. A., Lopez, O. L., Kuller, L. H., Carmichael, O. T. & Becker, J. T. Age, Alzheimer disease, and brain structure. Neurology 73, 1899–1905 (2009).
Ho, A. J. et al. The effects of physical activity, education, and body mass index on the aging brain. Hum. Brain Mapp. 32, 1371–1382 (2010).
Jagust, W., Harvey, D., Mungas, D. & Haan, M. Central obesity and the aging brain. Arch. Neurol. 62, 1545–1548 (2005).
Knopman, D. S. Go to the head of the class to avoid vascular dementia and skip diabetes and obesity. Neurology 71, 1046–1047 (2008).
Raji, C. A. et al. Brain structure and obesity. Hum. Brain Mapp. 31, 353–364 (2010).
Taki, Y. et al. Relationship between body mass index and gray matter volume in 1,428 healthy individuals. Obesity (Silver Spring) 16, 119–124 (2008).
den Heijer, T. et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 46, 1604–1610 (2003).
Gold, S. M. et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50, 711–719 (2007).
Korf, E. S., White, L. R., Scheltens, P. & Launer, L. J. Brain aging in very old men with type 2 diabetes: the Honolulu-Asia Aging Study. Diabetes Care 29, 2268–2274 (2006).
Hayashi, K. et al. Association of cognitive dysfunction with hippocampal atrophy in elderly Japanese people with type 2 diabetes. Diabetes Res. Clin. Pract. 94, 180–185 (2011).
Bruehl, H., Sweat, V., Tirsi, A., Shah, B. & Convit, A. Obese adolescents with type 2 diabetes mellitus have hippocampal and frontal lobe volume reductions. Neurosci. Med. 2, 34–42 (2011).
den Heijer, T. et al. Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology 64, 263–267 (2005).
Korf, E. S., White, L. R., Scheltens, P. & Launer, L. J. Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study. Hypertension 44, 29–34 (2004).
Wiseman, R. M. et al. Hippocampal atrophy, whole brain volume, and white matter lesions in older hypertensive subjects. Neurology 63, 1892–1897 (2004).
Gadian, D. G. et al. Developmental amnesia associated with early hypoxic–ischaemic injury. Brain 123, 499–507 (2000).
Fujioka, M. et al. Hippocampal damage in the human brain after cardiac arrest. Cerebrovasc. Dis. 10, 2–7 (2000).
Fujioka, M. et al. Human hippocampal damage after cardiac arrest. Intensive Care Med. 22, S94 (1996).
Petito, C. K., Feldmann, E., Pulsinelli, W. A. & Plum, F. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37, 1281–1286 (1987).
Di Paola, M. et al. Hippocampal atrophy is the critical brain change in patients with hypoxic amnesia. Hippocampus 18, 719–728 (2008).
Horstmann, A. et al. Resuscitating the heart but losing the brain: brain atrophy in the aftermath of cardiac arrest. Neurology 74, 306–312 (2010).
McIlroy, S. P., Dynan, K. B., Lawson, J. T., Patterson, C. C. & Passmore, A. P. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 33, 2351–2356 (2002).
den Heijer, T. et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126, 170–175 (2003).
Firbank, M. J., Narayan, S. K., Saxby, B. K., Ford, G. A. & O'Brien, J. T. Homocysteine is associated with hippocampal and white matter atrophy in older subjects with mild hypertension. Int. Psychogeriatr. 22, 804–811 (2010).
Videbech, P. & Ravnkilde, B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am. J. Psychiatry 161, 1957–1966 (2004).
Campbell, S. & MacQueen, G. An update on regional brain volume differences associated with mood disorders. Curr. Opin. Psychiatry 19, 25–33 (2006).
Steffens, D. C. et al. Hippocampal volume in geriatric depression. Biol. Psychiatry 48, 301–309 (2000).
Steffens, D. C. et al. Hippocampal volume and incident dementia in geriatric depression. Am. J. Geriatr. Psychiatry 10, 62–71 (2002).
McKinnon, M. C., Yucel, K., Nazarov, A. & MacQueen, G. M. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. J. Psychiatry Neurosci. 34, 41–54 (2009).
Maller, J. J. et al. Hippocampal volumetrics in treatment-resistant depression and schizophrenia: the devil's in de-tail. Hippocampus 22, 9–16 (2012).
Dotson, V. M., Davatzikos, C., Kraut, M. A. & Resnick, S. M. Depressive symptoms and brain volumes in older adults: a longitudinal magnetic resonance imaging study. J. Psychiatry Neurosci. 34, 367–375 (2009).
Wrench, J. M., Wilson, S. J., Bladin, P. F. & Reutens, D. C. Hippocampal volume and depression: insights from epilepsy surgery. J. Neurol. Neurosurg. Psychiatry 80, 539–544 (2009).
Zou, K. et al. Changes of brain morphometry in first-episode, drug-naive, non-late-life adult patients with major depression: an optimized voxel-based morphometry study. Biol. Psychiatry 67, 186–188 (2010).
Cheng, Y. Q. et al. Brain volume alteration and the correlations with the clinical characteristics in drug-naive first-episode MDD patients: a voxel-based morphometry study. Neurosci. Lett. 480, 30–34 (2010).
Bremner, J. D., Southwick, S. M., Darnell, A. & Charney, D. S. Chronic PTSD in Vietnam combat veterans: course of illness and substance abuse. Am. J. Psychiatry 153, 369–375 (1996).
Gurvits, T. V. et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol. Psychiatry 40, 1091–1099 (1996).
Bremner, J. D. et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report. Biol. Psychiatry 41, 23–32 (1997).
Bonne, O. et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am. J. Psychiatry 158, 1248–1251 (2001).
Agartz, I., Momenan, R., Rawlings, R. R., Kerich, M. J. & Hommer, D. W. Hippocampal volume in patients with alcohol dependence. Arch. Gen. Psychiatry 56, 356–363 (1999).
Schuff, N. et al. Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder. Biol. Psychiatry 50, 952–959 (2001).
Neylan, T. C. et al. Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. Biol. Psychiatry 68, 494–496 (2010).
Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 5, 1242–1247 (2002).
De Bellis, M. D., Hall, J., Boring, A. M., Frustaci, K. & Moritz, G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol. Psychiatry 50, 305–309 (2001).
Nixon, K., Morris, S. A., Liput, D. J. & Kelso, M. L. Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders. Alcohol 44, 39–56 (2010).
Orrison, W. W. et al. Traumatic brain injury: a review and high-field MRI findings in 100 unarmed combatants using a literature-based checklist approach. J. Neurotrauma 26, 689–701 (2009).
Bigler, E. D. et al. Hippocampal volume in normal aging and traumatic brain injury. AJNR Am. J. Neuroradiol. 18, 11–23 (1997).
Ariza, M. et al. Hippocampal head atrophy after traumatic brain injury. Neuropsychologia 44, 1956–1961 (2006).
Beauchamp, M. H. et al. Hippocampus, amygdala and global brain changes 10 years after childhood traumatic brain injury. Int. J. Dev. Neurosci. 29, 137–143 (2011).
Bigler, E. D. Brain imaging and behavioral outcome in traumatic brain injury. J. Learn. Disabil. 29, 515–530 (1996).
Bigler, E. D. et al. Traumatic brain injury, alcohol and quantitative neuroimaging: preliminary findings. Brain Inj. 10, 197–206 (1996).
Bigler, E. D., Clark, E. & Farmer, J. Traumatic brain injury: 1990s update—introduction to the special series. J. Learn. Disabil. 29, 512–513 (1996).
Himanen, L. et al. Cognitive functions in relation to MRI findings 30 years after traumatic brain injury. Brain Inj. 19, 93–100 (2005).
Serra-Grabulosa, J. M. et al. Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury. J. Neurol. Neurosurg. Psychiatry 76, 129–131 (2005).
Tate, D. F. & Bigler, E. D. Fornix and hippocampal atrophy in traumatic brain injury. Learn. Mem. 7, 442–446 (2000).
DeKosky, S. T., Ikonomovic, M. D. & Gandy, S. Traumatic brain injury—football, warfare, and long-term effects. N. Engl. J. Med. 363, 1293–1296 (2010).
Costanza, A. et al. Review: contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates. Neuropathol. Appl. Neurobiol. 37, 570–584 (2011).
Nemetz, P. N. et al. Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. Am. J. Epidemiol. 149, 32–40 (1999).
Johnson, V. E., Stewart, W. & Smith, D. H. Widespread tau and amyloid-β pathology many years after a single traumatic brain injury in humans. Brain Pathol. http://dx.doi.org/10.1111/j.1750-3639.2011.00513.x.
Middleton, L. E. & Yaffe, K. Promising strategies for the prevention of dementia. Arch. Neurol. 66, 1210–1215 (2009).
Macey, P. M. et al. Brain morphology associated with obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 166, 1382–1387 (2002).
Yaouhi, K. et al. A combined neuropsychological and brain imaging study of obstructive sleep apnea. J. Sleep Res. 18, 36–48 (2009).
Morrell, M. J. et al. Changes in brain morphology in patients with obstructive sleep apnoea. Thorax 65, 908–914 (2010).
Yamada, N. et al. Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology 152, 2634–2643 (2011).
Musen, G. et al. Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes 55, 326–333 (2006).
Hershey, T. et al. Hippocampal volumes in youth with type 1 diabetes. Diabetes 59, 236–241 (2009).
Grundy, S. M. et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100, 1134–1146 (1999).
Perantie, D. C. et al. Prospectively determined impact of type 1 diabetes on brain volume during development. Diabetes 60, 3006–3014 (2011).
Bruehl, H., Wolf, O. T. & Convit, A. A blunted cortisol awakening response and hippocampal atrophy in type 2 diabetes mellitus. Psychoneuroendocrinology 34, 815–821 (2009).
Bruehl, H. et al. Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res. 1280, 186–194 (2009).
Trudeau, F., Gagnon, S. & Massicotte, G. Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus. Eur. J. Pharmacol. 490, 177–186 (2004).
Joëls, M. & Baram, T. Z. The neuro-symphony of stress. Nat. Rev. Neurosci. 10, 459–466 (2009).
Campbell, S. & Macqueen, G. The role of the hippocampus in the pathophysiology of major depression. J. Psychiatry Neurosci. 29, 417–426 (2004).
Erickson, K. I. et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl Acad. Sci. USA 108, 3017–3022 (2011).
Lazarov, O., Mattson, M. P., Peterson, D. A., Pimplikar, S. W. & van Praag, H. When neurogenesis encounters aging and disease. Trends Neurosci. 33, 569–579 (2010).
Fotuhi, M., Standaert, D. G., Testa, C. M., Penney, J. B. Jr & Young, A. B. Differential expression of metabotropic glutamate receptors in the hippocampus and entorhinal cortex of the rat. Brain Res. Mol. Brain Res. 21, 283–292 (1994).
Rybnikova, E., Glushchenko, T., Churilova, A., Pivina, S. & Samoilov, M. Expression of glucocorticoid and mineralocorticoid receptors in hippocampus of rats exposed to various modes of hypobaric hypoxia: putative role in hypoxic preconditioning. Brain Res. 1381, 66–77 (2011).
Appenzeller, S., Carnevalle, A. D., Li, L. M., Costallat, L. T. & Cendes, F. Hippocampal atrophy in systemic lupus erythematosus. Ann. Rheum. Dis. 65, 1585–1589 (2006).
Sankar, R., Auvin, S., Mazarati, A. & Shin, D. Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain. Acta Neurol. Scand. Suppl. 186, 16–20 (2007).
Cunningham, C. et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol. Psychiatry 65, 304–312 (2009).
Tateno, M. & Saito, T. Biological studies on alcohol-induced neuronal damage. Psychiatry Investig. 5, 21–27 (2008).
Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat. Neurosci. 1, 69–73 (1998).
Starkman, M. N. et al. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Biol. Psychiatry 46, 1595–1602 (1999).
Huang, C. W. et al. Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer's disease. J. Clin. Neurosci. 16, 1283–1286 (2009).
Wu, A., Ying, Z. & Gomez-Pinilla, F. Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury. J. Neurotrauma 24, 1587–1595 (2007).
Erickson, K. I. et al. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 19, 1030–1039 (2009).
Verghese, J. et al. Leisure activities and the risk of dementia in the elderly. N. Engl. J. Med. 348, 2508–2516 (2003).
Draganski, B. et al. Neuroplasticity: changes in grey matter induced by training. Nature 427, 311–312 (2004).
Ilg, R. et al. Gray matter increase induced by practice correlates with task-specific activation: a combined functional and morphometric magnetic resonance imaging study. J. Neurosci. 28, 4210–4215 (2008).
Draganski, B. et al. Temporal and spatial dynamics of brain structure changes during extensive learning. J. Neurosci. 26, 6314–6317 (2006).
Fortin, M. et al. Wayfinding in the blind: larger hippocampal volume and supranormal spatial navigation. Brain 131, 2995–3005 (2008).
Maguire, E. A. et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc. Natl Acad. Sci. USA 97, 4398–4403 (2000).
Woollett, K. & Maguire, E. A. Acquiring “the knowledge” of London's layout drives structural brain changes. Curr. Biol. 21, 2109–2114 (2011).
Smith, P. F., Darlington, C. L. & Zheng, Y. Move it or lose it—is stimulation of the vestibular system necessary for normal spatial memory? Hippocampus 20, 36–43 (2010).
Brandt, T. et al. Vestibular loss causes hippocampal atrophy and impaired spatial memory in humans. Brain 128, 2732–2741 (2005).
Smith, P. F., Geddes, L. H., Baek, J. H., Darlington, C. L. & Zheng, Y. Modulation of memory by vestibular lesions and galvanic vestibular stimulation. Front. Neurol. 1, 141 (2010).
Duerden, E. G. & Laverdure-Dupont, D. Practice makes cortex. J. Neurosci. 28, 8655–8657 (2008).
May, A. Experience-dependent structural plasticity in the adult human brain. Trends Cogn. Sci. 15, 475–482 (2011).
Bezzola, L., Mérillat, S., Gaser, C. & Jäncke, L. Training-induced neural plasticity in golf novices. J. Neurosci. 31, 12444–12448 (2011).
Yaffe, K., Barnes, D., Nevitt, M., Lui, L. Y. & Covinsky, K. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch. Intern. Med. 161, 1703–1708 (2001).
Larson, E. B. Physical activity for older adults at risk for Alzheimer disease. JAMA 300, 1077–1079 (2008).
Geda, Y. E. et al. Physical exercise, aging, and mild cognitive impairment: a population-based study. Arch. Neurol. 67, 80–86 (2010).
Erickson, K. I. et al. Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study. Neurology 75, 1415–1422 (2010).
Pajonk, F. G. et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch. Gen. Psychiatry 67, 133–143 (2010).
Hölzel, B. K. et al. Investigation of mindfulness meditation practitioners with voxel-based morphometry. Soc. Cogn. Affect. Neurosci. 3, 55–61 (2008).
Luders, E., Toga, A. W., Lepore, N. & Gaser, C. The underlying anatomical correlates of long-term meditation: larger hippocampal and frontal volumes of gray matter. Neuroimage 45, 672–678 (2009).
Hölzel, B. K. et al. Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Res. 191, 36–43 (2011).
Tendolkar, I. et al. One-year cholesterol lowering treatment reduces medial temporal lobe atrophy and memory decline in stroke-free elderly with atrial fibrillation: evidence from a parallel group randomized trial. Int. J. Geriatr. Psychiatry 27, 49–58 (2012).
Canessa, N. et al. Obstructive sleep apnea: brain structural changes and neurocognitive function before and after treatment. Am. J. Respir. Crit. Care Med. 183, 1419–1426 (2011).
Nordanskog, P. et al. Increase in hippocampal volume after electroconvulsive therapy in patients with depression: a volumetric magnetic resonance imaging study. J. ECT 26, 62–67 (2010).
Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).
Sheline, Y. I., Gado, M. H. & Kraemer, H. C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).
Warner-Schmidt, J. L. & Duman, R. S. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16, 239–249 (2006).
Perera, T. D. et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J. Neurosci. 27, 4894–4901 (2007).
Yucel, K. et al. Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl.) 195, 357–367 (2007).
Yucel, K. et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 33, 361–367 (2008).
Gazdzinski, S. et al. Chronic cigarette smoking modulates injury and short-term recovery of the medial temporal lobe in alcoholics. Psychiatry Res. 162, 133–145 (2008).
Singleton, R. H., Yan, H. Q., Fellows-Mayle, W. & Dixon, C. E. Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J. Neurotrauma 27, 1091–1099 (2010).
Aiguo, W., Zhe, Y. & Gomez-Pinilla, F. Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil. Neural Repair 24, 290–298 (2010).
Lobnig, B. M., Krömeke, O., Optenhostert-Porst, C. & Wolf, O. T. Hippocampal volume and cognitive performance in long-standing type 1 diabetic patients without macrovascular complications. Diabet. Med. 23, 32–39 (2006).
Sheline, Y. I., Sanghavi, M., Mintun, M. A. & Gado, M. H. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J. Neurosci. 19, 5034–5043 (1999).
Ashtari, M. et al. Hippocampal/amygdala volumes in geriatric depression. Psychol. Med. 29, 629–638 (1999).
Bremner, J. D. et al. Hippocampal volume reduction in major depression. Am. J. Psychiatry 157, 115–118 (2000).
Janssen, J. et al. Hippocampal volume and subcortical white matter lesions in late life depression: comparison of early and late onset depression. J. Neurol. Neurosurg. Psychiatry 78, 638–640 (2007).
Hedges, D. W. et al. Reduced hippocampal volume in alcohol and substance naive Vietnam combat veterans with posttraumatic stress disorder. Cogn. Behav. Neurol. 16, 219–224 (2003).
Winter, H. & Irle, E. Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. Am. J. Psychiatry 161, 2194–2200 (2004).
Jatzko, A. et al. Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods. J. Affect. Disord. 94, 121–126 (2006).
Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).
Carrion, V. G. et al. Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder. Biol. Psychiatry 50, 943–951 (2001).
Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924–932 (2003).
Groussard, M. et al. When music and long-term memory interact: effects of musical expertise on functional and structural plasticity in the hippocampus. PloS ONE 5, e13225 (2010).
The authors would like to thank Dr M. Haan, Dr T. den Heijer, E. Mayeda, Dr V. Carrion, Dr C. Weems and Dr G. Musen for sharing their data on hippocampal volumetry.
The authors declare no competing financial interests.
About this article
Cite this article
Fotuhi, M., Do, D. & Jack, C. Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol 8, 189–202 (2012). https://doi.org/10.1038/nrneurol.2012.27
Hippocampus Segmentation for Preterm and Aging Brains Using 3D Densely Connected Fully Convolutional Networks
IEEE Access (2020)
Train the brain with music (TBM): brain plasticity and cognitive benefits induced by musical training in elderly people in Germany and Switzerland, a study protocol for an RCT comparing musical instrumental practice to sensitization to music
BMC Geriatrics (2020)
Occupational Physical Stress Is Negatively Associated With Hippocampal Volume and Memory in Older Adults
Frontiers in Human Neuroscience (2020)