Review
Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: review and meta-analysis

https://doi.org/10.1016/j.neuropsychologia.2004.04.006Get rights and content

Abstract

Poor memory ability and small hippocampal volume measurements in magnetic resonance images co-occur in neurological patients. Numerous studies have examined the relationship between memory performance and hippocampal volumes in participants without neurological or psychiatric disorders, with widely varying results. Three hypotheses about volume–memory relationships in the normal human brain are discussed: “bigger is always better”, a neuropsychological view that volume decreases due to normal aging are accompanied by memory decline, and a developmental perspective that regressive events in development may result in negative correlations between hippocampal volume and memory ability. Meta-analysis of results from 33 studies led to little support for the bigger-is-better hypothesis. A negative relationship between hippocampal volume and memory (smaller is better) was significant for studies with children, adolescents, and young adults. For studies with older adults, the most striking observation was extreme variability: the evidence for a positive relationship between hippocampal size and episodic memory ability in older adults was surprisingly weak. Some of the variability in results from older adults was associated with statistical methods of normalizing for age and head size, which are discussed.

Introduction

Most, if not all, of the cerebral cortex is likely to subserve the learning and retrieval of facts and events, with the engagement of specific regions dependent on the nature of the material learned (see Damasio, 1989; McClelland, McNaughton, & O’Reilly, 1995 for theoretical accounts, and Köhler, Moscovitch, Wincocur, Houle, & McIntosh, 1998; Nyberg, Habib, McIntosh, & Tulving, 2000; Senkfor, Van Petten, & Kutas, 2002; Wheeler, Peterson, & Buckner, 2000 for empirical reports). Despite general acceptance of the idea that memory is not localized to one neural structure, there is overwhelming evidence that the medial temporal lobe (MTL) plays a central role in episodic memory for diverse material, via its interactions with distributed cortical regions (Scoville & Milner, 1957). The MTL consists of multiple cortical areas, including the hippocampal formation, surrounding entorhinal, perirhinal, and posterior parahippocampal regions within the parahippocampal gyrus in humans, and part of the temporal pole (Insausti et al., 1998a, Insausti et al., 1998b). Although many cases of human domain-general amnesia have damage to multiple regions of the medial temporal lobe, or to the diencephalon (Aggleton & Brown, 1999; Brown & Aggleton, 2001; Mayes, 2000; Smith & Bigel, 2000), lesions restricted to the hippocampus alone result in memory deficits in both humans and nonhuman primates (Rempel-Clower, Zola, Squire, & Amaral, 1996; Zola & Squire, 2000). The latter conclusion was drawn from postmortem examination of the affected brains, but the availability of high-resolution magnetic resonance images has led to a more widespread research effort to tie hippocampal pathology to memory impairment over the last decade.

MR scans are used to identify and/or confirm the location of damage after a frank neural insult such as stroke, hypoxia, or closed head injury. But an additional advantage of a noninvasive method is the possibility of identifying subtle neural damage when the insult is not as obvious. Recent studies have examined hippocampal volumes in individuals with childhood seizures, posttraumatic stress disorder, borderline personality disorder, depression, high risk of schizophrenia due to affected relatives, an ApoE-4 allele, and high estrogen levels (Bremner et al., 1995; Cohen, Small, Lalonde, Friz, & Sunderland, 2001; den Heijer et al., 2003, Driessen et al., 2000; Fennema-Notestine, Stein, Kennedy, Archibald, & Jernigan, 2002; Lawson et al., 2000, O’Driscoll et al., 2001, Plassman et al., 1997, Seidman et al., 2002; Sheline, Sanghavi, Mintun, & Gado, 1999; Simpson, Baldwin, Burns, & Jackson, 2001; Stein, Koverola, Hanna, Rochia, & McClarty, 1997; VanLandingham, Heinz, Cavazoa, & Lewis, 1998). Particularly strong attention has focused on the possibility of detecting Alzheimer’s disease before its clinical onset, when interventions might be more effective (see Chetelat & Baron, 2003; Kantarci et al., 2002, Wolf et al., 2003 for recent reviews).

Some clinical investigations have included measures of memory performance in additional to MR measures. When pathology is clearly present, these studies have largely succeeded in demonstrating quantitative relationships between hippocampal volumes and memory. Positive correlations between hippocampal volume and memory performance have been frequently reported in Alzheimer’s patients, for instance, as well as in other varieties of dementia, and in amnesic patients of mixed etiology (Barber, McKeith, Ballard, Gholkar, & O’Brien, 2001; Cahn et al., 1998, de Toledo-Morrell et al., 2000, Deweer et al., 1995; Jernigan et al., 2001, Jernigan et al., 2001; Köhler, Black, et al., 1998; Kopelman et al., 2001; Mizuno, Wakai, Takeda, & Sobue, 2000; Mungas et al., 2002, Petersen et al., 2000, Wilson et al., 1996). Such correlations have also been observed in samples for which memory performance is at the borderline of clinical impairment, and a pathological process is suspected, as in older adults with mild cognitive impairment (Jack et al., 2000, Soininen et al., 1994).1

These clinical studies, and the expanding application of MR volumetry to diverse populations, raise a fundamental question: what is the relationship between hippocampal volume and memory ability in the normal brain? Given that the measured size of hippocampi varies a good deal across healthy individuals, and memory abilities also vary, is there a detectable structure–function relationship? When this question is posed bluntly, the response of many cognitive neuroscientists is likely to be “no”, in part because macroscopic size is the crudest of neurobiological metrics, and in part because the question elicits memories of the failures of phrenology a century ago. In response, it might be argued that the cognitive psychology of the 21st century is more sophisticated than what the phrenologists had to work with, so that it may be more plausible to imagine size/function relationships for “episodic memory” than for the various “faculties” proposed by Gall and Spurzheim (but see Uttal, 2001 for a thoughtful and critical discussion of the history and current status of cognitive taxonomies and the limits of localization). More to the point, a survey of the literature indicates that a modern exercise in searching for size/function relationships is already underway. Numerous recent studies report significant correlations between hippocampal volumes and memory across individuals without a neurological or psychiatric diagnosis. However, numerous studies have also failed to find such relationships; these null results are less frequently cited, perhaps because they often occur in brief descriptions of results from a control group and are overshadowed by results from a patient group.

The discrepancy among published reports may result from random variability around a mean of zero correlation. Alternatively, both significant and null results across studies could arise from a subtle but genuine relationship. By analogy, the impact on cognitive function of white matter hyperintensities (WMH) observed in MR images from healthy older adults on cognitive function was subject to debate for some time, as the first several studies variously reported a negative relationship with cognitive performance (Rao, Mittenberg, Bernardin, Haughton, & Leo, 1989; Schmidt et al., 1991), or no detectable relationship (Hunt et al., 1989, Mirsen et al., 1991; Tupler, Coffey, Logue, Djang, & Fagan, 1992). In that case, pooling results from multiple studies to obtain a larger combined N was successful in demonstrating a moderate negative impact of WMHs on cognitive performance (Gunning-Dixon & Raz, 2000). The present paper evaluates whether pooling results from multiple studies in a meta-analysis will similarly show a relationship between hippocampal volumes and memory ability. Below, I first describe alternative hypotheses about this relationship, which guide the subsequent analyses.

Section snippets

Bigger is better

Three general hypotheses about the possible relationship between hippocampal volume and memory ability can be imagined. The first and simplest is the bigger is better (BIB) hypothesis, that regardless of the causal factors underlying the size of a structure, a larger structure should result in stronger function. This hypothesis seems to be implicit in some reports, but the investigators who have explicitly considered the BIB hypothesis have rejected it, because they observed significant

Search and inclusion criteria

Papers reporting relationships between hippocampal volumes and memory measures were located by a search of the Medline and PsycLit databases using the keyword combination (hippocampus OR hippocampal OR medial temporal) AND (memory OR recognition OR recall OR neuropsychological) AND (volume OR volumetric OR atrophy), and by examining the references of those papers. Results were included when they met all of the following criteria: (1) publication in English; (2) participants without a

Common correlation across studies, and heterogeneity of the results

The common correlation between hippocampal volume and memory performance across all 33 studies (weighted by sample size) was 0.071 (Ztest=3.00, P<0.005). Although the estimated correlation across studies was significantly positive, Table 1 shows a great deal of variability across studies: reported correlations range from positive 0.55 to negative 0.55. Fig. 1 shows the distribution of reported correlations, which appears to deviate from normal. The heterogeneity test confirmed the visual

Limitations of meta-analyses

A potential hazard of any meta-analysis is the so-called “file drawer problem”: studies that are unpublished due to null or difficult-to-interpret results. Some protections against this problem are built into the present topic. The first stems from the expense, effort, and relative novelty of relating structural MR data to cognition, so that investigators are likely to be strongly motivated to publish, and editors likely to show a similar interest. The second protection applies to a subset of

Acknowledgements

I am grateful to Patrick Davidson and Elizabeth Glisky for discovering some of the relevant papers in the literature, and to Trudy Kuo for comments on the manuscript. Four anonymous reviewers also provided extremely constructive comments on a previous version of this paper. Financial support was provided by the National Institute of Aging (AG14792).

References (151)

  • V.H Hackert et al.

    Hippocampal head size associated with verbal memory performance in nondemented elderly

    Neuroimage

    (2002)
  • H Hampel et al.

    Age transformation of combined hippocampus and amygdala volume improves diagnostic accuracy in Alzheimer’s disease

    Journal of the Neurological Sciences

    (2002)
  • T.L Jernigan et al.

    Effect of age on tissues and regions of the cerebrum and cerebellum

    Neurobiology of Aging

    (2001)
  • J Klekamp et al.

    Morphometric study on the postnatal growth of the hippocampus in Australian Aborigines and Caucasians

    Brain Research

    (1991)
  • S Köhler et al.

    Memory impairments associated with hippocampal versus parahippocampal-gyrus atrophy: An MR volumetry study in Alzheimer’s disease

    Neuropsychologia

    (1998)
  • S Köhler et al.

    Networks of domain-specific and general regions involved in episodic memory for spatial location and object identity

    Neuropsychologia

    (1998)
  • M.P Laakso et al.

    Diagnosis of Alzheimer’s disease: MRI of the hippocampus vs. delayed recall

    Neuropsychologia

    (2000)
  • J Lieberman et al.

    Ziskind Somerfeld Research Award: Longitudinal study of brain morphology in first episode schizophrenia

    Biological Psychiatry

    (2001)
  • D.H Mathalon et al.

    Correction for head size in brain-imaging measurements

    Psychiatry Research: Neuroimaging

    (1993)
  • R.F McGivern et al.

    Sex differences in visual recognition memory: Support for a sex-related difference in attention in adults and children

    Brain and Cognition

    (1997)
  • K Mizuno et al.

    Medial temporal atrophy and memory impairment in early stage of Alzheimer’s disease: An MRI volumetric and memory assessment study

    Journal of the Neurological Sciences

    (2000)
  • G.A O’Driscoll et al.

    Amygdala-hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients

    Psychiatry Research: Neuroimaging

    (2001)
  • M Peters et al.

    Unsolved problems in comparing brain sizes in Homo Sapiens

    Brain and Cognition

    (1998)
  • J.P Aggleton et al.

    Episodic memory, amnesia and the hippocampal-anterior thalamic axis

    Behavioral and Brain Sciences

    (1999)
  • W.R Atchley et al.

    Statistical properties of ratios. I. Empirical results

    Systematic Zoology

    (1976)
  • R Barber et al.

    A comparison of medial and lateral temporal lobe atrophy in dementia with Lewy bodies and Alzheimer’s disease: Magnetic resonance imaging volumetric study

    Dementia and Geriatric Cognitive Disorders

    (2001)
  • W.W Beatty et al.

    RBANS performance: Influences of sex and education

    Journal of Clinical and Experimental Neuropsychology

    (2003)
  • I Bourdeaux et al.

    Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism

    Journal of Clinical Endrocrinology and Metabolism

    (2002)
  • J.D Bremner et al.

    MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder

    American Journal of Psychiatry

    (1995)
  • M.W Brown et al.

    Recognition memory: What are the roles of the perirhinal cortex and hippocampus?

    Nature Reviews Neuroscience

    (2001)
  • D.A Cahn et al.

    Structural MRI correlates of recognition memory in Alzheimer’s disease

    Journal of the International Neuropsychological Society

    (1998)
  • H Christensen et al.

    An analysis of diversity in the cognitive performance of elderly community dwellers: Individual differences in change scores as a function of age

    Psychology and Aging

    (1999)
  • Coffey, C. E. (2000). Anatomic imaging of the aging human brain. In: C. E. Coffey, J. L. Cummings (Eds.), Textbook of...
  • R.M Cohen et al.

    Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women

    Neurology

    (2001)
  • A Convit et al.

    Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly

    Proceedings of the National Academy of Sciences of the United States of America

    (2003)
  • E Courchesne et al.

    Normal brain development and aging: Quantitative analysis at in vivo MR imaging in healthy volunteers

    Radiology

    (2000)
  • W.M Cowan et al.

    Regressive events in neurogenesis

    Science

    (1984)
  • L de Toledo-Morrell et al.

    Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer’s disease

    Hippocampus

    (2000)
  • I.J Deary et al.

    Cerebral white matter abnormalities and lifetime cognitive change: A 67-year followup of the Scottish Mental Survey of 1932

    Psychology and Aging

    (2003)
  • T den Heijer et al.

    Higher estrogen levels are not associated with larger hippocampi and better memory performance

    Archives of Neurology

    (2003)
  • P.A Devolder

    Comparison of within-group variabilities across older and younger adults: A meta-analysis

    Experimental Aging Research

    (1991)
  • B Deweer et al.

    Memory disorders in probable Alzheimer’s disease: The role of hippocampal atrophy as shown with MRI

    Journal of Neurology, Neurosurgery and Psychiatry

    (1995)
  • M Driessen et al.

    Magnetic resonance imaging volumes of the hippocampus and amygdala in women with borderline personality disorder and early traumatization

    Archives of General Psychiatry

    (2000)
  • I Driscoll et al.

    The aging hippocampus: Cognitive, biochemical and structural findings

    Cerebral Cortex

    (2003)
  • A.T Du et al.

    Atrophy rates of entorhinal cortex in AD and normal aging

    Neurology

    (2003)
  • Edwards, A. L. (1963). Experimental design in psychological research. New York: Holt, Rinehart and...
  • J.K Foster et al.

    The hippocampus and delayed recall, bigger is not necessarily better?

    Memory

    (1999)
  • Y Ge et al.

    Age-related total gray and white matter changes in normal adult brain. Part I: Volumetric MR imaging analysis

    American Journal of Neuroradiology

    (2002)
  • J.N Giedd et al.

    Brain development during childhood and adolescence: A longitudinal MRI study

    Nature Neuroscience

    (1999)
  • J.N Giedd et al.

    Quantitative MRI of the temporal lobe, amygdala, and hippocampus in normal human development: Ages 4–18 years

    Journal of Comparative Neurology

    (1996)
  • Cited by (496)

    View all citing articles on Scopus
    View full text