0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Hippocampal Volume Reduction in Schizophrenia as Assessed by Magnetic Resonance Imaging:  A Meta-analytic Study FREE

Michael D. Nelson, MA; Andrew J. Saykin, PsyD; Laura A. Flashman, PhD; Henry J. Riordan, PhD
[+] Author Affiliations

From the Department of Psychology, Dartmouth College, Hanover (Mr Nelson and Dr Saykin); the Brain Imaging Laboratory, Department of Psychiatry (Mr Nelson and Drs Saykin, Flashman, and Riordan), and the Department of Radiology (Dr Saykin), Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon; and the New Hampshire Hospital, Concord (Drs Saykin and Flashman), NH.


Arch Gen Psychiatry. 1998;55(5):433-440. doi:10.1001/archpsyc.55.5.433.
Text Size: A A A
Published online

Background  Although many quantitative magnetic resonance imaging studies have found significant volume reductions in the hippocampi of patients with schizophrenia compared with those of normal control subjects, others have not. Therefore, the issue of hippocampal volume differences associated with schizophrenia remains in question.

Methods  Two meta-analyses were conducted to reduce the potential effects of sampling error and methodological differences in data acquisition and analysis. Eighteen studies with a total patient number of 522 and a total control number of 426 met the initial selection criteria.

Results  Meta-analysis 1 yielded mean effect sizes of 0.37 (P<.001) for the left hippocampus and 0.39 (P<.001) for the right, corresponding to a bilateral reduction of 4%. Meta-analysis 2 indicated that the inclusion of the amygdala in the region of interest significantly increased effect sizes across studies (effect size for the left hippocampus and amygdala, 0.67; for the right, 0.72), whereas variables such as illness duration, total slice width, magnet strength, the use of the intracranial volume as a covariate, measurement reliability, and study quality did not. No laterality differences were observed in these data.

Conclusions  Schizophrenia is associated with a bilateral volumetric reduction of the hippocampus and probably of the amygdala as well. These findings reinforce the importance of the medial temporal region in schizophrenia and are consistent with frequently reported memory deficits in these patients. Future quantitative magnetic resonance imaging studies evaluating the hippocampal volume should measure the hippocampus and amygdala separately and compare the volumetric reduction in these structures to that observed in other gray matter areas.

Figures in this Article

THE HIPPOCAMPUS has long been considered an essential component of the medial temporal lobe memory system.1,2 The literature on both humans and animals has established that hippocampal lesions result in memory deficits.1,2 Patients with schizophrenia also have been shown to suffer from memory dysfunction, and several studies suggest that this selective impairment exceeds the global neuropsychological deficits reported.35 Specific deficits have been found in verbal3,59 and visual memory,5 including semantic memory10 and encoding,8 digit span,6,7 and design reproduction.6,7,11 Although there is some evidence to suggest that patients with schizophrenia are less significantly impaired on recognition tasks,3,6,11 this finding is somewhat equivocal.8

Recent studies have attempted to elucidate the anatomical correlates of memory impairment in schizophrenia as part of the general search for neuropathological correlates of the illness. Although some postmortem research has suggested that schizophrenia is associated with abnormal hippocampal pyramidal cell density12 and orientation,13,14 other studies15,16 have failed to support these findings. In addition, schizophrenia has been correlated with smaller neuron size in the CA1 region, subiculum, and layer II of the entorhinal cortex.17 Abnormalities also have been reported in the mossy fiber pathway,18 which arises from the axons of hippocampal granule cells and travels to the pyramidal cells of the CA3 region.19 Other postmortem evidence has suggested that schizophrenia is associated with reductions in overall volume of the hippocampus12,20,21 and parahippocampal gyrus.22

Although postmortem techniques are useful in determining the neurohistological correlates of disease, their findings can be influenced by error variance associated with several variables, including the cause of death. Magnetic resonance imaging (MRI) allows for the in vivo volumetric measurement of various cerebral structures, and these techniques have been applied to the study of schizophrenia. Schizophrenia has been associated with an increased volume of the following brain components: total cerebrospinal fluid,23,24 overall ventricular cerebrospinal fluid,24,25 lateral ventricles,2630 the third ventricle,26,27,29,31 and the caudate.32 Decreases in volume have been found in the following structures: whole brain,24 global gray matter,33 thalamus,25,34 prefrontal cortex and white matter,24,32 temporal lobe gray matter,26,29 superior temporal gyrus,35 amygdala,31,32 parahippocampal gyrus,35,36 and corpus callosum.37 Magnetic resonance imaging volumetry has also been applied to the question of hippocampal volume differences in patients with schizophrenia, with inconclusive results. Many studies have reported substantial reductions of hippocampal volume in patients with schizophrenia when compared with normal control subjects,28,29,31,32,35,3846 but others have not.26,4755 In this context, the term "reduced" refers only to a smaller relative volume in patients compared with normal control subjects. Even less clear is the issue of laterality differences in hippocampal volume.56 Considering that studies with negative findings are less likely to be published, definitive conclusions regarding hippocampal volume and laterality have remained elusive.

There are a number of reasons why results may have been equivocal. For example, the reported differences in hippocampal volume in patients with schizophrenia may be due in large part to sampling error and/or methodological variations such as magnet field strength, slice thickness, and the adjustment of hippocampal volume for either hemispheric or total intracranial volume. One of the best methods for controlling the effects of such mediating variables is the use of meta-analytic techniques.57 Meta-analysis provides a quantitative method for integrating research findings within a given body of literature so that a more definitive overall conclusion can be reached. Meta-analytic reviews have recently been conducted on MRI studies of ventricular enlargement,30 corpus callosum size in patients with schizophrenia,37 and ventricular size in patients with bipolar disorder.58 Because these studies helped to clarify many unresolved issues, a meta-analytic review of the literature evaluating hippocampal volumes is likely to be a useful tool in addressing the question of brain structural differences in schizophrenia.

This meta-analytic study was conducted to test 2 major hypotheses. First, patients with schizophrenia were predicted to have significantly smaller hippocampal volumes compared with normal control subjects. Second, we hypothesized that a moderator variable analysis would reveal important variables that could account for the divergence of results in the literature and thus inform future studies.

STUDY SELECTION

Published reports that evaluated hippocampal volume differences between patients with schizophrenia and normal control subjects using MRI techniques were obtained through the use of computerized databases, including MEDLINE and PsychINFO, and by searching the bibliographies of relevant studies. This search identified 33 studies published between 1988 and 1997. To be included, published studies had to meet several initial criteria: means and SDs for hippocampal volumes had to be reported, a normal comparison group must have been evaluated, the region of interest (ROI) must have included the hippocampus alone or the hippocampal-amygdala complex, the mean patient age must have been between 25 and 40 years, and the study could not have used duplicate subjects from another included study. As many early studies were unable to distinguish between the hippocampus and the amygdala because of technical limitations, studies that measured the 2 structures together were not excluded. Four studies were excluded because of subject duplication,35,45,59,60 3 because means and SDs were not reported,50,61,62 6 because the hippocampal area was measured instead of the volume,49,53,6366 1 because control subjects were not included,67 1 because the parahippocampal gyrus was included in the ROI,68 and 1 because it evaluated elderly patients (mean age, 78.1 years).69 Therefore, 18 studies were ultimately included in this meta-analytic study, including data from our laboratory.70 Demographic information on patients and normal control subjects is provided in Table 1, and scan-related information and mean hippocampal volumes are reported in Table 2.

Table Graphic Jump LocationTable 1. Demographic Information for 522 Patients With Schizophrenia and 426 Control Subjects*
Table Graphic Jump LocationTable 2. Scan Information for 522 Patients With Schizophrenia Compared With 426 Control Subjects*
GENERAL META-ANALYTIC METHODS

All analyses were conducted according to the methods of Hedges and Olkin71 as implemented by DStat,72 a commercially available software program designed specifically for meta-analytic research. The DStat program computes both effect sizes and 95% confidence intervals. All analyses were conducted in several steps. First, Hedges g (an estimate of effect size) was computed for each study by subtracting the mean patient volume (mp) from the mean control volume (mc) and dividing by the pooled SD (s) according to the following formula72:

Although Hedges g does provide an estimate of effect size, it is susceptible to bias introduced by a low sample size.72,73 Therefore, DStat was used to transform Hedges g into an unbiased measure of effect size, the Cohen d. Individual values of d were then combined across studies and weighted according to their variance (v) using the following formulas71:

where wi represents the individual weight for a given study. If more than 1 mean was reported (eg, separate volumes for men and women), a global mean for each hippocampus was computed using the weighted average of the individual means, a strategy that has been used previously in meta-analyses.58

Laterality differences were evaluated by converting the effect size for each subset (left vs right) into the Fisher Zr and computing the difference between the 2 hippocampi (eg, subtracting the Zr associated with the left hippocampus from the Zr associated with the right hippocampus) according to the following formulas74:

Significance (P) for Cohen q was computed in the following way75:

where Z1=q=Z is associated with the experimental hypothesis (D′0) and Z0=Z is associated with the null hypothesis (D=0). SQRT signifies square root; D, overall effect size.

Readers interested in further details of meta-analytic techniques are referred to the work of Hunter and Schmidt,57 Hedges and Olkin,71 Rosenthal,73 and Cooper and Hedges.76

Meta-analysis 1

All 18 studies were included in the initial overall meta-analysis. During the initial analyses, however, it was determined that a significant outlier was present in the data set (Figure 1). Because the exclusion of outliers serves to increase the accuracy of the overall meta-analytic model through the reduction of extraneous variance,71,72 all further analyses were conducted excluding the outlier. An overall effect size (D) for each hippocampus was then obtained by computing the weighted mean across the remaining 17 studies.

Place holder to copy figure label and caption
Figure 1.

Funnel plot (sample size vs effect size) for the 18 studies included in the initial meta-analysis. Note the presence of an outlier in the data set (lower left).

Graphic Jump Location
Meta-analysis 2

A second meta-analysis was conducted to evaluate possible moderator variables (factors that could affect results between studies). Each study was coded on several theoretically relevant variables (mean illness duration, total slice width, magnet strength, the adjustment of hippocampal volume for either hemispheric or intracranial volume, the inclusion of the amygdala in the ROI, and measurement reliability), and the studies were classified into subsets of each individual variable. As in previous meta-analyses,37 studies were rated on several quality factors that were also treated as possible moderator variables. The first factor evaluated the completeness of the demographic information reported and the degree of patient-control matching. This dimension included patient-control matching by sex, age, handedness, height, weight, education level, and parental socioeconomic status. The reporting of demographic information, including illness duration, age at illness onset, diagnostic criteria, and the source of comparison subjects, was also considered. Studies were assigned 1 point for each item addressed, except in the case of patient-control matching by education level.

Because matching by education level may result in the selection of either high-functioning patients or low-functioning control subjects (or both),77,78 studies were assigned no points if such matching was used and 1 point if it was not. The second factor was related to overall scan quality and included magnet strength, slice plus gap width, measurement reliability, the adjustment of hippocampal volume for hemispheric or total intracranial volume, and the inclusion of the amygdala in the ROI. Scores on each of these factors were then transformed into percentages. The third factor measured overall study quality, which was created by averaging the percentages from the first 2 factors.

Potential differences in effect size between variable subsets were analyzed using the method of Hedges and Olkin71 as implemented by the categorical modeling feature in DStat. This procedure computes mean effect sizes and 95% confidence intervals for each variable subset and allows for the testing of the influence of each individual factor on the overall results. Because possible moderator variables were evaluated in a univariate manner, a Bonferroni correction was used, resulting in a critical P value of .005.

Results of both meta-analyses are provided in Table 3. The mean effect sizes and confidence intervals for left and right hippocampi are reported for each variable subset. Note that model P refers to the probability that a given variable affected results across studies for the left and right hippocampi. The results from the overall meta-analysis indicate that schizophrenia is significantly associated with bilaterally reduced hippocampal volume (DL=0.37; DR=0.39; P<.001 for both). As shown in Figure 2, these results correspond to a bilateral reduction of approximately 4%. The large number of significant mean effect sizes shown in Table 3 reflects the overall consistency of bilaterally reduced hippocampal volume. Similar effects were observed at most levels of the potential moderator variables. No laterality differences were seen in these data.

Place holder to copy figure label and caption
Figure 2.

Percentage reduction in the hippocampal-amygdala complex (H+A) in patients with schizophrenia. With 1 exception, the studies measuring the amygdala alone also provided hippocampal measurements. The combined H+A studies do not overlap with the other groups. See the "Comment" section for details.

Graphic Jump Location

Only the inclusion of the amygdala in the ROI had a significant (P<.005) influence on effect sizes between studies, with those studies that measured both structures together having higher mean effect sizes (left, 0.67; right, 0.72), equaling a bilateral reduction of 8% (Figure 2). To further assess this potential relationship, studies32,48,52,54,68 that measured the amygdala separately were evaluated, 4 of which were included in the hippocampal analyses.33,48,52,54 Results of this analysis indicated a similar association between schizophrenia and volumetric reduction of the amygdala. The mean effect sizes were 0.29 for the left amygdala and 0.30 (P<.05 for both) for the right, equal to an approximately 4.5% reduction in volume (Figure 2). None of the other putative moderator variables had a significant effect on the results.

These meta-analyses produced several main results. First, there is a significant association between schizophrenia and bilateral volumetric reduction of the hippocampus. Second, the inclusion of the amygdala in the ROI significantly increased the magnitude of this relationship. No differences in volumetric reduction were observed between the left and right hippocampi. Finally, it appears that publication bias in favor of positive findings is unlikely to be a significant confounding variable in this literature because many of the studies evaluated in this meta-analysis reported results that were either nonsignificant or opposite the hypothesized direction (Figure 1 and Table 2).

These results have theoretical and methodological implications. Our finding of significant bilateral hippocampal volume reduction is consistent with the nature of the memory and cytoarchitectural abnormalities associated with schizophrenia. Patients with schizophrenia show specific memory deficits consistent with both left37,9,11 and right57,11 hippocampal disease. Schizophrenia also has been associated with reduced hippocampal pyramidal cell density, most notably in the left anterior CA3 and CA4 regions.12

The finding that the inclusion of the amygdala in the hippocampal ROI significantly increased the mean effect size suggests that volumetric reduction of the amygdala may also be associated with schizophrenia. Note that in Figure 2 the reduction observed in those studies that measured the hippocampus and the amygdala together ("Combined H+A") was approximately 8%. Because most of the studies in the group in which the hippocampus and the amygdala were measured together had large slice widths (Table 2), however, the greater hippocampus-amygdala reduction observed in these studies could be due to partial volume effects or other measurement factors. Therefore, we recommend measuring the hippocampus and amygdala separately and in their entirety so that the volume of each structure can be assessed independently. The ability of modern scanners to delineate the alveus allows for the accurate separation of the amygdala from the anterior hippocampus.79

Although neither the magnet strength nor the slice width had a significant effect on the quantitative volumetric measurement of the hippocampus in this sample, future MRI assessment of relatively small brain structures (ie, hippocampus) should be conducted using the best available scanning technology. For example, the total slice width has been shown to have a significant effect on the volumetric MRI measurement.80 Using a calibrated phantom, Luft et al80 demonstrated that slice widths greater than 3.0 mm lead to significantly increased error rates. Furthermore, it has been strongly recommended that MRI data be acquired or at least reformatted into a plane perpendicular to the long axis of the hippocampus, a process that helps correct for individual variations in head position.79

Although the adjustment of the volume of small cerebral structures for hemispheric or total intracranial volume has been thought to facilitate the accuracy of their measurement,79 the results of the moderator variable analysis failed to confirm this hypothesis. Therefore, it is unlikely that the observed differences in the hippocampal volume in patients with schizophrenia are due to a reduction in overall brain volume. Because people with larger heads and brains tend to have larger hippocampi,39,79 however, this correction appears warranted because it helps control for the confounding influence of overall brain volume.

Differences in interrater reliability, scan quality, demographic or subject matching quality, and overall quality did not influence the overall effect size in these meta-analyses. This may be due to a range restriction and the lack of variability in these dimensions, which were of consistently good quality across studies. These dimensions are clearly important. Large differences in interrater reliability can contribute to interstudy variation.79 Also, the matching of patients and normal control subjects and the reporting of clinical and demographic information are necessary components of any quantitative MRI investigation involving clinical populations.

There are several limitations of this meta-analytic study. First, given the nature of the selection of studies that were included, there is no guarantee that many studies reporting either nonsignificant or countertheoretical results were not published. This problem is unlikely to have significantly influenced the overall conclusions of this study, however, because many of the analyzed studies did report negative results. Second, meta-analytic studies have been criticized for including studies of varying methods.57 The inclusion of studies using different methodological techniques in this case revealed an important moderator variable that may account for some of the discrepancies in the published literature. Third, it was not possible to adequately compare the level of hippocampal volume reduction with that of other gray matter structures (except the amygdala) in these patients. Therefore, it is unclear whether our results are indicative of specific hippocampal volume reduction or a more general reduction in gray matter in patients with schizophrenia.24,26,29,3133,35,36,56,81 Fourth, the influence of gender and handedness on hippocampal volume reduction could not be evaluated because of the inclusion of mostly right-handed men in the available studies. Finally, the total number of studies was sufficient for univariate analyses but not for multivariate meta-analytic techniques assessing conjoint and interactive effects of moderator variables.

Future research on the cerebral morphometric correlates of schizophrenia should focus on several issues. First, longitudinal studies should be undertaken to assess the independent effects of patient age and illness duration on the volume of the hippocampus and other structures. Such an approach is important because neuroanatomical abnormalities may be present early in the disease25,50,51,67,82 and consequently interact with normal aging. Second, more female and left-handed subjects should be sampled to evaluate possible volumetric differences related to gender and handedness. Third, the relationship between the pattern of clinical symptoms and cognitive profile of patients with schizophrenia and the volume of implicated structures such as the parahippocampal gyrus, amygdala, prefrontal cortex, cingulate gyrus, and thalamus should be investigated. Fourth, concurrent volumetric and functional MRI studies should be undertaken to address the functional consequences and correlates of reduced hippocampal volume and differential role of the left and right hippocampus. Fifth, the volumetric reduction of the hippocampus vs that of other gray matter structures should be compared because, as noted earlier, such reductions have been associated with schizophrenia, including the first episode of the illness.50,51,67,82 Sixth, the relative involvement of the anterior and posterior hippocampus in the disease process of schizophrenia should be compared. Because these 2 subdivisions of the hippocampus have different afferent and efferent connections,67 it is possible that they may be differentially affected in schizophrenia. Seventh, studies should report the anatomical boundaries used to separate the hippocampus and amygdala in enough detail to allow others to replicate them because differences in these boundaries have the potential to affect volumetry results.79 Finally, future studies need to elucidate the underlying mechanism of reduced hippocampal and amygdalar volume in advancing an etiologic understanding of this illness. Recent neurobiological studies in other mammalian species have indicated that environmental factors such as enrichment83 and psychosocial stress84 can alter neurogenesis in the hippocampus. The possible developmental interactions among genetic and other neurobehavioral risks and environmental advantages and stressors should be a fruitful area of investigation in schizophrenia.

Accepted for publication October 31, 1997.

This research was supported in part by the New Hampshire Hospital, Concord; grant RO1-NS28813 from the National Institutes of Health, Bethesda, Md; a grant from the National Alliance for Research on Schizophrenia and Depression, Chicago, Ill; and grant IIRG-94-133 from the Alzheimer's Association, Chicago.

We thank Lee Friedman, PhD; Howard C. Hughes, PhD; Sterling Johnson, PhD; Virginia Reed, PhD; Cynthia Smith, PhD; and 6 anonymous reviewers for their valuable comments on earlier versions of the manuscript.

Reprints: Andrew Saykin, PsyD, Department of Psychiatry, Dartmouth Medical School, 1 Medical Center Dr, Lebanon, NH 03756 (e-mail: saykin@dartmouth.edu).

Squire  LRZola-Morgan  S The medial temporal lobe memory system. Science. 1991;2531380- 1386
Milner  B Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg. 1972;19421- 446
Saykin  AJGur  RCGur  REMozley  DMozley  LHResnick  SMKester  DBStafiniak  P Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry. 1991;48618- 624
McKenna  PJTamlyn  DLund  CEMortimer  AMHammond  SBaddeley  AD Amnesic syndrome in schizophrenia. Psychol Med. 1990;20967- 972
Saykin  AJShtasel  DLGur  REKester  DBMozley  LHStafiniak  PGur  RC Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51124- 131
Beatty  WWJocic  ZMonson  NStaton  RD Memory and frontal lobe dysfunction in schizophrenia and schizoaffective disorder. J Nerv Ment Dis. 1993;181448- 453
Goldberg  TETorrey  EFGold  JMRagland  JDBigelow  LBWeinberger  DR Learning and memory in monozygotic twins discordant for schizophrenia. Psychol Med. 1993;2371- 85
Gold  JMRandolph  CCarpenter  CJGoldberg  TEWeinberger  DR Forms of memory failure in schizophrenia. J Abnorm Psychol. 1992;101487- 494
Sengel  RALovallo  WR Effects of cueing on immediate and recent memory in schizophrenics. J Nerv Ment Dis. 1983;171426- 430
Tamlyn  DMcKenna  PJMortimer  AMLund  CEHammond  SBaddeley  AD Memory impairment in schizophrenia: its extent, affiliations and neuropsychological character. Psychol Med. 1992;22101- 115
Calev  AKorin  YKugelmass  SLerer  B Performance of chronic schizophrenics on matched word and design recall tasks. Biol Psychiatry. 1987;22699- 709
Jeste  DVLohr  JB Hippocampal pathologic findings in schizophrenia: a morphometric study. Arch Gen Psychiatry. 1989;461019- 1024
Conrad  AJAbebe  TAustin  RForsythe  SScheibel  AB Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry. 1991;48413- 417
Kovelman  JAScheibel  AB A neurohistological correlate of schizophrenia. Biol Psychiatry. 1984;191601- 1621
Altshuler  LLConrad  AJKovelman  JAScheibel  AB Hippocampal pyramidal cell orientation in schizophrenia: a controlled neurohistologic study of the Yakovlev collection. Arch Gen Psychiatry. 1987;441094- 1098
Christison  GWCasanova  MFWeinberger  DRRawlings  RKleinman  JE A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Arch Gen Psychiatry. 1989;461027- 1032
Arnold  SEFranz  BRGur  RCGur  REShapiro  RMMoberg  PJTrojanowski  JQ Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry. 1995;152738- 748
Goldsmith  SKJoyce  JN Alterations in hippocampal mossy fiber pathway in schizophrenia and Alzheimer's disease. Biol Psychiatry. 1995;37122- 126
Kandel  ER Cellular mechanisms of learning and the biological basis of individuality. Kandel  ERSchwartz  JHJessell  TMeds.Principles of Neural Science 3rd ed. New York, NY Elsevier Science1991;chap 65
Bogerts  BFalkai  PGreve  BSchneider  TPfeiffer  U The neuropathology of schizophrenia: past and present. J Hirnforsch. 1993;34193- 205
Bogerts  BMeertz  EBausch-Schonfeldt  R Basal ganglia and limbic system pathology in schizophrenia: a morphometric study of brain volume and shrinkage. Arch Gen Psychiatry. 1985;42784- 791
Colter  NBattal  SCrow  TJJohnstone  ECBrown  RBurton  C White matter reduction in the parahippocampal gyrus of patients with schizophrenia [letter]. Arch Gen Psychiatry. 1987;441023
Gur  REMozley  DResnick  SMShtasel  DKohn  MZimmerman  RHerman  GAtlas  SGrossman  RErwin  RGur  RC Magnetic resonance imaging in schizophrenia, I: volumetric analysis of brain and cerebrospinal fluid. Arch Gen Psychiatry. 1991;48407- 412
Andreasen  NCFlashman  LFlaum  MArndt  SSwayze  V  IIO'Leary  DSEhrhardt  JCYuh  WTC Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA. 1994;2721763- 1769
Corey-Bloom  JJernigan  TArchibald  SHarris  MJJeste  DV Quantitative magnetic resonance imaging of the brain in late-life schizophrenia. Am J Psychiatry. 1995;152447- 449
Zipursky  RBMarsh  LLim  KODeMent  SShear  PKSullivan  EVMurphy  GMCsernansky  JGPfefferbaum  A Volumetric MRI assessment of temporal lobe structures in schizophrenia. Biol Psychiatry. 1994;35501- 516
Bornstein  RASchwarzkopf  SBOlson  SCNasrallah  HA Third-ventricle enlargement and neuropsychological deficit in schizophrenia. Biol Psychiatry. 1992;31954- 961
Bogerts  BAshtari  MDegreef  GAlvir  JMJBilder  RMLieberman  JA Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res. 1990;351- 13
Suddath  RLChristison  GWTorrey  BFCasanova  MFWeinberger  DR Anatomical abnormalities in the brain of monozygotic twins discordant for schizophrenia. N Engl J Med. 1990;322789- 794
Raz  SRaz  N Structural abnormalities in the major psychoses: a quantitative review of the evidence from computerized imaging. Psychol Bull. 1990;10893- 106
Rossi  AStratta  PMancini  FGallucci  MMattei  PCore  LDi Michelle  VCasacchia  M Magnetic resonance imaging findings of amygdala-anterior hippocampus shrinkage in male patients with schizophrenia. Psychiatry Res. 1994;5243- 53
Breier  ABuchanan  RWElkashef  AMunson  RCKirkpatrick  BGellad  F Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry. 1992;49921- 926
Zipursky  RBLim  KOSullivan  EVBrown  BWPfefferbaum  A Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49195- 205
Andreasen  NCArndt  SSwayze  V  IICizadlo  TFlaum  MO'Leary  DEhrhardt  JCYuh  WTC Thalamic abnormalities in schizophrenia visualized through magnetic resonance imaging averaging. Science. 1994;266294- 298
Shenton  MEKikinis  RJolesz  FAPollak  SDLeMay  MWible  CGHokama  HMartin  JMetcalf  DColeman  MMcCarley  RW Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med. 1992;327604- 612
Brown  RColter  NCorsellis  JACrow  TJFrith  CDJagoe  RJohnstone  ECMarsh  L Postmortem evidence of structural brain changes in schizophrenia: differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry. 1986;4336- 42
Woodruff  PWRMcManus  ICDavid  AS Meta-analysis of corpus callosum size in schizophrenia. J Neurol Neurosurg Psychiatry. 1995;58457- 461
Fukuzako  HFukuzako  THashiguchi  THokazono  YTakeuchi  KHirakawa  KUeyama  KTakigawa  MKajiya  YNakago  MFujimoto  T Reduction in hippocampal formation volume is caused mainly by its shortening in chronic schizophrenia: assessment by MRI. Biol Psychiatry. 1996;39938- 945
Flaum  MSwayze  VW  IIO'Leary  DSYuh  WTCEhrhardt  JCArndt  SVAndreasen  NC Effects of diagnosis, laterality, and gender on brain morphology in schizophrenia. Am J Psychiatry. 1995;152704- 714
Bogerts  BLieberman  JAAshtari  MBilder  RMDegreef  GLerner  GJohns  CMasiar  S Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia. Biol Psychiatry. 1993;33236- 246
Buchanan  RWBreier  AKirkpatrick  BElkashef  AMunson  RCGellad  FCarpenter  WT  Jr Structural abnormalities in deficit and nondeficit schizophrenia. Am J Psychiatry. 1993;15059- 65
McCarley  RWShenton  MEO'Donnell  BFFaux  SFKikinis  RNestor  PGJolesz  FA Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 1993;50190- 197
Bogerts  BFalkai  PGreve  B Evidence of reduced temporolimbic structure volumes in schizophrenia. Arch Gen Psychiatry. 1991;48956- 957Letter
Becker  TElmer  KSchneider  FSchneider  MGrodd  WBartels  MHeckers  SBeckmann  H Confirmation of reduced temporal limbic structure volume on magnetic resonance imaging in male patients with schizophrenia. Psychiatry Res. 1996;67135- 143
Becker  TElmer  KMechela  BSchneider  FTaubert  SSchroth  GGrodd  WBartels  MBeckmann  H MRI findings in medial temporal lobe structures in schizophrenia. Eur Neuropsychopharmacol. 1990;183- 86
Dauphinais  DDeLisi  LECrow  TJAlexandropolous  KColter  NTuma  IGershon  ES Reduction in temporal lobe size in siblings with schizophrenia: a magnetic resonance imaging study. Psychiatry Res. 1990;35137- 147
Torres  IJFlashman  LAO'Leary  DSSwayze  VAndreasen  NC Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls. Biol Psychiatry. 1997;421087- 1096
Swayze  VW  IIAndreasen  NCAlliger  RJYuh  WTCEhrhardt  JC Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry. 1992;31221- 240
Blackwood  DHRYoung  AHMcQueen  JKMartin  MJRoxborough  HMMuir  WJSt Clair  DMKean  DM Magnetic resonance imaging in schizophrenia: altered brain morphology associated with P300 abnormalities and eye tracking dysfunction. Biol Psychiatry. 1991;30753- 769
DeLisi  LETew  WXie  SHoff  ALSakuma  MKushner  MLee  GShedlack  KSmith  AMGrimson  R A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry. 1995;38349- 360
DeLisi  LEHoff  ALSchwartz  JEShields  GWHalthore  SNGupta  SMHenn  FAAnand  AK Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study. Biol Psychiatry. 1991;29159- 175
Kawasaki  YMaeda  YUrata  KHigashima  MYamaguchi  NSuzuki  MTakashima  TIde  Y A quantitative magnetic resonance imaging study of patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1993;242268- 272
Young  AHBlackwood  DHRRoxborough  HMcQueen  JKMartin  MJKean  M A magnetic resonance imaging study of schizophrenia: brain structure and clinical symptoms. Br J Psychiatry. 1991;158158- 164
Hoff  ARiordan  HO'Donnel  DStritzke  PNeale  CBoccio  AAnand  AKDeLisi  LE Anomalous lateral sulcus asymmetry and cognitive function in first-episode schizophrenia. Schizophr Bull. 1992;18257- 272
Kelsoe  JRCadet  JLPickar  DWeinberger  DR Quantitative neuroanatomy in schizophrenia: a controlled magnetic resonance imaging study. Arch Gen Psychiatry. 1988;45533- 541
Yurgelun-Todd  DAKinney  DKSherwood  ARRenshaw  PF Magnetic resonance in schizophrenia. Semin Clin Neuropsychiatry. 1996;14- 19
Hunter  JESchmidt  FL Methods of Meta-Analysis: Correcting Error and Bias in Research Findings.  London, England Sage Publications1990;
Elkis  HFriedman  LWise  AMeltzer  HY Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry. 1995;52735- 746
Nestor  PGShenton  MEMcCarley  RWHaimson  JSmith  RSO'Donnell  BKimble  MKikinis  RJolesz  FA Neuropsychological correlates of MRI temporal lobe abnormalities in schizophrenia. Am J Psychiatry. 1993;1501849- 1855
Goldberg  TETorrey  EFBerman  KFWeinberger  DR Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatry Res. 1994;5551- 61
Weinberger  DRBerman  KFSuddath  RTorrey  EF Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry. 1992;149890- 897
Weinberger  DRBerman  KFTorrey  EF Correlations between abnormal hippocampal morphology and prefrontal physiology in schizophrenia. Clin Neuropharmacol. 1992;15(suppl 1, pt A)393A- 394A
Egan  MFDuncan  CCSuddath  RLKirch  DGMirsky  AFWyatt  RJ Event-related potential abnormalities correlate with structural brain alterations and clinical features in patients with chronic schizophrenia. Schizophr Res. 1994;11259- 271
Marsh  LSuddath  RLHiggins  NWeinberger  DR Medial temporal lobe structures in schizophrenia: relationship of size to duration of illness. Schizophr Res. 1994;11225- 238
Colombo  CAbbruzzese  MLivian  SScotti  GLocatelli  MBonfanti  AScarone  S Memory functions and temporal-limbic morphology in schizophrenia. Psychiatry Res. 1993;5045- 56
DeLisi  LEDauphinais  IDGershon  ES Perinatal complications and reduced size of brain limbic structures in familial schizophrenia. Schizophr Bull. 1988;14185- 191
Bilder  RMBogerts  BAshtari  MWu  HAlvir  JMJody  DReiter  GBell  LLieberman  JA Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia. Schizophr Res. 1995;1747- 58
Waldo  MCCawthra  EAdler  LEDubester  SStaunton  MNagamoto  HBaker  NMadison  ASimon  JScherzinger  ADrebing  CGerhardt  GFreedman  R Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings. Schizophr Res. 1994;1293- 106
Howard  RMellers  JPetty  RBonner  DMenon  RAlmeida  OGraves  MRenshaw  CLevy  R Magnetic resonance imaging volumetric measurements of the superior temporal gyrus, hippocampus, parahippocampal gyrus, frontal and temporal lobes in late paraphemia. Psychol Med. 1995;25495- 503
Flashman  LASaykin  AJCarrol  KEBono  DBMcAllister  TWWeaver  JBMamourian  AKahn  EMManschreck  TC Relation of hippocampal and neocortical volumetry to functional MRI memory activation in patients with schizophrenia.  Paper presented at: 10th Annual Meeting of the Society for Research in Psychopathology October 28, 1995 Iowa City, Iowa
Hedges  LVOlkin  I Statistical Methods for Meta-analysis.  New York, NY Academic Press Inc1985;
Johnson  BT DStat: Software for the Meta-analytic Review of Research Literatures.  Hillsdale, NJ Lawrence Erlbaum Associates1989;
Rosenthal  R Meta-analytic Procedures for Social Research.  London, England Sage Publications1986;
Rosenthal  R Parametric measures of effect size. Cooper  HHedges  LVeds.The Handbook of Research Synthesis New York, NY Russell Sage Foundation1994;231- 244
Hays  WL Statistics. 5th ed. Fort Worth, Tex Harcourt Brace College Publishers1991;
Cooper  HedHedges  LVed The Handbook of Research Synthesis.  New York, NY Russell Sage Foundation1994;
Resnick  SM Matching for education in studies of schizophrenia [letter]. Arch Gen Psychiatry. 1992;49246
Goldberg  TETorrey  EFWeinberger  DR Matching for education in studies of schizophrenia [letter]. Arch Gen Psychiatry. 1992;49246
Jack  CR  JrTheodore  WHCook  MMcCarthy  G MRI-based hippocampal volumetrics: data acquisition, normal ranges, and optimal protocol. Magn Reson Imaging. 1995;131057- 1064
Luft  ARSkalej  MWeite  DKolb  RKlose  U Reliability and exactness of MRI-based volumetry: a phantom study. J Magn Reson Imaging. 1996;6700- 704
Harvey  IRon  MABoulay  DUWicks  DLewis  SWMurray  RM Reduction of cortical volume in schizophrenia on magnetic resonance imaging. Psychol Med. 1993;23591- 604
Lim  KOHarris  DBeal  MHoff  ALMinn  KCsernansky  JGFaustman  WOMarsh  LSullivan  EVPfefferbaum  A Gray matter deficits in young onset schizophrenia are independent of age of onset. Biol Psychiatry. 1996;404- 13
Kempermann  GKuhn  HGGage  FH More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386493- 495
Gould  EMcEwen  BSTanapat  PPatima  GLiisa  AM Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;172492- 2498

Figures

Place holder to copy figure label and caption
Figure 1.

Funnel plot (sample size vs effect size) for the 18 studies included in the initial meta-analysis. Note the presence of an outlier in the data set (lower left).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Percentage reduction in the hippocampal-amygdala complex (H+A) in patients with schizophrenia. With 1 exception, the studies measuring the amygdala alone also provided hippocampal measurements. The combined H+A studies do not overlap with the other groups. See the "Comment" section for details.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Information for 522 Patients With Schizophrenia and 426 Control Subjects*
Table Graphic Jump LocationTable 2. Scan Information for 522 Patients With Schizophrenia Compared With 426 Control Subjects*

References

Squire  LRZola-Morgan  S The medial temporal lobe memory system. Science. 1991;2531380- 1386
Milner  B Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg. 1972;19421- 446
Saykin  AJGur  RCGur  REMozley  DMozley  LHResnick  SMKester  DBStafiniak  P Neuropsychological function in schizophrenia: selective impairment in memory and learning. Arch Gen Psychiatry. 1991;48618- 624
McKenna  PJTamlyn  DLund  CEMortimer  AMHammond  SBaddeley  AD Amnesic syndrome in schizophrenia. Psychol Med. 1990;20967- 972
Saykin  AJShtasel  DLGur  REKester  DBMozley  LHStafiniak  PGur  RC Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry. 1994;51124- 131
Beatty  WWJocic  ZMonson  NStaton  RD Memory and frontal lobe dysfunction in schizophrenia and schizoaffective disorder. J Nerv Ment Dis. 1993;181448- 453
Goldberg  TETorrey  EFGold  JMRagland  JDBigelow  LBWeinberger  DR Learning and memory in monozygotic twins discordant for schizophrenia. Psychol Med. 1993;2371- 85
Gold  JMRandolph  CCarpenter  CJGoldberg  TEWeinberger  DR Forms of memory failure in schizophrenia. J Abnorm Psychol. 1992;101487- 494
Sengel  RALovallo  WR Effects of cueing on immediate and recent memory in schizophrenics. J Nerv Ment Dis. 1983;171426- 430
Tamlyn  DMcKenna  PJMortimer  AMLund  CEHammond  SBaddeley  AD Memory impairment in schizophrenia: its extent, affiliations and neuropsychological character. Psychol Med. 1992;22101- 115
Calev  AKorin  YKugelmass  SLerer  B Performance of chronic schizophrenics on matched word and design recall tasks. Biol Psychiatry. 1987;22699- 709
Jeste  DVLohr  JB Hippocampal pathologic findings in schizophrenia: a morphometric study. Arch Gen Psychiatry. 1989;461019- 1024
Conrad  AJAbebe  TAustin  RForsythe  SScheibel  AB Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry. 1991;48413- 417
Kovelman  JAScheibel  AB A neurohistological correlate of schizophrenia. Biol Psychiatry. 1984;191601- 1621
Altshuler  LLConrad  AJKovelman  JAScheibel  AB Hippocampal pyramidal cell orientation in schizophrenia: a controlled neurohistologic study of the Yakovlev collection. Arch Gen Psychiatry. 1987;441094- 1098
Christison  GWCasanova  MFWeinberger  DRRawlings  RKleinman  JE A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Arch Gen Psychiatry. 1989;461027- 1032
Arnold  SEFranz  BRGur  RCGur  REShapiro  RMMoberg  PJTrojanowski  JQ Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry. 1995;152738- 748
Goldsmith  SKJoyce  JN Alterations in hippocampal mossy fiber pathway in schizophrenia and Alzheimer's disease. Biol Psychiatry. 1995;37122- 126
Kandel  ER Cellular mechanisms of learning and the biological basis of individuality. Kandel  ERSchwartz  JHJessell  TMeds.Principles of Neural Science 3rd ed. New York, NY Elsevier Science1991;chap 65
Bogerts  BFalkai  PGreve  BSchneider  TPfeiffer  U The neuropathology of schizophrenia: past and present. J Hirnforsch. 1993;34193- 205
Bogerts  BMeertz  EBausch-Schonfeldt  R Basal ganglia and limbic system pathology in schizophrenia: a morphometric study of brain volume and shrinkage. Arch Gen Psychiatry. 1985;42784- 791
Colter  NBattal  SCrow  TJJohnstone  ECBrown  RBurton  C White matter reduction in the parahippocampal gyrus of patients with schizophrenia [letter]. Arch Gen Psychiatry. 1987;441023
Gur  REMozley  DResnick  SMShtasel  DKohn  MZimmerman  RHerman  GAtlas  SGrossman  RErwin  RGur  RC Magnetic resonance imaging in schizophrenia, I: volumetric analysis of brain and cerebrospinal fluid. Arch Gen Psychiatry. 1991;48407- 412
Andreasen  NCFlashman  LFlaum  MArndt  SSwayze  V  IIO'Leary  DSEhrhardt  JCYuh  WTC Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging. JAMA. 1994;2721763- 1769
Corey-Bloom  JJernigan  TArchibald  SHarris  MJJeste  DV Quantitative magnetic resonance imaging of the brain in late-life schizophrenia. Am J Psychiatry. 1995;152447- 449
Zipursky  RBMarsh  LLim  KODeMent  SShear  PKSullivan  EVMurphy  GMCsernansky  JGPfefferbaum  A Volumetric MRI assessment of temporal lobe structures in schizophrenia. Biol Psychiatry. 1994;35501- 516
Bornstein  RASchwarzkopf  SBOlson  SCNasrallah  HA Third-ventricle enlargement and neuropsychological deficit in schizophrenia. Biol Psychiatry. 1992;31954- 961
Bogerts  BAshtari  MDegreef  GAlvir  JMJBilder  RMLieberman  JA Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res. 1990;351- 13
Suddath  RLChristison  GWTorrey  BFCasanova  MFWeinberger  DR Anatomical abnormalities in the brain of monozygotic twins discordant for schizophrenia. N Engl J Med. 1990;322789- 794
Raz  SRaz  N Structural abnormalities in the major psychoses: a quantitative review of the evidence from computerized imaging. Psychol Bull. 1990;10893- 106
Rossi  AStratta  PMancini  FGallucci  MMattei  PCore  LDi Michelle  VCasacchia  M Magnetic resonance imaging findings of amygdala-anterior hippocampus shrinkage in male patients with schizophrenia. Psychiatry Res. 1994;5243- 53
Breier  ABuchanan  RWElkashef  AMunson  RCKirkpatrick  BGellad  F Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry. 1992;49921- 926
Zipursky  RBLim  KOSullivan  EVBrown  BWPfefferbaum  A Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49195- 205
Andreasen  NCArndt  SSwayze  V  IICizadlo  TFlaum  MO'Leary  DEhrhardt  JCYuh  WTC Thalamic abnormalities in schizophrenia visualized through magnetic resonance imaging averaging. Science. 1994;266294- 298
Shenton  MEKikinis  RJolesz  FAPollak  SDLeMay  MWible  CGHokama  HMartin  JMetcalf  DColeman  MMcCarley  RW Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med. 1992;327604- 612
Brown  RColter  NCorsellis  JACrow  TJFrith  CDJagoe  RJohnstone  ECMarsh  L Postmortem evidence of structural brain changes in schizophrenia: differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry. 1986;4336- 42
Woodruff  PWRMcManus  ICDavid  AS Meta-analysis of corpus callosum size in schizophrenia. J Neurol Neurosurg Psychiatry. 1995;58457- 461
Fukuzako  HFukuzako  THashiguchi  THokazono  YTakeuchi  KHirakawa  KUeyama  KTakigawa  MKajiya  YNakago  MFujimoto  T Reduction in hippocampal formation volume is caused mainly by its shortening in chronic schizophrenia: assessment by MRI. Biol Psychiatry. 1996;39938- 945
Flaum  MSwayze  VW  IIO'Leary  DSYuh  WTCEhrhardt  JCArndt  SVAndreasen  NC Effects of diagnosis, laterality, and gender on brain morphology in schizophrenia. Am J Psychiatry. 1995;152704- 714
Bogerts  BLieberman  JAAshtari  MBilder  RMDegreef  GLerner  GJohns  CMasiar  S Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia. Biol Psychiatry. 1993;33236- 246
Buchanan  RWBreier  AKirkpatrick  BElkashef  AMunson  RCGellad  FCarpenter  WT  Jr Structural abnormalities in deficit and nondeficit schizophrenia. Am J Psychiatry. 1993;15059- 65
McCarley  RWShenton  MEO'Donnell  BFFaux  SFKikinis  RNestor  PGJolesz  FA Auditory P300 abnormalities and left posterior superior temporal gyrus volume reduction in schizophrenia. Arch Gen Psychiatry. 1993;50190- 197
Bogerts  BFalkai  PGreve  B Evidence of reduced temporolimbic structure volumes in schizophrenia. Arch Gen Psychiatry. 1991;48956- 957Letter
Becker  TElmer  KSchneider  FSchneider  MGrodd  WBartels  MHeckers  SBeckmann  H Confirmation of reduced temporal limbic structure volume on magnetic resonance imaging in male patients with schizophrenia. Psychiatry Res. 1996;67135- 143
Becker  TElmer  KMechela  BSchneider  FTaubert  SSchroth  GGrodd  WBartels  MBeckmann  H MRI findings in medial temporal lobe structures in schizophrenia. Eur Neuropsychopharmacol. 1990;183- 86
Dauphinais  DDeLisi  LECrow  TJAlexandropolous  KColter  NTuma  IGershon  ES Reduction in temporal lobe size in siblings with schizophrenia: a magnetic resonance imaging study. Psychiatry Res. 1990;35137- 147
Torres  IJFlashman  LAO'Leary  DSSwayze  VAndreasen  NC Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls. Biol Psychiatry. 1997;421087- 1096
Swayze  VW  IIAndreasen  NCAlliger  RJYuh  WTCEhrhardt  JC Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry. 1992;31221- 240
Blackwood  DHRYoung  AHMcQueen  JKMartin  MJRoxborough  HMMuir  WJSt Clair  DMKean  DM Magnetic resonance imaging in schizophrenia: altered brain morphology associated with P300 abnormalities and eye tracking dysfunction. Biol Psychiatry. 1991;30753- 769
DeLisi  LETew  WXie  SHoff  ALSakuma  MKushner  MLee  GShedlack  KSmith  AMGrimson  R A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry. 1995;38349- 360
DeLisi  LEHoff  ALSchwartz  JEShields  GWHalthore  SNGupta  SMHenn  FAAnand  AK Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study. Biol Psychiatry. 1991;29159- 175
Kawasaki  YMaeda  YUrata  KHigashima  MYamaguchi  NSuzuki  MTakashima  TIde  Y A quantitative magnetic resonance imaging study of patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 1993;242268- 272
Young  AHBlackwood  DHRRoxborough  HMcQueen  JKMartin  MJKean  M A magnetic resonance imaging study of schizophrenia: brain structure and clinical symptoms. Br J Psychiatry. 1991;158158- 164
Hoff  ARiordan  HO'Donnel  DStritzke  PNeale  CBoccio  AAnand  AKDeLisi  LE Anomalous lateral sulcus asymmetry and cognitive function in first-episode schizophrenia. Schizophr Bull. 1992;18257- 272
Kelsoe  JRCadet  JLPickar  DWeinberger  DR Quantitative neuroanatomy in schizophrenia: a controlled magnetic resonance imaging study. Arch Gen Psychiatry. 1988;45533- 541
Yurgelun-Todd  DAKinney  DKSherwood  ARRenshaw  PF Magnetic resonance in schizophrenia. Semin Clin Neuropsychiatry. 1996;14- 19
Hunter  JESchmidt  FL Methods of Meta-Analysis: Correcting Error and Bias in Research Findings.  London, England Sage Publications1990;
Elkis  HFriedman  LWise  AMeltzer  HY Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry. 1995;52735- 746
Nestor  PGShenton  MEMcCarley  RWHaimson  JSmith  RSO'Donnell  BKimble  MKikinis  RJolesz  FA Neuropsychological correlates of MRI temporal lobe abnormalities in schizophrenia. Am J Psychiatry. 1993;1501849- 1855
Goldberg  TETorrey  EFBerman  KFWeinberger  DR Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatry Res. 1994;5551- 61
Weinberger  DRBerman  KFSuddath  RTorrey  EF Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am J Psychiatry. 1992;149890- 897
Weinberger  DRBerman  KFTorrey  EF Correlations between abnormal hippocampal morphology and prefrontal physiology in schizophrenia. Clin Neuropharmacol. 1992;15(suppl 1, pt A)393A- 394A
Egan  MFDuncan  CCSuddath  RLKirch  DGMirsky  AFWyatt  RJ Event-related potential abnormalities correlate with structural brain alterations and clinical features in patients with chronic schizophrenia. Schizophr Res. 1994;11259- 271
Marsh  LSuddath  RLHiggins  NWeinberger  DR Medial temporal lobe structures in schizophrenia: relationship of size to duration of illness. Schizophr Res. 1994;11225- 238
Colombo  CAbbruzzese  MLivian  SScotti  GLocatelli  MBonfanti  AScarone  S Memory functions and temporal-limbic morphology in schizophrenia. Psychiatry Res. 1993;5045- 56
DeLisi  LEDauphinais  IDGershon  ES Perinatal complications and reduced size of brain limbic structures in familial schizophrenia. Schizophr Bull. 1988;14185- 191
Bilder  RMBogerts  BAshtari  MWu  HAlvir  JMJody  DReiter  GBell  LLieberman  JA Anterior hippocampal volume reductions predict frontal lobe dysfunction in first episode schizophrenia. Schizophr Res. 1995;1747- 58
Waldo  MCCawthra  EAdler  LEDubester  SStaunton  MNagamoto  HBaker  NMadison  ASimon  JScherzinger  ADrebing  CGerhardt  GFreedman  R Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings. Schizophr Res. 1994;1293- 106
Howard  RMellers  JPetty  RBonner  DMenon  RAlmeida  OGraves  MRenshaw  CLevy  R Magnetic resonance imaging volumetric measurements of the superior temporal gyrus, hippocampus, parahippocampal gyrus, frontal and temporal lobes in late paraphemia. Psychol Med. 1995;25495- 503
Flashman  LASaykin  AJCarrol  KEBono  DBMcAllister  TWWeaver  JBMamourian  AKahn  EMManschreck  TC Relation of hippocampal and neocortical volumetry to functional MRI memory activation in patients with schizophrenia.  Paper presented at: 10th Annual Meeting of the Society for Research in Psychopathology October 28, 1995 Iowa City, Iowa
Hedges  LVOlkin  I Statistical Methods for Meta-analysis.  New York, NY Academic Press Inc1985;
Johnson  BT DStat: Software for the Meta-analytic Review of Research Literatures.  Hillsdale, NJ Lawrence Erlbaum Associates1989;
Rosenthal  R Meta-analytic Procedures for Social Research.  London, England Sage Publications1986;
Rosenthal  R Parametric measures of effect size. Cooper  HHedges  LVeds.The Handbook of Research Synthesis New York, NY Russell Sage Foundation1994;231- 244
Hays  WL Statistics. 5th ed. Fort Worth, Tex Harcourt Brace College Publishers1991;
Cooper  HedHedges  LVed The Handbook of Research Synthesis.  New York, NY Russell Sage Foundation1994;
Resnick  SM Matching for education in studies of schizophrenia [letter]. Arch Gen Psychiatry. 1992;49246
Goldberg  TETorrey  EFWeinberger  DR Matching for education in studies of schizophrenia [letter]. Arch Gen Psychiatry. 1992;49246
Jack  CR  JrTheodore  WHCook  MMcCarthy  G MRI-based hippocampal volumetrics: data acquisition, normal ranges, and optimal protocol. Magn Reson Imaging. 1995;131057- 1064
Luft  ARSkalej  MWeite  DKolb  RKlose  U Reliability and exactness of MRI-based volumetry: a phantom study. J Magn Reson Imaging. 1996;6700- 704
Harvey  IRon  MABoulay  DUWicks  DLewis  SWMurray  RM Reduction of cortical volume in schizophrenia on magnetic resonance imaging. Psychol Med. 1993;23591- 604
Lim  KOHarris  DBeal  MHoff  ALMinn  KCsernansky  JGFaustman  WOMarsh  LSullivan  EVPfefferbaum  A Gray matter deficits in young onset schizophrenia are independent of age of onset. Biol Psychiatry. 1996;404- 13
Kempermann  GKuhn  HGGage  FH More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386493- 495
Gould  EMcEwen  BSTanapat  PPatima  GLiisa  AM Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;172492- 2498

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 460

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com