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Fetal Hypoxia and Structural Brain Abnormalities in Schizophrenic Patients, Their Siblings, and Controls
Tyrone D. Cannon, PhD;
Theo G. M. van Erp, MA;
Isabelle M. Rosso, PhD;
Matti Huttunen, MD, PhD;
Jouko Lönnqvist, MD;
Tiia Pirkola, MA;
Oili Salonen, MD, PhD;
Leena Valanne, MD;
Veli-Pekka Poutanen, MSc;
Carl-Gustav Standertskjöld-Nordenstam, MD
Arch Gen Psychiatry. 2002;59:35-41.
ABSTRACT
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Background Cortical gray matter reductions and cerebrospinal fluid (CSF) increases
are robust correlates of schizophrenia, but their relationships to obstetric
and other etiologic risk factors remain to be established.
Methods Structured diagnostic interviews, obstetric hospital records, and magnetic
resonance imaging scans of the brain were obtained for 64 schizophrenic or
schizoaffective patients (representative of all such probands in a Helsinki,
Finland, birth cohort), along with 51 of their nonpsychotic full siblings
and 54 demographically similar controls without family histories of psychosis.
Results Fetal hypoxia predicted reduced gray matter and increased CSF bilaterally
throughout the cortex in patients (gray matter effect sizes, -0.31 to -0.56;
CSF effect sizes, 0.25 to 0.47) and siblings (gray matter effect sizes, 0.33
to 0.47; CSF effect sizes, 0.17 to 0.33), most strongly in the temporal lobe.
Effect sizes were 2 to 3 times greater among cases born small for their gestational
age. Hypoxia also correlated significantly with ventricular enlargement, but
only among patients (effect size, 0.31). In contrast, fetal hypoxia was not
related to white matter among patients and siblings, nor to any tissue type
in any region among controls. The associations were independent of family
membership, overall brain volume, age, sex, substance abuse, and prenatal
infection.
Conclusions Fetal hypoxia is associated with greater structural brain abnormalities
among schizophrenic patients and their nonschizophrenic siblings than among
controls at low genetic risk for schizophrenia. This pattern of results points
to a gene-environment interaction account of the disorder's neurodevelopmental
pathogenesis.
INTRODUCTION
STRUCTURAL BRAIN abnormalities are robust correlates of schizophrenia,
but their causes have not been conclusively established.1-3
Neuromotor and cognitive deficits in preschizophrenic children4-6
and cortical laminar neuron displacement in schizophrenic patients at autopsy7-10 suggest
that at least some of the anatomical changes associated with schizophrenia
are neurodevelopmental in origin.11 Genetic
influences in schizophrenia are substantial,12
but the mode of inheritance is complex. It involves at least several genes13 and certain neurally disruptive environmental exposures,
such as obstetric complications (OCs).14-27
Of the many types of OCs found to predict schizophrenia, fetal hypoxia has
shown the strongest association, accounting for a greater proportion of liability
than exposure to infections during gestation, fetal growth retardation, and
other obstetric factors.27 Because no study
using objective birth records has found that hypoxic OCs are more frequent
in the first-degree relatives of schizophrenic patients than in the general
population,17-24
these complications do not appear to be consequences of genetic liability
to schizophrenia. It is also unlikely that these early influences cause schizophrenia
on their own because more than 90% of individuals who experience fetal hypoxia,
even in its severe form, do not develop schizophrenia.17-18,25-26
Hypoxic OCs must thus act additively or interactively with genetic factors
in influencing disease liability.27
In a prior computed tomography study, we found evidence supporting the
gene-environment interaction model with respect to the contribution of fetal
hypoxia to subcortical abnormalities in schizophrenic patients.28
Ventricular-brain ratio increased in association with a history of hypoxia-associated
OCs among offspring of schizophrenic parents, but not among offspring of controls,
whereas sulcal-brain ratio varied with degree of genetic loading for schizophrenia,
but not with the obstetric factors examined. These findings suggest that a
genetic factor in schizophrenia may render the fetal brain particularly susceptible
to periventricular tissue damage following hypoxia. The interpretability of
this evidence is restricted, however, by the limited localizing significance
of cerebrospinal fluid (CSF)–based anatomical measures2
and the questionable generalizability of findings from offspring of mothers
with unusually severe forms of schizophrenia.29
In addition, a magnetic resonance imaging (MRI) study of monozygotic twins
discordant for schizophrenia found larger ventricles and smaller temporal
lobe volumes in the affected compared with unaffected co-twins, differences
that must reflect nongenetic influences30; these
intrapair differences in ventricular and hippocampal size are related to higher
rates of OCs in the affected co-twins.31
We have previously reported on differences in regional brain morphology,
assessed by MRI, in schizophrenic patients, their nonschizophrenic siblings,
and controls at low genetic risk for schizophrenia.32
Patients and their siblings had reduced gray matter and increased sulcal CSF
in the frontal and temporal regions bilaterally, but not in posterior regions.
Patients, but not siblings, also showed ventricular enlargement and reduced
global white matter compared with controls. As part of this study, we also
collected subjects' original obstetric hospital records. A history of hypoxia-associated
OCs, but not prenatal infection or fetal growth retardation, was found to
predict an increased risk of early-onset schizophrenia.18
In this analysis, we used the same samples to determine whether fetal hypoxia
was differentially related to ventricular enlargement and temporal-lobe volume
reduction among patients and siblings at elevated risk for schizophrenia,
compared with controls at low genetic risk.
PARTICIPANTS AND METHODS
SAMPLE
Participants were drawn from the total population of individuals born
in Helsinki, Finland, in 1955 and all their full siblings (N = 7840 and N
= 12 796, respectively), using methods previously described.12, 32 National computerized databases were
used to screen the cohort for a history of psychiatric disorders requiring
treatment, and potential probands were randomly selected from this total pool.
Eligibility was restricted to probands with a lifetime DSM-III-R33 diagnosis of schizophrenia
or schizoaffective disorder on direct interview. About 75% of those approached
gave informed consent and met the inclusion criteria. Studied probands were
equivalent to the remainder of the proband population in terms of year of
birth, nuclear family size, sex, age at first inpatient admission, history
of substance disorder, and work disability, but the studied group had an average
of 1.5 more hospital admissions than the nonstudied group.32
An attempt was made to recruit at least one nonschizophrenic sibling of each
studied proband, but this was possible in only 62 of the 80 cases. In addition,
56 nonschizophrenic control subjects (from 28 sibling pairs) were chosen from
the same birth cohort, after excluding those with a personal or family history
of psychiatric treatment. Control subjects were similar to probands and their
siblings on demographic variables. All subjects were interviewed using the
Structured Clinical Interview for DSM-III-R disorders34 administered by psychologists and psychiatric social
workers with extensive prior training; siblings and controls were also interviewed
on the Cluster A items from the Personality Disorder Examination.35 Diagnostic reliability was excellent ( = 0.94
± 0.02),36 and final diagnoses were made
by consensus among 3 independent raters.
Missing obstetric hospital records (n = 21) and/or technical problems
with the MRI scans (n = 7) excluded 27 subjects from the analysis. Table 1 shows that the patient, sibling,
and control groups were balanced on substance abuse and major demographic
and obstetric variables.
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Table 1. Demographic Characteristics in 3 Comparison Groups*
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OBSTETRIC RECORDS
A researcher blind to diagnosis and imaging results used a standard
form to code information from the original antenatal clinic and obstetric
hospital records on maternal health, fetal monitoring, prenatal and perinatal
complications, and neonatal conditions. Obstetric variables used in the analyses
were small for gestational age status (ie, birth weight at or below the 10th
percentile for a given gestational age), any maternal infection (rubella,
influenza, etc) during gestation, and fetal hypoxia. Fetal hypoxia was scored
as present if the subject was coded as blue at birth or neonatally or had
2 or more complications that were significantly related to birth or neonatal
asphyxia in the overall sample. Complications included umbilical cord knotted
or wrapped tightly around the neck, placental infarcts, third-trimester bleeding,
preeclampsia, anemia during pregnancy, anorexia during pregnancy, fetal heart
rate/rhythm deviations, and breech presentation. Prematurity was removed from
the hypoxia definition previously used18 to
permit evaluation of the effects of hypoxia as a function of developmental
status. As nearly all of the subjects born prematurely (ie,  2 weeks) were
small for their gestational age, and vice versa, the 2 categories were collapsed
together.
IMAGING PROCEDURES
Images were acquired using a standard dual-echo sequence with 5-mm slice
thickness and segmented into gray matter, white matter, and CSF using an adaptive,
3-dimensional, Bayesian algorithm38 previously
validated for this purpose.39 These volumes
were separated by hemisphere and region using operationally defined boundaries
for the frontal and temporal lobes.40 In addition,
a "posterior" region was defined as all tissue exclusive of the frontal and
temporal lobes. Tracings were performed blindly with respect to diagnosis
and birth history, and interrater reliabilities were excellent (intraclass
correlations > 0.93). Additional details pertaining to MRI acquisition and
analysis procedures are provided elsewhere.32
STATISTICAL ANALYSES
The data were analyzed using the general linear-mixed model with repeated
measures. We corrected for dependency (ie, correlation) among multiple observations
from the same family and the same individual by treating family, and person
nested within family, as random variables and adjusting the model error terms
accordingly. Measures of gray matter, white matter, sulcal CSF, and ventricular
CSF were analyzed separately, with hemisphere and, where appropriate, region
(frontal, temporal, posterior) treated as within-subject, repeated-measures
variables. We tested the hypothesis that fetal hypoxia is more strongly associated
with brain morphology in the presence of genetic susceptibility to schizophrenia
by modeling the risk group x fetal hypoxia interaction, both overall
and in interaction with hemisphere and region, as a fixed-effect predictor.
To determine whether these effects vary by prematurity/small for gestational
age status, we also modeled the risk group x fetal hypoxia x small
for gestational age status interaction, both overall and in interaction with
hemisphere and region. Whenever one of these terms significantly predicted
brain volume, contrast analysis was performed to compare subjects with and
without a history of hypoxia in each risk group, after collapsing across nonsignificant
within-subject dimensions. This approach maintained the hypothesis-wise type
I error rate of 0.05 by evaluating a predictor's contribution to a dependent
measure only if its effect was significant at the multivariate level. Maternal
infection during pregnancy was included as a predictor to control for its
possible confounding of the association between hypoxic OCs and brain volumes.
There were too few subjects with a history of maternal infection for a meaningful
test of its potential interaction with risk group. In addition, the analyses
controlled for overall brain volume, age at examination, sex, and history
of substance disorder because these individual-difference factors may account
for some variability in regional brain volumes. To correct for between-region
differences in region of interest size, regional tissue volumes were expressed
as percentage ratios of overall regional volumes (eg, frontal gray matter
ratio = [frontal gray matter volume / total frontal volume] x 100).
RESULTS
FETAL HYPOXIA
Mixed-model, repeated-measures analyses of regional and hemispheric
gray matter, white matter, and CSF brain ratios showed that fetal hypoxia
is a significant predictor of gray matter (F1,111 = 14.6, P<.001) and total sulcal CSF (F1,144 = 8.3, P = .005). Analyses also showed that fetal hypoxia interacted
significantly with risk group in the prediction of overall gray matter (F2,95 = 6, P = .003), with nonsignificant trends
in this direction for overall sulcal CSF (F2,125 = 2.7, P = .07) and overall ventricular CSF (F2,135 = 2.7, P = .07). For both gray matter (F10,785 = 6.8, P<.001) and sulcal CSF (F10,785 = 7.0, P<.001), the risk group x fetal hypoxia interaction
term varied significantly as a function of region, but not as a function of
hemisphere or region within hemisphere. As shown in Table 2, while there were significant reductions in gray matter
associated with fetal hypoxia in all regions among patients and siblings,
the magnitude of this association was greatest in the temporal lobe for both
groups. The same pattern was present with regard to regional sulcal enlargement
among patients, while among siblings, hypoxia was significantly associated
with sulcal enlargement only in the temporal lobe. Fetal hypoxia was also
associated with a significant increase in ventricular CSF, but only among
patients. In contrast, fetal hypoxia was not significantly related to white
matter in any group and was not significantly related to any tissue type in
any region for controls.
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Table 2. Regional Gray (GM) and White Matter (WM), Sulcal (SCSF), and
Ventricular Cerebrospinal Fluid (VCSF) Brain Ratios by Risk Group and Fetal
Hypoxia*
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PREMATURITY/SMALL FOR GESTATIONAL AGE STATUS
There was a main effect of small for gestational age status on gray
matter (F1,125 = 4.8, P = .03) and sulcal
CSF (F1,152 = 3.8, P = .05). The risk
group x fetal hypoxia interaction term varied nonsignificantly as a
function of small for gestational age status for gray matter (F5,98
= 1.9, P = .10), with a significant trend in this
direction for sulcal CFS (F5,128 = 2.5, P
= .04), depicted in Figure 1 and Figure 2, respectively. The associations of
fetal hypoxia with gray matter reduction and sulcal enlargement in the patients
and their siblings were substantially greater (ie, the effect sizes were 2-3
times larger) among those born prematurely and/or small for their gestational
age. Among subjects born at full term and/or at normal size for their gestational
age, fetal hypoxia was associated with a significant reduction in gray matter
only in the patients. In contrast, small for gestational age status was unrelated
to gray matter or sulcal CSF in the absence of hypoxia, and there were no
significant relationships between fetal hypoxia and gray matter or sulcal
CSF in the controls, regardless of developmental status at birth.
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Figure 1. Least square mean ± SEM
overall gray matter–brain ratios of schizophrenic patients, siblings,
and controls, as a function of fetal hypoxia and small for gestational age
status. Of the 64 probands, 51 were normal size at birth (10 with and 41 without
a history of fetal hypoxia), and 13 were small for their gestational age (5
with and 8 without a history of fetal hypoxia). Of the 51 siblings, 37 were
normal size at birth (8 with and 29 without a history of fetal hypoxia), and
14 were small for gestational age (5 with and 9 without a history of fetal
hypoxia). Of the 54 controls, 42 were normal size at birth (8 with and 34
without a history of fetal hypoxia), and 12 were small for gestational age
(4 with and 8 without a history of fetal hypoxia).
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Figure 2. Least square mean ± SEM
overall sulcal cerebrospinal fluid–brain ratios of schizophrenic patients,
siblings, and controls as a function of fetal hypoxia and small for gestational
age status. Group sample sizes were as given in the legend to Figure 1.
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PRENATAL INFECTION
Infection had a significant overall main effect on gray matter (F1,108 = 7.8, P = .006) and sulcal CSF (F1,137 = 6.2, P = .014), but not on white matter
or ventricular CSF. Subjects with a history of maternal infection during gestation
had lower gray matter– and higher sulcal CSF–brain ratios than
those who did not (mean ± SEM, 54.3 ± 0.7 vs 56.3 ± 0.3
for gray matter; 10.5 ± 1.0 vs 8.0 ± 0.4 for sulcal CSF).
COVARIATES
Total brain volume significantly predicted gray matter (F1,149 = 19.1, P<.001), white matter (F1,132 = 29.1, P<.001), and ventricular CSF (F1,128 = 4.8, P = .03) volumes. Age at scanning
and substance abuse significantly predicted gray matter volume
(F1,138 = 6.7, P = .01; F1,100 = 3.6, P
= .04, respectively). Sex did not significantly predict any volumes after
controlling for total brain volume.
COMMENT
The principal finding of this study is that a history of fetal hypoxia
is associated with increased structural brain abnormalities among schizophrenia
patients and their nonschizophrenic siblings, but not among controls at low
genetic risk for the disorder. In the following paragraphs, we consider the
major competing explanations of our findings followed by their potential implications.
First, the association between fetal hypoxia and altered neuroanatomy
could be accounted for by other OCs that both increase risk for schizophrenia
and disrupt the brain via mechanisms other than, or in addition to, oxygen
insufficiency. However, we considered the 2 most prominent such candidates,
prenatal infection and fetal growth retardation, and found that neither was
significantly correlated with either fetal hypoxia or adult schizophrenia.
Furthermore, controlling for these 2 factors statistically did not modify
the significance or magnitude of the associations between fetal hypoxia and
brain morphology in patients or siblings. Still, some cases of fetal growth
retardation may be expected to stem from conditions, such as placental insufficiency,
that cause mild but chronic fetal hypoxia.41
In keeping with this view, the associations of fetal hypoxia with brain morphology
were greatly magnified among the patients and siblings born small for their
gestational age. However, because fetal growth retardation did not predict
significant alterations in brain morphology in the absence of hypoxia, growth
retardation per se does not compete with hypoxia as the mechanism underlying
these associations.
One could also argue that our findings suggest an influence other than
hypoxia because some of its well-characterized macroscopic brain sequelae,
such as periventricular white matter damage, were not observed. However, the
neural sequelae of hypoxia are numerous and dependent on the severity and
timing of the insult. At the cellular level, they vary in severity from alterations
in neurite outgrowth to neuronal cell death.42
Only in the latter case would a loss of both gray and white matter be expected.
In the former case, immature neurons may survive the hypoxic insult but still
have a compromised elaboration of synaptic interconnections.42
Studies in fetal sheep have shown that hypoxia secondary to chronic placental
insufficiency is associated with reduced cortical thickness and increased
cortical neuronal density, without any observable neuronal loss or white matter
damage.43 These reductions in neuropil volume
should manifest as reductions in gray but not white matter volume at the macroscopic
level. The pattern of morphologic changes associated with hypoxia in this
study is thus compatible with an animal model of chronic fetal hypoxia. Also
supporting this interpretation is the fact that more than 80% of subjects
in the fetal hypoxia group were positive for markers of both prenatal and
birth asphyxia.
Another possibility is that the effects of hypoxia would be confounded
with shared genetic or environmental influences that increase the likelihood
of hypoxic complications among patients and their unaffected siblings. However,
the siblings did not have higher rates of hypoxia-associated OCs than the
controls,18 indicating an absence of covariation
between these OCs and genetic risk status. Although covariation between hypoxia
and a shared environmental influence cannot be excluded entirely, twin and
adoption studies have shown that shared environment plays a negligible role
in the overall etiology of schizophrenia.12, 44
Moreover, it is difficult to imagine a systematic environmental influence
that would manifest as greater susceptibility to hypoxic-ischemic brain injury
and that would be shared by siblings discordant for schizophrenia but not
by demographically matched controls. The most plausible of such candidates
are prenatal viral infection and fetal growth retardation, which were neither
more common in patients and siblings nor responsible for the significant hypoxia
effects.
We can also exclude the possibility that our findings are a consequence
of selecting a nonrepresentative sample of probands. This study used a random,
population-based sampling method that resulted in excellent correspondence
between studied and nonstudied probands on major demographic and clinical
variables. Furthermore, because the sibling and control groups were well matched
on the presence of major psychiatric disorders, our findings are not due to
an excess of nonschizophrenia-related mental illness among siblings.
It would thus appear that hypoxia-associated OCs are related in some
manner to the neurodevelopmental pathogenesis of schizophrenia. In the context
of a disorder with polygenic inheritance,45
OCs may act either additively or interactively with genetic factors in increasing
risk for schizophrenia on a continuum of liability.27
The additive model predicts that hypoxia should have an equivalent degree
of influence on continuous markers of disease liability, regardless of the
degree of genetic background for the disorder. The interaction model predicts
that fetal hypoxia should have a differential relationship with continuous
markers of disease liability in those at elevated genetic risk for schizophrenia
compared with those at low genetic risk. Our finding that fetal hypoxia is
associated with increased signs of brain abnormalities in both patients and
their siblings, but not among low-risk controls, is thus consistent with the
gene-interaction model. Also supporting this model is our earlier study, which
found that hypoxic complications predict increased risk for schizophrenia
and greater ventricular enlargement among offspring of schizophrenic parents,
but not among offspring of nonschizophrenic parents.20, 28
Cortical sulcal enlargement did not vary by obstetric history among those
at genetic risk for schizophrenia in the Danish study,28
as it did in the present study, which most likely reflects the greater reduction
in signal at the cortical surface (due to partial volume artifacts) associated
with computed tomography compared with MRI.
The gene-environment interaction model makes 2 additional predictions
that can be tested with this sample: (1) fetal hypoxia should occur more frequently
among schizophrenic patients than among their siblings, and (2) the association
between fetal hypoxia and continuous liability indicators should be differential
in the patients compared with their siblings. While rates of fetal hypoxia
did not differ by risk group in this study, a prior report on this sample
found that hypoxia-associated OCs were elevated among cases with an early
age at onset, but not among later-onset cases or among siblings of either
group.18 Moreover, the odds of early-onset schizophrenia
increased 2.9 times per hypoxic OC within families.18
Because this report examined the relationship of OCs and brain morphology
rather than diagnosis, and because of the limited sample sizes available,
early-onset and later-onset cases were collapsed together in the analyses.
The fact that most patients with a history of fetal hypoxia were early-onset
cases raises the possibility that hypoxia exposure is confounded with other
factors that determine age at onset. However, the associations between fetal
hypoxia and brain morphology remained significant after the patients' data
were reanalyzed with age at onset as an additional covariate (F1,54
= 7.8, P = .007 for gray matter; F1,54
= 4.8, P = .03 for sulcal CSF; and F1,54
= 7.9, P = .007 for ventricular CSF).
Consistent with the second prediction, the effect of hypoxia was significantly
greater among patients than siblings for both gray matter (F6,535
= 6.53, P<.001) and sulcal CSF (F6,535
= 6.20, P<.001) and was present only among patients
for ventricular CSF (Table 2).
Thus, while unaffected siblings show some sensitivity to the schizophrenia-promoting
effects of fetal hypoxia, this sensitivity differs from that observed in patients
both quantitatively (for cortical measures) and qualitatively (for ventricular
enlargement).
These findings add to the growing evidence that at least some of the
brain abnormalities in schizophrenic patients are neurodevelopmental in origin.11 That ventricular enlargement and reduced cortical
gray matter volume were correlated with an adverse condition at birth clearly
suggests an early origin for these abnormalities, although it in no way excludes
participation of later neurodevelopmental46
or neurodegenerative47 processes. It also appears
likely that genes predisposing to schizophrenia may render the fetal brain
especially vulnerable to hypoxic OCs. This finding encourages the search for
genes that heighten the brain's vulnerability to hypoxic/ischemic neuronal
injury.
This study has several limitations. We used T2-weighted images with
a large slice thickness (5 mm), which are more prone to partial volume artifact
than higher-resolution, T1-weighted images. Such effects are magnified in
the presence of sulcal enlargement and may therefore interact with diagnostic
status. However, because the primary impact of a partial volume artifact is
to lower the signal-to-noise ratio, thereby reducing the power to detect true
associations, the presence of such an interaction in these data would most
likely have led to an underestimation of effect sizes in the patient and sibling
groups. This study also employed relatively gross anatomical divisions, making
it unclear whether the associations between hypoxia and gray matter loss in
the posterior region reflect volume reductions in subcortical structures,
occipital-parietal cortices, or both. An effect on posterior gray matter appears
likely because approximately 80% of the volume of the posterior region refers
to the occipital-parietal cortex. An association of hypoxia with subcortical
abnormalities also seems probable given its correlation with ventricular enlargement,
which in schizophrenia is associated with periventricular gray matter reduction.48-49
Because most subjects with a history of fetal hypoxia were positive
for markers of both prenatal and perinatal hypoxia, we were unable to examine
whether hypoxia occurring at different times in development (expected to result
in differential patterns of regional brain injury50-51)
is differentially relevant to structural brain abnormalities in schizophrenia.
In addition, our definition of hypoxia exposure was limited to complications
that were recorded in the birth records of the Finnish health system during
the 1950s. While these records are of high quality and yield obstetric measures
that are clearly superior to those obtained via retrospective maternal interview,
more direct, quantitative methods for assaying fetal blood oxygenation52-53 would permit a more sensitive test
of our hypotheses.
AUTHOR INFORMATION
Accepted for publication June 6, 2001.
This research was supported by grant MH48207 from the National Institute
of Mental Health, Bethesda, Md.
We thank Ulla Mustonen, MSW, and Liisa Varonen, PhD, for their contributions
to subject recruitment and assessment; Antti Tanskanen, MS, for his contributions
to the register searches and database creation; Mary O'Brien, PhD, for her
contributions to the diagnostic procedures and reliability assessment; and
Raquel Gur, MD, PhD, Bruce Turetsky, MD, Michelle Yan, PhD, and other investigators
at the Mental Health Clinical Research Center, Department of Psychiatry, University
of Pennsylvania, Philadelphia (grant MH43880), for their contributions to
the imaging methods and analysis procedures used in this study.
Corresponding author and reprints: Tyrone D. Cannon, PhD, Department
of Psychology, University of California, Los Angeles, 1285 Franz Hall, Los
Angeles, CA 90095 (e-mail: cannon{at}psych.ucla.edu).
From the Departments of Psychology (Drs Cannon and Rosso and Mr van
Erp), Psychiatry and Biobehavioral Sciences, and Human Genetics (Dr Cannon),
University of California, Los Angeles; the Department of Mental Health, National
Public Health Institute of Finland, Helsinki (Drs Huttunen and Lönnqvist
and Ms Pirkola); and the Department of Radiology, University of Helsinki (Drs
Salonen, Valanne, and Standertskjöld-Nordenstam and Mr Poutanen).
REFERENCES
| |
1. Cannon TD. Abnormalities of brain structure and function in schizophrenia: implications
for etiology and pathophysiology. Ann Med. 1996;28:533-539.
ISI
| PUBMED
2. Buchanan RW, Carpenter WT. The neuroanatomies of schizophrenia. Schizophr Bull. 1997;23:367-372.
3. Pfefferbaum A, Marsh L. Structural brain imaging in schizophrenia. Clin Neurosci. 1995;3:105-111.
ISI
| PUBMED
4. Rosso IM, Bearden CE, Hollister JM, Gasperoni TL, Sanchez LE, Hadley T, Cannon TD. Childhood neuromotor dysfunction in schizophrenia patients and their
unaffected siblings: a prospective cohort study. Schizophr Bull. 2000;26:367-378.
5. Cannon TD, Bearden CE, Hollister JM, Rosso IM, Sanchez LE, Hadley T. Childhood cognitive functioning in schizophrenia patients and their
unaffected siblings: a prospective cohort study. Schizophr Bull. 2000;26:379-393.
6. Walker EF. Developmentally moderated expressions of the neuropathology underlying
schizophrenia. Schizophr Bull. 1994;20:453-480.
7. Akbarian S, Bunney WE Jr, Potkin SG, Wigal SB, Hagman JO, Sandman CA, Jones EG. Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase
cells in frontal lobe of schizophrenics implies disturbances of cortical development. Arch Gen Psychiatry. 1993;50:169-177.
FREE FULL TEXT
8. Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG. Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase
neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry. 1993;50:178-187.
FREE FULL TEXT
9. Arnold SE, Hyman BT, Van Hoesen GW, Damasio AR. Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. Arch Gen Psychiatry. 1991;48:625-632.
FREE FULL TEXT
10. Benes FM, McSparren J, Bird ED, San Giovanni JP, Vincent SL. Deficits in small interneurons in prefrontal and cingulate cortices
of schizophrenic and schizoaffective patients. Arch Gen Psychiatry. 1991;48:996-1001.
FREE FULL TEXT
11. Cannon TD. Neurodevelopmental influences in the genesis and epigenesis of schizophrenia:
an overview. Appl Prev Psychol. 1998;7:47-62.
FULL TEXT
|
ISI
12. Cannon TD, Kaprio J, Lönnqvist J, Huttunen MO, Koskenvuo M. The genetic epidemiology of schizophrenia in a Finnish twin cohort:
a population-based modeling study. Arch Gen Psychiatry. 1998;55:67-74.
FREE FULL TEXT
13. O'Donovan MC, Owen MJ. The molecular genetics of schizophrenia. Ann Med. 1996;28:541-546.
ISI
| PUBMED
14. Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal
complications: a 28-year follow-up of the 1966 North Finland general population
birth cohort. Am J Psychiatry. 1998;155:355-364.
FREE FULL TEXT
15. Eagles JM, Gibson I, Bremner MH, Clunie F, Ebmeier KP, Smith NC. Obstetric complications in DSM-III schizophrenics
and their siblings. Lancet. 1990;335:1139-1141.
FULL TEXT
|
ISI
| PUBMED
16. Kinney DK, Levy DL, Yurgelun-Todd DA, Medoff D, LaJonchere CM, Radford-Paregol M. Season of birth and obstetrical complications in schizophrenics. J Psychiatr Res. 1994;28:499-509.
FULL TEXT
|
ISI
| PUBMED
17. Cannon TD, Rosso IM, Hollister JM, Bearden CE, Sanchez LE, Hadley T. A prospective cohort study of genetic and perinatal influences in the
etiology of schizophrenia. Schizophr Bull. 2000;26:351-366.
18. Rosso IM, Cannon TD, Huttunen MO, Huttunen T, Lönnqvist J, Gasperoni TL. Obstetric risk factors for early-onset schizophrenia in a Finnish birth
cohort. Am J Psychiatry. 2000;157:801-807.
FREE FULL TEXT
19. Gunther-Genta F, Bovet P, Hohlfeld P. Obstetric complications and schizophrenia: a case-control study. Br J Psychiatry. 1994;164:165-170.
FREE FULL TEXT
20. Mirdal GK, Mednick SA, Schulsinger F, Fuchs F. Perinatal complications in children of schizophrenic mothers. Acta Psychiatr Scand. 1974;50:553-568.
ISI
| PUBMED
21. Marcus J, Auerback J, Wilkinson L, Burack CM. Infants at risk for schizophrenia: the Jerusalem infant development
study. Arch Gen Psychiatry. 1981;38:703-713.
FREE FULL TEXT
22. Fish B, Marcus J, Hans SL, Auerbach JG, Perdue S. Infants at risk for schizophrenia: sequelae of a genetic neurointegrative
defect. Arch Gen Psychiatry. 1992;49:221-235.
FREE FULL TEXT
23. Hanson DR, Gottesman II, Heston LL. Some possible childhood indicators of adult schizophrenia inferred
from children of schizophrenics. Br J Psychiatry. 1976;129:142-154.
FREE FULL TEXT
24. Rieder RO, Broman SH, Rosenthal D. The offspring of schizophrenics, II: perinatal factors and IQ. Arch Gen Psychiatry. 1977;34:789-799.
FREE FULL TEXT
25. Buka SL, Tsuang MT, Lipsitt LP. Pregnancy/delivery complications and psychiatric diagnosis: a prospective
study. Arch Gen Psychiatry. 1993;50:151-156.
FREE FULL TEXT
26. Done DJ, Johnstone EC, Frith CD, Golding J, Shepherd PM, Crow TJ. Complications of pregnancy and delivery in relation to psychosis in
adult life: data from the British perinatal mortality survey sample. BMJ. 1991;302:1576-1580.
27. Cannon TD. On the nature and mechanisms of obstetric influences in schizophrenia:
a review and synthesis of epidemiologic studies. Int Rev Psychiatry. 1997;9:387-397.
FULL TEXT
|
ISI
28. Cannon TD, Mednick SA, Parnas J, Schulsinger F, Praestholm J, Vestergaard A. Developmental brain abnormalities in the offspring of schizophrenic
mothers, I: contributions of genetic and perinatal factors. Arch Gen Psychiatry. 1993;50:551-564.
FREE FULL TEXT
29. Parnas J, Cannon TD, Jacobsen B, Schulsinger H, Schulsinger F, Mednick SA. Lifetime DSM-III-R diagnostic outcomes in
offspring of schizophrenic mothers: results from the Copenhagen high-risk
study. Arch Gen Psychiatry. 1993;50:707-714.
FREE FULL TEXT
30. Suddath RL, Christison GW, Torrey EF, Casanova MF, Weinberger DR. Anatomical abnormalities in the brains of monozygotic twins discordant
for schizophrenia. N Engl J Med. 1990;322:789-794.
ABSTRACT
31. McNeil TF, Cantor-Graae E, Weinberger DR. Relationship of obstetric complications and differences in size of
brain structures in monozygotic twin pairs discordant for schizophrenia. Am J Psychiatry. 2000;157:203-212.
FREE FULL TEXT
32. Cannon TD, van Erp TGM, Huttunen M, Lönnqvist J, Salonen O, Valanne L, Poutanen VP, Standertskjöld-Nordenstam CG, Gur RE, Yan M. Regional gray matter, white matter, and cerebrospinal fluid distributions
in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry. 1998;55:1084-1091.
FREE FULL TEXT
33. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. Washington, DC: American Psychiatric Association; 1987.
34. Spitzer RL, Williams JB, Gibbon M. Instruction Manual for the Structured Clinical Interview
for DSM-III-R (SCID). Washington, DC: American Psychiatric Association; 1987.
35. Loranger AW, Sussman VL, Oldham JM, Russakoff LM. Personality Disorder Examination. A Structured Interview
for Making Diagnosis of DSM-III-R Personality Disorders. White Plains, NY: Cornell Medical College; 1985.
36. Cohen J. A coefficient of agreement for nominal scales. Educ Psychol Meas. 1960;20:37-46.
FULL TEXT
|
ISI
37. Rahaula U. The quantitative strength of the social strata of Finnish society. Sosiaalinen-Aikakauskirja. 1970;63:347-362.
38. Yan MX, Karp JS. An adaptive Bayesian approach to 3-dimensional MR brain segmentation. In: Bizais Y, Barillot C, Di Paola R, eds. Information
Processing in Medical Imaging. New York, NY: Kluwer Academic Publishers;
1995:201-213.
39. Goldszal A, Davatzikos C, Pham DL, Yan MX, Bryan RN, Resnick SM. An image processing system for qualitative and quantitative volumetric
analysis of brain imaging. J Comput Assist Tomogr. 1998;22:827-837.
FULL TEXT
|
ISI
| PUBMED
40. Turetsky BT, Cowell PE, Gur RC, Grossman RI, Shtasel DL, Gur RE. Frontal and temporal lobe brain volumes in schizophrenia: relationship
to symptomatology and clinical subtype. Arch Gen Psychiatry. 1995;52:1061-1070.
FREE FULL TEXT
41. Richardson BS, Bocking AD. Metabolic and circulatory adaptations to chronic hypoxia in the fetus. Comp Biochem Physiol A Mol Integr Physiol. 1998;119:717-723.
FULL TEXT
| PUBMED
42. Nyakas C, Buwalda B, Luiten PGM. Hypoxia and brain development. Prog Neurobiol. 1996;49:1-51.
ISI
| PUBMED
43. Rees S, Mallard C, Breen S, Stringer M, Cock M, Harding R. Fetal brain injury following prolonged hypoxemia and placental insufficiency:
a review. Comp Biochem Physiol A Mol Integr Physiol. 1998;119:653-660.
FULL TEXT
| PUBMED
44. Kendler KS, Gruenberg AM, Kinney DK. Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish
adoption study of schizophrenia. Arch Gen Psychiatry. 1994;51:456-468.
FREE FULL TEXT
45. Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle. Cambridge, England: Cambridge University Press; 1982.
46. Keshavan MS, Anderson S, Pettegrew JW. Is schizophrenia due to excessive synaptic pruning in the prefrontal
cortex? the Feinberg hypothesis revisited. J Psychiatr Res. 1994;28:239-265.
FULL TEXT
|
ISI
| PUBMED
47. Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon TD, Bilker W, Gur RC. A follow-up magnetic resonance imaging study of schizophrenia: relationship
of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry. 1998;55:145-152.
FREE FULL TEXT
48. Brown R, Colter N, Corsellis JAN, Crow TJ, Frith CD, Jagoe R, Johnstone EC, Marsh 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;43:36-42.
FREE FULL TEXT
49. Lesch A, Bogerts B. The diencephalon in schizophrenia: evidence for reduced thickness of
the periventricular grey matter. Eur Arch Psychiatry Neurol Sci. 1984;234:212-219.
FULL TEXT
| PUBMED
50. Barkovich AJ, Hallam D. Neuroimaging in perinatal hypoxic-ischemic injury. Ment Retard Dev Disabil Res Rev. 1997;3:28-41.
51. Volpe JJ. Hypoxic-ischemic encephalopathy: neuropathology and pathogenesis. In: Neurology of the Newborn. 3rd ed. Philadelphia,
Pa: WB Saunders; 1995:279-312.
52. Low JA. The role of blood gas and acid-base measurement in the diagnosis of
intrapartum fetal asphyxia. Am J Obstet Gynecol. 1988;159:1235-1240.
ISI
| PUBMED
53. Buescher U, Hertwig K, Wolf C, Dudenhausen JW. Erythropoietin in amniotic fluid as a marker of chronic fetal hypoxia. Int J Gynaecol Obstet. 1998;60:257-263.
FULL TEXT
| PUBMED
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Whalley et al.
Neuroscientist 2005;11:238-249.
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