The hippocampus in families with schizophrenia in relation to obstetric complications
Introduction
There is clear-cut evidence that schizophrenia is a brain disorder. Structural brain abnormalities and neurocognitive deficits are among the most frequently replicated findings supporting this view. Highly consistent magnetic resonance imaging (MRI) shows enlarged ventricles as well as smaller temporal lobe and limbic system volumes, particularly in the hippocampus. A number of MRI studies also show a reduction of hippocampal size (meta-analytically reviewed in Lawrie and Abukmeil, 1998, Nelson et al., 1998, Wright et al., 2000) and altered hippocampal shape (Csernansky et al., 2002, Tepest et al., 2003). DeLisi et al. (1988) were the first to publish an MRI study on hippocampal size in patients with schizophrenia and their healthy siblings. Smaller hippocampal volumes have been observed in both prodromal and first-episode subjects (Bogerts et al., 1990, Lawrie et al., 1999, Velakoulis et al., 1999, Joyal et al., 2002, Pantelis et al., 2003) showing that hippocampal involvement is not secondary to the illness or its treatment. A study examining individuals with chronic schizophrenia and first-episode psychosis reported bilateral hippocampal volume decrease in chronic schizophrenia, while in patients with first-episode schizophrenia a reduction in hippocampal volume was only found on the left side and only in a subgroup of first-episode patients with schizophrenia but not schizophreniform psychosis (Velakoulis et al., 2006). Twin-studies (Narr et al., 2002) as well as studies including first-degree relatives (Seidman et al., 1999, Seidman et al., 2002, Seidman et al., 2003) suggest that hippocampal volume reduction may also be part of the underlying genetic predisposition to schizophrenia. However, studies considering obstetric complications (OC) seem to show some additional effect on hippocampal volume reduction in schizophrenia (DeLisi et al., 1988, Stefanis et al., 1999).
Studying first-degree relatives of patients is a valuable strategy to investigate vulnerabilities to schizophrenia. This search has become more interesting since first risk genes like dysbindin and neuregulin 1 have been described (Straub et al., 2002, Stefansson et al., 2002). Although the genetic risk for schizophrenia outweighs causal factors contributing to the illness, environmental factors such as OC also contribute substantially to the etiology. In their meta-analysis Verdoux et al. (1997) not only found a significant association between schizophrenia and obstetric complications but also a correlation between early age of onset and OCs, especially prenatal asphyxia.
Based on this multifactorial model we wanted to test whether compared to controls family members suffering from schizophrenia as well as their unaffected first-degree relatives both show smaller hippocampal volume and whether OCs contribute to this deficit.
Section snippets
Subjects
Subjects were recruited while being treated as inpatients at the Departments of Psychiatry of the Universities of Düsseldorf and Bonn. The sample consisted of 50 patients with schizophrenia (ICD-10: F20 (n = 41)) or schizoaffective disorder (ICD-10: F25 (n = 9)), hereafter referred to as schizophrenic subjects, 88 first-degree relatives of the schizophrenic subjects lacking the diagnosis of schizophrenia (59 non-psychiatric relatives without ICD-10 diagnosis; 29 psychiatric relatives with the
Demographic variables
The three diagnostic groups (schizophrenic patients, first-degree relatives, control subjects) differed significantly with regard to age (F = 14.80; p < 0.0005) due to inclusion of patients' parents in the first-degree relative group, weight (F = 9.57; p < 0.0005) and center of imaging (Düsseldorf or Bonn) (Chi2 = 24.37; p < 0.0005). There were no significant differences detected for the demographic variables gender (Chi2 = 4.22; p = 0.12), education (primary school vs. higher degree) (Chi2 =
Discussion
This MRI study compared hippocampal volumes of 50 schizophrenic patients, their 88 non-psychotic first-degree relatives and 53 control subjects. The aim of this study was to determine whether obstetric complications contribute to the hippocampal volume reduction seen in schizophrenic patients and their first-degree relatives.
Compared to controls schizophrenic patients showed a reduction in hippocampal volume on the left (− 14%) and a trend toward volume reduction on the right hemisphere (− 15%).
Role of funding source
The funding source did in no respect influence the authors in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the paper for publication.
Contributors
Florian Ebner wrote the first draft of the manuscript and managed the literature searches.
Ralf Tepest did the image preprocessing, wrote the protocol for MR measurements and did the analyses of morphometric data.
Indra Dani did the morphometric measurements.
Ute Pfeiffer did the morphometric measurements and recruitment of subjects.
Thomas G Schulze did the recruitment of subjects.
Marcella Rietschel contributed in designing the study concerning genetical aspects.
Wolfgang Maier contributed in
Conflict of interest
For all authors there are no conflicts of interest.
Acknowledgement
Supported by the Deutsche Forschungsgemeinschaft (DFG); Grant no.: Fa 241/2 (1–3).
References (33)
- et al.
Multimodal image coregistration and partitioning — a unified framework
Neuroimage
(1997) - et al.
Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia
Psychiatry res.
(1990) - et al.
Mini-mental state. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
A volumetric MRI study of the entorhinal cortex in first episode neuroleptic-naive schizophrenia
Biol. Psychiatry
(2002) - et al.
Magnetic resonance imaging of brain in people at high risk of developing schizophrenia
Lancet
(1999) - et al.
Obstetric complications as antecedents of schizophrenia: empirical effects of using different obstetric complications scales
J. Psychiat. Res.
(1994) - et al.
Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison
Lancet
(2003) - et al.
Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis
Biol. Psychiatry
(1999) - et al.
Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications
Biol. Psychiatry
(1999) - et al.
Neuregulin 1 and susceptibility to schizophrenia
Am. J. Hum. Genet.
(2002)
Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia
Am. J. Hum. Genet.
Hippocampal deformities in the unaffected siblings of schizophrenia subjects
Biol. Psychiatry
A classification of hand preference by association analysis
Br. J. Psychol.
Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping
Am. J. Psychiatry
Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study
Neuropsychopharmacology
Perinatal complications and reduced size of brain limbic structures in familial schizophrenia
Schizophr. Bull.
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Obstetric Complications and Brain Imaging in Schizophrenia: A Systematic Review
2020, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingCitation Excerpt :Cannon et al. suggested that the degree of brain abnormalities was predicted by the interaction of OCs and genetic risk (73), while Gilbert et al. argued that the effect of OCs was inversely correlated with gray matter volume when taking into consideration a sample of subjects at ultra-high risk for psychosis and control subjects (74). Other authors found an interaction effect of OCs and genetic background on VBR (53) or in hippocampal volumes, but for the latter it was not specific for patients with schizophrenia (75). McDonald et al. demonstrated that probands with schizophrenia had enlarged lateral ventricles, both in cases with multiply affected families and in those nonfamilial schizophrenia patients, but there were differences between subjects’ relatives, so while an enlargement in left lateral ventricles was shown to exist in multiply affected families, in nonfamilial relatives ventricle size did not differ from that of control subjects (57).
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2015, Psychiatry Research - NeuroimagingCitation Excerpt :Genetic variations in multiple genes including but not limited to NRG1, DISC1, DTNBP1 and BDNF in schizophrenia affect hippocampal function (Heckers and Konradi, 2010). On the other hand, hippocampal volume is also influenced by environmental factors like fetal hypoxia (Van Erp et al., 2002) and obstetric complications (Ebner et al., 2008). Hence, hippocampal volume appears to be determined by complex interactions between gene and environmental factors.
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2012, NeuroImageCitation Excerpt :Functional, biochemical, molecular and histopathological findings also point towards left hippocampal involvement in schizophrenia (Gothelf et al., 2000). Family studies have also implicated the left hippocampus in the patients with schizophrenia, but less consistently in their unaffected relatives (Ebner et al., 2008; McDonald et al., 2002; Schulze et al., 2003). The left hippocampal volume, significantly correlated with cognitive deficits and possibly pointing towards neurodevelopmental insults, has been postulated to be a vulnerability indicator for schizophrenia (Rametti et al., 2007; Seidman et al., 2002; Toulopoulou et al., 2004) thus, lending support to our own findings.