The hippocampus in families with schizophrenia in relation to obstetric complications

doi:10.1016/j.schres.2008.06.007

Schizophrenia Research

Volume 104, Issues 1–3, September 2008, Pages 71-78

https://doi.org/10.1016/j.schres.2008.06.007 Get rights and content

Abstract

Background

Hippocampal volume reduction is a well replicated finding in schizophrenia. Evidence indicates a contribution of genetic and environmental factors, especially the influence of obstetric complications to this volume reduction. The aim of this study was to compare hippocampal volume of schizophrenic patients as well as and their relatives with control subjects and to quantify the additional contribution of obstetric complications.

Methods

T1 weighted MRI brain scans of 50 schizophrenic patients, 88 first-degree relatives and 53 healthy control subjects were used to perform volumetric measurements on the left and right hippocampus. A set of clinical measures including obstetric complications were recorded for all family members.

Results

Numerically our measurements revealed a hippocampal volume reduction in schizophrenic patients (left: − 14%, right: − 15%) and, although less pronounced, in their unaffected relatives (left: − 6%, right: − 10%). Noted differences in hippocampal volume between schizophrenic patients and controls were only significant for the left side. Hippocampal volumes of patients and their relatives with obstetric complications were reduced bilaterally.

Conclusions

Hippocampal volume reduction is present in schizophrenic patients and their first-degree relatives, suggesting an influence of genetic factors.. In addition, however, obstetric complications have also been shown to play a major role.

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).

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Obstetric Complications and Brain Imaging in Schizophrenia: A Systematic Review
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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).
Schizophrenia is a complex disorder in which clinical symptomatology typically reflects underlying brain abnormalities that coalign with multiple physical health comorbidities. The pathogenesis of schizophrenia involves the interplay between genetic and environmental factors, with obstetric complications widely described as key players in elevating the risk of psychosis. In this regard, understanding the anatomical and functional alterations associated with obstetric complications may help to elucidate potential mechanisms through which birth complications could contribute to schizophrenia pathogenesis. We conducted a systematic review of the extant literature describing brain abnormalities and obstetric complications in patients with schizophrenia and related disorders in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A total of 471 studies were retrieved and screened, and 33 studies met inclusion criteria for our review. Studies varied considerably in their methods, with 11 studies employing computed tomography, 1 using magnetic resonance spectroscopy, and 21 using magnetic resonance imaging. The scientific quality of the included studies was assessed and documented. Obstetric complications increase the risk of provoking brain abnormalities. These abnormalities range from decreased gray matter volume and abnormal brain–ventricle ratios to a reduction of volume in limbic regions—which relate to what is commonly observed in schizophrenia. However, current evidence from neuroimaging studies remains scant in relation to establishing obstetric complications as an independent risk factor for schizophrenia.
Dermatoglyphic correlates of hippocampus volume: Evaluation of aberrant neurodevelopmental markers in antipsychotic-naïve schizophrenia
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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.
Schizophrenia is a disorder of aberrant neurodevelopment is marked by abnormalities in brain structure and dermatoglyphic traits. However, the link between these two (i.e. dermatoglyphic parameters and brain structure) which share ectodermal origin and common developmental window has not been explored extensively. The current study examined dermatoglyphic correlates of hippocampal volume in antipsychotic-naïve schizophrenia patients in comparison with matched healthy controls. Ridge counts and asymmetry measures for palmar inter-digital areas (a-b, b-c, c-d) were obtained using high resolution digital scans of palms from 89 schizophrenia patients [M:F=48:41] and 48 healthy controls [M:F=30:18]. Brain scans were obtained for subset of subjects including 26 antipsychotic-naïve patients [M:F=13:13] and 29 healthy controls [M:F=19:10] using 3 T-MRI. Hippocampal volume and palmar ridge counts were measured by blinded raters with good inter-rater reliability using valid methods. Directional asymmetry (DA) of b-c and bilateral hippocampal volume were significantly lower in patients than controls. Significant positive correlation was found between DA and ridge count of b-c with bilateral anterior hippocampal volume. Study demonstrates the utility of dermatoglyphic markers in identifying structural changes in the brain which may form the basis for neurodevelopmental pathogenesis in schizophrenia.
Meta-analysis of associations between human brain volume and intelligence differences: How strong are they and what do they mean?
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Positive associations between human intelligence and brain size have been suspected for more than 150 years. Nowadays, modern non-invasive measures of in vivo brain volume (Magnetic Resonance Imaging) make it possible to reliably assess associations with IQ. By means of a systematic review of published studies and unpublished results obtained by personal communications with researchers, we identified 88 studies examining effect sizes of 148 healthy and clinical mixed-sex samples (>8000 individuals). Our results showed significant positive associations of brain volume and IQ (r = .24, R² = .06) that generalize over age (children vs. adults), IQ domain (full-scale, performance, and verbal IQ), and sex. Application of a number of methods for detection of publication bias indicates that strong and positive correlation coefficients have been reported frequently in the literature whilst small and non-significant associations appear to have been often omitted from reports. We show that the strength of the positive association of brain volume and IQ has been overestimated in the literature, but remains robust even when accounting for different types of dissemination bias, although reported effects have been declining over time. While it is tempting to interpret this association in the context of human cognitive evolution and species differences in brain size and cognitive ability, we show that it is not warranted to interpret brain size as an isomorphic proxy of human intelligence differences.
Transmitting biological effects of stress in utero: Implications for mother and offspring
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The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus ‘programming’ the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period.
Hippocampal volume and the brain-derived neurotrophic factor Val66Met polymorphism in first episode psychosis
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Small hippocampi and impaired memory are common in patients with psychosis and brain-derived neurotrophic factor (BDNF) plays a critical role in hippocampal neuroplasticity and memory. A common BDNF allele (Val66Met) has been the focus of numerous studies but results from the few BDNF-imaging studies are complex and contradictory. The objective of this study was to determine the association between Val66Met and hippocampal volume in patients with first episode psychosis. Secondary analyses explored age-related associations and the relationship between Val66Met and memory.
Hippocampal volume and BDNF genotyping were obtained for 58 patients with first-episode psychosis and 39 healthy volunteers. Patients were recruited from an early psychosis program serving a catchment-area population.
Hippocampal volume was significantly smaller in patients than controls (F_1,92 = 4.03, p < 0.05) and there was a significant group-by-allele interaction (F_1,92 = 3.99, p < 0.05). Hippocampal volume was significantly smaller in patients than controls who were Val-homozygotes but no group differences were found for Met carriers. Findings were not affected by diagnosis, antipsychotic medication, or age, and there was no change in hippocampal volume during a one-year follow-up. Val-homozygous patients had worse immediate and delayed memory than their Met counterparts.
Results suggest the effects of the BDNF Val66Met allele may be different in patients with psychosis than in healthy adults. Hippocampal volume in patient and control Met allele carriers was very similar suggesting that illness-related factors have minimal influence in this group. In contrast, Val homozygosity was related to smaller hippocampi and poorer memory functioning only in patients with psychosis.
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Citation 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.
Abnormalities of the P300 event related potential (ERP) and of hippocampal structure are observed in individuals with psychotic disorders and their unaffected relatives. The understanding and clinical management of psychotic disorders are largely based on the descriptive Kraepelinian distinction between ‘dementia praecox’ and ‘manic depressive psychosis’, and not dependant on any well demarcated biological underpinnings. The hippocampus is postulated to be one of the main P300 generators, yet it remains unknown whether hippocampal volume decrements are associated with P300 deficits in psychosis, and whether any association is shared across non-affective and affective psychotic disorders.
228 subjects from the Maudsley Family Psychosis Study comprising 55 patients with non-affective psychosis, 23 patients with psychotic bipolar disorder, 98 unaffected relatives, and 52 unrelated controls contributed structural MRI and ERP data. To study the relationship between hippocampal volume and P300 ERP, a seemingly unrelated regression methodology was used, accounting for whole brain volumes, clinical groups, age and gender in the analysis.
An association between left hippocampal volume and P300 latency in the combined sample comprising non-affective and affective psychotic patients, their relatives and controls was observed. There was an inverse relationship between brain structure and function in that prolongation of P300 latencies was associated with smaller left hippocampal volumes. On subdividing the sample based on Kraepelinian dichotomy, this association remained significant only for the non-affective psychosis group, comprising patients and their unaffected relatives.
Based on our findings, P300 latency, a measure of the speed of neural transmission, appears to be related to the size of the left hippocampus in schizophrenia, but not in psychotic bipolar disorder. It seems that underlying neuro-biological characteristics could help in unravelling the traditional Kraepelinian differentiation between the two major psychoses. The specificity of this brain structure–function association for schizophrenia opens the scope for further research using integration of multimodal biological data for objective categorisation of psychosis.

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The hippocampus in families with schizophrenia in relation to obstetric complications

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Demographic variables

Discussion

Role of funding source

Contributors

Conflict of interest

Acknowledgement

Neuroimage

Psychiatry res.

J. Psychiatr. Res.

Biol. Psychiatry

Lancet

J. Psychiat. Res.

Lancet

Biol. Psychiatry

Biol. Psychiatry

Am. J. Hum. Genet.

Am. J. Hum. Genet.

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.