Effects of obstetric complications on brain morphology in schizophrenia : four MRI studies
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AbstractMagnetic resonance imaging (MRI) studies have shown the brains of schizophrenia patients to have smaller hippocampi, larger ventricles, and reduced cortical thickness and regional brain volumes, as compared to the brains of mentally healthy subjects. The abnormal brain morphology may reflect subtle deviances from normal brain development. Early adverse somatic events, in the current thesis studied in the form of obstetric complications (OCs), in the pre-, peri-, or postnatal periods can cause or influence a deviant neurodevelopment. In scientific studies, it has been demonstrated that occurrence of OCs increase the risk of schizophrenia. Moreover, results from experimental animal studies demonstrate that different OCs cause both abnormal changes in brain morphology and behaviour that parallel what is observed in schizophrenia. In humans, OCs have been related to smaller hippocampi, larger lateral ventricles, and reduced cortical volume in schizophrenia patients with as compared to patients without a history of OCs. Taken together, these findings suggest that early somatic trauma such as OCs may exert an influence on neurodevelopment, detectable in the brain decades later. The main aim of this PhD thesis was to investigate the relationship between a history of (OCs) and brain morphology in patients with schizophrenia. The subaims were to study 1) if such a putative effect could explain some of the differences in brain morphology observed between schizophrenia patients and healthy controls, and 2) if the effect of OCs on hippocampal volume, if demonstrated, is modified by genetic variation (allele variation in single nucleotide polymorphisms). The subject sample included in the current four studies comprises 54 schizophrenia patients and 54 healthy control subjects. They all underwent clinical examination, genotyping, and MRI scanning at the Karolinska Institutet and Karolinska University Hospital in Stockholm, Sweden. Automated software tools were used to obtain measures of basal ganglia nuclei and hippocampal volumes, cortical thickness, and cortical folding patterns. Information on OCs was independently collected from original birth records. The main findings were that OCs are not associated with basal ganglia volumes (study I) or cortical thickness (study II), but significantly associated with reduced cortical folding in the left pars triangularis (Broca’s area) (study III) and with altered hippocampal volumes (study IV). The effect of OCs on hippocampal volume appeared to be modulated by allele variation in the hypoxia-regulated GRM3 gene (study IV). Furthermore, schizophrenia patients did not differ from healthy control subjects with respect to the rate or severity of OCs per se; the effects of OCs on basal ganglia volumes, cortical thickness, and cortical gyrification; or the gene*OCs interaction effect on hippocampal volume. In conclusion, while some brain structures (cortical thickness, basal ganglia volumes) were unaffected by a history OCs, OCs influenced other aspects of brain morphology (hippocampal volume, cortical folding) in the same way in both patients with schizophrenia and healthy controls. The differences in brain morphology found between schizophrenia patients and healthy controls were not effects of OCs. Genetic variation may modulate the effect of OCs on hippocampal volume.
List of papers
|Study I: Haukvik UK, McNeil T, Nesvåg R, Söderman E, Jönsson EG, Agartz I. No effect of obstetric complications on basal ganglia volumes in schizophrenia. Progress in Neuro-psychopharmacology and Biological Psychiatry 2010;34:619-623. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.pnpbp.2010.02.024|
|Study II: Haukvik UK, Lawyer G, Bjerkan PS, Hartberg CB, Jönsson EG, McNeil T, Agartz I. Cerebral cortical thickness and a history of obstetric complications in schizophrenia. Journal of Psychiatric Research 2009; 43:1287-1293. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.jpsychires.2009.05.001|
|Study III: Haukvik UK, Schaer M, Nesvåg R, McNeil T, Hartberg CB, Jönsson E, Eliez S, Agartz I. Cortical folding in Broca’s area relates to obstetric complications in schizophrenia patients and healthy controls. Psychological Medicine FirstView Article : pp 1-9, Published online: 26 October 2011. Copryright Cambridge University Press 2011. The published version of this paper is available at: https://doi.org/10.1017/S0033291711002315|
|Study IV: Haukvik UK, Saetre P, McNeil T, Bjerkan PS, Andreassen OA, Werge T, Jönsson EG, Agartz I. An exploratory model for GxE interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia related genes. Progress in Neuro-psychopharmacology and Biological Psychiatry 2010;34:1259-1265. The published version of this paper is available at: https://doi.org/10.1016/j.pnpbp.2010.07.001|