BackgroundVarious lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls.MethodologyWe examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms.ResultsSchizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women.ConclusionOur first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a “differential susceptibility” effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin.
The Geschwind-Behan-Galaburda (GBG) hypothesis links cerebral lateralisation with prenatal testosterone exposure. Digit ratio measures in adults have been established as potential markers of foetal sex hormonal milieu. The aim of the study was to evaluate the sex-dependent interaction of digit ratio measures and cerebral lateralization as well as their neurohemodynamic correlates using functional MRI (fMRI). Digit ratio measures-ratio of index finger (2D) length to ring finger (4D) length (2D:4D) and difference between 2D:4D of two hands, i.e., right minus left (DR-L)-were calculated using high resolution digital images in 70 right-handed participants (42 men) based on reliable and valid method. fMRI was acquired during the performance of a spatial working memory task in a subset of 25 individuals (14 men), and analysed using Statistical Parametric Mapping 8 (SPM8) and the Laterality Index toolbox for SPM8. Men had significantly less bilateral 2D:4D than women. There was a significant negative correlation between right 2D:4D and 2-Back task accuracy (2BACC) in women. A significant sex-by-right 2D:4D interaction was observed in left parahippocampal gyrus activation. Additionally, sex-by-DR-L interaction was observed in left IPL activation. DR-L showed a significant positive correlation with the whole brain Laterality Index (LI), and LI, in turn, demonstrated a significant negative correlation with 2BACC. Our study observations suggest several novel sex-differential relationships between 2D:4D measures and fMRI activation during spatial working memory task performance. Given the pre-existing background data supporting digit ratio measures as putative indicator of prenatal sex hormonal milieu, our study findings add support to the Geschwind-Behan-Galaburda (GBG) hypothesis.
Neurodevelopmental aberrations influenced by neurotrophic factors are among the important paradigms to understand schizophrenia pathogenesis. Among various neurotrophic factors, Brain-Derived Neurotrophic Factor (BDNF) is strongly implicated by previous research studies. Evaluating co-morbidity free, antipsychotic-naïve schizophrenia patients for BDNF levels and examining the correlates of this factor with symptoms might facilitate elucidation of its pathogenetic role without confounds of potential influencing factors. In this study, 59 co-morbidity free, antipsychotic-naïve schizophrenia patients were compared with 60 healthy controls for serum BDNF levels. In addition, the relationship between Schneiderian First Rank Symptoms (FRS) and BDNF level in patients was examined. As a group, schizophrenia patients (28.8 ± 11.7 ng/mL) had significantly lower serum BDNF than healthy controls (34.9 ± 8.2 ng/mL) after controlling for the potential confounding effects of age and sex (F = 7.8; p = 0.006). Further analyses revealed FRS status to have significant effect on plasma BDNF after controlling for the potential confounding effects of age and sex (F = 4.5; p = 0.01). Follow-up post hoc analyses revealed FRS(+) patients to have significant deficit in plasma BDNF level in comparison with healthy controls (p = 0.002); however, FRS(−) patients did not differ from healthy controls (p = 0.38). Our study observations add further support to the role for BDNF in schizophrenia pathogenesis and suggest a potential novel link between deficient BDNF and FRS.
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