Dania Jose

Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

Background Various 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. Methodology We 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. Results Schizophrenia 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. Conclusion Our 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.

Revisiting Geschwind's hypothesis on brain lateralisation: A functional MRI study of digit ratio (2D:4D) and sex interaction effects on spatial working memory

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.

Relationship between Brain-Derived Neurotrophic Factor and Schneiderian First Rank Symptoms in Antipsychotic-Naïve Schizophrenia

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.

Clinical correlates of caudate volume in drug-naïve adult patients with obsessive–compulsive disorder

The neurobiological basis of obsessive-compulsive disorder (OCD) has been theorized to reflect a dysfunction of cortico-striato-thalamo-cortical circuits, of which the caudate nucleus forms a critical component. However, structural imaging studies of the caudate in OCD are relatively scarce. To ascertain the clinical correlates of caudate volume in OCD, we report magnetic resonance imaging findings in a large sample of drug-naïve OCD patients in comparison with group-matched healthy controls. In this study, caudate volume was measured in coronal magnetic resonance brain images (high resolution 1-mm slice thickness) of 49 DSM-IV OCD patients and compared with that of 39 matched healthy controls. The caudate volume was measured separately for the head and body of the caudate. Analysis of covariance (ANCOVA) did not reveal significant differences in caudate volume between OCD patients and controls (whole group), with age, sex and intracranial volume as covariates. However, on examining the sexual dimorphism in the volume differences, male patients compared to male controls had significantly larger right caudate volume. The volume of the left caudate body showed a significant negative correlation with the total severity score on the Yale-Brown Obsessive-Compulsive Scale (YBOCS) on partial correlation analysis. Our study failed to show significant differences in caudate volumes between OCD patients and controls. However, it demonstrated a robust relationship between volume of the left caudate body and the severity of OCD. Additionally, there was a sexual dimorphism in caudate volume in OCD.

Cerebellar volume deficits in medication-naïve obsessive compulsive disorder

Even though conventional neurobiological models of obsessive compulsive disorder (OCD) commonly demonstrate abnormalities involving fronto-striatal circuits, there is emerging evidence regarding the role of posterior brain structures such as cerebellum. In this study, we examined the cerebellar regional volume in a large sample of medication-naïve OCD patients compared to matched healthy controls (HC). In 49 medication naïve right handed OCD patients and 39 age and sex matched HC, sub-region wise volume of cerebellum was extracted from the T1 weighted images using Spatially Unbiased Infra tentorial Template (SUIT) toolbox and compared using hypothesis driven, region of interest approach after clinical assessment with standard scales. After controlling for age, sex and ICV, the subjects with OCD had significantly smaller cerebellum compared to HC, especially in the posterior lobe sub-regions - lobule VI and left crus 1. This study gives preliminary evidence for region specific cerebellar volumetric deficits in the pathophysiological of OCD. Regional cerebellar volume deficits conform to the abnormal connectivity of cerebellum to specific cortical regions and it is indicative of involvement of regions outside the conventional fronto-striatal circuitry. This might be important in the context of cognitive deficits seen in OCD.

Neurohemodynamic Correlates of Washing Symptoms in Obsessive‑compulsive Disorder: A Pilot fMRI Study Using Symptom Provocation Paradigm

Background: Obsessive-compulsive disorder (OCD) is increasingly being viewed as a multidimensional heterogeneous disorder caused due to the dysfunction of several closely related, overlapping frontostriatal circuits. A study investigating the dimensional construct in treatment naïve, co-morbidity free patients with identical handedness is likely to provide the necessary homogeneity and power to elicit neural correlates of the various symptom dimensions, and overcome the limitations of previous studies. Materials and Methods: Nine DSM-IV OCD patients with predominant contamination-related obsessive-compulsive symptoms (age=29.8±7.1 years; five males: four females; years-of-education=13.9±1.6, YBOCS total score=28.8±4.7, DYBOCS Contamination dimension score=10.7±1.8) and nine healthy controls matched one to one with the patients for age, sex, and years of education (age=27.8±5.4, five males: four females; years-of-education=14.9±3.0), were examined during symptom provocation task performance in 3TMRI. Paired samples t test of brain activation differences (contamination relevant pictures – neutral pictures), limited to apriori regions of interest was done using SPM8 (uncorrected P<0.005). Results: Patients found significantly more pictures to be anxiety provoking in comparison to healthy controls. Patients were found to have deficient activation in the following areas in comparison with healthy controls: bilateral anterior prefrontal, dorsolateral prefrontal, orbitofrontal, anterior cingulate, insular and parietal cortices, precuneus, and caudate. Conclusions: Results underscore the importance of frontal, striatal, parietal, and occipital areas in the pathophysiology of OCD. Divergence of findings from previous studies might be attributed to the absence of confounding factors in the current study and may be due to production of intense anxiety in patients.

Clinical correlates of nucleus accumbens volume in drug-naïve, adult patients with obsessive–compulsive disorder

Background: Reward-processing deficits have been demonstrated in obsessive–compulsive disorder (OCD) and this has been linked to ventral striatal abnormalities. However, volumetric abnormalities of the nucleus accumbens (NAcc), a key structure in the reward pathway, have not been examined in OCD. We report on the volumetric abnormalities of NAcc and its correlation with illness severity in drug-naïve, adult patients with OCD. Method: In this cross-sectional study of case–control design, the magnetic resonance imaging (MRI) 1.5-T (1-mm) volume of NAcc was measured using 3D Slicer software in drug-naïve OCD patients (n = 44) and age, sex and handedness-matched healthy controls (HCs) (n = 36) using a valid and reliable method. OCD symptoms were assessed using the Yale–Brown Obsessive Compulsive Scale (Y-BOCS) Symptom checklist and severity and the Clinical Global Impression-Severity (CGI-S) scale. Results: There was no significant difference in NAcc volumes on either side between OCD patients and HCs (F = 3.45, p = 0.07). However, there was significant negative correlation between the right NAcc volume and Y-BOCS compulsion score (r = −0.48, p = 0.001). Conclusions: Study observations suggest involvement of the NAcc in the pathogenesis of OCD, indicating potential reward-processing deficits. Correlation between the right NAcc volume deficit and severity of compulsions offers further support for this region as a candidate for deep brain stimulation treatment in OCD.

Plasma cytokines in minimally treated schizophrenia

In schizophrenia, plasma cytokines abnormalities offer vital support for immunopathogenetic basis. However, most of the previous studies on plasma cytokines are confounded by examination of antipsychotic-treated schizophrenia patients. In this study, we examined a large sample of antipsychotic-naïve/free schizophrenia patients (N = 75) in comparison with healthy controls (N = 102). Plasma cytokines (Interleukins ([IL] 2, 4, 6, 10, 17), Tumor necrosis factor [TNF] and Interferon gamma [IFN-g]) were assessed using cytometric bead array assay. Schizophrenia patients showed significantly greater levels of IL-6 and lower levels of IL-17 as well as IFN-g in comparison to healthy controls. However, after taking censoring into account and adjusting for potential confounders (sex, age, BMI and smoking), only IL-6 was found to be elevated in patients. Cytokine profile showed differential and pathogenetically relevant correlation with clinical symptoms. Together, these observations offer further support to immunological component in schizophrenia pathogenesis.

Dermatoglyphic correlates of hippocampus volume: Evaluation of aberrant neurodevelopmental markers in antipsychotic-naïve schizophrenia

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.

Corpus callosum abnormalities in medication-naïve adult patients with obsessive compulsive disorder.

Emerging evidence demonstrates widespread abnormalities involving white matter (WM) tracts connecting different cortical regions in obsessive-compulsive disorder (OCD). The corpus callosum (CC), the largest inter-hemispheric tract connecting the association cortices, has been shown to be affected in OCD. This study examines CC abnormalities in a large sample of medication-naïve OCD patients in comparison to matched healthy controls (HCs). We examined the mid-sagittal area of the CC in medication-naïve OCD patients (n=49) in comparison with age-, sex-, and handedness-matched HCs (n=38). Witelsons method was used to measure the sub-regions of the CC - namely, the genu, body, isthmus and splenium - with good inter-rater reliability. The area of the body of the CC and total CC area were significantly larger in OCD patients than in HCs after controlling for age, sex and intracranial area. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) compulsion score had a significant negative correlation with the areas of the isthmus and splenium of the CC in addition to the total CC area. The region-specific differences in the body of the CC and the region-specific association of severity score with posterior regions of the CC might be indicative of the involvement of additional areas like the dorsolateral prefrontal cortex, posterior parietal areas, occipital and association cortices in OCD that extend beyond the conventional orbito-fronto-striatal circuitry that is often posited to be involved in OCD.