Differences in brain structure between males and females diagnosed with schizophrenia

Advances in cerebral neuroimaging techniques have helped our understanding of mental illnesses, such as schizophrenia. Few findings remain consistent and are often contradictory, making it difficult to draw informative conclusions about the disease. Several factors play a role in both diverging and converging results. Imaging technique and analyses, number of patients involved, age of patients, age at onset of the disease, diagnostic criteria, antipsychotic treatment effects, social status, comorbidities, are among some of the reasons. Despite well established cerebral sex differences in healthy population, it is only in recent years that neuroimaging studies in schizophrenia have addressed sex differences as a major possible explanation for discrepant neuroimaging finding.  The aim of this thesis is to help understand the role of sex on brain structures in schizophrenia, by conducting studies that control as much as possible for other variables and by using MRI automated analyses for patients and controls matched for age and sex. This work will briefly present findings in schizophrenia in general, and then an extensive review of the literature on sex differences in schizophrenia will be presented. From it, we are able to conclude that sex differences have been reported with rare exception in almost all aspects involved in the life of patients with schizophrenia.   Chapters 1. The first study investigated sex differences in cortical gyrification in schizophrenia patients (SZ). In addition, considering that schizophrenia is a disease of “clinical symptoms” that determine the quality of life of patients afflicted by it, we explored the relation between cortical gyrification and symptoms in males and females with schizophrenia. The role of sex on cortical gyrification and its association with symptoms has been scarcely investigated in patients with schizophrenia. In this study, 3T T1 images were acquired from 48 schizophrenia patients (24 males [SZ-M] and 24 females [SZ-F]) and 48 normal controls [NC] (24 males [NC-M] and 24 females [NC-F]) matched for age, sex, and handedness. Gyrification Index (GI) analyses for each hemisphere and four cerebral regions (frontal, temporal, parietal, and occipital) were performed using the fully automated CIVET pipeline. Patients had significant lower values of the overall GI relative to normal controls and SZ-M had significant lower right hemispheric GI values compared to NC-M. This was not observed in either NC-F or in SZ. No gender difference in GI values decreases with age were observed in NC. In patients, GI decreases with age were greater in SZ-M than SZ-F, with a more progressive deterioration in the right hemisphere in both patient groups. Significant GI value reductions in association with duration of illness were observed in SZ-M but not in SZ-F. Patient groups had lower GI in bilateral frontal, temporal, and parietal lobes than controls. SZ-F had significant lower GI values in left frontal, bilateral temporal and left parietal lobe compared to NC-F. No significant correlations were found between GI values and symptom scores in either group of patients. Since GI reflects, in part, alterations in cerebral development and connectivity, the decrease in GI observed in patients is in agreement with the neurodevelopmental model of disconnectivity in schizophrenia, and may explain the worse prognosis and social outcome observed in male patients. Furthermore, we emphasize the importance of age and duration of illness when comparing males and females with schizophrenia. Observed differences between male and female patients may reflect a more diffuse and generalized cortical loss in males. Female patients had cortical loss in specific regions, while preserving cortical gyrification in compensatory regions. Our latter finding -no significant correlation between GI values and symptom scores- was of particular interest and was unexpected in view of neuroimaging findings of correlations between positive symptoms and temporal lobe abnormalities. 2.  In the second study, we examined the association between symptoms and brain structure using gray (GMD) and white matter (WMD) densities. Voxel-based morphometry (VBM8.0 with Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra [DARTEL]) and Automatic Linear Modeling (SPSS21.0 ALM) were used on 3T T1 MPRAGE images acquired from 40 schizophrenia patients (SZ) and 41 normal controls (NC). We found that SZ had lower GMD in the anterior cingulate cortex and left middle temporal gyrus, and higher GMD in the left posterior cingulate in comparison to NC. SZ had significantly lower WMD in the left inferior fronto-rectal and the left posterior parietal regions in comparison to NC. Significant positive correlations were found between positive symptoms and GMD in the left insula and right caudate, and between negative symptoms and GMD in the right middle frontal and the posterior lobe of the right cerebellum (uvula). Inverse relationships between GMD in the right parietal (precuneus), the left posterior lobe of the cerebellum (uvula) and positive symptoms, and between GMD in the left anterior lobe of the cerebellum and negative symptoms were observed in SZ. In addition, positive correlations were found between WMD in the right middle frontal lobe, and between positive symptoms and WMD in the right superior frontal region with negative symptoms. Negative correlations were found between positive symptoms and WMD in the right inferior occipital and the right occipital cuneus, while negative symptoms correlated negatively with the WMD of the left superior frontal.   When symptom clusters were analyzed, conceptual disorganization symptom positively correlated with both total GMD and WMD. While increases in GMD were associated with decreased severity of lack of spontaneity and hallucinations symptom, increases in total WMD were associated with decreased severity of hostility and grandiosity symptoms. Comparison between male subjects revealed decreased GMD in male schizophrenia patients, while no differences were observed between females across groups. No correlations were found in female groups between GMD, WMD, CSF, or total brain volume and individual symptoms. In males with schizophrenia, significant negative correlation between ideas of grandiosity and WMD, a positive correlation between disorientation and WMD, and attention deficits and GMD and WMD were found. The current data suggest region-specific GMD and WMD association with negative and positive symptoms. In addition, it reveals that such associations are different in male and female schizophrenia patients.  3. The third study investigated the relationships of GMD and WMD with memory accuracy for emotionally negative, positive, and neutral pictures in schizophrenia patients relative to normal controls. Schizophrenia is characterized by an amalgam of cognitivo-socio-emotional deficits. The relationship between emotion processing on cognition and neurobiological underpinnings merit more attention than it has received so far. Memory deficits are among the most common deficits in schizophrenia and have a widespread impact on cognition in general. Additionally, consistently with the major theme of the present thesis, we investigated the effect of gender on the observed effect. Forty one, right-handed medicated patients with schizophrenia (SZ) and 40 right-handed normal controls (NC) matched by age and sex were assessed for memory accuracy using negative, positive and neutral pictures taken from the International Affective Picture System (IAPS). Imaging methods and analyses were similar to our second study. Fifteen minutes after presentation of selected IAPS images (incidental encoding), subjects were asked to recognize the previously seen images among other images. We found higher GMD in NC in the right posterior parietal cortex, lentiform, putamen, and caudate, as well as the left inferior orbitofrontal cortex, in relation with the negative images accuracy. NC had higher GMD in the left temporal and fusiform regions in relation with the positive images accuracy, and higher GMD in the left anterior cerebellum in relation with neutral images. Schizophrenia subjects had higher GMD in the left inferior occipital cortex in relation with the negative images accuracy, but GMD was not correlated with positive or neutral images accuracy in this group. WMDs correlations were higher in NC in the left postcentral parietal region for negative images; in the left inferior temporal, left precuneus parietal, and left frontal regions for positive images; and in the left middle temporal region for neutral images. Schizophrenia patients had higher WMD in the left lingual occipital for negative images; in the left angular parietal for positive images; and in the right superior temporal region for neutral images. While examining the two sexes separately, we observed inverse correlations between WMD and both negative and positive pictures in male patients. In addition, only in male controls, GMD positively correlated with negative pictures and this correlation was absent in female SZ subjects and NC females. These findings support the hypothesis of fronto-temporal regional atrophy in schizophrenia. Schizophrenia patients have relatively increased occipito-parietal WMD, advancing the hypothesis that the core pathophysiological problem underlying recall memory in SZ may be related to disruptive alterations in the coordination of large-scale brain networks, and this may be affected by structural deficits that are more evident in male patients. It is recommended that future studies should use the connectomes or the brain networks approach to investigate the effect of sex on memory deficits in schizophrenia.  Our overall findings point out to the importance of sex in modulating the clinical and functional manifestations of schizophrenia. We believe that controlling for covariates as age, duration of illness, social status, etc. is insufficient and that future studies in schizophrenia should systematically separate male and female findings, if we wish to understand this complex and devastating mental illness.

Keyphrases: Substance grise, Schizophrenia, Sex differences, Magnetic resonance imaging, Positive and negative symptoms, Cognitivo-emotion deficits, Gyrification index, Gray matter densities, White matter densities.