Sex-specific differences in the psychosis high-risk state and schizophrenia

Sexual dimorphisms in schizophrenia have been well documented in a range of areas including symptomatology, treatment response, and outcome. However, one of the most robust findings is the earlier onset of illness in males. More specifically, age of onset in males tends to occur in late teens to early 20s, whereas females typically show an onset to illness approximately 3-5 years later (20-30 years of age), with another period of conversion to illness observed just after the onset of menopause (40-50 years of age). Females have also been shown to respond better to treatment, to recover to a greater degree even in the absence of medication, and to show a more benign course of illness. Since much of this research has been conducted with individuals with established diagnoses, there is less known about sex-specific differences in those individuals who are at clinical high-risk for developing psychosis (CHR). Given the demonstrated impact of sex on illness course and outcome, the investigation of sex-specific pathologies in CHR individuals could lead to the identification of biomarkers which might be crucial for developing more effective sex-specific therapeutic interventions. A promising indicator of a CHR state for psychosis is working memory impairments. Specifically, deficits in verbal working memory have been repeatedly shown to be more severe in CHR individuals who later convert to psychosis compared to those who do not.

This project aims to characterize sexual dimorphism of language areas in the brain by investigating the white matter tracts relevant to verbal working memory in CHR patients (who lateron convert to psychosis or do not) compared to healthy controls (HC). Two-tensor unscented Kalman filter tractography, followed by an automated, atlas-guided fiber clustering approach, will be used to identify the superior longitudinal fasciculi (SLF) I, II and III, and the superior occipitofrontal fasciculus (SOFF). Fractional anisotropy (FA) of tissue is the primary measure of interest. First analysis revealed a significantly greater right>left asymmetry of the SLF-III in CHR females compared to HC females, but no hemispheric difference between CHR vs. HC males. Moreover, the laterality index of SLF-III for CHR females correlated negatively with Backward Digit Span performance, suggesting a greater rightward asymmetry was associated with poorer working memory functioning. This finding of sexual dimorphism in white matter asymmetry in a language-related area of the brain in CHR highlights the need for a deeper understanding of the role of sex in the high-risk state. Future work investigating early sex-specific pathophysiological mechanisms, may lead to the development of novel personalized treatment strategies aimed at preventing transition to a more chronic and difficult-to-treat disorder.