Sex differences of gray matter morphology in cortico-limbic-striatal neural system in major depressive disorder

Abstract

Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naïve participants with MDD. Participants included 29 medication-naïve individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyzes of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p < 0.05, corrected) in the left ventral prefrontal cortex, right amygdala, right hippocampus and bilateral caudate when comparing the MDD and HC groups. Posthoc analyzes showed that females with MDD had significant GM decreases in limbic regions (p < 0.05, corrected), compared to female HC; while males with MDD demonstrated significant GM reduction in striatal regions, (p < 0.05, corrected), compared to HC males. The observed sex-related patterns of abnormalities within the cortico-limbic-strial neural system, such as predominant prefrontal-limbic abnormalities in MDD females vs. predominant prefrontal-striatal abnormalities in MDD males, suggest differences in neural circuitry that may mediate sex differences in the clinical presentation of MDD and potential targets for sex-differentiated treatment of the disorder.

Introduction

Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). Studies have consistently shown that MDD is more prevalent in females than males (Kessler et al., 2005, 1994; Kuehner, 2003). Females with MDD are more likely to show increased anxiety including higher rates of comorbid anxiety disorders (Kornstein et al., 2000; Marcus et al., 2005), while males with MDD are more likely to show more psychomotor agitation and to have comorbid substance abuse disorders (Kessler et al., 1997; Marcus et al., 2005; Roeloffs et al., 2001). Although females with MDD are more likely to attempt suicide than males (Marcus et al., 2005), males with MDD are more likely to be successful when they attempt suicide, and thus are at higher risk for completed suicide (Blair-West et al., 1999; Oquendo et al., 2001). While sex differences in the clinical presentation of MDD are apparent, the neural mechanisms that underlie these differences remain unclear.

The cortico-limbic-striatal neural system including the prefrontal cortex (PFC), amygdala, hippocampus and striatum, is implicated in the dysfunctional regulation of emotion in MDD (Drevets, 1998; Marchand, 2010). The sexually dimorphic development of cortico-limbic-striatal neural system has been implicated to contribute to sex differences in psychiatric disorders (Giedd et al., 1997, 1996; Lenroot et al., 2007; Neufang et al., 2009; Teicher et al., 2004). For example, regions (PFC, amygdala and hippocampus) subserving emotions might be related with increased depression or anxiety risk in females (Davis et al., 2012; Kessler et al., 1993; Lieberwirth et al., 2012), and regions (PFC and striatum) subserving impulse control might be associated with increased risk for substance abuse (Nagoshi et al., 1991; Nolen-Hoeksema & Hilt, 2006). Additionally, preclinical studies indicate particular vulnerability to stress in the PFC-amygdala/hippocampus system in females, with estrogen-dependent effects observed, while this system appears relatively resilient in males. However, males may be more vulnerable to stress effects on the PFC-striatum system than females; for example, estrogen has been shown to be protective in caudate (Arnsten & Shansky, 2004; Dluzen & McDermott, 2000; McEwen, 2010; Shansky et al., 2010). The sexually dimorphic features in cortico-limbic-striatal neural system may reflect the sex differences in clinical observations of MDD, such as MDD females with more comorbid anxiety disorders, and MDD males with more comorbid substance abuse and higher risk for completed suicide.

Sex differences in cortico-limbic-striatal morphology have been reported in human brain studies (Biswal et al., 2010; Cosgrove et al., 2007; Goldstein et al., 2001). Recently, our group found sexually dimorphic effects of child maltreatment (CM) on cortico-limbic-striatal morphology in adolescents. In adolescent females, CM was associated with more robust effects in brain regions that subserve emotional regulation, including the PFC, amygdala and hippocampus, whereas in adolescent males, effects were more prominent in brain regions that subserve impulse control, including PFC and striatum (Edmiston et al., 2011). Several morphological studies using region of interest (ROI) tracing technique examined sex differences in the cortico-limbic-striatal neural system in MDD; however there are some inconsistencies in findings (Frodl et al., 2002; Hastings et al., 2004; Vakili et al., 2000). In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in gray matter (GM) density and volume within the cortico-limbi-striatal neural system in medication-naïve participants with MDD. Given the sex differences in clinical features of MDD, we anticipated that GM morphological alterations in cortico-limbic-striatal brain regions subserving emotional regulation might be more prominent in MDD females, while GM morphological changes in MDD males might be more apparent in region subserving impulse control.