Investigating sex differences in the relationship between conduct disorder and brain structure and neural activity during emotion processing

INVESTIGATING SEX DIFFERENCES IN THE RELATIONSHIP BETWEEN CONDUCT DISORDER AND BRAIN STRUCTURE AND NEURAL ACTIVITY DURING EMOTION PROCESSING Irini Areti Eugenia Smaragdi Conduct disorder (CD) is a psychiatric disorder characterised by aggressive and rulebreaking behaviour. It is a debilitating disorder that brings substantial costs for affected individuals, their families and society more generally. It can lead to educational failure, unemployment, mental health issues, and in some cases, criminality in adulthood. The prevalence of CD is over two times higher in males compared to females, but it is still one of the most common reasons for referral to child and adolescent mental health services in the UK for both sexes. Although there is evidence that males and females with CD differ in terms of risk factors, clinical presentation, and adult outcomes of the disorder, little research has been devoted to studying these potential sex differences, and the vast majority of research has thus far focused on males. There is increasing evidence to suggest that alterations in brain structure and function may contribute to the risk of developing CD. Despite this, few studies have investigated whether such effects are observed in females with CD. This study is part of the Female Neurobiology and Treatment of Conduct Disorder (FemNAT-CD) study, which is a large-scale European collaboration between 11 universities and psychiatric clinics ii aiming to investigate the neurobiology of female CD and sex differences in CD. The current study selected 96 adolescents with CD (48 females) and 102 sex-, age-, and puberty-matched healthy controls (14-18 years old) that had undergone magnetic resonance imaging (MRI) at four of the sites. We investigated common and sex-dependent associations between CD and brain structure using two independent approaches: voxelbased morphometry and surface-based morphometry. In addition, we tested for shared and sex-dependent effects on brain activity during emotion processing using functional MRI, in a sub-set of the CD and healthy control participants (n=103). We also tested the validity of collapsing across childhood-onset and adolescent-onset forms of CD, and repeated each analysis to assess the influence of ADHD comorbidity. Across the three studies, males and females showed common and distinct abnormalities in brain structure and function. Structurally, males and females with CD both showed lower cortical thickness and grey matter volume, and increased gyrification in prefrontal cortex relative to controls, while there were sex-by-diagnosis interactions in some areas, such as the insula and amygdala. These appeared to be driven by structural alterations in males but not females with CD. Furthermore, CD-related associations with brain structure were sometimes in the opposite directions in males and females: relative to controls, males with CD showed higher, and females with CD showed lower, superior frontal gyrus surface area and gyrification. Sex-by-diagnosis interactions were also seen for amygdala activity during processing of angry facial expressions (i.e., males with CD showed higher, and females with CD lower, activity relative to their respective control groups). These results were largely unrelated to CD age-of-onset, IQ differences, and ADHD comorbidity. This study provides the first robust evidence for sex differences in the relationship between CD and brain structure and neural activity during emotion processing. Overall, the findings from the three studies suggest that there may be important sex differences in the neurobiological basis of CD. This highlights the importance of studying males and females