br Material and methods br Results br

Material and methods
Results
Discussion To our knowledge, our study is the first VBM study to report a gender-by-diagnosis interaction in individuals with ADHD. The interaction effect was found in the ventral ACC, where girls with ADHD showed increased GM volumes when compared to TD girls, while boys with ADHD exhibited decreased volumes when compared to TD boys. In the only previous VBM study considering potential gender effects, no interaction between gender and diagnosis of ADHD were found, possibly due to the large age range (7–17 years) of the participants included, spanning different ep4 antagonist maturational stages (Yang et al., 2008). Our results are, however, consistent with previous evidence of gender-by-diagnosis interaction in structural brain imaging (Mahone et al., 2011; Dirlikov et al., 2014), electroencephalography (Clarke et al., 2001; Hermens et al., 2004) and functional brain imaging studies of children with ADHD (Ernst et al., 1994; Valera et al., 2010). Thus, our data adds to an increasing number of neuroimaging studies by documenting opposite alterations in brain structure in boys and girls with ADHD, possibly underlying gender-related differences in symptomatology (Hinshaw et al., 2006; Skogli et al., 2013). Our interaction finding was located in a large cluster centered in the ventral ACC (Brodmann areas (b.a.): 24 and 32; pregenual and subgenual parts). Characterized by a strong anatomical connectivity with core emotion-processing regions such as the amygdala, the periaqueductal grey matter and the hippocampus, the ventral ACC is known to play a key role in top-down emotional regulation (Etkin et al., 2011). It is involved in the inhibition of conditioned fear through extinction, in the automatic regulation of emotional conflict, or when self-distracting from a fear-conditioned stimulus (Bush et al., 2000; Etkin et al., 2011). It is also implicated in the production of positive emotions, which can serve to regulate and diminish negative emotions (Etkin et al., 2011). Dysregulation of both positive and negative emotions is recognized as an important feature of ADHD (Sjowall et al., 2013; Shaw et al., 2014; Villemonteix et al., 2014). However, to date, few sMRI studies of childhood ADHD have reported GM volumes alterations in brain regions supporting emotion processing or its integration with cognitive control processes (Carmona et al., 2005; Plessen et al., 2006; Frodl et al., 2010; Sasayama et al., 2010). In particular, meta-analyses of VBM studies in children with ADHD did not detect disorder related- structural abnormalities in the ACC (Nakao et al., 2011; Frodl and Skokauskas, 2012). Interestingly, though, the majority of these studies were carried out in children who received medication treatment for ADHD (Nakao et al., 2011; Frodl and Skokauskas, 2012). When treatment was considered as a covariate, studies with more untreated children were associated with decreased GM volumes in the right ACC (Frodl and Skokauskas, 2012). One ROI study also reported that treatment-naïve children with ADHD exhibit smaller right ACC volumes compared with controls, whereby this is not the case for treated children (Semrud-Clikeman et al., 2006). Exposure to psychostimulants may therefore represent a confounding factor when investigating ADHD related- GM volume alterations in this brain region. Here, never-medicated girls with ADHD showed increased GM volumes when compared to TD girls in the ventral ACC, while never-medicated boys with ADHD exhibited decreased GM volumes when compared to TD boys. Decreased GM volumes in the right ACC have been found in healthy boys exhibiting aggression and defiance (Boes et al., 2008), and decreased cortical thickness in the ventral ACC has been associated with increased levels of aggression in children close to pathological levels of impulsive aggression (Ducharme et al., 2011). A known genetic risk factor for impulsive aggression, the low expression variant of the X-linked monoamine oxidase A (MAOA) gene, is also known to be associated with decreased GM volumes in the ventral ACC (Meyer-Lindenberg et al., 2006). Based on these findings, we hypothesize that decreased GM volumes in boys with ADHD may represent a risk factor for developing externalizing symptoms such as anger outbursts and impulsive reactive aggressions (Skogli et al., 2013).