A mega-analysis of cortical structure and subcortical volumes in conduct disorder in youth: Influence of sex, age-of-onset and callous-unemotional traits
Creators: name: Gao, Yidian
name: Staginnus, Marlene
name: De Brito, Stephane
name: Fairchild, Graeme
name: Aghajani, Moji
name: Klapwijk, Eduard
name: Cecil, Charlotte
name: Baskin–Sommers, Arielle
name: Pine, Daniel
name: Raine, Adrian
name: Walton, Esther
name: Thompson, Paul
name: Thomopoulos, Sophia
name: Jahanshad, Neda
name: Sully, Kate
name: Zhou, Jiawei
name: Oosterling, Maaike
name: Walsh, Nicholas
name: Hagan, Cindy
name: Kypta-Vivanco, Alexandra
name: Toschi, Nicola
name: Passamonti, Luca
name: Goodyer, Ian
name: Minosse, Silvia
name: Jackson, Rebecca
name: Michalska, Kalina
name: Glenn, Dana
name: Hyde, Luke
name: Westerman, Heidi
name: Monk, Christopher
name: Mitchell, Colter
name: Burt, S.
name: Blair, James
name: Bajaj, Sahil
name: Dietrich, Andrea
name: Hoekstra, Pieter
name: Franke, Barbara
name: Buitelaar, Jan
name: Lamers, Kim
name: Dykstra, Anouk
name: Naaijen, Jill
name: Glennon, Jeffrey
name: Viding, Essi
name: Sethi, Arjun
name: Roberts, Ruth
name: Philips, Harriet
name: Marsh, Abigail
name: Ploe, Montana
name: Berluti, Kathryn
name: Cardinale, Elise
name: Craig, Michael
name: Murphy, Declan
name: Vermeiren, Robert
name: van der Wee, Nic
name: Boateng, Charlotte
name: Colins, Olivier
name: Sukhodolsky, Denis
name: Ibrahim, Karim
name: Stevens, Michael
name: Yao, Shuqiao
name: Jiang, Yali
name: Zhong, Xue
name: Zhang, Jibiao
name: Ming, Qingsen
name: Ma, Ren
name: Wang, Xiaoping
name: Zhou, Jiansong
name: Chen, Hui
name: Chen, Xianliang
name: Benegal, Vivek
name: Holla, Bharath
name: Schumann, Gunter
name: Freitag, Christine
name: Stadler, Christina
name: Konrad, Kerstin
name: Raschle, Nora
name: Rogers, Jack
name: Cubillo, Ana
name: Kohls, Gregor
name: Martinelli, Anne
name: Cornwell, Harriet
name: Smaragdi, Areti
name: Gonzalez-Madruga, Karen
name: Pauli, Ruth
name: Townend, Sophie
name: Chester, Sally
name: Townsend, Christopher
name: Jabeen, Nimrah
name: Sonuga-Barke, Edmund
name: Barker, Edward
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Developmental Psychology
subject: Life Sciences
subject: Cognitive Psychology
subject: Neuroscience and Neurobiology
subject: Social and Behavioral Sciences
subject: Psychology
subject: FOS: Psychology
subject: conduct disorder
subject: ENIGMA
subject: Mega-analysis
subject: Structural MRI study

description: Conduct disorder (CD) is one of the most common childhood psychiatric disorders and is characterised by a repetitive and pervasive pattern of aggressive or antisocial behaviours, such as physical aggression towards other humans or animals, theft, property damage and rule violations (APA, 2013). The worldwide prevalence of CD is estimated to be 2-2.5%, with a prevalence of 3-4% in boys and 1-2% in girls (Maughan et al., 2004). Overall, CD is a leading cause of referral to child and adolescent mental health services and places an enormous burden on the affected individuals, their families and society (Erksine et al., 2014; Rivenbark et al., 2018). Although neuroimaging studies have reported alterations in brain structure in CD and supported the view that CD is a neurodevelopmental disorder, a major concern of the diagnostic criteria for CD (e.g., initiating physical fights) is that they are entirely based on behavioural symptoms, and can be shared with other disorders (e.g., ADHD, Substance Use Disorder, Tourette's disorder or Bipolar Disorder), and are therefore less informative about the underlying psychological states/cognitions or neural substrates which drive the symptoms (Blair et al., 2005; Fairchild et al., 2019). A comprehensive and thorough understanding of the underlying pathophysiology of CD may help address this question and help refine diagnostic approaches. Neuroimaging studies on CD have shown altered neural responses in tasks involving emotional processing and executive function (Alegria et al., 2016; Noordermeer et al., 2016; Raschle et al., 2015) and reductions in grey matter volume (Noordermeer et al., 2016; Raschle et al., 2015; Rogers &amp; De Brito, 2016) across a number of cortical (e.g., ventromedial prefrontal and insular cortices) and subcortical (e.g., amygdala and basal ganglia) regions critical for emotion processing and regulation, reinforcement-based decision-making, executive function and empathic responding (Fairchild et al., 2019). Although these discoveries marked pivotal advances in our understanding of CD, the evidence base suffers from two important limitations. First, inconsistent findings and a lack of replication are common; demographic and clinical features of the samples, as well as methodological factors, have likely contributed to this. For example, CD is a heterogeneous disorder with subtypes based on the age-of-onset of symptoms (childhood-onset versus adolescence-onset, which is defined by whether severe antisocial behaviours emerge before or after 10 years of age), and the presence or absence of callous-unemotional (CU) traits (encompassed by the ‘with limited prosocial emotions’ specifier in the DSM-5; APA, 2013). However, most primary magnetic resonance imaging (MRI) studies of CD have not examined the influence of these subtypes on their findings. Potential sex differences in the relationship between CD and brain structure might also have contributed to the inconsistent findings (Smaragdi et al., 2017). Most studies of CD have focused only on males and hence it is currently understudied/unclear whether females with CD show similar alterations. Relatedly, studies that have investigated mixed-sex samples were largely underpowered to test for sex-by-diagnosis interactions and may hence have contributed to the inconsistencies observed in the literature. Second, most of the neuroimaging studies had small sample sizes, increasing the risk for false positives and false negatives (Button et al., 2013), as well as resulting in limited power to test differences between CD subtypes or explore heterogeneity. In this context, our understanding of CD-related brain structural alterations could be improved through a large-scale coordinated and harmonised analysis of the vast amounts of existing data to map brain differences in heterogeneous CD patients worldwide. In 2009, the Enhancing NeuroImaging Genetics through Meta-Analyses (ENIGMA) consortium (http://enigma.ini.usc.edu) was established to pool brain imaging data from existing cohorts across the world in order to better understand brain structure, function, and disease, based on meta- and mega-analyses of brain imaging and genetic data (Bearden &amp; Thompson, 2017; Thompson et al., 2020). The ENIGMA-Antisocial Behavior (ASB) working group aims to clarify associations between CD, conduct problems (CPs), psychopathy, or antisocial personality disorder and alterations in brain structure and function by using ENIGMA’s highly powered consortium approach to overcome the limitations of small studies with low power and uncertain reproducibility. Therefore, the proposed study will focus on examining the cortical and subcortical correlates of CD using a mega-analysis (i.e., individual participant data meta-analysis) of structural MRI (sMRI) data, considering the influence of subtypes and testing for possible sex-specific effects. In addition to those with a CD diagnosis, there is a considerable amount of youths demonstrating elevated CP (Ghandour et al., 2019; Deighton et al., 2019), but who have not been assessed with diagnostic instruments and/or have not received a clinical diagnosis of CD. It is of interest if the findings from case-control comparisons of brain structure can be generalised to undiagnosed youths with elevated CP. As youths with a CD diagnosis are often recruited from specialised settings (e.g., clinics, mental health services or youth offending services), studying youths with elevated CP recruited through non-specialised settings would reduce selection bias and increase the generalisability of findings to a broader population (Horga et al., 2014). Neuroimaging studies have demonstrated structural brain alterations in youths with elevated CP, including decreased grey matter volume in the insula, amygdala, frontal and temporal regions (Raschle et al., 2015; Rogers &amp; De Brito, 2016). A longitudinal study also reported altered trajectories of cortical thickness development in the dorsolateral prefrontal cortex and the anterior cingulate cortex (ACC), and volume of the hippocampus in youths showing elevated CP (Oostermeijer et al., 2016). Hence, both CP and CD appear to be related to similar and overlapping MRI findings of lower volume in the prefrontal cortex and limbic system. However, to date, no study has directly investigated if and how the cortical and subcortical alterations in youths with elevated CP overlap with the findings in youths with CD. Comparing youths with CD, elevated CP and TD will help clarify the neural mechanisms underlying antisocial behaviours in the clinical population, and extend the results to a more heterogeneous group of undiagnosed individuals showing elevated CP. Based on the ENIGMA-ASB datasets and using large-scale mega-analytical methods, the proposed study will also include an elevated CP group to identify the shared brain alterations underlying elevated antisocial behaviours as well as the specific alterations limited to youths with CD through the large-scale mega-analysis. Research Questions: (1) Do youths with CD show differences in cortical thickness, surface area and/or subcortical volume compared to TD youths? (2) How are sex, age-of-onset and CU traits related to brain alterations in CD? (3) Can alterations detected in youths with CD be generalised to youths with elevated CP?