Areti Smaragdi

RESEARCH OUTPUT

Selected publications

1. Dimensional Associations Between Conduct Problems and Brain Structure Across 18 International Cohorts in ENIGMA.Journal of the American Academy of Child and Adolescent Psychiatry · 2026
   OBJECTIVE: Although conduct problems (CPs) are continuously distributed, little is known about how dimensional measures of CPs map onto brain structure. Therefore a large sample was used to comprehensively assess associations between dimensionally measured CPs and brain structure. METHOD: T1-weighted structural brain magnetic resonance imaging scans from 14,160 youths (5-21 years old, 46.2% female) across 18 international case-control, community-based, and population-based cohorts were preprocessed using ENIGMA-standardized protocols. Regression models examined associations between CPs and cortical thickness, surface area, and subcortical volumes, adjusting for age, sex, and intracranial volume. Moderation by sex, age, and callous-unemotional traits was also investigated. RESULTS: Widespread but small (β = -0.02 to -0.07) negative associations were observed between CPs and surface area (total surface area, 23/34 regions), cortical thickness (average thickness, 15/34 regions), and amygdalar and hippocampal volumes. Sex was a key moderator, with many surface area associations limited to boys and some thickness associations limited to girls. Some associations were stronger in younger children and at lower levels of callous-unemotional traits. The impact of adjusting for IQ and other psychopathology varied by outcome (eg, most surface area findings survived IQ adjustment, whereas cortical thickness associations did not). CONCLUSION: CPs were associated with subtle, yet widespread, alterations in brain structure. Findings overlapped with differences observed in categorically measured conduct disorder, but novel associations with cortical thickness were identified. This provides further evidence that neuroanatomical differences are not limited to youth with clinically elevated CPs. Our findings have potential implications for neurocognitive models of CPs as they extend beyond the regions highlighted in these models. STUDY REGISTRATION INFORMATION: Investigating dimensional relationships between conduct problems and brain structure: an ENIGMA mega-analysis; https://osf.io/nzj3r/.

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2. Brain Age in Conduct Disorder:: A Mega-Analysis of the ENIGMA Antisocial Behavior Working Group.bioRxiv : the preprint server for biology · 2026
   Conduct disorder (CD) is the leading global cause of mental health burden in children and adolescents and has recently been hypothesized to be a neurodevelopmental disorder. Although prior research has identified neuroanatomical differences associated with CD, it remains unclear whether these differences reflect atypical brain development. Here, we investigated the difference between an individual's brain age and chronological age as a proxy for variations in brain maturation. Using a pretrained model, we estimated brain age from structural neuroimaging data obtained from 1,119 youth with CD and 1,183 typically developing controls across 14 international cohorts participating in the ENIGMA-Antisocial Behavior Working Group. Youth with CD exhibited a statistically robust but small acceleration in brain age compared to typically developing youth (around 0.50 years), which was restricted to the adolescence-onset subtype of the disorder. Our large-scale, coordinated analysis provides the first evidence of accelerated neurodevelopment as a potential mechanism underlying CD.

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3. Maltreatment and parenting in youth with primary and secondary callous-unemotional traits: Anxiety matters.JCPP advances · 2025
   BACKGROUND: Youth with conduct disorder (CD) and high callous-unemotional (CU) traits are not a homogenous group and can be disaggregated into primary and secondary subgroups. However, there are inconsistencies in defining primary and secondary subgroups, with some studies using anxiety, others using maltreatment and still others using both features to identify subgroups. There is a paucity of work comparing primary and secondary subgroups with typically developing (TD) youth on experiences of maltreatment and parenting as well as a lack of studies investigating sex differences. METHODS: In a large sample of TD youth (n = 946, 66% female) and youth with CD (n = 885, 60% female), we used latent profile analysis in youth with CD aged between 9 and 18 years to address four aims: (i) to demonstrate how primary and secondary subgroup membership differs when anxiety, maltreatment, or both are used as continuous indicators, (ii) to compare primary and secondary subgroups with TD youth on abuse and neglect measures, and (iii) to compare primary and secondary subgroups with TD youth on parenting experiences, and (iv) to examine whether the results were consistent across sexes. RESULTS: Anxiety without maltreatment yielded the best fitting and most theoretically interpretable classification of primary and secondary subgroups across both sexes (Bayesian information criterion = 17832.33, Entropy = 0.75, Lo-Mendell-Rubin: p 0.05). CONCLUSIONS: We provide evidence that anxiety and maltreatment cannot be used interchangeably to identify youth with primary versus secondary CU traits. Anxiey yielded the best fitting and most theoretically interpretable classifications across both sexes. Our results signify the need for researchers and clinicians to adopt a unified approach to defining primary and secondary subgroups of CU traits using anxiety in both sexes.

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4. Testing the ecophenotype hypothesis: Differences in white matter microstructure in youth with conduct disorder with versus without a history of childhood abuse.Development and psychopathology · 2025
   Childhood maltreatment is a key risk factor for conduct disorder (CD), and the "ecophenotype hypothesis" suggests that maltreatment-related versus non-maltreatment-related CD are neurobiologically distinct. This may explain inconsistent findings in previous structural connectivity studies of CD. We tested this hypothesis by comparing youth with CD with (CD/+) versus without (CD/-) childhood physical or sexual abuse in white-matter microstructure. Diffusion tensor imaging data were collected from 100 CD and 169 control participants aged 9-18 years. Using Tract-Based Spatial Statistics, we compared the CD and control groups in fractional anisotropy, and axial, radial and mean diffusivity, then compared the CD/+ (n = 39) and CD/- (n = 61) subgroups and controls. The combined CD group had higher fractional anisotropy in the corpus callosum than controls. When divided by abuse history, only the CD/- subgroup exhibited higher corpus callosum fractional anisotropy than controls; the CD/+ subgroup did not differ from controls. Comparing the CD subgroups, the CD/+ subgroup displayed higher superior longitudinal fasciculus axial diffusivity than the CD/- subgroup. Notably, sex-stratified analyses yielded different findings in all-male and all-female samples. Findings support the ecophenotype hypothesis, demonstrating microstructural differences between the CD/+ and CD/- subgroups and emphasizing the importance of considering abuse/maltreatment (and sex) in future studies.

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5. Brain Responses During Face Processing in Conduct Disorder: Considering Sex and Callous-Unemotional Traits.Biological psychiatry · 2025
   BACKGROUND: Functional magnetic resonance imaging studies of conduct disorder (CD) have mostly been limited to males. Here, we examined whether male and female youths with CD showed similar or distinct alterations in brain responses to emotional faces, using a large sample of male and female youths with CD. We also investigated the influence of callous-unemotional (CU) traits. METHODS: Brain responses to angry, fearful, and neutral faces were assessed in 161 youths with CD (74 female) and 241 typically developing (TD) youths (139 female) ages 9 to 18 years. Categorical analyses tested for diagnosis effects (CD vs. TD and CD with high levels of CU traits [CD/HCU] vs. low levels of CU traits [CD/LCU] vs. TD) and sex × diagnosis interactions. RESULTS: When processing faces in general (all faces vs. baseline), youths with CD exhibited lower amygdala responses compared with TD youths, which seemed to be driven by the CD/HCU subgroup. Sex × CU subgroup interactions were identified in the amygdala (CD/LCU females TD males) and anterior insula (CD/HCU females > CD/LCU females; CD/HCU males < CD/LCU males). CONCLUSIONS: The findings for males support an influential neurocognitive model of CD. However, the association between CU traits and brain response to facial expressions differed in females and males with CD, suggesting distinct pathophysiological processes.

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