Does the Relationship between Age and Brain Structure Differ in Youth with Conduct Disorder?

Conduct disorder (CD) is characterised by persistent antisocial and aggressive behaviour and typically emerges in childhood or adolescence. Although several authors have proposed that CD is a neurodevelopmental disorder, very little evidence is available about brain development in this condition. Structural brain alterations have been observed in CD, and some indirect evidence for delayed brain maturation has been reported. However, no detailed analysis of age-related changes in brain structure in youth with CD has been conducted. Using cross-sectional MRI data, this study aimed to explore differences in brain maturation in youth with CD versus healthy controls to provide further understanding of the neurodevelopmental processes underlying CD. 291 CD cases (153 males) and 379 healthy controls (160 males) aged 9-18 years (Mage = 14.4) were selected from the European multisite FemNAT-CD study. Structural MRI scans were analysed using surface-based morphometry followed by application of the ENIGMA quality control protocols. An atlas-based approach was used to investigate group differences and test for group-by-age and group-by-age-by-sex interactions in cortical thickness, surface area and subcortical volumes. Relative to healthy controls, the CD group showed lower surface area across frontal, temporal and parietal regions as well as lower total surface area. No significant group-by-age or group-by-age-by-sex interactions were observed on any brain structure measure. These findings suggest that CD is associated with lower surface area across multiple cortical regions, but do not support the idea that CD is associated with delayed brain maturation, at least within the age bracket considered here.

Identifying cortical structure markers of resilience to adversity in young people using surface-based morphometry.

Previous research on the neurobiological bases of resilience in youth has largely used categorical definitions of resilience and voxel-based morphometry methods that assess gray matter volume. However, it is important to consider brain structure more broadly as different cortical properties have distinct developmental trajectories. To address these limitations, we used surface-based morphometry and data-driven, continuous resilience scores to examine associations between resilience and cortical structure. Structural MRI data from 286 youths (Mage = 13.6 years, 51% female) who took part in the European multi-site FemNAT-CD study were pre-processed and analyzed using surface-based morphometry. Continuous resilience scores were derived for each participant based on adversity exposure and levels of psychopathology using the residual regression method. Vertex-wise analyses assessed for correlations between resilience scores and cortical thickness, surface area, gyrification and volume. Resilience scores were positively associated with right lateral occipital surface area and right superior frontal gyrification and negatively correlated with left inferior temporal surface area. Moreover, sex-by-resilience interactions were observed for gyrification in frontal and temporal regions. Our findings extend previous research by revealing that resilience is related to surface area and gyrification in frontal, occipital and temporal regions that are implicated in emotion regulation and face or object recognition.

Impaired Punishment Learning in Conduct Disorder.

OBJECTIVE: Conduct disorder (CD) has been associated with deficits in the use of punishment to guide reinforcement learning (RL) and decision making. This may explain the poorly planned and often impulsive antisocial and aggressive behavior in affected youths. Here, we used a computational modeling approach to examine differences in RL abilities between CD youths and typically developing controls (TDCs). Specifically, we tested 2 competing hypotheses that RL deficits in CD reflect either reward dominance (also known as reward hypersensitivity) or punishment insensitivity (also known as punishment hyposensitivity). METHOD: The study included 92 CD youths and 130 TDCs (aged 9-18 years, 48% girls) who completed a probabilistic RL task with reward, punishment, and neutral contingencies. Using computational modeling, we investigated the extent to which the 2 groups differed in their learning abilities to obtain reward and/or to avoid punishment. RESULTS: RL model comparisons showed that a model with separate learning rates per contingency explained behavioral performance best. Importantly, CD youths showed lower learning rates than TDCs specifically for punishment, whereas learning rates for reward and neutral contingencies did not differ. Moreover, callous-unemotional (CU) traits did not correlate with learning rates in CD. CONCLUSION: CD youths have a highly selective impairment in probabilistic punishment learning, regardless of their CU traits, whereas reward learning appears to be intact. In summary, our data suggest punishment insensitivity rather than reward dominance in CD. Clinically, the use of punishment-based intervention techniques to achieve effective discipline in patients with CD may be a less helpful strategy than reward-based techniques.

Action initiation and punishment learning differ from childhood to adolescence while reward learning remains stable.

Theoretical and empirical accounts suggest that adolescence is associated with heightened reward learning and impulsivity. Experimental tasks and computational models that can dissociate reward learning from the tendency to initiate actions impulsively (action initiation bias) are thus critical to characterise the mechanisms that drive developmental differences. However, existing work has rarely quantified both learning ability and action initiation, or it has relied on small samples. Here, using computational modelling of a learning task collected from a large sample (N = 742, 9-18 years, 11 countries), we test differences in reward and punishment learning and action initiation from childhood to adolescence. Computational modelling reveals that whilst punishment learning rates increase with age, reward learning remains stable. In parallel, action initiation biases decrease with age. Results are similar when considering pubertal stage instead of chronological age. We conclude that heightened reward responsivity in adolescence can reflect differences in action initiation rather than enhanced reward learning.

Testing the Ecophenotype Model: Cortical Structure Alterations in Conduct Disorder With Versus Without Childhood Maltreatment.

BACKGROUND: Childhood maltreatment is common in youths with conduct disorder (CD), and both CD and maltreatment have been linked to neuroanatomical alterations. Nonetheless, our understanding of the contribution of maltreatment to the neuroanatomical alterations observed in CD remains limited. We tested the applicability of the ecophenotype model to CD, which holds that maltreatment-related psychopathology is (neurobiologically) distinct from psychopathology without maltreatment. METHODS: Surface-based morphometry was used to investigate cortical volume, thickness, surface area, and gyrification in a mixed-sex sample of participants with CD (n = 114) and healthy control subjects (HCs) (n = 146), ages 9 to 18 years. Using vertexwise general linear models adjusted for sex, age, total intracranial volume, and site, the control group was compared with the overall CD group and the CD subgroups with (n = 49) versus without (n = 65) maltreatment (assessed by the Children's Bad Experiences interview). These subgroups were also directly compared. RESULTS: The overall CD group showed lower cortical thickness in the right inferior frontal gyrus. CD youths with a history of maltreatment showed more widespread structural alterations relative to HCs, comprising lower thickness, volume, and gyrification in inferior and middle frontal regions. Conversely, CD youths with no history of maltreatment only showed greater left superior temporal gyrus folding relative to HCs. When contrasting the CD subgroups, those with maltreatment displayed lower right superior temporal gyrus volume, right precentral gyrus surface area, and gyrification in frontal, temporal, and parietal regions. CONCLUSIONS: Consistent with the ecophenotype model, findings indicated that CD youths with versus without maltreatment differ neurobiologically. This highlights the importance of considering maltreatment history in neuroimaging studies of CD and other disorders.

Emotion processing in maltreated boys and girls: Evidence for latent vulnerability.

Evidence of alterations in emotion processing in maltreated youth has been hypothesized to reflect latent vulnerability for psychopathology. However, previous studies have not systematically examined the influence of psychopathology on the results. Here, we examined emotion recognition and learning in youth who differed in terms of presence vs. absence of maltreatment and psychopathology and tested for potential sex effects. Maltreatment and psychopathology were assessed in 828 youth (514 females) aged 9-18 years using diagnostic interviews and self- and parent-report questionnaires. Emotion recognition was assessed via identification of morphed facial expressions of six universal emotions. For emotion learning, reward and punishment values were assigned to novel stimuli and participants had to learn to correctly respond/withhold response to stimuli to maximize points. A three-way interaction of maltreatment by psychopathology by emotion indicated that when psychopathology was low, maltreated youth were less accurate than non-maltreated youth for happy, fear and disgust. A three-way interaction of sex, maltreatment and emotion indicated that maltreated girls and boys were impaired for fear, but girls showed an impairment for happy, while boys for disgust. There were no effects of maltreatment, psychopathology, or sex on reward learning. However, a two-way interaction between sex and maltreatment showed that maltreated girls were worse at learning from punishment relative to non-maltreated girls, while maltreated boys were better than non-maltreated boys. The study provides the first clear evidence of latent-vulnerability in emotion recognition in maltreated youth and suggests that girls and boys might be characterized by distinct profiles of emotion recognition and learning following maltreatment.

The Underlying Mechanisms in the Association Between Traumatic Brain Injury in Childhood and Conduct Disorder Symptoms in Late Adolescence.

The present study examined i) the direct association between traumatic brain injury (TBI) in childhood and conduct disorder symptoms in adolescence, ii) whether this effect is mediated by impulsivity and/or callous unemotional traits (CU traits), and iii) whether these indirect effects are moderated by childhood family adversity and adolescent substance use. Utilising data from the Avon Longitudinal Study of Parents and Children (ALSPAC), participants with head injury information up to 12 years (4.5 years, 5.4 years, 6.5 years, 8.6 years, 11.7 years) were identified and categorised into a TBI (n = 409), orthopaedic injury (n = 1469) or non-injury group (n = 5685). Psychosocial factors such as impulsivity at 13 years, CU traits at 13 years, childhood family adversity (between birth to 4 years) and substance use at 14 years were collated for moderated mediation analyses. Conduct disorder symptoms were assessed at 16 years of age. TBI and conduct disorder symptoms were positively associated, and this association was mediated by impulsivity but not CU traits. The indirect effects were higher in magnitude for individuals with higher levels of childhood family adversity. Adolescent substance use was not found to moderate the indirect effects between TBI and conduct disorder symptoms. These results were specific to TBI individuals, and not in participants with orthopaedic injury and no reported injuries. Targeting impulsivity and early family adversity may alleviate the risk of conduct disorder symptoms following TBI in childhood. These findings have important implications for informing neuro-rehabilitative and preventative measures in clinical and community settings.

Association between childhood maltreatment and callous-unemotional traits in youth: A meta-analysis.

Callous-unemotional (CU) traits (i.e., lack of remorse or guilt, callous lack of empathy, deficient concern for the feelings of others) in youth with conduct problems confer risk for a particularly severe and persistent form of antisocial behaviour. Previous research has linked childhood maltreatment as a potential risk factor for CU traits, both primary (i.e., genetically underpinned) and secondary (i.e., environmentally influenced) variants, but findings have been inconsistent, and the association has not yet been tested in a meta-analysis. To address this gap, we conducted a meta-analysis to assess the nature and strength of the associations between childhood maltreatment and its subtypes with CU traits and potential variants (i.e., primary and secondary CU traits). A systematic search identified 29 eligible studies including 9,894 participants (42% female) between the ages of 3 and 18 years (Mage=14.22 years, SD = 1.07). Results revealed a significant moderate positive association between childhood maltreatment and CU traits. All subtypes of maltreatment bar sexual abuse were significantly associated with CU traits. However, it was not possible to compare primary and secondary CU traits directly due to inconsistencies in how they are defined. The limitations posed by current research signal the need for clinical and operational guidelines on how to define primary and secondary CU traits. Additionally, prospective longitudinal, genetically informed research is needed to clarify if maltreatment is a causal risk factor for CU traits.

Machine learning classification of conduct disorder with high versus low levels of callous-unemotional traits based on facial emotion recognition abilities.

Conduct disorder (CD) with high levels of callous-unemotional traits (CD/HCU) has been theoretically linked to specific difficulties with fear and sadness recognition, in contrast to CD with low levels of callous-unemotional traits (CD/LCU). However, experimental evidence for this distinction is mixed, and it is unclear whether these difficulties are a reliable marker of CD/HCU compared to CD/LCU. In a large sample (N = 1263, 9-18 years), we combined univariate analyses and machine learning classifiers to investigate whether CD/HCU is associated with disproportionate difficulties with fear and sadness recognition over other emotions, and whether such difficulties are a reliable individual-level marker of CD/HCU. We observed similar emotion recognition abilities in CD/HCU and CD/LCU. The CD/HCU group underperformed relative to typically developing (TD) youths, but difficulties were not specific to fear or sadness. Classifiers did not distinguish between youths with CD/HCU versus CD/LCU (52% accuracy), although youths with CD/HCU and CD/LCU were reliably distinguished from TD youths (64% and 60%, respectively). In the subset of classifiers that performed well for youths with CD/HCU, fear and sadness were the most relevant emotions for distinguishing them from youths with CD/LCU and TD youths, respectively. We conclude that non-specific emotion recognition difficulties are common in CD/HCU, but are not reliable individual-level markers of CD/HCU versus CD/LCU. These findings highlight that a reduced ability to recognise facial expressions of distress should not be assumed to be a core feature of CD/HCU.

Cortical and subcortical grey matter correlates of psychopathic traits in a Japanese community sample of young adults: sex and configurations of factors' level matter!

While neuroimaging research has examined the structural brain correlates of psychopathy predominantly in clinical/forensic male samples from western countries, much less is known about those correlates in non-western community samples. Here, structural magnetic resonance imaging data were analyzed using voxel- and surface-based morphometry to investigate the neuroanatomical correlates of psychopathic traits in a mixed-sex sample of 97 well-functioning Japanese adults (45 males, 21-39 years; M = 27, SD = 5.3). Psychopathic traits were assessed using the Self-Report Psychopathy Scale (SRP-SF; 4th Edition). Multiple regression analysis showed greater Factor 1 scores were associated with higher gyrification in the lingual gyrus, and gray matter volume in the anterior cingulate cortex and amygdala/hippocampus border. Total psychopathy and Factor 1 scores interacted with sex to, respectively, predict cortical thickness in the precuneus and gyrification in the superior temporal gyrus. Finally, Factor 1 and Factor 2 traits interacted to predict gyrification in the posterior cingulate cortex. These preliminary data suggest that, while there may be commonalities in the loci of structural brain correlates of psychopathic traits in clinical/forensic and community samples, the nature of that association might be different (i.e. positive) and may vary according to sex and configurations of factors' level.

Individual differences in sensitivity to the early environment as a function of amygdala and hippocampus volumes: An exploratory analysis in 12-year-old boys.

Children differ in their response to environmental exposures, with some being more sensitive to contextual factors than others. According to theory, such variability is the result of individual differences in neurobiological sensitivity to environmental features, with some individuals generally more affected by both negative and/or positive experiences. In this exploratory study we tested whether left and right amygdala and hippocampus volumes (corrected for total brain size) account for individual differences in response to environmental influences in a sample of 62 boys. Cumulative general environmental quality, ranging from low to high, was measured across the first 9 years and child behavior was reported by teachers when boys were 12-13 years old. According to analyses, only the left amygdala volume - not any of the other brain volumes - emerged as an important brain region for sensitivity to positive environmental aspects. Boys with a larger left amygdala benefited significantly more from higher environmental quality than boys with a smaller left amygdala whilst not being more vulnerable to lower quality. Besides providing preliminary evidence for differences in environmental sensitivity due to brain structure, the results also point to the left amygdala as having a specific role regarding the response to environmental influences.

Sex differences in psychiatric comorbidity and clinical presentation in youths with conduct disorder.

BACKGROUND: Conduct disorder (CD) rarely occurs alone but is typically accompanied by comorbid psychiatric disorders, which complicates the clinical presentation and treatment of affected youths. The aim of this study was to investigate sex differences in comorbidity pattern in CD and to systematically explore the 'gender paradox' and 'delayed-onset pathway' hypotheses of female CD. METHODS: As part of the FemNAT-CD multisite study, semistructured clinical interviews and rating scales were used to perform a comprehensive phenotypic characterization of 454 girls and 295 boys with CD (9-18 years), compared to 864 sex- and age-matched typically developing controls. RESULTS: Girls with CD exhibited higher rates of current major depression, anxiety disorders, post-traumatic stress disorder and borderline personality disorder, whereas boys with CD had higher rates of current attention-deficit/hyperactivity disorder. In line with the 'gender paradox' hypothesis, relative to boys, girls with CD showed significantly more lifetime psychiatric comorbidities (incl. Alcohol Use Disorder), which were accompanied by more severe CD symptoms. Female and male youths with CD also differed significantly in their CD symptom profiles and distribution of age-of-onset subtypes of CD (i.e. fewer girls with childhood-onset CD). In line with the 'delayed-onset pathway' hypothesis, girls with adolescent-onset CD showed similar levels of dimensional psychopathology like boys with childhood-onset CD, while boys with adolescent-onset CD had the lowest levels of internalizing psychopathology. CONCLUSIONS: Within the largest study of CD in girls performed to date, we found compelling evidence for sex differences in comorbidity patterns and clinical presentation of CD. Our findings further support aspects of the 'gender paradox' and 'delayed-onset pathway' hypotheses by showing that girls with CD had higher rates of comorbid lifetime mental disorders and functional impairments, and they usually developed CD during adolescence. These novel data on sex-specific clinical profiles of CD will be critical in informing intervention and prevention programmes.

Differentiating brain function of punishment versus reward processing in conduct disorder with and without attention deficit hyperactivity disorder.

OBJECTIVES: Conduct disorder (CD) and attention-deficit/hyperactivity disorder (ADHD) are reported to co-occur in about 30-50% of affected individuals. Research suggests that poor reinforcement-based decision-making may contribute to impaired social functioning in both youths with CD and ADHD. Considering its frequent co-occurrence this raises the question whether decision-making deficits in both disorders have a disorder-specific and/or shared neurobiological basis. METHODS: 138 participants with CD, ADHD, or CD + ADHD, and typically developing controls (TDCs) aged 9-18 years (48% girls) were included in the study. Participants completed a reinforcement-based decision-making task in the fMRI scanner, investigating decision-making capabilities under different reinforcement contingencies (i.e. punishment vs. reward). Whole-brain and ROI analyses were used to test for potential group differences. RESULTS: For punishment versus reward contingencies, relative to TDCs, youths with CD + ADHD displayed lower brain activity in dorsal striatum (incl. caudate), middle temporal gyrus (MTG), inferior frontal gyrus (IFG) and lateral occipital cortex, and they showed lower activity in dorsal striatum (incl. putamen), orbitofrontal cortex (OFC) and IFG relative to participants with ADHD. All other group comparisons were found to be non-significant. CONCLUSIONS: Participants with comorbid CD + ADHD are neurobiologically the most severely impaired group regarding reinforcement-based decision-making, particularly in response to punishment.

Sex matters: association between callous-unemotional traits and uncinate fasciculus microstructure in youths with conduct disorder.

Among youths with conduct disorder, those with callous-unemotional traits are at increased risk for persistent antisocial behaviour. Although callous-unemotional traits have been found to be associated with white-matter brain abnormalities, previous diffusion imaging studies were conducted in small samples, preventing examination of potential sex by callous-unemotional traits interaction effects on white matter. Here, we used tract-based spatial statistics at a whole-brain level and within regions of interest to compare the white matter correlates of callous-unemotional traits in female vs. male youths with conduct disorder, in a sample (n = 124) recruited through a multi-site protocol. A sex-specific association between callous-unemotional traits and white matter was found in the left uncinate fasciculus, where callous-unemotional traits were positively associated with axial diffusivity in males, while an opposite pattern was found in females. These findings are in line with previous studies suggesting that the uncinate fasciculus is a key tract implicated in the development of psychopathy, but also add to recent evidence showing that sexual dimorphism needs to be taken into account when examining the structural correlates of mental disorders in general, and callous-unemotional traits in conduct disorder in particular.

SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study.

Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual's sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, prefrontal cortex, and supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD, which in turn may relate to observable variations in GMV across the brain.

Cortical and subcortical gray matter volume in psychopathy: A voxel-wise meta-analysis.

Voxel-based morphometry (VBM) studies of gray matter volume (GMV) in psychopathy have produced inconsistent results and few have been replicated. Therefore, to clarify GMV abnormalities associated with psychopathy as operationalized by Hare (2003), we conducted a meta-analysis of VBM studies using both categorical and dimensional analyses. We identified seven studies eligible for the categorical meta-analysis (136 men with psychopathy vs 150 male controls) and 11 studies (N = 519) eligible for dimensional metaregressions. First, we used seed-based d mapping with permutation of subject images for voxel-based meta-analyses. Statistical parametric maps of GMV were available for four (57%) of the studies included in the categorical meta-analysis and for five (45%) of the studies included in the dimensional metaregression analyses, with peak coordinates available for the remaining studies. Second, we used metadata of a large-scale neuroimaging database to provide an objective and quantitative account of psychological processes attributed to the brain regions we identified in our group meta-analysis and metaregressions. Men with psychopathy exhibited reliable GMV abnormalities circumscribed to the left hemisphere in the dorsolateral prefrontal cortex and the medial orbitofrontal cortex. Total psychopathy scores and Factors 1 and 2 scores were all related to decreased GMV within those two prefrontal regions, as well as decreased GMV in a wider set of regions encompassing midline, temporal, parietal, occipital, and subcortical structures. We discuss how decreased GMV in those regions likely account for the impairments in the emotion, cognition, action, and perception domains seen in the disorder. (PsycInfo Database Record (c) 2021 APA, all rights reserved).