Investigating structural and functional neural correlates in children and adolescents with antisocial behavior

Antisocial behavior is highly prevalent in young and adult populations worldwide and constitutes a major public health problem due to the huge burden on the individual as well as the significant economic burden on society. A better understanding of the underlying neurobiological mechanisms of antisocial behavior is warranted to improve current diagnostics (e.g. early detection of children at risk) and effective prevention/treatment programs. So far, neuroimaging studies have indicated neural atypicalities in youths with antisocial behavior; however, the direction and location of these brain alterations vary across studies. These ambiguities are most likely caused by the heterogeneity of the young samples with antisocial behavior studied, especially regarding sex, clinical diagnoses, and the presence of callous-unemotional traits. The central aim of this dissertation was to further the neuroscientific knowledge of antisocial behavior in children and adolescents by investigating the underlying structural and functional neurobiological characteristics, with an extra focus on possible sex differences and callous-unemotional traits. First, we examined the current neuroimaging literature, through meta-analyses, with the purpose of overcoming the heterogeneity of antisocial behavior and generating a common “overlapping” pattern of structural and functional atypicalities in youths with antisocial behavior. Secondly, the relation between callous-unemotional traits and brain structure was investigated separately for sex and independently of psychiatric comorbidities. Thirdly, this work investigated the white matter integrity within a homogenous group of girls with conduct disorder –the severe variant of antisocial behavior– in comparison to typically developing peers. This work expands our current knowledge on the structural and functional neural correlates in children and adolescents with antisocial behavior in several ways. For one, our meta-analytic results indicate a consistent pattern of gray matter reductions and hypoactivations in brain areas within the prefrontal and limbic cortex. These findings fit a recently proposed neurobiological model that connects alterations within similar brain regions with the behavioral dispositions of antisocial behavior (e.g. dysfunctions in empathy, emotional learning, and decision making). Secondly, we observed a positive relation between callous-unemotional traits and bilateral insula volume in a large international population of typically developing boys, but not in girls, independent of psychiatric disorders. This demonstrates that callous-unemotional traits have a sex-specific neurobiological basis beyond psychiatric samples. Thirdly, this work presents novel findings of white-matter integrity alterations in the body of the corpus callosum of girls with antisocial behavior, indicating possible reduced interhemispheric processing and consequent emotion processing abilities. In short, the present thesis provides original findings regarding the neurobiology of antisocial behavior in youths and emphasizes the importance of callous-unemotional traits and sex differences. Our results encourage future studies to further investigate the developmental trajectories and potential neural markers of antisocial behavior in order to enhance early detection and improve intervention programs, which could ultimately reduce antisocial behavior and delinquency in our society

Atypical dorsolateral prefrontal activity in females with conduct disorder during effortful emotion regulation

BACKGROUND: Conduct disorder (CD), which is characterized by severe aggressive and antisocial behavior, is linked to emotion processing and regulation deficits. However, the neural correlates of emotion regulation are yet to be investigated in adolescents with CD. Furthermore, it remains unclear whether CD is associated with deficits in emotional reactivity, emotion regulation, or both. METHODS: We used functional magnetic resonance imaging to study effortful emotion regulation by cognitive reappraisal in 59 female adolescents 15 to 18 years of age (30 with a CD diagnosis and 29 typically developing (TD) control adolescents). RESULTS: Behaviorally, in-scanner self-report ratings confirmed successful emotion regulation within each group individually but significant group differences in emotional reactivity and reappraisal success when comparing the groups (CD < TD). Functional magnetic resonance imaging results revealed significantly lower activation in left dorsolateral prefrontal cortex and angular gyrus in CD compared with TD adolescents during emotion regulation, but no group differences for emotional reactivity. Furthermore, connectivity between left dorsolateral prefrontal cortex and the bilateral putamen, right prefrontal cortex, and amygdala was reduced in CD compared with TD adolescents during reappraisal. Callous-unemotional traits were unrelated to neural activation, but these traits correlated negatively with behavioral reports of emotional reactivity. CONCLUSIONS: Our results demonstrate reduced prefrontal brain activity and functional connectivity during effortful emotion regulation in female adolescents with CD. This sheds light on the neural basis of the behavioral deficits that have been reported previously. Future studies should investigate whether cognitive interventions are effective in enhancing emotion-regulation abilities and/or normalizing prefrontal and temporoparietal activity in female adolescents with CD

Atypical Dorsolateral Prefrontal Activity in Female Adolescents With Conduct Disorder During Effortful Emotion Regulation

BACKGROUND: Conduct disorder (CD), which is characterized by severe aggressive and antisocial behavior, is linked to emotion processing and regulation deficits. However, the neural correlates of emotion regulation are yet to be investigated in adolescents with CD. Furthermore, it remains unclear whether CD is associated with deficits in emotional reactivity, emotion regulation, or both. METHODS: We used functional magnetic resonance imaging to study effortful emotion regulation by cognitive reappraisal in 59 female adolescents 15 to 18 years of age (30 with a CD diagnosis and 29 typically developing (TD) control adolescents). RESULTS: Behaviorally, in-scanner self-report ratings confirmed successful emotion regulation within each group individually but significant group differences in emotional reactivity and reappraisal success when comparing the groups (CD < TD). Functional magnetic resonance imaging results revealed significantly lower activation in left dorsolateral prefrontal cortex and angular gyrus in CD compared with TD adolescents during emotion regulation, but no group differences for emotional reactivity. Furthermore, connectivity between left dorsolateral prefrontal cortex and the bilateral putamen, right prefrontal cortex, and amygdala was reduced in CD compared with TD adolescents during reappraisal. Callous-unemotional traits were unrelated to neural activation, but these traits correlated negatively with behavioral reports of emotional reactivity. CONCLUSIONS: Our results demonstrate reduced prefrontal brain activity and functional connectivity during effortful emotion regulation in female adolescents with CD. This sheds light on the neural basis of the behavioral deficits that have been reported previously. Future studies should investigate whether cognitive interventions are effective in enhancing emotion-regulation abilities and/or normalizing prefrontal and temporoparietal activity in female adolescents with CD

Resting autonomic nervous system activity is unrelated to antisocial behaviour dimensions in adolescents: Cross-sectional findings from a European multi-centre study

Purpose: Autonomic nervous system (ANS) functioning has long been studied in relation to antisocial behaviour, but relevant measures (heart rate, heart rate variability, pre-ejection period, respiration rate) have rarely been considered together. This study investigated the relationship between these measures and antisocial behaviour. Methods: Using a sample of 1010 youths with (47.8%) and without conduct disorder (52.2%) aged between 9 and 18. years (659 females, 351 males, mean age = 14.2. years, SD = 2.4), principal component analysis (PCA) was applied to various measures of psychopathology and antisocial behavior. Structural equation modelling was performed in order to test whether the ANS measures predicted PCA-dimensions. Cluster analysis was used in order to classify patterns of ANS activity. Analyses were performed separately for males/females and controlled for body-mass-index, age, caffeine use, cigarette smoking, sports, socioeconomic status, medication, cardiac problems. Results: The PCA yielded three components: antisocial behaviour/comorbid psychopathology, narcissistic traits, and callous-unemotional traits. ANS measures were only weakly correlated with these components. Cluster analysis yielded high and low arousal clusters in both sexes. When controlling for covariates, all associations disappeared. Conclusion: Our findings suggest that resting ANS measures are only weakly related to antisocial behaviour and indicate that smoking should be considered as an important covariate in future psychophysiological studies

Eye gaze patterns and functional brain responses during emotional face processing in adolescents with conduct disorder

Background: Conduct disorder (CD) is characterized by severe aggressive and antisocial behavior. Initial evidence suggests neural deficits and aberrant eye gaze pattern during emotion processing in CD; both concepts, however, have not yet been studied simultaneously. The present study assessed the functional brain correlates of emotional face processing with and without consideration of concurrent eye gaze behavior in adolescents with CD compared to typically developing (TD) adolescents. Methods: 58 adolescents (23CD/35TD; average age = 16 years/range = 14-19 years) underwent an implicit emotional face processing task. Neuroimaging analyses were conducted for a priori-defined regions of interest (insula, amygdala, and medial orbitofrontal cortex) and using a full-factorial design assessing the main effects of emotion (neutral, anger, fear), group and the interaction thereof (cluster-level, p < .05 FWE-corrected) with and without consideration of concurrent eye gaze behavior (i.e., time spent on the eye region). Results: Adolescents with CD showed significant hypo-activations during emotional face processing in right anterior insula compared to TD adolescents, independent of the emotion presented. In-scanner eye-tracking data revealed that adolescents with CD spent significantly less time on the eye, but not mouth region. Correcting for eye gaze behavior during emotional face processing reduced group differences previously observed for right insula. Conclusions: Atypical insula activation during emotional face processing in adolescents with CD may partly be explained by attentional mechanisms (i.e., reduced gaze allocation to the eyes, independent of the emotion presented). An increased understanding of the mechanism causal for emotion processing deficits observed in CD may ultimately aid the development of personalized intervention programs

Structural and functional neuroimaging findings in youths with AB co-localize in right dorsomedial prefrontal cortex (dmPFC) and left insular cortex.

<p>2-D slices displaying the thresholded and binarized ALE maps of significant overlap (P<0.05, FDR-corrected) in studies of structural (green) and functional (red) alterations in adolescents with AB (TD>AB) as well as a conjunction analysis (blue) overlaid on the Colin T1-template in MNI space. The upper-row including left cut-out as well as right surface-model highlight the right dmPFC where structural and functional alterations co-localize. The lower-row including left cut-out as well as right surface-model illustrate left insular cortex/claustrum where structural and functional alterations overlap.</p

Characteristics of the studies in adolescents with AB included in current functional meta-analysis.

<p>CD = Conduct disorder. CP = Conduct problems. ODD = Oppositional defiant disorder. PT = with psychopathic traits. CU+ = with high callous-unemotional traits. CU- = with low callous-unemotional traits. TD = Typically developing participants.</p><p>Characteristics of the studies in adolescents with AB included in current functional meta-analysis.</p

Structural and Functional Alterations in Right Dorsomedial Prefrontal and Left Insular Cortex Co-Localize in Adolescents with Aggressive Behaviour: An ALE Meta-Analysis

<div><p>Recent neuroimaging work has suggested that aggressive behaviour (AB) is associated with structural and functional brain abnormalities in processes subserving emotion processing and regulation. However, most neuroimaging studies on AB to date only contain relatively small sample sizes. To objectively investigate the consistency of previous structural and functional research in adolescent AB, we performed a systematic literature review and two coordinate-based activation likelihood estimation meta-analyses on eight VBM and nine functional neuroimaging studies in a total of 783 participants (408 [224AB/184 controls] and 375 [215 AB/160 controls] for structural and functional analysis respectively). We found 19 structural and eight functional foci of significant alterations in adolescents with AB, mainly located within the emotion processing and regulation network (including orbitofrontal, dorsomedial prefrontal and limbic cortex). A subsequent conjunction analysis revealed that functional and structural alterations co-localize in right dorsomedial prefrontal cortex and left insula. Our results are in line with meta-analytic work as well as structural, functional and connectivity findings to date, all of which make a strong point for the involvement of a network of brain areas responsible for emotion processing and regulation, which is disrupted in AB. Increased knowledge about the behavioural and neuronal underpinnings of AB is crucial for the development of novel and implementation of existing treatment strategies. Longitudinal research studies will have to show whether the observed alterations are a result or primary cause of the phenotypic characteristics in AB.</p></div

Systematic literature research.

<p>Literature research according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the revised Quality Of Reporting Of Meta-analyses (QUOROM) statement (59) resulting in 17 neuroimaging studies included in the current meta-analyses.</p

Results of the structural and functional ALE-meta analyses and conjunction analysis of structure and functional alterations in adolescents with AB.

<p>All x, y, z-coordinates represent local maxima in MNI space. AB = Aggressive Behaviour. Volume = Volume (mm3). TD = Typically developing controls. H = Hemisphere. BA = Brodmann areas. R = Right; L = Left.</p><p>Results of the structural and functional ALE-meta analyses and conjunction analysis of structure and functional alterations in adolescents with AB.</p