Identifying structural brain markers of resilience to adversity in young people using voxel-based morphometry

There is increasing evidence that resilience in youth may have a neurobiological basis. However, the existing literature lacks a consistent way of operationalizing resilience, often relying on arbitrary judgments or narrow definitions (e.g., not developing PTSD) to classify individuals as resilient. Therefore, this study used data-driven, continuous resilience scores based on adversity and psychopathology to investigate associations between resilience and brain structure in youth. Structural MRI data from 298 youth aged 9–18 years (M$_{age}$ = 13.51; 51% female) who participated in the European multisite FemNAT-CD study were preprocessed using SPM12 and analyzed using voxel-based morphometry. Resilience scores were derived by regressing data on adversity exposure against current/lifetime psychopathology and quantifying each individual’s distance from the regression line. General linear models tested for associations between resilience and gray matter volume (GMV) and examined whether associations between resilience and GMV differed by sex. Resilience was positively correlated with GMV in the right inferior frontal and medial frontal gyri. Sex-by-resilience interactions were observed in the middle temporal and middle frontal gyri. These findings demonstrate that resilience in youth is associated with volume in brain regions implicated in executive functioning, emotion regulation, and attention. Our results also provide evidence for sex differences in the neurobiology of resilience

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

White matter microstructure of the extended limbic system in male and female youth with conduct disorder

BackgroundPrevious studies of conduct disorder (CD) have reported structural and functional alterations in the limbic system. However, the white matter tracts that connect limbic regions have not been comprehensively studied. The uncinate fasciculus (UF), a tract connecting limbic to prefrontal regions, has been implicated in CD. However, CD-related alterations in other limbic tracts, such as the cingulum and the fornix, have not been investigated. Furthermore, few studies have examined the influence of sex and none have been adequately powered to test whether the relationship between CD and structural connectivity differs by sex. We examined whether adolescent males and females with CD exhibit differences in structural connectivity compared with typically developing controls.MethodsWe acquired diffusion-weighted magnetic resonance imaging data from 101 adolescents with CD (52 females) and 99 controls (50 females). Data were processed for deterministic spherical deconvolution tractography. Virtual dissections of the UF, the three subdivisions of the cingulum [retrosplenial cingulum (RSC), parahippocampal and subgenual cingulum], and the fornix were performed and measures of fractional anisotropy (FA) and hindrance-modulated orientational anisotropy (HMOA) were analysed.ResultsThe CD group had lower FA and HMOA in the right RSC tract relative to controls. Importantly, these effects were moderated by sex – males with CD significantly lower FA compared to male controls, whereas CD and control females did not differ.ConclusionsOur results highlight the importance of considering sex when studying the neurobiological basis of CD. Sex differences in RSC connectivity may contribute to sex differences in the clinical presentation of CD

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.</p

Sex differences in risk-based decision making in adolescents with conduct disorder

Altered decision making processes and excessive risk-seeking behaviours are key features of conduct disorder (CD). Previous studies have provided compelling evidence of abnormally increased preference for risky options, higher sensitivity to rewards, as well as blunted responsiveness to aversive outcomes in adolescents with CD. However, most studies published to date have focused on males only; thus, it is not known whether females with CD show similar alterations in decision making. The current study investigated potential sex differences in decision making and risk-seeking behaviours in adolescents with CD. Forty-nine adolescents with CD (23 females) and 51 control subjects (27 females), aged 11-18 years, performed a computerised task assessing decision making under risk—the Risky Choice Task. Participants made a series of decisions between two gamble options that varied in terms of their expected values and probability of gains and losses. This enabled the participants’ risk preferences to be determined. Taking the sample as a whole, adolescents with CD exhibited increased risk-seeking behaviours compared to healthy controls. However, we found a trend towards a sex-by-group interaction, suggesting that these effects may vary by sex. Follow-up analyses showed that males with CD made significantly more risky choices than their typically developing counterparts, while females with CD did not differ from typically developing females in their risk-seeking behaviours. Our results provide preliminary evidence that sex may moderate the relationship between CD and alterations in risk attitudes and reward processing, indicating that there may be sex differences in the developmental pathways and neuropsychological deficits that lead to 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

Investigating the fronto-limbic and hypothalamic-pituitary-adrena axis systems in conduct disorder

In this thesis, I report studies investigating the neurobiology of conduct disorder (CD) – a disorder diagnosed in children and adolescents who display a persistent pattern of disruptive and aggressive behaviour. My particular focus is on the role of frontal, limbic and hypothalamic-pituitary-adrenal (HPA) axis systems, and especially whether CD-related alterations in these systems differ between males and females. A range of different imaging techniques were applied to data from the Neurobiological and Treatment of Adolescent Female Conduct Disorder study (Fem-NAT-CD). In study 1 (Chapter 4), we employed surface-based morphometry techniques to assess frontal and limbic (cortical and subcortical) brain structures. Similar patterns of CD-related related reductions in cortical volume, thickness, and surface area in the superior frontal gyrus were seen in both sexes. The second study (Chapter 5) assessed the shape of subcortical limbic structures. Youths with CD exhibited shape deformations (i.e., inward) in the shell of the nucleus accumbens compared to controls, independent of sex. The third study (Chapter 6) used spherical deconvolution basedtractography and virtually dissected key fronto-limbic white matter tracts, namely: the uncinate fasciculus, fornix, and the subgenual, retrosplenial and parahippocampal bundles of the cingulum. We observed reduced fractional anisotropy in the retrosplenial cingulum in the CD group relative to healthy controls. However, this result was moderated by sex: males with CD showed reduced, while females with CD showed increased fractional anisotropy compared to sex-matched healthy controls. Finally, we investigated sex differences in HPA axis function (Chapter 7) by measuring cortisol response during the Trier Social Stress Test for Children. Both males and females with CD showed blunted cortisol response to stress, and such effects were not explained by low levels of self-rated fear or anxiety. In a small, proof of concept analysis we observed a positive correlation between cortical volume of the superior frontal gyrus and cortisol reactivity. I conclude that the neurobiological basis of CD is relatively similar in males and females. Thus, previous findings in males with CD may also apply for females with CD. Suggestions for future research are presented and clinical implications are discussed

Neuroendocrine Stress Response in Female and Male Youths With Conduct Disorder and Associations With Early Adversity

Objective: Conduct disorder (CD) involves aggressive and antisocial behavior and is associated with blunted cortisol stress response in male youths. Far less is known about cortisol stress responsivity in female youths with CD or other neuroendocrine responses in both sexes. Although CD is linked to early adversity, the possibility that neuroendocrine alterations may mediate the relationship between early adversity and CD has not been systematically investigated. Method: Within the European FemNAT-CD multi-site study, salivary cortisol, testosterone, the testosterone/cortisol ratio, oxytocin, and psychological stress response to a standardized psychosocial stress test (the Trier Social Stress Test [TSST]), together with common pre- and postnatal environmental risk factors, were investigated in 130 pubertal youths with CD (63% female, 9-18 years of age) and 160 sex-, age-, and puberty-matched healthy controls (HCs). Results: The TSST induced psychological stress in both CD and HCs. In contrast, female and male youths with CD showed blunted cortisol, testosterone, oxytocin, and testosterone/cortisol stress responses compared to HCs. These blunted stress responses partly mediated the relationship between environmental risk factors and CD. Conclusion: Findings from this unique sample, including many female youths with CD, provide evidence for a widespread attenuated stress responsivity of not only stress hormones, but also sex hormones and neuropeptides in CD and its subgroups (eg, with limited prosocial emotions). Results are the first to demonstrate blunted neuroendocrine stress responses in both female and male youths with CD. Early adversity may alter neuroendocrine stress responsivity. Biological mechanisms should be investigated further to pave the way for personalized intervention, thereby improving treatments for CD.</p