Different Whole-Brain Functional Connectivity Correlates of Reactive-Proactive Aggression and Callous-Unemotional Traits in Children and Adolescents with Disruptive Behaviors

Background: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. Methods: The large sample of children and adolescents aged 8–18 years (n = 207; mean age = 13.30 ± 2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. Results: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled. For cases, reactive and proactive aggression scores related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. Conclusions: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths

Specific cortical and subcortical alterations for reactive and proactive aggression in children and adolescents with disruptive behavior.

Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated associations between aggression subtypes, CU traits and ADHD symptoms in predefined regions of interest. T1-weighted magnetic resonance images were acquired from 158 children and adolescents with disruptive behavior (ODD/CD) and 96 controls in a multi-center study (aged 8-18). Aggression subtypes were assessed by questionnaires filled in by participants and their parents. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models. Proactive aggression was negatively associated with amygdala volume (b = -10.7, p = 0.02), while reactive aggression was negatively associated with insula volume (b = -21.7, p = 0.01). No associations were found with CU traits or ADHD symptomatology. Classical group comparison showed that children and adolescents with disruptive behavior had smaller volumes than controls in (bilateral) vmPFC (p = 0.003) with modest effect size and a reduced shape in the anterior part of the left ventral striatum (p = 0.005). Our study showed negative associations between reactive aggression and volumes in a region involved in threat responsivity and between proactive aggression and a region linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure which may provide useful insights for clinical practice

Validation of the Transition Readiness and Appropriateness Measure (TRAM) for the Managing the Link and Strengthening Transition from Child to Adult Mental Healthcare in Europe (MILESTONE) study

OBJECTIVE:Young people moving from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS) are faced with significant challenges. To improve this state of affairs, there needs to be a recognition of the problem and initiatives and an urgent requirement for appropriate tools for measuring readiness and outcomes at the transfer boundary (16-18 years of age in Europe). The objective of this study was to develop and validate the Transition Readiness and Appropriateness Measure (TRAM) for assessing a young person's readiness for transition, and their outcomes at the transfer boundary. DESIGN:MILESTONE prospective study. SETTING:Eight European Union (EU) countries participating in the EU-funded MILESTONE study. PARTICIPANTS:The first phase (MILESTONE validation study) involved 100 adolescents (pre-transition), young adults (post-transition), parents/carers and both CAMHS and AMHS clinicians. The second phase (MILESTONE cohort study and nested cluster randomised trial) involved over 1000 young people. RESULTS:The development of the TRAM began with a literature review on transitioning and a review of important items regarding transition by a panel of 34 mental health experts. A list of 64 items of potential importance were identified, which together comprised the TRAM. The psychometric properties of the different versions of the TRAM were evaluated and showed that the TRAM had good reliability for all versions and low-to-moderate correlations when compared with other established instruments and a well-defined factor structure. The main results of the cohort study with the nested cluster randomised trial are not reported. CONCLUSION:The TRAM is a reliable instrument for assessing transition readiness and appropriateness. It highlighted the barriers to a successful transition and informed clinicians, identifying areas which clinicians on both sides of the transfer boundary can work on to ease the transition for the young person. TRIAL REGISTRATION NUMBER:ISRCTN83240263 (Registered 23 July 2015), NCT03013595 (Registered 6 January 2017); Pre-results

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control

Recurrence of iga nephropathy after kidney transplantation in adults

Background and objectives: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. Design, setting, participants, & measurements: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 “The Post-Transplant Glomerular Disease” study centers in Europe, North America, and South America. Results: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donorspecific antibodies (hazardratio, 2.59; 95%confidence interval, 1.09 to 6.19).Afterkidneytransplantation,development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. Conclusions: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss

Cohort profile : demographic and clinical characteristics of the MILESTONE longitudinal cohort of young people approaching the upper age limit of their child mental health care service in Europe

Purpose: The presence of distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) impacts continuity of mental health treatment for young people. However, we do not know the extent of discontinuity of care in Europe nor the effects of discontinuity on the mental health of young people. Current research is limited, as the majority of existing studies are retrospective, based on small samples or used non-standardised information from medical records. The MILESTONE prospective cohort study aims to examine associations between service use, mental health and other outcomes over 24 months, using information from self, parent and clinician reports. Participants: Seven hundred sixty-three young people from 39 CAMHS in 8 European countries, their parents and CAMHS clinicians who completed interviews and online questionnaires and were followed up for 2 years after reaching the upper age limit of the CAMHS they receive treatment at. Findings to date: This cohort profile describes the baseline characteristics of the MILESTONE cohort. The mental health of young people reaching the upper age limit of their CAMHS varied greatly in type and severity: 32.8% of young people reported clinical levels of self-reported problems and 18.6% were rated to be ‘markedly ill’, ‘severely ill’ or ‘among the most extremely ill’ by their clinician. Fifty-seven per cent of young people reported psychotropic medication use in the previous half year. Future plans: Analysis of longitudinal data from the MILESTONE cohort will be used to assess relationships between the demographic and clinical characteristics of young people reaching the upper age limit of their CAMHS and the type of care the young person uses over the next 2 years, such as whether the young person transitions to AMHS. At 2 years follow-up, the mental health outcomes of young people following different care pathways will be compared. Trial registration number: NCT03013595

Parent-Mediated Interventions for Infants under 24 Months at Risk for Autism Spectrum Disorder:A Systematic Review of Randomized Controlled Trials

Prodromal symptoms of Autism Spectrum Disorder (ASD) have been detected within the first year of life. This review evaluated evidence from randomized controlled trials (RCTs) of parent-mediated interventions for infants under 24 months who are at risk for ASD. Electronic databases, including grey literature, were searched up till November 2019. Seven RCTs were identified. There was substantial heterogeneity in recruitment, outcome measures and effect size calculations. Interventions did not reduce the risk of later ASD diagnosis and post-intervention effects on infant outcomes were inconsistent, with five studies reporting significant improvements across both treatment and control groups. Moderate level of evidence of intervention effects on parental interaction skills and the small number of RCTs, and significant limitations restrict generalizability across studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10803-021-05148-9

Development and Psychometric Properties of the Multi-System Profile of Symptoms Scale in Patients with Rett Syndrome

Background: Rett Syndrome (RTT) is a rare, neurodevelopmental disorder characterised by a range of problematic symptoms. There is yet to be a robust instrument to adequately capture the range of disease severity across the lifespan. In this study, we aimed to develop and assess the validity of an RTT-specific electronic Observer Reported Outcome (eObsRO), the Multi-System Profile of Symptoms Scale (MPSS). Methods: The study was conducted in two phases. Phase 1 consisted of a systematic literature review, focus groups, expert feedback, and a pilot test of the new scale. Modifications were made based on preliminary analysis and feedback collected in the pilot phase. Phase 2 consisted of the validation of the questionnaire based on two samples (Sample 1, n = 18; Sample 2, n = 106). Participants were all parents or caregivers of individuals with RTT. Results: The MPSS consists of 12 validated sub-scales (mental health problems, autonomic problems, cardiac problems, communication problems, problems in social behaviour, problems in engagement, gastrointestinal problems, problems in motor skills, neurological problems, orofacial problems, respiratory problems, and sleep problems), which explore symptom frequency in the past month and a supplement to the scale consisting of five sub-scales (sensory problems, immune dysfunction and infection, endocrine problems, skeletal problems, and dermatological problems), which is designed to capture symptom changes over a longer time period. The frequency of symptoms was rated on a 10-point slider scale, which then was automatically transformed into a 0 to 5 Likert score. All 12 sub-scales showed strong internal consistency (α ≥ 0.700) and good stability, ranging from 0.707 to 0.913. Pearson’s correlation showed a statistically significant (r = 0.649) correlation between the MPSS and the Rett Syndrome Behaviour Questionnaire (RSBQ) total score and significant correlations between sub-scales with items that were presented in both the MPSS and RSBQ. Conclusions: The MPSS is a psychometrically validated eObsRO using the HealthTrackerTM platform and has the potential to be used in clinical trials

Les retrouvailles des époux dans la littérature et les arts : quelques exemples de l'Antiquité à nos jours

International audienceLa scène des retrouvailles des époux place au centre de la narration les thèmes éternels de l'amour et de la mort ainsi que de l'amour humain entre l'homme et la femme qui renvoie à l’amour entre Dieu et l’humanité. La fin de l’Odyssée – modèle archétypal de la scène – a inspiré directement, sous la forme de la réécriture, ou indirectement, sous la forme de l’allusion, un nombre croissant d’interprétations dans la littérature et les arts au fil des siècles. Homère établit un schéma narratif qui réapparaît aux moments cruciaux de la tradition, d’Euripide à Boccace, de Shakespeare à Goldoni. Les interprétations de la scène présentes dans ce volume forment un faisceau de motifs qui reviennent d’un auteur à l’autre, bien que déclinés de façon différente. Leur dénominateur commun est le processus d’initiation que les personnages vivent lors de la reconnaissance qui, selon l’intuition d’Euripide évoquée au début du livre, a «quelque chose de divin». Le mythe de la reconnaissance entre époux prend, au XXe siècle, la forme dramatique de son contraire. Des auteurs comme Pirandello, Savinio, Giono, Márai, Moravia mettent en doute l’identité et constatent l’impossibilité d’une réelle connaissance de l’autre. Les retrouvailles manquées s’avèrent alors être un point de départ idéal pour une réflexion sur l’œuvre d’art : si l’accord entre l’homme et la femme devient impossible, l’artiste peut continuer à explorer le thème de la recherche d’unification intérieure en réfléchissant sur la création artistique. C’est en particulier ce que feront les cinéastes après Voyage en Italie de Rossellini. SOMMAIRE -*- Avant-propos / Silvia D'Amico et Maryline Maigron -1-Quelque chose de divin dans la reconnaissance / Piero Boitani -2- Retrouvailles platoniciennes : le discours d'Aristophane dans le "Banquet" et son héritage / Michele Corradi -3- Réécrire et interpréter des retrouvailles problématiques (Décaméron, X, 10) : Grisélidis chez Boccace, Pétrarque et Chaucer / Massimo Lucarelli -4- De l'époux retrouvé à l'époux retranché : incursions dans l'art européen, de Giotto au post-modernisme / Daniela Amsallem -5- Le rôle de la "visio" dans la rencontre des amants. Un topos traditionnel à l'heure de la Renaissance / Michele Mastroianni -6- Eternelles retrouvailles : une lecture d'"Antoine et Cléopâtre" de Shakespeare / Mathilde La Cassagnère -7- Carlo Goldoni ou l'exploration comico-pathétique / Lucie Comparini -8- Amères retrouvailles dans "Il fu Mattia Pascal" de Luigi Pirandello / Emanuela Montalto -9- "Santa Messalina" de Bruno Corra ou des retrouvailles à la manière futuriste / Barbara Meazzi -10- "Capitaine Ulysse" d'Alberto Savinio ou l'agnition (im)possible / Giulia Ferri -11- Les retrouvailles manquées et le complexe de Télémaque (Giono, Marai, Moravia) / Silvia D'Amico -12- Les retrouvailles des époux dans "Voyage en Italie" de Roberto Rossellini ou le miracle de l'amour / Maryline Maigron

Distinct associations between fronto-striatal glutamate concentrations and callous-unemotional traits and proactive aggression in disruptive behavior

Disruptive behavior is associated with societally and personally problematic levels of aggression and has been linked to abnormal structure and function of fronto-amygdala-striatal regions. Abnormal glutamatergic signalling within this network may play a role in aggression. However, disruptive behavior does not represent a homogeneous construct, but can be fractionated across several dimensions. Of particular interest, callous-unemotional (CU) traits have been shown to modulate the severity, neural and behavioural characterisation, and therapeutic outcomes of disruptive behaviour disorders (DBDs) and aggression. Further, individuals showing disruptive behavior differ to the extent that they engage in subtypes of aggression (i.e., proactive [PA] and reactive aggression [RA]) which may also represent distinct therapeutic targets. Here we investigated how glutamate signalling within the fronto-amygdala-striatal circuitry was altered along these dimensions in youths showing disruptive behavior (n = 140) and typically developing controls (TD, n = 93) within the age-range of 8-18 years. We used proton magnetic resonance spectroscopy (H-MRS) in the anterior cingulate cortex (ACC), striatum, amygdala and insula and associated glutamate concentrations with continuous measures of aggression and CU-traits using linear mixed-effects models. We found evidence of a dissociation for the different measures and glutamate concentrations. CU traits were associated with increased ACC glutamate ('callousness': b = .19, t (108) = 2.63, p = .01, r = .25; 'uncaring': b = .18, t (108) = 2.59, p = .011, r = .24) while PA was associated with decreased striatal glutamate concentration (b = -.23, t (28) = -3.02, p = .005, r = .50). These findings suggest dissociable correlates of CU traits and PA in DBDs, and indicate that the ACC and striatal glutamate may represent novel pharmacological targets in treating these different aspects