Community Research and Development Information Service - CORDIS


MATRICS Report Summary

Project ID: 603016
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - MATRICS (Multidisciplinary Approaches to Translational Research In Conduct Syndromes)

Project Context and Objectives:
MATRICS is based on the principle that aggression can be understood based on aberrant arousal mechanisms altering top-down control mechanisms of aggressive behaviour, empathy and the balance between rational and emotional decision making. This premise is characterized in a series of preclinical and clinical workpackages which apply this principle to aggression in juvenile conduct disorder (CD) using both current and novel arousal-modifying pharmacological strategies and preventative bio-/neuro-feedback approaches to remediate aggression. MATRICS dissects aggression not only in terms of reactive and instrumental aggression but also examines the role of the modifier callous unemotional (CU) traits. This CU traits modifier is an important addition to existing diagnostic constructs of CD in DSM-V and is associated with increased aggression and antisocial behaviour with high criminal impact. The improved clinical management of aggression in CD+/-CU traits is an important aspiration of MATRICS. In a series of 11 multidisciplinary scientific workpackages (WPs) and 3 supporting WPs (project management, ethics and dissemination); this is assessed.
WP1 and WP2 focus on animal models of aggression and altered stress reactivity (during early life and adolescence) both in terms of their aggressive and cognitive phenotype (WP1) and their multiparametric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) assessment (WP2). Together, they identify the neural circuits underlying aggressive phenotypes and its relationship to altered arousal, anxiety and cognition. WP1 additionally assesses pharmacological strategies to remediate aggression. WP3/4 mines existing imaging genetic datasets (NeuroIMAGE; IMAGEN) to validate the findings from WP1/2 and also establishes new data collection in CD+/-CU cohorts encompassing phenotypic, MRI, 1H-MRS biosampling and arousal measures. WP5 will generate a genetic landscape of CD based on existing genome wide association study data sets. The top-ranked targets will be confirmed in the brain / blood biomaterial from animal models in WP1 and blood / saliva human CD samples (in WP3/4). This material will also be used in WP5 to assess the ability of environmental triggers to leave epigenetic (methylomics / microRNA) marks which are associated with increased aggression. WP6 switches focus to implement phase IIb clinical trial studies in medication tested in WP1 and aims to assess clinical and phenotypic changes in CD cohorts. WP7 aims to alter arousal and stress reactivity in a series of bio- / neuro-feedback studies in childhood and adolescent CD cohorts respectively as preventative strategies to reduce aggressive behaviour. WP8 utilises hair samples collected in animal models (WP1) and human CD samples (WP3/4) to produce immunopluripotent stem cells (IPSCs) which are then directed to become cortical and hypothalamic neurons for further electrophysiological characterisation in WP8 and epigenetic profiling in WP5. WP9 explores gene-environment relationships in existing population datasets and in those within WP3/4 in assessing how different enviromental risk factors for CD translate into genetic and molecular mechanisms using a candidate gene approach. The causal modelling of aggression with other psychological markers in existing datasets is an important focus of WP10. WP10 also utilises Bayesian machine learning approaches to integrate multi-parametric data sets collected across WP1/2 and WP3/4/5/8 respectively. WP11 has the responsibility for maintaining ethical oversight over all studies in WP1-10 and also coordinates training activities for those WPs involved in clinical studies. WP12 coordinates the dissemination of MATRICS output to different stakeholders; patient groups; profession societies, journals and conferences; the media and the general public. WP12 is responsible for any valorisation of MATRICS output while WP13 ensures professional project management of MATRICS via its coordination of scientific content, finances and administration.
Project Results:
MATRICS WP1 has established an aggressive and antisocial phenotype in the BALB/cJ mouse which is accompanied by high anxiety, inattention and reversal learning deficits. These aggressive and anxiety changes are reversible by administration of the psychostimulant methylphenidate. In vivo MRI / 1H-MRS studies of this mouse model demonstrate decreased fractional anisotropy diffusion tensor imaging (DTI) markers and decreased inhibitory tone in cortical control regions. These changes in cortical inhibition are confirmed in transcriptomic expression changes in two independent animal models (BALB/cJ mice and (peripubertal stress) PPS rats). Peripubertal stress is not only associated with increased aggression but also changes in cortical and amygdala markers of inhibition. However ex-vivo brain MRI imaging of the BALB/cJ model has documented marked volumetric and white matter changes in a number of brain regions. Documentation of ex vivo MRI changes in structural, volume or DTI measures in the PPS model is complete. WP1 has also demonstrated that BALB/cJ mice display insensitivity to punishment learning (analogous to that seen in humans with high callous unemotional traits). Furthermore, decreased fear conditioning in BALB/cJ mice that show less 'empathic-like' licking behaviour in response to the distress of another animal is normalised by a novel candidate drug treatment. Data collection (psychology, hormone and eye tracking) in the CU2 study in WP3 comparing empathy in healthy controls and clinical cohorts with CD+/-CU and autism is now complete and being utilised for causal modelling in WP10. In the WP3 NeuroIMAGE cohort, differences in white matter integrity between children with ADHD and ADHD plus ODD/CD have been observed. Comorbid ODD/CD was associated with lower FA in left fronto-temporal and striatal white matter (WM), which appeared independent of ADHD symptoms, and was dimensionally associated with antisocial behaviour in ADHD+ODD/CD, but not in ADHD-only (van Ewijk et al., 2016). We also compared ADHD to ADHD plus ODD/CD on neurocognitive functioning (Noordermeer et al 2015). ADHD+ODD was associated with more and more severe abnormalities in tests of cool executive functioning (EF), hot EF and temporal processing. Further, WP3 has shown changes in the amygdala and whole-brain BOLD responses to dynamic angry facial expressions in adolescents in the IMAGEN sample and explored the extent to which gender moderates conduct problems and CU traits. Adolescents with conduct problems showed hyperactivity of the amygdala and a number of regions across the brain, including the thalamus and hippocampus, when they experienced a greater number of stressful life events. There were no differences in magnitude of the BOLD response as a result of CU traits, but the correlation between the regions under the influence of this effect differed according to whether adolescents showed high or low CU traits (Cattrell et al., Am J Psychiatry, 2017, in press). On a fMRI reward task, participants with ADHD+ODD/CD showed more brain activation in the left dorsolateral prefrontal cortex during anticipation of rewards (Veroude et al., 2017). Data collection in the MATRICS CD cohort for WP3/4 is nearing completion (currently n=201). Using the 1H-MRS PRESS acquisition sequence in the insula, anterior cingulate cortex, striatum and amygdala-hippocampus complex, data collection in the MATRICS CD cohort has been performed and is under analysis. WP5 has produced draft genetic landscapes of CD (based on CD GWAS data) and the BALB/cJ mouse (based on transcriptomic data). Reduced-representation bisulfite sequencing (RRBS) and whole genome sequencing is now underway in relevant brain regions from the animal models in WP1 with the human samples from WP3/4 to follow. Epigenetics is planned in the material being collected within WP1/3/4. WP6 has reviewed current pharmacotherapy and notes effect sizes for methylphenidate and risperidone ranging from 0.61 to 1.26 with anti-aggressive effects of psychostimulants confirmed. The clinical report form (CRF), CANTAB licenses and autonomic monitors are now in place for the clinical pharmacology WP (6) and data collection is about to start. Using data from the Mannheim Risk Study, WP7 has established that skin conductance during faces versus shapes and reward processing were inversely related to reactive aggression and aggression during later life, respectively. Interestingly, individuals with CD and high impulsivity exhibit a decreased fMRI BOLD response in the ventral striatum and the OFC during reward anticipation and blunted amygdala activity during emotion processing. Aggression during later life proved to be related to increased caudate activity during reward delivery. Targeting of arousal associated brain regions in neurofeedback is now underway at two sites with a third to follow. WP8 has assessed the stability of epigenetic signatures induced by cytokine stimulation following reprogramming of somatic cells to IPSCs while also modelled the impact of maternal stress (a CD risk factor) on embryonic neural development. WP8 has examined the acute impact of stress mediators on gene expression in human neural IPSC neurons, and the impact of stress on the cellular memory as retained in differentiated neurons. A number of mRNAs are differentially expressed. Some that are acutely activated following stress, others that remain activated in mature neurons derived from stressed progenitor cells. This will be further examined in upcoming human neural IPSC lines from those with CD+CU traits. WP9 has assessed the impact of maternal smoking, alcohol use and cannabis use during pregnancy on the risk for potential CD and compute a summary odds ratio point estimate over all studies to be 2.27, 3.05 and 1.57 respectively. This data is now being confirmed in an independent population cohort (ALSPAC data set) and GWAS analyses have been performed for aggressive and antisocial traits in the ALPSPAC cohort. WP10 has established a likely driving mechanism from gender to attention deficit (AD) to aggression in two independent data sets and produced a novel approach (the ‘Joint Causal Inference’ framework), specifically aimed at merging data sets from different sources and under different (experimental) conditions. Furthermore, this approach has been deployed psychometrically to fractionate different questionnaires relevant to the study of MATRICS. One important moderator intelligence (IQ) has been studied in depth in collaboration with colleagues within the FEM-NAT CD consortium, to assess the relationship between psychopathic traits and aggression. WP11, 12 and 13 have harmonized ethical approval across all sites, produced a project website, newsletter and Twitter account, established and consulted a scientific and ethical advisory board (with independent experts) and secured a special issue in Neuroscience and Biobehavioral Reviews (IF=10.5) on Conduct Disorder, dedicated symposia at EFCAP 2016 and ECNP 2017. Furthermore, WP12 has worked together to produce a special issue on aggression in ECAP as a cross-consortia initiative. Project management has been excellent with good communication between partners, administrators and the establishment of an early career scientist group which increases the impact of MATRICS for early career researchers including soft skill training.
Potential Impact:
Conduct Disorder (CD) in juveniles is characterized by severe aggression and a repetitive and persistent pattern of behaviour through which the basic rights of others and major age-appropriate societal norms or rules are violated. CD has a prevalence of 3% in school-age children and adolescents (Lahey et al. 1999. CD has a lifetime persistent course in half of the cases, with increased risk of transition to ASPD and criminality (Wicks-Nelson 2003). In particular CD cases with callous unemotional traits cause the greatest amount of criminal damage due to its severity and high degree of re-offending. The proper treatment and prevention of societal and criminal risk requires an improvement in the understanding of the biological substrates of aggression and CD+/-CU traits profile. CD+/-CU trait positive juveniles are responsible for a disproportionate amount of serious violent offences within those held under juvenile detention systems. MATRICS will integrate the neurobiology of brain and the body (particularly the autonomic nervous system) and psychometric cognitive batteries with clinical assessment measures, epigenetic and MRI readouts. In particular, we will focus on altered top-down prefrontal cortical control over the amygdala, insula and autonomic nervous system (altered structure and functional connectivity within and between these neural substrates; Rolls & Grabenhorst 2008). This will be employed in juvenile CD+/-CU traits to improve pharmacological treatment and neurofeedback based preventative strategies. MATRICS is expected to perform the following:
1) Datamine existing clinical integrated MRI-genetic-phenotypes databases for examining the neural, biomarker, genetic and environmental factors underlying CD/aggression.
2) Measure neural systems activity and physiological arousal and stress markers at rest and under a stressful challenge in children and adolescents with CD. These data will be integrated with matching epigenetic, genetic (whole genome sequencing), expression profiling from neural progenitor cells (directed to become cortical and hypothalamic neurons) derived from IPSCs, blood microRNA and clinical phenotypic markers.
3) Examine whether and how the neural, genetic, epigenetic, cognitive and environmental factors underlying CD/aggression are gender-specific.
4) Subtype newly collected CD populations in order to reduce clinical and biological heterogeneity and enable stratification for future personalised medicine approaches.
5) Utilize bioinformatic tools and Bayesian machine learning to a) identify new potentially ‘druggable’ targets from multi-level data and b) create novel integrated biomarkers for directing future diagnostic, therapeutic and prognostic approaches.
6) Develop novel animal models and instrumental aggression tasks and assess matching behavioural, epi(genetic) and neural MRI/MRS markers for pharmaceutical screening and proof­of­concept studies.
7) Assess main environmental effects and (epi)gene-enviroment interactions in aggression using existing large scale multi-site CD and (juvenille) population cohorts, and assess their effects on neural measures.
8) Conduct pilot studies with promising medication and preventative (neuro/biofeedback) techniques in low aroused young children at high-risk for CD, and in adolescent CD patients.
9) Produce end­user tools incorporating the data and systems analysis for use by health professionals to optimize subclinical and clinical diagnosis and preventative / treatment intervention selection in patients with CD.
10) Disseminate and valorize the outcomes of MATRICS to ensure the highest degree of clinical impact in the prevention, treatment and management of CD.
11) Make publicly available the databases on biomarker, neural, genetic, epigenetic and environmental factors involved in aggression phenotypes in animal and human studies that will be collected by MATRICS.

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