To clarify the neural underpinnings of aggressive behaviour and to reveal potential targets for therapy, WP02 assesses the development of structural, metabolic and functional brain connectivity in the fronto-striatal and fronto-limbic circuits by means of multi-parametric MRI in a rodent model selected from WP01. For optimal translation to human neuroimaging studies in WP03 and WP04, similar MRI protocols are applied. Importantly, our comprehensive multi-parametric experimental MRI approach will enable standardized and well-controlled assessment of neural underpinnings of aggressive behaviour. This will provide relevant translational information for the human/clinical studies. Furthermore, our rich datasets can be ideally used for optimization of tools for marker determination.
This preclinical WP phenotypes rodent models of traits underlying reactive and instrumental aggression and characterizes their autonomic nervous system activity and reactivity. The focus lies on “environmental” models which dysregulate the HPA axis and then mining these for (epi)genetic changes. In addition, in a selection of the most promising model/tasks, ‘real-time’ brain oxygen and glutamate levels are monitored to map onto WP3 data sets on reactive and instrumental task related aggression changes in fMRI BOLD and 1H MRS Glx/GABA. Finally, blood samples from the same animal model selection are taken for genetic/epigenetic/microRNA profiling within WP05 and cross-compared with human conduct disorder data sets.
To clarify the neural underpinnings of aggressive behaviour and to reveal potential targets for therapy, WP02 assesses the development of structural, metabolic and functional brain connectivity in the fronto-striatal and fronto-limbic circuits by means of multi-parametric MRI in a rodent model selected from WP01. For optimal translation to human neuroimaging studies in WP03 and WP04, similar MRI protocols are applied. Importantly, our comprehensive multi-parametric experimental MRI approach will enable standardized and well-controlled assessment of neural underpinnings of aggressive behaviour. This will provide relevant translational information for the human/clinical studies. Furthermore, our rich datasets can be ideally used for optimization of tools for marker determination.
To date, human neuroimaging studies on the neural correlates of Conduct Disorder in the presence and absence of CU traits, and on reactive vs. impulsive aggression are absent or few, and based on small samples. WP03 aims to address these issues in large and well characterized samples.
WP04 focuses on investigating the role of glutamate and GABA levels in brain regions that are associated with control, empathy and value estimation using 1H MRS. The regions to be studied have been shown to increase aggression when dysregulated.
WP05 concentrates on the identification of genomic, epigenomic, transcriptomic and microRNA variation associated with aggressive behaviour using integrated –omics approaches across multiple sample cohorts.
WP06 works on developing a neuropsychopharmacological/autonomic response profile for four pharmacological treatments known to be effective in reducing aggression. While these compounds nor the neurotransmitter systems are not by themselves novel, this is to generate a reference data set (not present in the literature) against which to benchmark more novel mechanisms. This can then be used in the early identification of potential novel pharmacological treatments in general and more particularly those that differentially predict improvement between reactive and instrumental aggression.
Autonomic dysregulation is a reliable marker of aggression varying with the aggression subtype; the brain systems related to autonomic arousal regulation and aggression are uncovered by WP03. Early proposals to use biofeedback of arousal to normalize physiological deviance as in neurofeedback treatment of ADHD have not been followed by controlled biofeedback trials for pediatric aggression. WP07 thus provides two innovative approaches to the prevention/intervention of aggression: arousal modulation in young children at high risk for CD and with CD (low arousal and high CU traits), and real-time fMRI neurofeedback in adolescents with CD.
Overall, WP08 progresses from the generation of iPSCs from patients through to in vitro assays to identify phenotypes associated with reactive and impulsive aggression in CD +/- CU traits. However, the WP has an interactive component. It generates iPSCs from more focused CD patient cohorts and devises hypothesis-led phenotypic assays to address the mechanisms identified as being associated with CD, CU traits, and reactive and instrumental aggression.
While genetic factors undoubtedly play a role in the aetiology of CD, environmental risks are important as well. It is unclear what the relative contribution is of main environmental and gene -environment interaction effects, and what the neural and molecular pathways are that underlie main environmental and environment-interaction effects. WP09 addresses this in a series of focused objectives using large scale population and CD cohorts.
Many different sources of information related to the prediction of aggression and antisocial behavioural subtypes will be gathered throughout the project. The key challenge from a machine learning perspective is to integrate all this information. WP10 works on improving the state-of-the-art in machine learning techniques for relevance determination and biomarker discovery. This WP furthermore applies biomarker discovery methods to the data gathered in WPs 1 through 9 to establish predictive neural, genetic and molecular markers for conduct disorder, and develops as well as implements novel methods for causal discovery that can combine data from different sources and background knowledge. The developed methods are then to be implemented in a user-friendly software.
WP11 focuses on increasing the visibility of MATRICS by reaching out to the scientific community, industry, patient organisations and other interested or potential stakeholders. Moreover, the initiation of the next steps for full scale clinical trials of the most promising candidate drug identified in WP06 to treat childhood aggression and antisocial behaviour in CD populations is a key strategic objective of this WP and the whole consortium towards improving the treatment of aggression in these populations beyond the state of the art.
WP12 ensures that the highest standards for the scientific and medical ethical aspects of the proposed studies are set and met. To achieve this, regular (cross-site) training of the researchers in key areas of the project is conducted
As effective project management is a central element of successful research, WP13 makes sure that objectives are achieved and delivered on time. Moreover, it looks after the project’s finances and establishes a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run time of the project.