WP1 evaluates the neural substrates of impulsive and instrumental aggression by identifying neural, neurocognitive and biomarker mechanisms underlying aggressive/antisocial behaviour in high-risk children and adolescents (subjects with ADHD). Furthermore, a new sample of children with Conduct Disorder (CD), as well as of adolescents with CD is collected. In addition, this WP measures cognitive, physiological and motor components of empathy in children and adolescents with CD and examines whether different empathy components are differentially affected across the various aggression subtypes. Finally, WP1 integrates the findings of the different tasks and examines the common (cross-disorder) and the disorder-specific correlates of the aggressive/antisocial behaviour.

WP2 applies state-of-the-art MRI acquisition and analysis methods that enable serial assessment of whole-brain structural and functional neuronal networks in order to identify neural correlates of impulsive aggressive behaviour and to determine underlying mechanisms of effective treatment strategies.

WP3 covers the identification of genetic variants, both common and rare, which impact the susceptibility to aggressive behaviour. This is done by testing the association of candidate genes with aggressive traits in large sample sets with pre-existing whole genome sequencing (WGS) data, by using hypothesis-free approaches in large sample sets with pre-existing WGS data to search for genes or pathways, not previously implicated in aggressive traits, and finally by validating suggestive association results in large sample collections with aggression-related phenotypes.

WP4 focuses on the examination of the neurobiological mechanisms of aggression as a result of genetic variation in known and novel candidate genes. While WP3 and WP5 serve to identify genes moderating risk towards aggressive behaviours, with emphasis on specific aggression subgroups, here we scrutinize the neurobiological sequelae of such genetic variants.

WP5 concentrates on the evaluation of effects of aggression risk genes and gene-networks on brain structure, brain activity and brain connectivity of the NeuroIMAGE and the newly collected CD sample from WP1, also taking environmental influences into account. As aggression is a cross-disorder trait and continuous with aggression in the general population, WP5 also validates the observed effects of genes and networks on brain phenotypes in healthy individuals’ brain structure and function from the Nijmegen Longitudinal Study and a prospectively followed sample of healthy adolescents. Finally, this WP identifies brain structural and functional characteristics that mediate the effects of genetic and environmental risk factors on impulsive, aggressive behaviour and/or social impairment in the different samples.

WP6 covers the investigation of G x E and epigenetic programming of aggression subtype-related genes in humans and genetically modified mouse models. WP6 provides (i) a strong translational axis for endophenotypic profiling of human aggression in behavioural, (epi)genetic and neural terms and (ii) a platform for the elucidation of brain mechanisms and thereby the development of new therapies for aggression.

WP7 applies state-of-the-art analysis techniques to combine different sources of information on aggression. It also establishes novel, accurate predictive algorithms for aggression subtyping using neurobiological, genetic, as well as environmental markers and validates them in paediatric and adult populations. Another objective of this WP is to generate business development possibilities by marketing the predictor for clinical use and uncovering novel causal therapeutic interventions. The pipeline will be validated in two longitudinal childhood samples and tested for adult outcome: A) the Nijmegen Longitudinal Study and B) The Estonian Children Personality Behaviour and Health Study (ECPBHS).

WP8’s goal is to tackle the limitations of current behavioural and pharmacological treatments of paediatric aggression, since there is a need for innovative personalised treatment targeting the core brain and autonomous functions, such as arousal dysregulation in paediatric aggression implicated in aggression. WP8 will therefore establish the most consistent markers of distinguishing between instrumental and impulsive aggression, develop an innovative biofeedback training protocol for patients to learn self regulation of their individual specific physiological deficits in various naturalistic situations, and it will finally evaluate the effects of such personalized, deficit -specific biofeedback training for both forms of aggression in a controlled multicenter trial.

WP9 investigates the use of methylphenidate as a treatment for aggression in young adult male prisoners (age group: 18-24 years) with ADHD and high levels of impulsive behavior since there has been no systematic evaluation of the effects of methylphenidate, the first line treatment of ADHD [1] , on aggressive or violent behaviour in offender samples. Hence, open label studies are conducted, followed by an optimization of medication to maximize potential long-term benefits. Moreover, additional secondary outcome measures of engagement with educational, occupational and offender reduction programmes are investigated and a follow-up study of participating prisoners on release conducted.

WP10 deals with the identification of novel aggression treatment drugs. The aim of this WP is to use the zebrafish, a vertebrate aggression model, to screen novel small molecules. Promising drugs are further validated in the mouse aggression models developed in WP2 and WP6. The data gathered in this screen is entered into a database and molecules are categorised according to their behavioural profile. This research provides the basic information needed to identify novel pharmacological interventions for aggressive disorders and represents one of the business development opportunities of Aggressotype.

WP11 describes our approach to the ethical issues that are relevant to the whole process of preparing and performing the studies. Moreover, one of the project’s general aims is to perform all of the studies at the highest scientific levels. To achieve this, regular training of the researchers in key-areas of the program (i.e. through dedicated master classes concentrating on interdisciplinary education) is conducted. As females are still strongly underrepresented in the higher ranks of scientific research, a coaching program for female early career researchers is established within the Aggressotype programme. Furthermore, this WP deals with the dissemination of the project results.

WP12 focuses on effective project management, as it is a central element of successful research. This WP makes sure that objectives are achieved and delivered on time, and also looks after the project’s finances. In addition, it establishes a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project.