Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - AGGRESSOTYPE (Aggression subtyping for improved insight and treatment innovation in psychiatric disorders)

Project Context and Objectives:
Aggressotype is aimed at understanding the mechanisms underlying impulsive and aggressive behaviour in individuals with childhood psychiatric disorders, Attention Deficit Hyperactivity Disorder (ADHD) and conduct disorder (CD) in particular. Based on this insight, we aim at improving treatment and prevention of aggressive behaviour; we work on the optimization of existing treatments and the development of novel pharmacological and non-pharmacological ones. Importantly, we argue that the mechanisms underlying aggressive behaviour can only be sufficiently understood if aggression subtypes are considered, that might have different aetiologies. Extrapolating from research in animals, a subtyping into impulsive (reactive) and instrumental (proactive, premeditated) is postulated.
To achieve its aims and objectives, Aggressotype employs a multi- and interdisciplinary design, connecting across different levels of investigation, and balances work in existing samples with new data collection for optimal use of resources. The project consists of 12 work packages (WPs), including 10 scientific ones, as well as 2 coordinating WPs, one for ethics, training, and dissemination and one for the general management of the project.
WPs 1-6 are preclinical WPs, in which the investigation of mechanisms underlying aggressive behaviour is central. WP1 and WP2 are geared towards identifying the neural circuits contributing to aggression and clarifying differences in neural plasticity and neurochemistry underlying impulsive and instrumental aggression. WP1 uses existing and newly collected data from human samples of individuals with ADHD and CD for this purpose, WP2 investigates these points in mouse models. In WPs 3-6, it is our objective to define the genetic factors and their interaction with environmental factors involved in aggression, and increase our understanding of the biological pathways through which these factors act. WP3 works on gene identification using large, existing samples, WP4 uses zebrafish and mouse as well as cellular models to define biological pathways. In WP5, we use neuroimaging genetics models to investigate, how genetic risk factors for aggression act on the human brain. WP6 performs epigenetic studies in both animals (mouse) and existing human cohorts to clarify the interplay between genetic and environmental contributors to aggressive behaviour.
WPs 7-10 are working towards improving treatment and prevention of aggression in ADHD and CD. In WP7, we work on the prediction of aggressive behaviour based on biomarkers using the biological insights gained in WPs 1-6. In WP8, it is our aim to develop a new, non-pharmacological treatment for aggressive behaviour based on neurofeedback training. WP9 is testing the effectiveness of existing medication for ADHD, methylphenidate, in treating aggressive behaviour in young adult prison inmates, which have been diagnosed with ADHD. WP10 is using the zebrafish model to test novel compounds for their effect on aggressive behaviour, as a first step to develop improved pharmacological treatments.
WP11 has the responsibility for the ethical conduct of all studies within the Aggressotype project, covering both studies in humans and in animals. This WP also coordinates the dissemination activities of the project, in which we aim to reach different target groups including clinicians, researchers, the general public, but also policy makers. For this, we work in close collaboration with the patient organisation ADHD-Europe. In addition, this WP is responsible for training; in this, we see ourselves as responsible for training a new generation of researchers, which have to be able to work in an interdisciplinary manner.
WP12 is responsible for effective management of the Aggressotype consortium and its activities as well as for the contact with the EC.

Project Results:
In WP1, we accomplished data collection for a multicenter study together with the MATRICS Consortium on children with conduct disorder (CD). First analysis of the data suggests separate neural substrates for proactive and reactive forms of aggression. In several cohorts, we found evidence that inattention (rather than hyperactivity/impulsivity) may be causal to aggression in adolescents with Attention Deficit Hyperactivity Disorder (ADHD).
In WP2 (in conjunction with WP6), we showed that aggressive mice deficient for the Tph2 gene present with altered neurotransmitter levels in frontostriatal brain circuits. In addition, we found that BALB/cJ (compared to BALB/cByJ) mice, showed increased aggression, anxiety and rule-breaking behaviour, and had a number of MRI volumetric and white matter changes in regions associated with learning / memory. The stimulant methylphenidate reduced aggressive behaviour in BALB/cJ mice.
In WP3, we performed a large genome-wide association study (GWAS) of ADHD in >18.000 cases, identifying 12 novel risk loci. We also finished a preliminary GWAS of CD in ADHD in >4500 cases and completed genotyping of 3000 additional cases with CD.
In WP4, we characterized the molecular biology linking candidate genes with aggression through analyses in models based on zebrafish, mice, as well as in induced human neurons for several aggression risk genes. For several of those, we found monoamine oxidase (the product of the archetypical aggression gene MAOA) to be altered in its expression in relevant parts/cells of the brain. Importantly, we generated a new mouse model for the RBFOX1 gene, identified in WP3.
In WP5, we could deduce that MAOA alteration causes alterations in a broad network of functional connections in the brain. This was in line with findings in dopaminergic neurons induced from pluripotent stem cells, where we also observed an uncoordinated pattern of functional connectivity among the neurons. For AVPR1A, we were able to define a specific brain region altered in its volume, which was the amygdala, and for NOS1, we found distinct white matter connections to be altered. In genome-wide genetic overlap studies for ADHD, we found genetic links of this aggression-relevant disorder with total brain volume; genes involved in neurite outgrowth played a role in this overlap.
In WP6, we noticed distinct influence of environmental adversity on the severity of aggression, and identified epigenetic patterns that may mediate the genetic and environmental influences. Some of the gene-environment interactions could be validated in human cohorts.
WP7, responsible for the development of predictive algorithms for aggression, has developed a novel method for data reduction of genome-wide genetic data. With a new consortium partner, the researchers are developing correlation engines for data integration.
In WP8, we have started inclusion into our earlier developed novel biofeedback protocol for training of self-regulation.
In WP9, we observed clear aggression-reducing effects of methylphenidate in prisoners diagnosed with ADHD in a first trial. Based on this, we started a second, placebo-controlled randomized controlled trial, which is currently recruiting.
In WP10, we repeated testing of the 25 most promising of the 108 potentially aggression-reducing compounds we had tested in larval zebrafish. A total of four compounds were taken forward, and several – including methylphenidate - were confirmed in mouse models.
WP11, responsible for ethics, training, and dissemination, has further developed a well-appreciated training program for our early career scientists, and has organized several activities to communicate our research to patients and the public. We are working together with the other 3 EU-funded consortia on aggression, through collaborative activities for young researchers, symposia, and special issues in scientific journals.
WP12 is successfully managing Aggressotype, keeping communication optimal through regular meetings and clear reporting schedules.

Potential Impact:
Maladaptive aggression is a commonly observed trait in psychiatric disorders, especially in the paediatric conduct disorders of interest to this project, Attention Deficit Hyperactivity Disorder (ADHD) and conduct disorder (CD). These disorders are the most frequent psychiatric disorders in childhood and adolescence, with over 5% and up to 10% of the population below age 18 years affected (Freitag et al., 2010; Green et al., 2005); more than 5.4 million children and adolescents in the European Union are affected (Ezpeleta et al., 2001). Costs of treatment and direct non-medical health care amount to over 6.2 billion Euro per year for this group. Importantly, the disorders are linked to lifelong serious impairment in social and occupational functioning, as ADHD symptoms persist into adulthood in 65% of cases. Both disorders are strong predictors of antisocial and substance use disorders, which underscores their huge impact on society. Costs associated with the adult outcome of ADHD and CD are at least 10 times higher than those for childhood disorders (Ezpeleta et al., 2001). The victims of aggression and the executive and judiciary legal systems are additional targets of societal impact of aggression. When systematically meta-analysing the frequency of psychiatric disorders in adolescent detainees, CD (46-53%) and ADHD (12-18%) were the most frequently observed diagnoses (Colins et al., 2010; Fazel et al., 2008). It can thus be assumed that persistence of CD and ADHD, under negative environmental conditions, opens up a detrimental developmental trajectory leading towards aggression, violence, and crime. Appropriate counteractive measures should ideally be prophylactic in nature, i.e. provided early after definite diagnoses of the disorders. Current behavioural and pharmacological treatment options for ADHD and CD are, however, insufficiently effective in treating aggression and have no proven curative potential.
Designing new, improved treatments requires a deeper understanding of the molecular, cellular and brain-circuit-based underpinnings of aggression than is currently available. Strategies to prevent (escalation of) aggression in those susceptible to it require better markers of susceptibility at the genetic, epigenetic and brain-level, which have not yet been forthcoming.

Aggressotype will yield the following concrete impacts on society and the economy, which - at the longer term - will reduce aggression impact on society and will reduce the economic burden caused by paediatric conduct disorders:
1. Improve aggression subtype characterization for the benefit of more effective research into underlying mechanisms and enable development of more individualized treatment strategies.
2. Develop flexible predictive algorithms based on combinations of molecular, environmental, neural, and/or cognitive/behavioural information allowing a stratification of risk groups for more effective, individualized treatment approaches and prediction of adult outcome.
3. Develop a novel non-pharmacological treatment programme based on neurofeedback, placed strategically at an early time point of disorder manifestation in order to lastingly prevent escalation of aggression.
4. Develop best-practice guidelines for aggression treatment in prison inmates.
5. Provide a model system for the efficient and cost-effective development of more effective pharmacological treatments for paediatric conduct disorder patients at high risk of aggressive behaviour.
6. Identify new leads for more effective pharmacological treatment of aggression as a first step towards more mechanism-based treatment.

Having the subtyping strategy and interdisciplinary approaches of Aggressotype in place, achieving these goals will be feasible.

List of Websites:
www.aggressotype.eu

Reported by

STICHTING KATHOLIEKE UNIVERSITEIT
Netherlands

Subjects

Life Sciences
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