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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MiND (Mastering skills in the training Network for attention deficit hyperactivity and autism spectrum Disorders)

Teaser

Summary

Psychiatric disorders are among the leading causes of morbidity in Europe. Despite high socio-economic impact and suffering of patients and relatives, we still know very little about the biological mechanisms underlying these disorders, and no curative treatments have been developed. Particularly serious are disorders that have an early onset and cause impairments during the entire lifespan, like attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD).
The goal of the European Training Network MiND was to train a new generation of interdisciplinary scientists (1) to perform research into the causes and mechanisms contributing to the highly heritable disorders ADHD and ASD and their comorbidity, and (2) to apply such research towards improving patientsâ€™ lives through better diagnostics and more effective, individualized (pharmacological and non-pharmacological) treatment options. The MiND strategic collaboration of world-leading academic groups, research-intensive commercial enterprises, and patient organisations aimed to deliver 15 young, scientifically excellent researchers, who are optimally prepared for private sector and academic careers.
The specific scientific and technological objectives of the MiND ETN included:
I) Improve the understanding of the overlap of the disorders and identify the neurobiological underpinnings.
II) Improve the understanding of the role and mechanisms of environmental risk factors contributing to the disorders.
III) Development of a complementary battery of novel cell, animal, and human models, and mapping of pathways from gene to disease and comorbidity.
IV) Development of novel approaches for prediction of prognosis and prevention.
V) Development of novel approaches towards treatment.

Work performed

For all scientific objectives, we have achieved important results, among which are the following:

I) We found the comorbidity of ADHD and ASD as well as related traits to be largely due to genetic factors and (non-shared) environmental factors. We found cognitive deficits in executive functioning to be more relevant to ADHD. We also found that emotion recognition problems are similarly frequent in ADHD as they are in ASD. Investigating mind-wandering, emotional lability, and sleep quality in adults with ADHD, we observed that all three contributed to ADHD severity.

II) Investigating effects of medication for ADHD on the risk for injuries in children and adolescents with comorbid neurodevelopmental disorders in Swedish population registries, we found a significant reduction in injuries during periods of medical treatment for ADHD. We also studied effects of environmental risk factors on cellular models of ADHD using neurons derived from induced stem cells of people carrying mutations of PARK2, a gene linked to ADHD and ASD: we observed an increased sensitivity of processes related to neuronal maturation when studying effects of early exposure to nicotine. We also found alterations in the gut microbiome to be linked to inattention in individuals with ADHD and healthy individuals. Studying epigenetic factors that might mediate the effects of environmental factors, our studies identified several genes of interest for further study.

III) We worked both on human genetics approaches to find novel genes for (comorbidity) of ADHD and ASD as well as on different models systems. We obtained evidence for the influence of parent of origin effects on ADHD risk and studied evolutionary aspects of ADHD and ASD. Studying deficiency of the ADHD risk gene ADGRL3 in a mouse model, we found increased impulsivity and locomotive activity and impairments of memory and learning. Neurotransmission through dopamine and neurohormones/peptides seemed to be involved. In Drosophila, we studied an ASD-related gene network, for which reduction of gene expression resulted in habituation learning defects. In zebrafish we studied two genes implicated in ADHD and ASD, ywhaz and reelin, determining their expression across the lifespan and identifying alterations of dopaminergic and serotonergic neurotransmission.

IV) In a study of reaction time variability, we found that attentional fluctuation in children with high ASD traits may be due to co-occurring ADHD traits. We found persistence of ADHD to be linked to genetic burden and to low grey matter volumes in frontal/cerebellar regions involved in top-down cognitive control. We also identified potential biomarkers for ADHD based on gene expression in blood cells. In genome-wide genetic studies, we found genetic burden for ADHD to also predict cocaine dependence.

V) We explored the druggable genome in ADHD by utilizing genome-wide association studies on ADHD and its co-morbid conditions. We identified several promising genetic loci for potential drug development. We studied several additional potential candidate drugs for ASD and ADHD in our zebrafish and Drosophila models. To study non-pharmacological treatments for ADHD, we performed a randomized controlled trial (RCT) of the meditation technique mindfulness, which shows promising first results.
In addition to the scientific progress, we have also completed the planned training events.

Final results

MiND has already had impact on different aspects of society, through scientific output and dissemination to patients and public.

Our scientific work is strongly contributing to the knowledge on the biology of ADHD and ASD (comorbidity). Our ESRs have already produced 23 papers, many additional are in advanced stages of preparation, and have presented their findings at many different conferences and meetings. Our ESRs are now finalizing their theses, and several have already found positions in academia and private sector, having obtained a set of skills that is highly likely to enable novel insights into the biology and treatment of ADHD and ASD.

Importantly, our work on the different new treatment approaches promises to produce valorisable results in the future. Our mindfulness RCT, could provide an important contribution better ADHD treatment. Also, we have gathered complementary evidence for an involvement of 14-3-3 proteins in the disorders, and identified promising (novel and existing) drugs altering the phenotypes associated with 14-3-3 activity alterations. Lastly, our microbiome research is a promising candidate for (non-pharmacological) treatment. Work on those subjects will continue beyond the finalization of MiND.

In MiND, we also have put strong emphasis on dissemination to patients and public. Each ESR engaged in communication activities with these target groups, e.g. through contributions to our blog â€˜Mind the Gapâ€™ (https://mind-the-gap.live/). Importantly, an open access mini-documentary was produced by our ESRs: https://www.youtube.com/watch?v=XmS7jUhB74A; released during ADHD Awareness Month 2018, it has already received over 20.000 views. The patient organisations involved in MiND contributed actively to our dissemination, e.g. with a patient information evening, at which poster presentations were given by MiND ESRs. Dissemination to patients and public was also stimulated through ESRs spending their intersectoral secondment at the patient organisations ASD-Europe or ADHD-Europe and through training given by the members of these organisations during several MiND courses.