Risk and Resilience in Developmental Diversity and Mental Health

Project Information

R2D2-MH

Grant agreement ID: 101057385

DOI

10.3030/101057385

EC signature date 23 May 2022

Start date 1 September 2022

End date 31 August 2027

Funded under

• Health

Total cost

€ 8 456 507,50

EU contribution

€ 8 456 503,75

Coordinated by

INSTITUT PASTEUR
France

Periodic Reporting for period 2 - R2D2-MH (Risk and Resilience in Developmental Diversity and Mental Health)

Reporting period: 2024-03-01 to 2025-08-31

Summary of the context and overall objectives of the project

Mental health (MH) conditions impact 38.2% of the EU population, costing EU economies €600 billion annually. A significant portion, €180 billion, is allocated to neurodevelopmental disorders (NDDs) due to their high prevalence (10%-15% of the population), early onset and persistence, frequent co-occurrence with MH conditions (e.g. anxiety and mood disorders, substance use disorders), increased risks for suicide, and medical comorbidities like epilepsy. NDDs encompass conditions such as autism, attention deficit/hyperactivity disorder (ADHD), intellectual disabilities (ID), and language/motor impairments. Individuals with NDDs and their families face greater discrimination and stigma, impacting mental well-being, functioning and quality of life. We need better approaches to diagnostics and interventions for NDDs and a better understanding of the factors contributing to MH outcomes.

The R2D2-MH Project (https://www.r2d2-mh.eu/) is a 5-year initiative co-funded by the European Commission. Its primary aim is to identify risk and resilience factors associated with NDD and associated outcomes (Figure 1). The consortium comprises 28 partners with diverse expertise worldwide. R2D2-MH has four main objectives:
1. Promote participatory research/medicine and reduce stigma surrounding MH.
2. Establish the largest European multi-scale dataset on early brain and MH diversity in humans.
3. Co-develop a first-generation predictive model for developmental diversities.
4. Identify biological mechanisms of resilience associated with diverse outcomes in developmental diversities.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

R2D2-MH's research strategy integrates both risk factors, such as genetic variations and preterm birth, and resilience factors to better understand trajectories of individuals with NDDs and deliver tailored tools. The project comprises seven Work Packages (WP, Figure 2):

- In WP1, we explore the genetic/environmental influences on risk and resilience in neurodiversity. Leveraging data augmentation and standardization on existing large-scale datasets, we seek to pinpoint genetic/environmental factors that offer protection or resilience against MH challenges. Our investigation extends to understanding how various factors during developmental stages modulate MH outcomes among carriers of genetic variations associated with NDD and/or individuals born preterm.

-In WP2, we employ brain imaging to uncover neurobiological markers indicative of both risk/resilience in the developing brain. Simultaneously, we embark on establishing brain organoid models to elucidate mechanisms that could be targeted for treatment or intervention.

- Moving to WP3, we use participatory research with stakeholders to co-produce new measures of MH. Our approach aligns with the bio-psycho-social framework outlined in the WHO’s International Classification of Functioning Disability and Health (ICF).

- In WP4, we develop the CareConnect platform, innovative digital phenotyping tools, alongside a positive psychology app tailored for parents of children with NDDs. These device aim to enhance family well-being and parenting styles. Additionally, we analyze the influence of genetic variations on responses to interventions for NDDs.

- In WP5, we aim to develop predictive models for NDDs that encompass both risk and resilience factors, offering a comprehensive understanding of these conditions.

- In WP6, we strive to engage stakeholders effectively, disseminate findings, foster communication, and facilitate training initiatives to ensure widespread impact and knowledge exchange.

- Lastly, in WP7 we coordinate the R2D2-MH project.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

During the first three years, R2D2-MH focused on data acquisition, establishing a repository harmonizing data from over half a million participants.

A distinctive feature is its participatory approach through co-creation groups (CCGs) with adults and adolescents with neurodevelopmental disorders (NDDs). CCG members co-authored "Neurodiverse Research Collaboration Within a European Biomedical Project: Limits and Possibilities" (Struyf et al., The Palgrave Handbook, 2024). Black et al. published on data harmonization (BMJ Mental Health, 2024), resilience (Clinical Psychology Review, 2024), and risk/resilience using WHO ICF (Scientific Reports, 2025). Leblond et al. reviewed autism genetics and brain imaging (Annual Review of Genetics, 2024).

Key publications advanced NDD understanding. Hens et al. discussed developmental diversity (Front. Psychiatry, 2023). Rolland et al. studied autism genetic variations (Nature Medicine, 2023). Charman et al. found higher autism sibling recurrence in mid-childhood (Autism Research, 2024). Wechsler et al. identified mental health as healthcare priority (The Lancet, 2025). Borglum & Demontis explored ADHD and cannabis genetics (Nature Mental Health, 2024). Wolke et al. reviewed resilience in longitudinal studies (2025).

Preterm birth studies examined trajectories (Zhou et al., European Child & Adolescent Psychiatry, 2025) and modifiable factors (Twilhaar & Wolke, Journal of Child Psychology and Psychiatry, 2025).

Brain imaging examined cortical thickness (Berg et al., Molecular Autism, 2023), connectivity (Leyhausen et al., Biol Psychiatry, 2023), and brain development (Pretzch et al., JAMA Psychiatry, 2024). Gu et al. linked polygenic scores to neurite density (Molecular Psychiatry, 2025). Ecker et al. linked neuroimaging to transcriptomes (Nature Communications, 2025). Caporale et al. benchmarked organoid multiplexing (Nature Methods, 2024).

Early development research revealed language-motor relationships (Leyan et al., Autism Research, 2023), (Perry et al., Developmental Science, 2024). Parent-child trait similarity may protect functioning (Wechsler et al., Journal of Child Psychology and Psychiatry, 2025). Amit et al. developed prediction models (JAMA Netw Open, 2024). Goldshtein et al. explored breastfeeding effects (JAMA Netw Open, 2025).

Finally, ADAPPT supports parents using positive psychology and mindfulness (Tonis et al., 2024).

PERT-Chart-interdependencies of R2D2-MH work packages

Risk, Resilience, and Developmental Diversity in Mental Health