An integrative approach to unravelling the aetiology of ASD and ADHD in early adulthood: neurophysiology and development in twins

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) are common childhood-onset neurodevelopmental disorders, which can co-occur. A diagnosis of ADHD and/or ASD typically gives rise to serious lifelong disabilities that cause considerable distress to individuals and their families. The transition from childhood to adulthood can be a particularly challenging time for young people with these disorders. These adults are more likely to experience a range of other behavioural and cognitive problems, yet these disorders go underdiagnosed in adults. This might reflect the presence of sub-threshold symptoms that do not meet the threshold for diagnosis but nevertheless are associated with cognitive impairment and/or mental health problems.

The applicant's previous work in children who underwent comprehensive behavioural assessment has suggested that electroencephalographic (EEG) measures of executive and social function provide sensitive and objective markers that discriminate between ADHD and ASD and additionally help us understand the overlap between the disorders. However, it is currently unclear whether the cognitive impairments, symptoms of ADHD/ASD and associated emotional and adaptive functioning issues stem in part from a common cause, or rather co-occurring problems resulting from multiple causes. It is therefore of vital importance to conduct these investigations within a genetically sensitive design.

To address this, we will collect data from two well-characterised twin sub-cohorts selected based on exhibiting high levels of ADHD and/or ASD symptoms in childhood. We will assess 300 twin pairs in person at ages 22-23 (200 twin pairs with at least one high-ADHD or high-ASD proband and 100 control pairs).

Our proposed research has three objectives:
(1) To investigate genetic and environmental origins of cognitive-neurophysiological biomarkers of ADHD and ASD and their overlap in young adulthood. Twin pairs will be assessed on executive function and social cognition tasks sensitive to ADHD and ASD symptoms. We will use innovative non-invasive mobile EEG technology to enable data collection in more familiar and natural settings, such as the home or workplace.
(2) To characterise the persistence of symptoms and cognitive impairment into adulthood following a childhood diagnosis of ASD or ADHD. We will use longitudinal multivariate twin analyses to test hypotheses about development of symptoms in emerging adulthood, and further phenotypic analyses to investigate cognitive impairment even in those with sub-threshold symptoms.
(3) To identify the overlap between adaptive functioning, mental health and neurophysiological function in young adults with ADHD and/or ASD. We will use the twin design to investigate the genetic and environmental origins of the overlap between symptoms, specific neurophysiological functions and mental health problems (anxiety and depression) and adaptive functioning.

This will be the first study to address the aetiology of ADHD and ASD and their overlap in young adulthood using quantitative genetic and neurophysiological approaches. These data will provide information on the cognitive profiles, symptoms, mental health and adaptive functioning of people with ADHD and ASD during a critical developmental period for achieving life satisfaction and wellbeing. By using sensitive EEG measures that can be collected across abilities and environments, this project will provide the foundation for identifying objective neurobiological indices of these disorders and their outcomes in young adult life. We anticipate that this work will pave the way for identifying optimal treatment targets for these disorders and the design of more specific interventions to prevent emotional and mental health problems from developing. The innovative use of mobile EEG has the potential to transform neurophysiological research and routine clinical evaluation for psychiatric disorders.

Aim: To investigate the aetiology and neurophysiology of ADHD and ASD and associated outcomes in young adulthood.

Objectives:

(1) To investigate genetic and environmental origins of cognitive-neurophysiological biomarkers of ADHD and ASD in emerging adulthood.

(2) Document the aetiological influences and cognitive impairments associated with persistence of ADHD and ASD following high levels of symptoms in middle childhood.

(3) To characterize the aetiological relationship between general functioning and mental health and neurophysiological function in young adults with ADHD and/or ASD.



Methodology:

The research will capitalise on two existing well-characterised sub-cohorts from the MRC-funded Twins Early Development Study (TEDS) that were enriched for ADHD and ASD symptoms in middle childhood (12-15 years). We will assess 300 twin pairs at ages 22-23 on a triad of measurements: (a) cognitive-neurophysiological assessments using EEG during tasks that the applicant and others have previous validated as sensitive to ADHD and ASD in childhood and adulthood; (b) in-person assessment using gold-standard diagnostic tools to obtain rates of ASD, ADHD and co-occurring ASD+ADHD in early adulthood; and (c) in-person interviews focused on mental health problems (anxiety and depression) and adaptive functioning.

We will estimate genetic and environmental sources of variance and co-variance between neurophysiological impairment, ADHD and ASD symptoms and mental health/functional outcomes using the quantitative genetic MZ-DZ twin design. Additional longitudinal analyses will investigate influences on stability of ADHD/ASD diagnosis/symptoms and cognitive impairment outcomes.

Scientific and clinical opportunities:

This project could substantially advance understanding of ADHD and ASD in young adulthood, including risk for poor outcomes, ultimately to provide optimal targets for effective intervention and treatment.

The impairments associated with ADHD and ASD constitute major problems that give rise to serious morbidity and distress to families. They result in many children and adults requiring special education and residential care at high costs to society. Identification of biomarkers of symptoms and outcomes that are rooted in neuroscience will have important implications for prevention, management and prognostics.

Who will benefit? Cognitive and mental health problems in young adulthood in those with a childhood diagnosis of ASD and ADHD have far-reaching and long-lasting impacts on the affected individuals, their families, and communities and health services. The proposed research has a broad range of potential beneficiaries from service users, parents, clinicians, developers of technology and the wider public, in addition to academics.

How will they benefit from this research? Five examples follow, with details including deliverables and metrics of success provided in Pathways to Impact.

Impact 1: Identification of profiles of cognitive risks and protective factors to develop personalised treatments and preventive interventions. Identification of more biologically meaningful subgroups in adults with ASD and ADHD and their overlap may aid in determining the degree of precision with which neurophysiology can be assessed for optimal diagnosis, and eventually determine who will benefit from intervention.

Impact 2: Provide information on why some adults persist with ADHD and/or ASD while others do not, and further to describe the developmental trajectory of ASD and ADHD from childhood to adulthood. Some individuals, for example, may be subthreshold in terms of symptoms but may have cognitive impairment. Improved understanding of the ASD and ADHD outcomes could raise awareness of the ongoing challenges for young people who had these disorders in childhood.

Impact 3: Identification of mental health and psychosocial outcomes of young adults who had childhood ASD or ADHD. Better understanding of the neurophysiology and aetiology of mental health and adaptive functioning in young adults with these disorders may identify targets for treatment. Young adults with social processing impairments, for example, may have further problems with social anxiety.

Impact 4: Creating a resource for spin-off and future studies. We will foster new collaborations to leverage the impact of the proposed research. Our findings could, for example, contribute to a future study on the progression of these disorders into middle age when new life challenges emerge.

Impact 5: Creating an opportunity for training. The PI will be in a position to train the named postdoctoral trainees, and the research assistants and placement students in advanced EEG analysis techniques, including through her extensive teaching at the IoPPN and elsewhere (see Pathways to Impact).

Findings will be communicated to:
(1) Researchers: To confirm the scientific rigour of findings through replication and development of research into potential treatments resulting from these data.
(2) Industry: To the manufacturers of the mobile EEG headset that we plan to use in the proposed study, Cognionics, to give feedback on the comfort and ease-of-use of the equipment.
(3) Clinicians: To increase clinician's knowledge base and explore the clinical significance and practical application of findings.
(4) Public and patients: To increase awareness and confidence in the approaches and to consider their ethical implications.