The underlying pathways to ADHD and its long-term outcomes

: a study of genetic risk factors and cognitive-brain markers

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable condition which has been associated with a wide-range of impairments in cognitive-neurophysiological functions and atypical brain features. This thesis uses a combination of cognitive-neurophysiological and longitudinal designs to investigate the associations of ADHD with autism spectrum disorder (ASD) and anxiety symptoms, as well as the genetic risk factors and brain markers of its persistence in the long term. 
The first set of studies in this thesis focuses on neurocognitive markers in ADHD and other psychiatric symptoms that frequently co-occur with the disorder, including autism and anxiety traits. In an investigation of ADHD and autism traits in a large population sample of children, detailed indices of reaction time variability, capturing attentional fluctuations, as well as reward-induced impairments in such measures, show specificity to ADHD traits. Building on previous studies suggesting that response inhibition and potentially certain other cognitive impairments may be attenuated in the presence of co-occurring anxiety in individuals with ADHD, a second study, using a wide range of cognitive and neurophysiological measures, suggests an overall poor malleability of these impairments in individuals with ADHD irrespective of their levels of anxiety. 
The second part of this thesis focuses on the genetic risk factors and the neurobiology of ADHD persistence and remission using data from a 6-year follow-up of individuals with childhood ADHD. First, novel insight into the underlying biology of ADHD outcomes emerges from analyses on volumetric brain measures in a subsample of individuals with ADHD who took part in an MRI scanning session at follow-up. These analyses suggest that ADHD persistence and ADHD remission show similar atypical brain structure (i.e., volume reductions), relative to comparison groups. The last study investigates whether polygenic risk for ADHD, which represents the summed effect of genetic variants associated with ADHD in the latest genome-wide study, is associated with ADHD persistence/remission. Analyses did not detect ADHD polygenic risk effects on the clinical outcomes of ADHD, but showed that high polygenic risk for ADHD characterises all individuals with a history of childhood ADHD, regardless of the current diagnostic status. 
Overall, the research summarised in this thesis informs on cognitive-neurophysiological processes that may underlie the association between ADHD and other psychiatric disorders, and sheds light on the biological determinants of the clinical outcomes of ADHD.

Date of Award	1 Feb 2019
Original language	English
Awarding Institution	King's College London
Supervisor	Jonna Kuntsi (Supervisor)