ebook_ADHD2019

34 Rohde, Buitelaar, Gerlach & Faraone The mechanisms underlying ADHD are complex and can be defined at different levels. Cognitive deficits are often but not always part of the disorder and inclu- de problems in executive functioning, reward processing, timing deficits, various aspects of attentional regulation and orientation, perceptual processes, arousal regulation and reaction time variability. The brain alterations seen in ADHD are very heterogeneous, found in all imaging modalities and both in brain structure and brain function and present a mixture of deviancy and delay. Alterations of the fronto-striatal, fronto-cerebellar and fronto-parietal circuits have been most often reported but this certainly is not the whole picture. The fronto-amygdalar circuits and the limbic brain, and the posterior areas of the brain seem to be involved as well. Individuals with ADHD show different patterns of alterations, and a focus on the “average individual with ADHD” and thus on case-control differences can be somewhat misleading and disguise substantial interindividual variation. 75, 109 Single neuroimaging findings have mostly very limited effect sizes. Sofar, despite clear evidence that individuals with ADHD have brains that at the group level are different from the “typical brain”, no single cognitive or bio- logical marker for ADHD has sufficient diagnostic or predictive value to be in- corporated in clinical work. There are several explanations for this disappointing situation. First, the clear limitations of our current categorical diagnostic systems as the DSM 110 and ICD 111 that force both clinicians and researchers into a binary decision: ADHD is present “yes or no”. In reality, ADHD can be conceptualized better as a high score (but with a still arbitrary cutoff point) on a complex conti- nuous trait with a normal distribution in the population. Second, the reliance on overly simplistic case-control designs in the study of biomarkers that underestima- te heterogeneity in both cases and controls. 75 Third, the lack of a stable, agreed upon and biologically valid concept of ADHD, and for matter of any psychiatric disorder, 112 which makes the current classification an even more unclear basis for informed biological research. The way forward is to define biologically more ho- mogeneous subtypes (“biotypes”) of ADHD, and such studies are under way but have still to deliver. 114 The Research Domain Criteria (RDoC) project has been initiated to develop and biologically validate new ways of classifying and unders- tanding mental health. 114 RDoC focuses on altered cross-disorder dimensions of functioning that span the full range of human behavior from typical to atypical and aims to integrate many levels of information from genetics/genomics and neural circuits to observable behavior and self-reports. Again, the promise of RDoC to improve understanding of ADHD in terms of varying degrees of dysfunctions in biological systems has still to be realized. Conflicts of interest Jan K. Buitelaar has been in the past 3 years a consultant to/member of advisory board of/and/or spe- aker for Janssen Cilag BV, Eli Lilly, Medice, Shire, Roche, and Servier. He is not an employee of any