Meta-analyses have their challenges. Statistical approaches can attenuate but do not completely remove the heterogeneity arising from differences in data acquisition between study centers. However, the field is advancing with a greater focus on harmonizing protocols and hardware across centers, developing methods to compensate for artifacts (such as those arising from in-scanner motion), and ensuring quality control procedures are uniform and objective.
Large samples, only attainable through collaboration, are critical for unraveling the etiology of ADHD, which is highly heritable (around 70% of the phenotype is under genetic control).6 A recent landmark was attained with the discovery of common genetic variants that conferred risk for the diagnosis at a genome wide level of significance.7 Each genetic variant confers tiny amounts of risk and thus large cohorts are needed to define which facets of the brain and cognition lie in the causal chain between genetic risk and ADHD symptoms.
The brain might itself provide phenotypes for future gene discovery, specifically neural features that are both heritable (and thus under genetic control) and strongly associated with ADHD.8 This goal can be attained by studying multigenerational, extended families with many members affected by ADHD. Using this approach, connectivity patterns within the cognitive network and its white matter tracts (specifically, the superior longitudinal fasciculus) emerge as both highly heritable and associated with symptoms.
ADHD imaging throughout the lifespan
There is increased recognition that ADHD is not just a disorder of childhood: approximately 20% will continue to have the full syndrome into adulthood, approximately 50% continue to have impairing symptoms, and the remainder have symptom remission.9 Understanding the neural mechanisms that underpin this variability in the adult outcomes of childhood ADHD can inform novel treatment approaches and might provide biomarkers to help predict outcome.
Why do symptoms remit in some children by adulthood, whereas in others, symptoms persist? One possibility is that symptom remission in adulthood is due to the correction of childhood neural anomalies, whereas clinical persistence is tied to the persistence of neural anomalies. Alternatively, remission might arise from neural reorganization as novel systems are recruited to help the individual compensate for core deficits of ADHD. These two models make different predictions about the “remitted” brain.
In the first model, neural features in those with symptom remission will resemble those seen among individuals never affected by ADHD. If, however, neural reorganization and compensation drives remission, then the “remitted” brain will differ from the never affected, albeit in potentially beneficial ways. Finally, it is also possible that some anomalies that reflect the childhood presence of ADHD could persist, regardless of clinical recovery. By this reckoning, both those who have symptom remission and those with symptom persistence will show very similar atypical neural features, despite different clinical presentation.
This question has been tackled by several cohort studies that have assessed children clinically as they grew into adulthood (Figure 2). Most neuroimaging was obtained only at the adult endpoint as many techniques were not widely used when the participants were children. These studies found that adults with persisting ADHD symptoms showed neural anomalies, often resembling those reported in other childhood studies.
Dr Shaw is an Earl Stadtman Investigator, Neurobehavioral Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, NIH; Adjunct Faculty National Institute of Mental Health, Bethesda, MD. Dr Shaw reports no conflicts of interest concerning the subject matter of this article.
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