Multimodal mapping of the brain's functional connectivity and the adult outcome of attention deficit hyperactivity disorder

Abstract

We have a limited understanding of why many children with attention deficit hyperactivity disorder do not outgrow the disorder by adulthood. Around 20-30% retain the full syndrome as young adults, and about 50% show partial, rather than complete, remission. Here, to delineate the neurobiology of this variable outcome, we ask if the persistence of childhood symptoms into adulthood impacts on the brain's functional connectivity. We studied 205 participants followed clinically since childhood. In early adulthood, participants underwent magnetoencephalography (MEG) to measure neuronal activity directly and functional MRI (fMRI) to measure hemodynamic activity during a task-free period (the "resting state"). We found that symptoms of inattention persisting into adulthood were associated with disrupted patterns of typical functional connectivity in both MEG and fMRI. Specifically, those with persistent inattention lost the typical balance of connections within the default mode network (DMN; prominent during introspective thought) and connections between this network and those supporting attention and cognitive control. By contrast, adults whose childhood inattentive symptoms had resolved did not differ significantly from their never-affected peers, both hemodynamically and electrophysiologically. The anomalies in functional connectivity tied to clinically significant inattention centered on midline regions of the DMN in both MEG and fMRI, boosting confidence in a possible pathophysiological role. The findings suggest that the clinical course of this common childhood onset disorder impacts the functional connectivity of the adult brain.

Keywords: attention deficit hyperactivity disorder; brain systems; default mode network; neuroimaging; outcome.

Fig. S1.

Methods overview. (A) The definition of each participant's connectivity matrix. (B) The extraction of group level connectivity patterns—the stable components. (C) Calculation of the degree of each individual's expression of each stable component. DAN, dorsal attention network; VAN, ventral attention network.

Fig. S2.

Similar internetwork patterns of connectivity in fMRI and MEG. (Left) Stable components extracted from fMRI resting state data. (Right) MEG stable components that showed a similar pattern of internetwork connectivity. Thicker lines represent more typical values in the distribution of all network connections in the component, and thinner lines are outliers. Six networks (nodes) are illustrated; MEG coverage of the affective network was spare and so is not shown. CC, cognitive control; DAN, dorsal attention network; VAN, ventral attention network.

Fig. 1.

Group differences in the expression of stable components associated with inattention, detected by MEG (Top) and fMRI (Bottom). The box plots show the expression of each component in the persistent ADHD, remitted, and never-affected groups. Throughout, the persistent ADHD group showed atypically high levels of expression of these components. The adjacent connectivity matrices (“heat maps”) show the strength of intra- and internetwork connectivity for each group. Hotter colors indicate stronger connectivity. The persistent ADHD group differs significantly from the never-affected and remitted ADHD groups. The latter two groups did not differ from one another. DAN, dorsal attention network; VAN, ventral attention network.

Fig. 2.

Patterns of network connectivity in components related to inattention (A) against those that are not (B). The thickness of the arrows corresponds to the strength of the connection. Inattention-related components showed more internetwork connectivity than unrelated components, particularly between the default mode and ventral attention network (VAN) and cognitive control network. DAN, dorsal attention network. (C) Scatterplot shows that the four inattention-related MEG components had a significantly lower ratio of intranetwork/internetwork default mode connections than those not associated with inattention.

Fig. 3.

Similarities in the spatial structure of the MEG and fMRI inattention-related components. Cortical regions are ranked according to their connectivity with all other regions (high “hot” color indicates greater deviation away from the mean connectivity). Atypically connected regions that overlapped in fMRI and MEG localized to midline structures (left precuneus and bilateral posterior cingulate gyrus) that are core components of the DMN.