Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point?

Functional neuroimaging studies have identified multiple nodes of dysfunction in frontostriatal and mesocorticolimbic networks in attention-deficit/hyperactivity disorder (ADHD). Yet relatively few studies have examined how structural and functional connectivity between nodes in these networks might relate to the behavioral symptoms of ADHD. Moreover, it is unknown whether abnormalities in connectivity are a primary cause of symptoms or arise secondary to common etiologic mechanisms. We review the most recent diffusion tensor imaging and functional magnetic resonance imaging studies of connectivity in ADHD to characterize associations between frontostriatal connectivity abnormalities and the behavioral symptoms of inattention and impulsivity in ADHD. Furthermore, we examine how structural and functional connectivity measures relate to environmental and genetic pathways to ADHD. Diffusion tensor imaging studies indicate that ADHD is associated with significant irregularities in white matter microstructure, especially in frontostriatal and select corticocortical tracts. Resting state functional magnetic resonance imaging studies implicate altered connectivity within a default mode network of structures active during introspective, task-free processes and disrupted interactions between this network and frontostriatal attentional systems. Deficits in functional connectivity within frontostriatal and mesocorticolimbic networks might give rise, in part, to ADHD symptoms. Conversely, structural connectivity deficits and ADHD symptoms might arise incidentally from a common etiologic mechanism, involving altered modulation of synaptic potentiation and pruning by dopamine and other factors during development. Collectively, these studies suggest that the core symptoms of ADHD might derive from dysregulated modulation of cortical plasticity in the developing brain, resulting in altered patterns of corticocortical connectivity that might persist into adulthood.