Elsevier

Biological Psychiatry

Volume 69, Issue 12, 15 June 2011, Pages 1168-1177
Biological Psychiatry

Review
Atypical Prefrontal Connectivity in Attention-Deficit/Hyperactivity Disorder: Pathway to Disease or Pathological End Point?

https://doi.org/10.1016/j.biopsych.2011.03.022Get rights and content

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.

Section snippets

Structural Connectivity Deficits in ADHD: DTI

Diffusion tensor imaging is a neuroimaging tool that has been used to quantify the microstructural integrity of white matter tracts. This technique exploits the fact that myelinated axons restrict water diffusion. Because water is repelled by the fatty myelin sheaths that coat axonal membranes, it tends to diffuse more readily in parallel to a white matter tract than perpendicular to it, in proportion to the degree of myelination and the orientation, regularity, and density of the axons in a

Functional Connectivity Deficits in ADHD: Resting-State fMRI and Task-Based Correlations

Hebbian theory asserts that “neurons that fire together, wire together,” meaning that when activity in one cell repeatedly elicits action potentials in a second cell, synaptic strength is potentiated (32). Functional connectivity analysis exploits this principle in reverse, estimating the strength of long-range connections by quantifying correlated activity in two areas of cortex. Functional connectivity analysis complements DTI studies, the latter estimating the structural integrity of white

The Default Mode Network in ADHD

For years, most fMRI studies assessed changes in brain activity that occur while performing some task of interest relative to a baseline condition, such as visual fixation. More recently, investigators have recognized that a distinct set of structures tend to be active at baseline—and relatively deactivated during task performance—reflecting a default mode of spontaneous activity in the brain at rest. This default mode network (DMN) comprises midline structures including the precuneus and

Functional Correlates of Frontostriatal Connectivity Deficits in ADHD

Another important question raised by the aforementioned studies is whether functional connectivity deficits have any direct impact on symptoms. Establishing causation is a major challenge in imaging studies of human subjects. One way to tackle this problem is by asking whether medications that treat symptoms also ameliorate connectivity deficits. Rubia et al. (51) examined methylphenidate effects on PFC function and attention by combining functional connectivity analysis and task-based fMRI

Causes and Consequences of Connectivity Deficits in ADHD

Several lines of evidence support the hypothesis that connectivity deficits might contribute directly to inattention, impulsivity, and other ADHD symptoms. Attention-deficit/hyperactivity disorder has been conceptualized as a disease of impaired executive function and of deficient inhibitory control in particular (4), processes subserved by a frontostriatal network including lateral PFC, anterior cingulate cortex, and posterior parietal cortex, with inputs from the dorsal striatum and

Summary and Conclusions

This review highlights several important findings from DTI and functional connectivity studies of ADHD as well as the difficulties inherent in drawing firm conclusions from this rapidly evolving field of study. Replication and cross-study comparisons have been complicated by the multitude of analytic techniques and measurements employed in various studies. Despite this heterogeneity, some consistent results are emerging. Diffusion tensor imaging studies indicate that ADHD is significantly

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