Attention-Deficit/Hyperactivity Disorder (ADHD) is increasingly being conceptualized as neurodevelopmental in origin although the mechanisms behind such altered development are likely to be complex. To date, structural magnetic resonance imaging (sMRI) studies suggest that subtle generalized volumetric deficits in white matter (WM) are a clear and consistently replicated neuroanatomic correlate of ADHD. These WM volumetric deficits are most pronounced in never-medicated patients with ADHD (Castellanos et al., 2002), suggesting that stimulant medications normalize white matter in patients with ADHD. The PI seeks to apply diffusion tensor imaging (DTI), a potentially powerful tool for examining abnormalities in white matter microstructure, to a developmental disorder of great public health significance. Developmental disorders like ADHD are particularly ripe for investigation using DTI since changes in brain structural integrity in neuropsychiatric conditions which may be subtle on a macrostructural level may be more reliably detected on the microstructural level allowing for new insights into the regional patterns of white matter involvement in ADHD.
Specific Aims : The working hypothesis for the present study is that the higher-level cognitive and behavioral functions disordered in ADHD may be the result of distributed abnormalities in the maturation of neural regions that produce detectable anatomic pathology in white matter. This study will test 3 main hypotheses: (a) Relative to normal controls (NC), children with ADHD will have lower white matter fractional anisotropy (FA) in regions where abnormalities have been detected in previous sMRI studies (e.g., fronto-cortical, fronto-striatal and corpus callosum). (b) Measures of prefrontal cortical white matter fractional anisotropy will be correlated with performance on selected neurocognitive tests thought to be subserved by frontal systems. [(c) ADHD patients compared with normals will have smaller caudate volume. As an exploratory aim, we propose to correlate frontal lobe FA values with both absolute and relative caudate volume of ADHD patients. Based on the working hypothesis of frontostriatal malfunction in ADHD, we predict that inferior frontal FA values will be positively correlated with caudate volume in children with ADHD.] Research Design and Methods: This study will recruit 30 never-medicated, 7 to 11 year old children with ADHD and 30 NC children matched on gender, age, handedness, ethnicity and socioeconomic status. Each subject will undergo an MRI, as well as cognitive and behavioral testing. By using both a region-of-interest and voxel-wise analysis, we will be able for the first time to characterize compromised white matter integrity in ADHD, as inferred by diffusion tensor imaging. Significance: Questions about the role of white matter abnormalities in ADHD can only be answered in never-medicated patients. Confirmation of an abnormality in white matter rnicrostructure in children with ADHD would establish the importance of white matter development in the pathophysiology of ADHD and would provide the basis for future studies to prospectively examine the effects of stimulant medications on white: matter development.
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