Quantitative characterization of brain microstructure and iron homeostasis in attention-deficit/hyperactivity disorder from childhood through adolescence

My investigation of brain microstructure and iron homeostasis in attention-deficit/hyperactivity disorder (ADHD) is based on recently developed magnetic resonance imaging (MRI) methods: diffusional kurtosis imaging (DKI) and magnetic field correlation (MFC) imaging. As brain microstructure and iron have been implicated as promising neurobiological markers of ADHD, the application of these advanced methods allowed me to validate previous findings as well as extract additional complementary information for refined characterization of these properties in the ADHD brain. Examining the prefrontal cortex with DKI, I was able to detect a flat developmental trajectory of white (WM) and gray matter (GM) microstructure in ADHD from 12 to 18 years of age. While supporting the prevailing theory that ADHD is a disorder affecting fronto-striatal WM, these findings are the first to provide direct evidence of atypical development of GM microstructure. I was able to replicate these findings using an optimized whole-brain DKI protocol in a larger separate cohort (8 to 18 years). Stagnant GM and WM microstructural development was observed in ADHD not only in the prefrontal cortex but in all cerebral lobes. Furthermore, I demonstrate that this distinct developmental trajectory is specific for ADHD patients without comorbidity. These patients also had significantly greater WM microstructural complexity than typically developing controls in bilateral frontal and parietal lobes, insula, corpus callosum and right external and internal capsules. Including ADHD patients with diverse comorbidities into the analyses masked these findings thus highlighting the confounding effects of comorbidity which have been largely unaccounted for in the ADHD literature on cerebral microstructure. Utilizing MFC imaging along with proton transverse relaxation rate measures R2, R2* and R2', I was able to detect reduced brain iron in ADHD as indexed only by MFC metrics in bilateral globus pallidus, caudate nucleus and thalamus despite normal levels of serum ferritin. Within these regions, low MFC metrics correlated to a higher behavioral index of executive functioning within the ADHD group suggesting reduced brain iron levels may correlate with higher symptom severity. These results support the existence of atypical brain microstructure and brain iron in ADHD and highlight the importance of accounting for comorbidity.