Brain iron levels in attention-deficit/hyperactivity disorder normalize as a function of psychostimulant treatment duration

Abstract

Brain iron homeostasis is a dopamine-related mechanism that may be modified with long-term psychostimulant treatment in attention-deficit/hyperactivity disorder (ADHD). We previously reported that while medication-naïve youth with ADHD have reduced brain iron compared to controls and psychostimulant-medicated patients, no differences were detected between the latter groups. In this follow-up study, we examined whether the duration of psychostimulant treatment correlates with the degree of iron normalization. Brain iron was indexed with MRI using an advanced method called magnetic field correlation (MFC) imaging and the conventional R2* proton transverse relaxation rate method. MFC was acquired in 30 psychostimulant-medicated youth with comorbid-free ADHD and 29 age-matched controls (all males). R2* was acquired in a subset of these individuals. Region-of-interest analyses for MFC and R2* group differences and within-group correlations with age and years of psychostimulant treatment were conducted in the globus pallidus (GP), putamen (PUT), caudate nucleus (CN), thalamus (THL) and red nucleus. No significant MFC and R2* group differences were detected. However, while all regional MFC and R2* significantly increased with age in the control group, MFC and R2* increased in the GP, PUT, CN and THL with psychostimulant treatment duration in the ADHD group to a greater degree than with age. Our findings suggest that while youth with ADHD may have less prominent age-related brain iron increases than that seen in typical development, long-term use of psychostimulant medications may compensate through a normalizing effect on basal ganglia iron. Longitudinal studies following ADHD patients before and after long-term psychostimulant treatment are needed to confirm these findings.

Keywords: ADHD; Brain iron; MRI; Magnetic field correlation; Psychostimulants; R2*.

Fig. 1

Brain iron indices in deep gray matter regions. Region-of-interest (ROI) analyses of magnetic field correlation (MFC) and the R2* relaxation rate brain iron indices were conducted on the globus pallidus (GP), putamen (PUT), caudate nucleus (CN), thalamus (THL) and red nucleus (RN). A. Consensus ROIs from the cohort with MFC data (n = 59). B. Consensus ROIs from the cohort with MFC and R2* data (n = 46).

Fig. 2

Brain iron indices increased with age in controls but increased with medication duration in individuals with ADHD. A. In the control group (green), magnetic field correlation (MFC) indices of brain iron significantly increased with age in the globus pallidus (GP), putamen (PUT), caudate nucleus (CN), thalamus (THL) and red nucleus (RN); Conversely, in the ADHD group, MFC significantly increased with psychostimulant medication (Rx) duration when controlling for age in the GP, PUT and THL (blue). This correlation was not observed with age when controlling for Rx duration (red). B. Similar results were found with R2* relaxation rate indices of brain iron. r: Pearson's correlation, r_s: Spearman's correlation (ranked values plotted), §: partial correlations (residual values plotted). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)