Mediation of symptom severity in the relationship between white matter alterations and functional impairment in attention deficit-hyperactivity disorder children: an AFQ and TBSS study

Abstract The present study aims to investigate the relationship between white matter alterations and functional impairment in attention-deficit/hyperactivity disorder (ADHD) children. Diffusion tensor imaging data were examined in a cross-sectional sample of 125 ADHD children and 73 typically developing controls. White matter integrity was analyzed using two complementary approaches: tract-based spatial statistics analysis (TBSS) and automated fiber quantification (AFQ). Our findings revealed both disrupted (the left inferior longitudinal fasciculus, ILF_L; the left inferior fronto-occipital fasciculus, IFOF_L) and enhanced (the left anterior thalamic radiation, ATR_L; the left cingulum cingulate, CHC_L; forceps major) white matter alterations in ADHD using complementary TBSS and AFQ methods. The multiple regression analyses showed that functional impairment was higher for higher mean fractional anisotropy (FA) (nodes 64–100) of the left anterior thalamic radiation (beta = 0.19, P = 0.04) and lower for higher mean FA value (nodes 50–55) of the left inferior fronto-occipital fasciculus (beta = −0.15, P = 0.02). Importantly, mediation analyses revealed that ADHD symptom severity partially mediated the relationship between white matter alterations and functional impairment. This study revealed bidirectional white matter alterations in ADHD, and emphasized the potential of the anterior thalamic radiation and inferior fronto-occipital fasciculus abnormality as biomarkers for assessing functional impairments and informing targeted therapeutic strategies to improve clinical outcomes.