Multi-Echo Resting-State Functional Magnetic Resonance Imaging Analysis of Attention-Deficit/Hyperactivity Disorder Severity and Motor Dysfunction in a Pediatric Sample of Neurofibromatosis Type 1

ABSTRACT Objectives Neurofibromatosis Type 1 (NF1) is a heterogeneous neurodevelopmental disorder where motor deficits and Attention-Deficit/Hyperactivity Disorder (ADHD) occur at higher rates than typical populations. To characterize network-level changes associated with these impairments, we compared functional connectivity in youth with NF1 to typically developing (TD) controls. In the NF1 cohort, we analyzed relationships between functional connectivity, motor impairment, and ADHD severity. Methods Thirty-two participants (16 NF1, 16 TD; 8-16 years) underwent resting-state functional magnetic resonance imaging. Seed-to-voxel analyses were conducted for network seeds (sensorimotor, default mode, salience, and dorsal attention). Group differences were tested across brain voxels, and we examined brain-behavior associations within the NF1 group by correlating functional connectivity with motor scores from the Physical and Neurological Examination of Subtle Signs (PANESS) and ADHD severity from the parent-reported ADHD Rating Scale. Results Youth with NF1 displayed cortico-cortical hyperconnectivity and cortico-subcortical hypoconnectivity within the sensorimotor network, and hyperconnectivity within and between default mode, dorsal attention, frontoparietal, and visuospatial networks. In youth with NF1, poorer motor performance was associated with reduced cortico-cortical intra-sensorimotor and sensorimotor-visuospatial connectivity. Greater inattentive symptoms were linked to decreased default mode-sensorimotor connectivity, increased default mode-visuospatial connectivity, and increased dorsal attention-frontoparietal connectivity. Default mode-sensorimotor/visuospatial hyperconnectivity correlated with worse total ADHD symptoms. Interpretations Ineffective integration across default mode, sensorimotor, and visuospatial networks may be linked to motor and attentional phenotypes in NF1 and may serve as a candidate biomarker, pending replication in larger, more heterogeneous samples. We also demonstrate preliminary evidence of compensatory hyperconnectivity in youth with NF1 presenting with co-occurring neurodevelopmental difficulties.