fNIRS insights into brain biomarkers of maple syrup urine disease (MSUD)

Maple syrup urine disease (MSUD) is a rare inherited disorder identified through newborn screening. Monitoring relies on using established biochemical biomarkers; however, neurodevelopmental outcomes remain variable despite metabolic control. Structural neuroimaging in MSUD has identified acute and chronic brain injury, but these approaches provide limited insight into functional brain physiology. Recent preclinical work by demonstrated altered resting-state functional connectivity in a mouse model of MSUD using functional near-infrared spectroscopy (fNIRS), suggesting that metabolic dysregulation directly impacts cortical function. The objective of this study was to translate preclinical fNIRS findings to humans with MSUD by evaluating the feasibility of fNIRS acquisition and exploring cortical hemodynamic and functional measures. fNIRS data were successfully acquired in MSUD cohort, demonstrating the feasibility of this approach in this population. Participants from two age groups (<8 years and ≥ 8 years) completed age-appropriate cognitive tasks (video tasks, and an N-back, respectively). Across both language and working memory paradigms, greater activation was observed in prefrontal regions relative to parietal and occipital areas, reflecting the cognitive demands of the tasks in both MSUD and controls. While group-level differences in hemoglobin concentration suggest potential alterations in cortical hemodynamics in MSUD. Although N-back task performance was broadly comparable between groups, differences in hemoglobin concentration suggest potential alterations in cortical hemodynamics in individuals with MSUD. These findings support the use of fNIRS as a practical and adjunctive neuroimaging modality for studying rare metabolic disorders and provide a foundation for future longitudinal studies aimed at identifying disease-specific functional biomarkers.