Abstract
Maple syrup urine disease is a rare metabolic disorder that results in neurodevelopmental injury despite dietary therapy. While structural neuroimaging has shown a characteristic pattern of edema and white matter injury, no functional neuroimaging studies of maple syrup urine disease have been performed. Using widefield optical imaging, we investigated resting-state functional connectivity in two brain-specific mouse models of maple syrup urine disease (an astrocyte-specific knockout and a whole-brain knockout). At 8 weeks, mouse functional neuroimaging was performed using a custom-built widefield optical imaging system. Imaging was performed before and after initiation of a high-protein diet for 1 week to mimic metabolic crisis, which we hypothesized would result in decreased functional connectivity strength. Data were analyzed using seed-based functional connectivity and cluster-based inference. Astrocyte-specific knockout mice developed increased contralateral functional connectivity within the posteromedial somatosensory cortex after diet initiation. Whole-brain knockout mice had a similar pattern present at baseline, which persisted after diet initiation. Thus, contrary to expectations, maple syrup urine disease resulted in increased functional connectivity strength, especially after diet initiation. While the underlying etiology of these changes is unclear, these results demonstrate that inborn errors of metabolism result in changes to functional connectivity networks. Further research may demonstrate functional neuroimaging biomarkers that could be translated to clinical care.