Abnormal Brain Iron Metabolism is Linked to Altered Neural Function in Isolated Laryngeal Dystonia.

Abstract

BACKGROUND Laryngeal dystonia (LD) is an isolated focal dystonia causing involuntary spasms in the laryngeal muscles that selectively impair speech production. LD is characterized as a functional and structural neural network disorder; however, the mechanistic aspects of network dysfunction in dystonia remain unknown. OBJECTIVE We hypothesized that iron-induced abnormal metabolic processes may underlie microstructural neuronal damage, contributing to altered neural activity within the dystonic network and, subsequently, the development of the dystonic state. METHODS We used 7 Tesla magnetic resonance imaging (MRI) at ultra-high field resolution for quantitative susceptibility mapping (QSM) of iron content, multi-echo multi-band resting-state functional MRI (fMRI) of brain activity and functional connectivity, positron emission tomography with [11C]flumazenil radioligand of GABAA neuroreceptor availability, and immunohistochemistry of postmortem brain tissue to investigate iron metabolism in LD patients and healthy controls. RESULTS The QSM analysis found increased iron content in primary sensorimotor and premotor cortices, inferior frontal, middle frontal, and middle temporal gyri, middle cingulate cortex, superior and inferior parietal lobules, insula, putamen, and cerebellum. Histopathology substantiated the neuroimaging findings by showing focal clusters of iron precipitates in these regions. Increased iron content in the supplementary motor area and middle cingulate cortex was associated with altered neural activity, while increased iron in the middle cingulate cortex, premotor cortex, and putamen had associations with GABAA receptor availability in LD patients. CONCLUSION Abnormal iron accumulations are likely to contribute to the imbalance of excitatory and inhibitory signaling within the dystonic neural network, leading to altered network dynamics that ultimately contribute to LD development. © 2025 International Parkinson and Movement Disorder Society.