Uncovering hypothalamic network disruption in ALS

Background: Structural MRI studies have shown hypothalamic atrophy and altered white matter (WM) connectivity in amyotrophic lateral sclerosis (ALS), as a possible substrate of hypermetabolism in this condition. However, hypothalamic functional connectivity and its association with clinical features in ALS remain unclear. This study explored hypothalamic resting-state functional connectivity (RS-FC) in ALS patients compared to controls and its relationship with disease severity defined by the ALS Functional Rating Scale (ALSFRS-r), body mass index (BMI), disease duration, progression rate, survival, hypothalamic volume, and WM integrity. Methods: Seventy-one ALS patients and 39 healthy controls underwent structural and RS functional MRI. The bilateral hypothalamus was segmented, and a seed-based RS-FC analysis was performed. Group differences in hypothalamic RS-FC and their correlations with ALSFRS-r scores, BMI, disease duration, progression rate, survival, hypothalamic volume, and WM integrity were assessed. Tract-based spatial statistics was performed to estimate the correlation between WM damage in ALS and hypothalamic RS-FC. Results: ALS patients showed increased hypothalamic RS-FC with caudate nuclei compared to controls. Additionally, greater disease severity correlated with increased hypothalamic RS-FC with the caudate nuclei and orbitofrontal cortex. Hypothalamic RS-FC mean values also associated with FA in the genu of corpus callosum and forceps minor and disease progression rate. No significant correlations were observed with other clinical features. Conclusions: These findings support hypothalamic alterations in ALS. Early detection of hypothalamic changes could be useful in prognostic stratification and evaluating intervention effects.