Functional Connectivity Gradients Reveal Cortical Hierarchical Reorganization Across the Cirrhosis–Hepatic Encephalopathy Spectrum

Abstract Background Hepatic encephalopathy (HE) is a common neurocognitive complication of cirrhosis, but how macroscale cortical hierarchy is reorganized across the cirrhosis–HE spectrum remains incompletely understood. We characterized functional connectome gradient alterations across clinically defined cirrhosis stages and examined their clinical correlates. Methods This cross-sectional study included 104 participants: 35 patients with HE, 33 with cirrhosis without HE (NHE), and 36 healthy controls. Resting-state functional MRI was used to derive the first three connectivity gradients (G1–G3). Group differences were assessed at global, network, and cortical-parcel levels, and associations with blood ammonia, liver disease severity, and cognition were examined in patients with cirrhosis. Results Both NHE and HE showed reduced G1 range and variance versus healthy controls, indicating compression of the sensorimotor-to-transmodal hierarchy. Both groups showed higher somatomotor G1 and lower control and default mode G1, whereas HE additionally showed lower limbic G1. The only significant HE–NHE parcel-level difference involved the right temporal pole. Higher ammonia was associated with higher somatomotor G1 and lower control and default mode G1, while greater liver disease severity was associated mainly with lower limbic and default mode G1. Poorer cognition showed broadly corresponding associations. G2 and G3 did not differ among groups, and the main findings remained robust in sensitivity analyses. Conclusion NHE and HE showed largely shared compression of the sensorimotor-to-transmodal hierarchy, with more selective HE-associated alterations, particularly in temporolimbic regions. These abnormalities were associated with ammonia burden, liver disease severity, and cognitive impairment, supporting altered cortical functional hierarchy as a clinically relevant systems-level phenotype across the cirrhosis–HE spectrum.