Neuromarkers from Whole-Brain Functional Connectivity Reveal the Cognitive Recovery Scheme for Overt Hepatic Encephalopathy after Liver Transplantation.

Neurocognitive impairment is present in cirrhosis and may be more severe in cirrhosis with overt hepatic encephalopathy (OHE). Liver transplantation (LT) can restore liver function, but how it reverses the impaired brain function is still unclear. MRI of resting-state functional connectivity can help reveal the underlying mechanisms that lead to these cognitive deficits and cognitive recovery. In this study, 64 patients with cirrhosis (28 with OHE; 36 without OHE) and 32 healthy control subjects were recruited for resting-state fMRI. The patients were scanned before and after LT. We evaluated presurgical and postsurgical neurocognitive performance in cirrhosis patients using psychomotor tests. Network-based statistics found significant disrupted connectivity in both groups of cirrhotic patients, with OHE and without OHE, compared with control subjects. However, the presurgical connectivity disruption in patients with OHE affected a greater number of connections than those without OHE. The decrease in functional connectivity for both OHE and non-OHE patient groups was reversed after LT to the level of control subjects. An additional hyperconnected network (i.e., higher connected than control subjects) was observed in OHE patients after LT. Regarding the neural–behavior relationship, the functional network that predicted cognitive performance in healthy individuals showed no correlation in presurgical cirrhotic patients. The impaired neural–behavior relationship was re-established after LT for non-OHE patients, but not for OHE patients. OHE patients displayed abnormal hyperconnectivity and a persistently impaired neural–behavior relationship after LT. Our results suggest that patients with OHE may undergo a different trajectory of postsurgical neurofunctional recovery compared with those without, which needs further clarification in future studies. Significance Statement After liver transplantation, brain functional impairment induced by cirrhosis shows some recovery in terms of both brain functional connectivity and cognitive task performance. However, cirrhotic patients with and without OHE present different recovery paths. We show that a hyperconnected network emerges for OHE patients only after liver transplantation, within which the connectivity is abnormally higher than that in healthy control subjects. Furthermore, the predictive power of the neuromarkers for cognitive task performance returns to normal in non-OHE patients only, but not in OHE patients. These findings suggest that OHE patients may exhibit functional reorganization in brain functional MRI after liver transplantation. That is, the brain connectivity responsible for cognitive task performance alters, and the brain–behavior relationship is reshaped.