The present fMRI study demonstrated that MHE patients had selectively impaired RSNs. Within six RSNs, the DAN showed decreased FC; the DMN, AN, and the VN displayed a bidirectional change of FC; while the SMN and the SRN were unchanged. We also found a relationship between venous blood ammonia levels/neuropsychological tests scores and FC in some specific regions of RSNs, including the middle and medial frontal gyrus, inferior parietal lobule, as well as anterior and posterior cingulate cortex/precuneus. This resting state fMRI study may be potentially helpful to the understanding of neuro-pathophysiological mechanism of cognition function changes in MHE.
The pattern of dorsal attention network (DAN) obtained in the present study was largely consistent with those mapped with the specific task-induced activation 
. DAN is involved in voluntary (top-down) orienting and shows activity increases after presentation of cues indicating where, when, or to what subjects should direct their attention. It is also involved in many higher-order cognitive tasks. Attention impairment in MHE patients has been proposed by many epidemiological studies 
. These attention deficits often in turn lead to learning impairment and difficulties of working memory. The diffusely decreased DAN FC of MHE in the present study is consistent with the disease hypothesis that a defect in attention is a fundamental aspect of this disease. The impaired DAN has not previously been well established in the literature, so our data may contribute to the understanding the attention deficit of MHE.
The DMN abnormalities in HE patients have been reported in some published fMRI studies. In a resting-state fMRI study, Zhang et al
. first demonstrated a decreased FC of middle frontal gyrus, posterior cingulate cortex/precuneus and angular gyrus within DMN in overt HE patients 
. A very recent study showed that the impairment of DMN FC still persisted after clinical recovery from previous episodes of overt HE in a group of cirrhotic patients 
. The findings of present study in decreased FC of right ACC and bilateral angular gurys in the mildest form of HE-MHE are in accordance with previous studies. However, our finding of increased FC of PCC in MHE was inconsistent with previous finding in overt HE. Based on the fact that all MHE patients in this study had no obvious magnification of HE, or any history of episodes of overt HE, we speculate that in the early phase of HE, there might be a compensatory or reorganization mechanism of DMN, an interpretation that is partially supported by the positive correlation between FC of PCC/precuneus and NCT-A scores of patients observed in the present study. The similar compensatory phenomenon was also reported in previous studies 
, e.g., in a task-driven fMRI study Zafiris et al
. found that when performing the critical flicker frequency task, nonmanifest hepatic encephalopathy patients showed enhanced single activity in the right temporal pole 
. Validity of this compensatory mechanism interpretation needs to be confirmed in further studies.
Many studies have demonstrated that MHE has a profound negative impact on the ability to drive a car and may be a significant factor behind motor vehicle accidents 
. The ability to drive a car requires coordination of attention, visual, auditory and vestibular input, which is potentially impaired in MHE patients 
. Except the decreased DAN FC, the present study also demonstrated both decreased and increased FC in VN and AN, suggesting disturbed cooperation of their corresponding function. Bilateral changes in FC have been reported in many other diseases, e.g., social anxiety disorder 
, and Alzheimer's disease 
. A decrease in functional activity could be related to functional impairment, while an increase could be interpreted as compensatory reallocation or recruitment of cognitive resource 
. Compensatory neural mechanism during the visual judgment and resting-state has been reported in nonmanifest hepatic encephalopathy patients 
. Whether there are also both impairment and compensatory or reorganization mechanism of the RSNs such as VN and AV in MHE patients needs further study in the future. In addition, we found no significant changes of the SMN and SRN in MHE patients when comparing to healthy controls, findings which support the hypothesis of this study that MHE patients have selective impaired RSNs.
In the correlative analysis, we found a negative correlation between blood ammonia of MHE patients and FC of the parietal cortex and medial frontal gyrus within DAN, suggesting functional impairment within DAN may partly arise from an excess of ammonia in the blood. This may be explained by the role of ammonia in the pathogenesis of HE. The degradation of ammonia, a main toxic substance in the brain, results in elevation of the glutamine level in astrocytes, consequently causes both swelling and dysfunction of these cells 
. The ammonia-related cellular alterations are considered to play an important key in the pathogenesis of MHE 
. We also found a positive correlation between the DST scores with FC of right ACC in DMN. ACC is a center mediating response selection and allocating attention resources when confronted with competing information-processing streams, it also severs to regular both cognitive and emotional processing 
. PET studies with 18
F-fluorodeoxyglucose also showed significant metabolism reductions in the ACC 
. DST, one of the neuropsychological tests which were most frequently used in defining MHE, mainly tests the domains of attention and psychomotor speed 
. So the impairment of ACC in MHE patients and positive correlation between DST are quit plausible.
Our study has some limitations. First, sample size for MHE patients is small, with variations in the age and disease on-set time, as well as potential effects of medication such as diuretics for controlling ascites in some patients, which might affect the statistical analysis and results of this study. Further studies in a larger population with similar treatment are needed to verify these findings. Secondly, the ICA method used in the study has its own limitations. Although the RSNs represent a finite set of spatiotemporal basis function from which task-networks are then dynamically assembled and modulated during different behavioral states, their neurophysiological meaning still remains unclear.
In conclusion, we observed selective impairments of RSN intrinsic FC in MHE patients, whose DAN, DMN, VN and AN had aberrant functional connectivity, while SMN, SRN were unaffected. Our fMRI study might potentially supply a novel way to understand the neuro-pathophysiological mechanism of cognition function changes in MHE.