Xi-Qi Zhu

Structural and functional cerebral impairments in cirrhotic patients with a history of overt hepatic encephalopathy

OBJECTIVE Diffuse brain atrophy has been observed in cirrhotic patients and recent reports have revealed the persistence of cognitive impairment after clinical resolution of overt hepatic encephalopathy. We sought to explore the continued influence of overt hepatic encephalopathy on neurological function by measuring brain resting-state inherent connectivity, based on an investigation of structural abnormalities. METHODS Neuropsychological tests and structural and functional magnetic resonance scanning were conducted in 20 healthy controls and 21 cirrhotic patients with a history of overt hepatic encephalopathy. The analysis of voxel-based morphometry and functional connectivity were performed to detect the alterations in brain structure and function, respectively. RESULTS Patients showed significantly worse performance in neuropsychological tests as compared with controls, despite apparently normal mental status. Analysis of voxel-based morphometry revealed a decrease in gray matter volume primarily in the midline regions, bilateral insular cortex and caudates, left parahippocampal gyrus, and right cerebellum posterior lobe, while the volume of the bilateral thalamus showed an increase. Of these regions, the posterior cingulate cortex with peak atrophy was selected as the origin for the analysis of functional connectivity. Typical patterns of a default mode network were identified in both groups. Decreased functional connectivity was found in the medial prefrontal gyrus, left inferior parietal lobule, and left middle temporal gyrus in the patients. CONCLUSIONS Both functional and structural impairments were evident after apparent recovery from overt hepatic encephalopathy, demonstrating that brain dysfunction induced by hepatic encephalopathy persisted after clinical resolution and provided a basis for further evolution of the disease.

Changes in the regional homogeneity of resting-state brain activity in minimal hepatic encephalopathy

Resting-state functional magnetic resonance imaging (fMRI) has facilitated the study of spontaneous brain activity by measuring low-frequency oscillations in blood-oxygen-level-dependent signals. Analyses of regional homogeneity (ReHo), which reflects the local synchrony of neural activity, have been used to reveal the mechanisms underlying the brain dysfunction in various neuropsychiatric diseases. However, it is not known whether the ReHo is altered in cirrhotic patients with minimal hepatic encephalopathy (MHE). We recruited 18 healthy controls and 18 patients with MHE. The ReHo was calculated to assess the strength of the local signal synchrony. Compared with the healthy controls, the patients with MHE had significantly decreased ReHo in the cuneus and adjacent precuneus, and left inferior parietal lobe, whereas the regions showing increased ReHo in patients with MHE included the left parahippocampal gyrus, right cerebellar vermis, and bilateral anterior cerebellar lobes. We found a positive correlation between the mean ReHo in the cuneus and adjacent precuneus and the score on the digit-symbol test in the patient group. In conclusion, the analysis of the regional homogeneity of resting-state brain activity may provide additional information with respect to a clinical definition of MHE.

Abnormal baseline brain activity in low-grade hepatic encephalopathy: A resting-state fMRI study

Resting-state functional magnetic resonance imaging (fMRI) has been used to detect the alterations of spontaneous neuronal activity in various neuropsychiatric diseases, but rarely in low-grade hepatic encephalopathy (HE), a common neuropsychiatric complication of liver cirrhosis. We conducted a resting-state fMRI in 19 healthy controls, 18 cirrhotic patients without HE, and 22 cirrhotic patients with low-grade HE. The amplitude of low-frequency fluctuations (ALFF) of fMRI signal was computed to measure the spontaneous neuronal activity. Several regions showing significant ALFF differences among three groups were the precuneus, occipital lobe, left frontal lobe and anterior/middle cingulate cortex, and left cerebellum posterior lobe. Compared to controls or patients without HE, patients with low-grade HE showed decreased ALFF in the precuneus and adjacent cuneus, visual cortex, and left cerebellum posterior lobe. Compared to controls, patients with low-grade HE showed higher ALFF in both cortical and subcortical regions, including the right middle cingulate gyrus, and left anterior/middle cingulate gyrus, inferior frontal gyrus, insula lobe, parahippocampal gyrus, middle temporal gyrus and lentiform nucleus; compared to patients without HE, patients with low-grade HE showed higher ALFF in the left medial frontal gyrus and anterior cingulate gyrus, bilateral superior frontal gyrus, and right middle frontal gyrus. Moreover, correlations between ALFF changes and poor neurocognitive performances were found in patients with low-grade HE. These results suggested the existence of aberrant brain activity at the baseline state in low-grade HE, which may be implicated in the neurological pathophysiology underlying HE.

Classification of Cirrhotic Patients with or without Minimal Hepatic Encephalopathy and Healthy Subjects Using Resting-State Attention-Related Network Analysis

Background Attention deficit is an early and key characteristic of minimal hepatic encephalopathy (MHE) and has been used as indicator for MHE detection. The aim of this study is to classify the cirrhotic patients with or without MHE (NMHE) and healthy controls (HC) using the resting-state attention-related brain network analysis. Methods and Findings Resting-state fMRI was administrated to 20 MHE patients, 21 NMHE patients, and 17 HCs. Three attention-related networks, including dorsal attention network (DAN), ventral attention network (VAN), and default mode network (DMN), were obtained by independent component analysis. One-way analysis of covariance was performed to determine the regions of interest (ROIs) showing significant functional connectivity (FC) change. With FC strength of ROIs as indicators, Linear Discriminant Analysis (LDA) was conducted to differentiate MHE from HC or NMHE. Across three groups, significant FC differences were found within DAN (left superior/inferior parietal lobule and right inferior parietal lobule), VAN (right superior parietal lobule), and DMN (bilateral posterior cingulate gyrus and precuneus, and left inferior parietal lobule). With FC strength of ROIs from three networks as indicators, LDA yielded 94.6% classification accuracy between MHE and HC (100% sensitivity and 88.2% specificity) and 85.4% classification accuracy between MHE and NMHE (90.0% sensitivity and 81.0% specificity). Conclusions Our results suggest that the resting-state attention-related brain network analysis can be useful in classification of subjects with MHE, NMHE, and HC and may provide a new insight into MHE detection.

White matter abnormalities correlate with neurocognitive performance in patients with HBV-related cirrhosis

BACKGROUND White matter (WM) abnormalities are common in cirrhotic patients and possibly contribute to hepatic encephalopathy (HE), a frequent neuropsychiatric complication of cirrhosis. However, little is known about these WM abnormalities and their relationship to neurocognitive deficits in patients with HBV-related cirrhosis. METHODS Three-dimensional T1-weighted magnetic resonance imaging and diffusion tensor imaging (DTI) scans were obtained from 67 patients with HBV-related cirrhosis and 40 controls. Voxel-based morphometry and voxel-based DTI were performed to detect macroscopic atrophy and damage to the microstructural integrity of the WM, respectively. Correlation analyses were performed to investigate the relationships between WM abnormalities and neurocognitive performances. RESULTS Patients with cirrhosis exhibited significantly decreased WM volume and fractional anisotropy (FA) values, especially in the corpus callosum, thalamus, extra-nuclear area, sensorimotor area, fusiform gyrus, lingual gyrus, and frontal lobes. These abnormalities were more severe with increasing Child-Pugh stage, minimal HE, and previous overt HE. Changes in the corpus callosum, frontal lobe, sensorimotor area, internal capsule, and temporal-occipital lobes were correlated with poor neurocognitive performance. Also, the significantly decreased global WM volume and mean FA value were correlated with poor neurocognitive performances. CONCLUSIONS Diffuse WM abnormalities are common in patients with HBV-related cirrhosis. Advanced liver disease and episodes of HE are two factors associated with WM abnormalities. The correlation between poor neurocognitive performance and WM abnormalities suggests that WM abnormalities may be one of mechanisms underlying neurocognitive deficits in patients with HBV-related cirrhosis.

Aberrant Resting-State Corticostriatal Functional Connectivity in Cirrhotic Patients with Hyperintense Globus Pallidus on T1-Weighted MR Imaging

Neurobiological and neuroimaging studies have emphasized the structural and functional alterations in the striatum of cirrhotic patients, but alterations in the functional connections between the striatum and other brain regions have not yet been explored. Of note, manganese accumulation in the nervous system, frequently reflected by hyperintensity at the bilateral globus pallidus (GP) on T1-weighted imaging, has been considered a factor affecting the striatal and cortical functions in hepatic decompensation. We employed resting-state functional magnetic resonance imaging to analyze the temporal correlation between the striatum and the remaining brain regions using seed-based correlation analyses. The two-sample t-test was conducted to detect the differences in corticostriatal connectivity between 44 cirrhotic patients with hyperintensity at the bilateral GP and 20 healthy controls. Decreased connectivity of the caudate was detected in the anterior/middle cingulate gyrus, and increased connectivity of the caudate was found in the left motor cortex. A reduction in functional connectivity was found between the putamen and several regions, including the anterior cingulate gyrus, right insular lobe, inferior frontal gyrus, left parahippocampal gyrus, and anterior lobe of the right cerebellum; increased connectivity was detected between the putamen and right middle temporal gyrus. There were significant correlations between the corticostriatal connectivity and neuropsychological performances in the patient group, but not between the striatal connectivity and GP signal intensity. These alterations in the corticostriatal functional connectivity suggested the abnormalities in the intrinsic brain functional organiztion among the cirrhotic patients with manganese deposition, and may be associated with development of metabolic encephalopathy. The manganese deposition in nervous system, however, can not be an independent factor predicting the resting-state brain dysfunction in real time.

Aberrant interhemispheric functional coordination in patients with HBV-related cirrhosis and minimal hepatic encephalopathy

Aberrant brain functional connectivity has been considered as the important mechanism underlying minimal hepatic encephalopathy (MHE); however, little is known about the change in interhemispheric connection in MHE patients. Twenty patients with HBV-related cirrhosis and MHE and 15 healthy controls were included in this study and underwent the resting-state fMRI scanning and diffusion tensor imaging. The functional connectivity between symmetric interhemispheric voxels was computed by a technique called voxel-mirrored homotopic connectivity (VMHC), in which the time series for each voxel in one hemisphere was correlated with that of its homotopic voxel. Diffusion tensor imaging was conducted to measure the mean diffusivity (MD) and fractional anisotropy (FA) values in corpus callosum (CC). Compared with controls, MHE patients showed decreased regional VMHC in medial frontal gyrus, superior frontal gryus, anterior cingulate gyrus, inferior parietal lobule, postcentral gyrus, lingual gyrus, and middle occipital gyrus. MHE patients had significant decreased FA value in CC genu and CC splenium and increased MD value in CC genu. Pearson correlation analyses showed that the VMHC in anterior cingulate gyrus/medial frontal gyrus was correlated with FA/MD values of CC genu. These findings may suggest aberrant interhemispheric coordination in MHE and may provide new insight into the disease-related mechanisms.

Predictive models of minimal hepatic encephalopathy for cirrhotic patients based on large-scale brain intrinsic connectivity networks

We aimed to find the most representative connectivity patterns for minimal hepatic encephalopathy (MHE) using large-scale intrinsic connectivity networks (ICNs) and machine learning methods. Resting-state fMRI was administered to 33 cirrhotic patients with MHE and 43 cirrhotic patients without MHE (NMHE). The connectivity maps of 20 ICNs for each participant were obtained by dual regression. A Bayesian machine learning technique, called Graphical Model-based Multivariate Analysis, was applied to determine ICN regions that characterized group differences. The most representative ICNs were evaluated by the performance of three machine learning methods (support vector machines (SVMs), multilayer perceptrons (MLP), and C4.5). The clinical significance of these potential biomarkers was further tested. The temporal lobe network (TLN), and subcortical network (SCN), and sensorimotor network (SMN) were selected as representative ICNs. The distinct functional integration patterns of the representative ICNs were significantly correlated with behavior criteria and Child-Pugh scores. Our findings suggest the representative ICNs based on GAMMA can distinguish MHE from NMHE and provide supplementary information to current MHE diagnostic criteria.