Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy
Introduction
Hepatic encephalopathy (HE) is a serious complication of liver failure with various etiologies. It brings about a spectrum of neuropsychiatric symptoms from subtle cognitive deficits detectable only by careful psychometric examination to clinically detectable deteriorating consciousness, and even death. Its probable pathophysiology and treatment have been reviewed (Córdoba, 2011, Felipo, 2013, Ferenci et al., 2002). Different degrees of hyperammonemia and neuroinflammation contribute to various neurological and psychiatric alterations. Recent studies using electroencephalography (EEG) (Felipo et al., 2012), magnetoencephalography (MEG) (Timmermann et al., 2002, Timmermann et al., 2003), and fMRI (Hsu et al., 2012, Lin et al., 2012, Qi et al., 2012, Zhang et al., 2012, Zhang et al., 2013) have all demonstrated impaired neuronal communication over specific brain networks or regions in patients with HE, e.g., altered thalamocortical coupling, impaired default mode network (DMN), or disrupted network efficiency. However, there has not yet been a study to investigate large-scale whole brain functional network dynamics with respect to cirrhotic patients with various degrees of HE.
The organization of functional brain networks has been related to various functional properties of the human brain, including different states of consciousness (Achard et al., 2012, Massimini et al., 2005, Schröter et al., 2012, Tononi and Edelman, 1998). Circadian cycle from wakefulness to sleep, injection or inhalation of general anesthetics, and various encephalopathies all induce altered states of consciousness and therefore provide valuable windows to study brain network organization related to human consciousness. To date, however, little is understood about the changes in large-scale complex brain networks associated with clinical and biochemical stages of encephalopathy. Therefore, we questioned how topological and spatial properties of functional brain networks were affected in patients with low, intermediate, and high grades of severity of hepatic encephalopathy, defined both clinically and by neuropsychological tests.
Here, we used a between-subjects resting-state fMRI design and large-scale graph theoretical methods to explore HE-related changes in functional brain networks. We measured topological metrics at global and nodal levels of network organization. We hypothesized that a pathological brain state of HE would cause diffuse and progressive brain network reorganization in topological and anatomical spaces rather than the more localized network dysfunctions that have been reported before. More specifically, based on prior data showing that clinically altered levels of consciousness (in comatose patients [Achard et al., 2012]) were associated with a disruption of nodal degree in the context of normal global network topology, we predicted hypothetically that the changes in consciousness in hepatic encephalopathy would also be associated with changes in nodal degree. We also expected that such changes in the degree of hub nodes might be related to changes of clinical neuropsychological exams and laboratory tests, e.g., the serum ammonia level. We also expected that such changes in the degree of hub nodes might be related to changes in the anatomical orientation of edges between nodes.
Section snippets
Sample
Non-alcoholic liver cirrhosis patients with varying degrees of hepatic encephalopathy (HE, n = 78) were recruited in the Kaohsiung Chang Gung Memorial Hospital. Age-, sex-, and education-matched normal controls (NC, n = 72) were recruited through local advertisements. Cirrhotic patients were diagnosed by clinical and imaging studies and classified using the Child–Pugh score (Child and Turcotte, 1964). Before the diagnosis of HE, cirrhotic patients underwent history taking, physical and neurological
Neuropsychological and clinical measures
Fig. 1 provides a schematic overview of clinical features and functional brain network changes in patients with hepatic encephalopathy (HE). Cirrhotic patients were classified into three subgroups (NoHE, MHE, and OHE) according to clinical evaluation and neuropsychological testing. Therefore, it was not surprising that deteriorating trends were observed for these measures, from NC to OHE (Table 2). Apart from the assigned neuropsychological tests, Glasgow Coma Scale (GCS) data were also
Discussion
Our results demonstrated that there was progressive degradation of functional brain networks in non-alcoholic cirrhotic patients with various degrees of hepatic encephalopathy. Network changes were identified before encephalopathy was clinical evident and network abnormalities demonstrated a strong exponential relationship to venous blood ammonia levels: hyperammonemia was associated with more severe network abnormalities as well as more severe clinical forms of encephalopathy. Moreover, the
Conclusion
We used graph theoretical methods to study effects of various degrees of hepatic encephalopathy (HE) on resting-state fMRI (rs-fMRI) in non-alcoholic cirrhotic patients. Our results demonstrated progressively greater abnormality of functional brain networks in patients with clinical and biochemical evidence of more severe HE. Progressive decrease of clustering and modularity of the functional brain networks happened even before the minimal HE (MHE). Since MHE ammonia increased with nonlinear
Acknowledgments and disclosures
This research was funded by the National Science Council, Taiwan (NSC 97-2314-B-182A-104-MY3). The Behavioural and Clinical Neuroscience Institute is supported by the Medical Research Council and the Wellcome Trust. Tun Jao is supported by the Ministry of Education, Taiwan. ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline; he holds stock in GSK.
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