title: Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy.
abstract: Functional properties of the brain may be associated with changes in complex brain networks. However, little is known about how properties of large-scale functional brain networks may be altered stepwise in patients with disturbance of consciousness, e.g., an encephalopathy. We used resting-state fMRI data on patients suffering from various degrees of hepatic encephalopathy (HE) to explore how topological and spatial network properties of functional brain networks changed at different cognitive and consciousness states. Severity of HE was measured clinically and by neuropsychological tests. Fifty-eight non-alcoholic liver cirrhosis patients and 62 normal controls were studied. Patients were subdivided into liver cirrhosis with no outstanding HE (NoHE, n=23), minimal HE with cognitive impairment only detectable by neuropsychological tests (MHE, n=28), and clinically overt HE (OHE, n=7). From the earliest stage, the NoHE, functional brain networks were progressively more random, less clustered, and less modular. Since the intermediate stage (MHE), increased ammonia level was accompanied by concomitant exponential decay of mean connectivity strength, especially in the primary cortical areas and midline brain structures. Finally, at the OHE stage, there were radical reorganization of the topological centrality-i.e., the relative importance-of the hubs and reorientation of functional connections between nodes. In summary, this study illustrated progressively greater abnormalities in functional brain network organization in patients with clinical and biochemical evidence of more severe hepatic encephalopathy. The early-than-expected brain network dysfunction in cirrhotic patients suggests that brain functional connectivity and network analysis may provide useful and complementary biomarkers for more aggressive and earlier intervention of hepatic encephalopathy. Moreover, the stepwise deterioration of functional brain networks in HE patients may suggest that hierarchical network properties are necessary for normal brain function.
authors.affiliation: Brain Mapping Unit and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tun
authors.initials: T
authors.lastname: Jao
authors.affiliation: Brain Mapping Unit and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schröter
authors.affiliation: Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chao-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Diagnostic Radiology, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Cheng
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan; Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Yi Zac
authors.initials: CY
authors.lastname: Lo
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan; Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kun-Hsien
authors.initials: KH
authors.lastname: Chou
authors.affiliation: Brain Mapping Unit and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
authors.forename: Ameera X
authors.initials: AX
authors.lastname: Patel
authors.affiliation: Department of Diagnostic Radiology, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: u64lin@yahoo.com.tw.
authors.forename: Wei-Che
authors.initials: WC
authors.lastname: Lin
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan; Brain Connectivity Lab, Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan. Electronic address: cplin@ym.edu.tw.
authors.forename: Ching-Po
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Brain Mapping Unit and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Alternative Discovery and Development, GlaxoSmithKline, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000641:Ammonia / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D005260:Female; D015600:Glasgow Coma Scale; D006501:Hepatic Encephalopathy / Q000097:blood / Q000503:physiopathology* / Q000523:psychology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000503:physiopathology; D009483:Neuropsychological Tests; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D000641:Ammonia
keywords: Brain networks; Consciousness; Hepatic encephalopathy; Liver cirrhosis; Resting-state fMRI