title: Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: implications for the gut-liver-brain axis.
abstract: Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. To evaluate the effect of rifaximin, a gut-specific antibiotic, on the gut-liver-brain axis in MHE.
  
  
  OBJECTIVE
  Rifaximin will reduce endotoxemia, enhance cognition, increase activation during working memory(N-back) and reduce activation needed for inhibitory control tasks.
  
  
  METHODS
  Cirrhotics with MHE underwent baseline endotoxin and cognitive testing, then underwent fMRI, diffusion tensor imaging and MR spectroscopy(MRS). On fMRI, two tasks; N-back (outcome: correct responses) and inhibitory control tests(outcomes: lure inhibition) were performed. All procedures were repeated after 8 weeks of rifaximin. RESULTS were compared before/after rifaximin.
  
  
  RESULTS
  20 MHE patients (59.7 years) were included; sixteen completed pre/post-rifaximin scanning with 92% medication compliance. Pre-rifaximin patients had cognitive impairment. At trial-end, there was a significantly higher correct 2-back responses, ICT lure inhibitions and reduced endotoxemia(p = 0.002). This was accompanied by significantly higher activation from baseline in subcortical structures (thalamus, caudate, insula and hippocampus) and left parietal operculum (LPO) during N-back, decrease in fronto-parietal activation required for inhibiting lures, including LPO during ICT compared to baseline values. Connectivity studies in N-back showed significant shifts in linkages after therapy in fronto-parietal regions with a reduction in fractional anisotropy (FA) but not mean diffusivity (MD), and no change in MRS metabolites at the end of the trial. A significant improvement in cognition including working memory and inhibitory control, and fractional anisotropy without effect on MD or MRS, through modulation of fronto-parietal and subcortical activation and connectivity was seen after open-label rifaximin therapy in MHE.
authors.affiliation: Division of Radiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA.
authors.forename: Vishwadeep
authors.initials: V
authors.lastname: Ahluwalia
authors.forename: James B
authors.initials: JB
authors.lastname: Wade
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Heuman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hammeke
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: Richard K
authors.initials: RK
authors.lastname: Sterling
authors.forename: R Todd
authors.initials: RT
authors.lastname: Stravitz
authors.forename: Velimir
authors.initials: V
authors.lastname: Luketic
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Siddiqui
authors.forename: Puneet
authors.initials: P
authors.lastname: Puri
authors.forename: Michael
authors.initials: M
authors.lastname: Fuchs
authors.forename: Micheal J
authors.initials: MJ
authors.lastname: Lennon
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kraft
authors.forename: HoChong
authors.initials: H
authors.lastname: Gilles
authors.forename: Melanie B
authors.initials: MB
authors.lastname: White
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Noble
authors.forename: Jasmohan S
authors.initials: JS
authors.lastname: Bajaj
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018988:Bacterial Translocation; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000382:microbiology / Q000517:prevention & control*; D063132:Connectome; D056324:Diffusion Tensor Imaging; D005260:Female; D059907:Functional Neuroimaging; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000209:etiology / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007266:Inhibition, Psychological; D007422:Intestines / Q000382:microbiology*; D008099:Liver / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D064307:Microbiota / Q000187:drug effects; D008875:Middle Aged; D064847:Multimodal Imaging; D009483:Neuropsychological Tests; D012294:Rifamycins / Q000494:pharmacology / Q000627:therapeutic use*; D000078262:Rifaximin
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins; D000078262:Rifaximin