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Clinical Trial
. 2014 Dec;29(4):1017-25.
doi: 10.1007/s11011-014-9507-6. Epub 2014 Mar 4.

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

Vishwadeep Ahluwalia  1 , James B Wade, Douglas M Heuman, Thomas A Hammeke, Arun J Sanyal, Richard K Sterling, R Todd Stravitz, Velimir Luketic, Mohammad S Siddiqui, Puneet Puri, Michael Fuchs, Micheal J Lennon, Kenneth A Kraft, HoChong Gilles, Melanie B White, Nicole A Noble, Jasmohan S Bajaj
Affiliations
Clinical Trial

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

Vishwadeep Ahluwalia et al. Metab Brain Dis. 2014 Dec.

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.

Hypothesis: 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.

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Figures

Figure 1
Figure 1
CONSORT diagram for the trial
Figure 2
Figure 2
Change in working memory and inhibitory control (A) Post-Rifaximin>Pre-Rifaximin for 2-back condition; (B) Post-Rifaximin>Pre-Rifaximin for Correct Inhibition to Lures (CIL) condition; all cluster corrected Z=1.8, p<0.05, color scale representing Z-scores (Red-Yellow), R: right hemisphere.
Figure 3
Figure 3
Change in functional connectivity during N-back. Psycho-physiological interaction (PPI) analysis for N-back PPI analysis showing differences in effective connectivity for Pre>Post-Rifaximin (Red-Yellow) and Post>Pre-Rifaximin (Blue-Light Blue) for seed areas (Green) left IFG (A), left precentral gyrus (B & C) and right precentral gyrus (D). (cluster corrected Z=1.8, p<0.05)
Figure 4
Figure 4
White matter tracts with significant differences in Fractional Anisotropy (FA) between pre and post-rifaximin states. FWM = Frontal White Matter, EC = External Capsule ILF = Inferior Longitudinal Fasciculus, Cing = Cingulum, L/R = Left/Right
See this image and copyright information in PMC

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