Aberrant salience network and its functional coupling with default and executive networks in minimal hepatic encephalopathy: a resting-state fMRI study

Hua-Jun Chen¹

¹The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, People's Republic of

Synopsis

Aberrant functional coupling of triple network in MHE

Purposes

Neurocognitive impairments, such as attention deficits, working memory problems, and impaired executive functions, are characteristics of minimal hepatic encephalopathy (MHE), a frequent complication of cirrhosis. However, the specific mechanism underlying such neural dysfunction remains incompletely understood. The salience network (SN) serves to identify salient stimuli and controls switching activity between the central executive network (CEN) and the default-mode network (DMN), which plays an important role in various high-level neurocognitive processes. Both functional and structural changes in the insular cortex (the pivotal area of the SN) have been demonstrated in cirrhotic patients in previous studies. Thus, it has been hypothesized that an aberrant SN and its functional coupling with the DMN/CEN occur in MHE, as the mechanisms underlying the neurocognitive dysfunction, and are associated with disease progression. The purposes of this study include: First, to explore functional alterations in the SN and its functional coupling with the default mode and central executive networks in MHE and, second, to assess any association between these alterations and neurocognitive impairment and disease progression.

Materials and Methods

In total, 20 cirrhotic patients with MHE, 23 cirrhotic patients without MHE (NHE), and 18 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. MHE was assessed based on psychometric hepatic encephalopathy score (PHES). High-model-order independent component analysis was performed to obtain the DMN (including three subsystems: the anterior, inferior-posterior, and superior-posterior DMN [a/ip/sp DMN]), SN, and CEN (including three subsystems: the left-ventral, right-ventral, and dorsal CEN [lv/rv/d CEN]). The intrinsic functional connectivity within (intra-iFC) and between (inter-iFC and time-lagged inter-iFC) distinct subsystems of the three networks was measured and correlated with the results of neurocognitive tests.

Results

MHE patients showed significantly worse performance in neurocognitive tests and lower PHES scores. One-way analysis of variance demonstrated differences in intra-iFC from the aDMN (in the bilateral anterior cingulate cortex), SN (in the right insular cortex), lvCEN (in the right inferior parietal lobule), and rvCEN (in the right inferior parietal lobule) among the three groups. MHE patients had decreased inter-iFC and time-lagged inter-iFC (centered on the SN) strength between the SN and ipDMN/spDMN/lvCEN and increased inter-iFC and time-lagged inter-iFC strength between the SN and aDMN, compared with HCs. A progressing trend in alterations in functional connectivity was found as the disease developed from NHE to MHE. In the MHE group, the inter-iFC between the ipDMN/spDMN and SN was significantly correlated with the PHES score.

Conclusion

An aberrant SN and its functional interaction with the DMN/CEN are core features of MHE that are associated with disease progression and may play an important role in the mechanisms underlying neurocognitive dysfunction in MHE patients.

Acknowledgements

This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (JX 10231801), a grant from the National Natural Science Foundation of China (no. 81501450), and a project funded by the China Postdoctoral Science Foundation.

References

1. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol; 2001;34(5):768-73.

2. Bajaj JS, Hafeezullah M, Franco J, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology; 2008;135(5):1591-600.

3. Bressler SL, Menon V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn Sci; 2010;14(6):277-90.

4. Manoliu A, Riedl V, Zherdin A, et al. Aberrant dependence of default mode/central executive network interactions on anterior insular salience network activity in schizophrenia. Schizophr Bull; 2014;40(2):428-37.

Figures

Figure 1. Spatial maps of the triple intrinsic networks. MHE, minimal hepatic encephalopathy, NHE, patients without MHE, HCs, healthy controls. a/ip/spDMN, anterior/inferior-posterior/superior-posterior DMN; lv/rv/dCEN, left-ventral/right-ventral/dorsal CEN; SN, salience network.

Figure 2. Significant differences in intra-network functional connectivity across the three groups. The brain areas with significantly altered intra-network functional connectivity are shown: (A) within aDMN, (B) within SN, (C) within lvCEN, and (D) within rvCEN. The Bar graphs show the results of post hoc comparisons between each pair of groups. Z values are derived from independent component analysis and indicate the functional connectivity strength within the network.

Figure 3. Inter-network intrinsic functional connectivity matrix. Pair-wise Pearson’s correlations between the time courses of the triple networks were Fisher Z-transformed and averaged across subjects for each group: (A) healthy controls, (B) NHE patients, and (C) MHE patients. (D) The marker + indicates a significant difference across the three groups (P < 0.05, FDR correction). The marker indicates a difference across the three groups (P < 0.05, uncorrected).

Figure 4. Between-group differences in inter-network intrinsic functional connectivity. (A) Red and blue two-way arrow indicate increased positive inter-network connectivity and decreased negative inter-network connectivity in MHE and NHE patients, respectively. (B) The markers * and † indicate a significant difference in inter-iFC between MHE and HC and between NHE and HC, respectively.

Figure 5. Between-group differences in time-lagged inter-network intrinsic functional connectivity. (A, C): Red and blue one-way arrows indicate increased positive connectivity and decreased negative connectivity (centered on SN) in MHE patients, respectively. (B, D): The markers *, †, and # indicate significant differences between MHE and HCs, NHE and HCs, and NHE and MHE, respectively.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)

1686