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Aberrant stability of brain functional architecture in cirrhotic patients with minimal hepatic encephalopathy

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Abstract

To investigate the stability changes of brain functional architecture and the relationship between stability change and cognitive impairment in cirrhotic patients. Fifty-one cirrhotic patients (21 with minimal hepatic encephalopathy (MHE) and 30 without MHE (NHE)) and 29 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and neurocognitive assessment using the Psychometric Hepatic Encephalopathy Score (PHES). Voxel-wise functional connectivity density (FCD) was calculated as the sum of connectivity strength between one voxel and others within the entire brain. The sliding window correlation approach was subsequently utilized to calculate the FCD dynamics over time. Functional stability (FS) is measured as the concordance of dynamic FCD. From HCs to the NHE and MHE groups, a stepwise reduction of FS was found in the right supramarginal gyrus (RSMG), right middle cingulate cortex, left superior frontal gyrus, and bilateral posterior cingulate cortex (BPCC), whereas a progressive increment of FS was observed in the left middle occipital gyrus (LMOG) and right temporal pole (RTP). The mean FS values in RSMG/LMOG/RTP (r = 0.470 and P = 0.001; r = −0.458 and P = 0.001; and r = −0.384 and P = 0.005, respectively) showed a correlation with PHES in cirrhotic patients. The FS index in RSMG/LMOG/BPCC/RTP showed moderate discrimination potential between the NHE and MHE groups. Changes in FS may be linked to neuropathological bias of cognitive impairment in cirrhotic patients and could serve as potential biomarkers for MHE diagnosis and monitoring the progression of hepatic encephalopathy.

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Data availability

Deidentified data will be shared on reasonable request with the qualified investigator.

Abbreviations

HE:

hepatic encephalopathy

MHE:

minimal hepatic encephalopathy

OHE:

overt hepatic encephalopathy

rs-fMRI:

resting state functional magnetic resonance imaging

BOLD:

blood oxygen level–dependent

FC:

functional connectivity

FCD:

functional connectivity density

dFC:

dynamic functional connectivity

FS:

functional stability

NHE:

cirrhotic patients without minimal hepatic encephalopathy

HC:

healthy control

PHES:

psychometric hepatic encephalopathy score

DPABI:

data processing & analysis of brain imaging toolbox

FD:

frame-wise displacement

GSR:

global signal regression

MNI:

Montreal Neurological Institute

KCC:

Kendall’s concordance coefficient

ANOVA:

the one-way analysis of variance

ROI:

regions of interests

ROC:

receiver operating characteristic

AUC:

the area under the ROC curve

RSMG:

right supramarginal gyrus

RMCC:

right middle cingulate cortex

LSFG:

left superior frontal gyrus

BPCC:

bilateral posterior cingulate cortex

LMOG:

left middle occipital gyrus

RTP:

right temporal pole

EEG:

electroencephalography

DMN:

default mode network

References

  • Allen, E. A., Damaraju, E., Plis, S. M., et al. (2014). Tracking whole-brain connectivity dynamics in the resting state. Cerebral Cortex, 24(3), 663–676.

    PubMed  Google Scholar 

  • Allen, E. A., Damaraju, E., Eichele, T., et al. (2018). EEG signatures of dynamic functional network connectivity states. Brain Topography, 31(1), 101–116.

    CAS  PubMed  Google Scholar 

  • Amodio, P., Montagnese, S., Gatta, A., et al. (2004). Characteristics of minimal hepatic encephalopathy. Metabolic Brain Disease, 19(3–4), 253–267.

    PubMed  Google Scholar 

  • Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage, 38(1), 95–113.

    PubMed  Google Scholar 

  • Bajaj, J. S., Wade, J. B., & Sanyal, A. J. (2009). Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy. Hepatology (Baltimore, Md), 50(6), 2014–2021.

    Google Scholar 

  • Bajaj, J. S., Pinkerton, S. D., Sanyal, A. J., et al. (2012). Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: A cost-effectiveness analysis. Hepatology (Baltimore, Md), 55(4), 1164–1171.

    Google Scholar 

  • Barkhof, F., Haller, S., & Rombouts, S. A. (2014). Resting-state functional MR imaging: A new window to the brain. Radiology, 272(1), 29–49.

    PubMed  Google Scholar 

  • Biswal, B., Yetkin, F. Z., Haughton, V. M., et al. (1995). Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magnetic Resonance in Medicine, 34(4), 537–541.

    CAS  PubMed  Google Scholar 

  • du Boisgueheneuc, F., Levy, R., Volle, E., et al. (2006). Functions of the left superior frontal gyrus in humans: A lesion study. Brain, 129(Pt 12), 3315–3328.

    PubMed  Google Scholar 

  • Chang, C., & Glover, G. H. (2010). Time-frequency dynamics of resting-state brain connectivity measured with fMRI. Neuroimage, 50(1), 81–98.

    PubMed  Google Scholar 

  • Chang, C., Liu, Z., Chen, M. C., et al. (2013). EEG correlates of time-varying BOLD functional connectivity. Neuroimage, 72, 227–236.

    PubMed  Google Scholar 

  • Chen, H. J., Zhu, X. Q., Jiao, Y., et al. (2012). Abnormal baseline brain activity in low-grade hepatic encephalopathy: A resting-state fMRI study. Journal of the Neurological Sciences, 318(1–2), 140–145.

    PubMed  Google Scholar 

  • Chen, H. J., Wang, Y., Zhu, X. Q., et al. (2014). Classification of cirrhotic patients with or without minimal hepatic encephalopathy and healthy subjects using resting-state attention-related network analysis. PLoS One, 9(3), e89684.

    PubMed  PubMed Central  Google Scholar 

  • Chen, H. J., Jiang, L. F., Sun, T., et al. (2015). Resting-state functional connectivity abnormalities correlate with psychometric hepatic encephalopathy score in cirrhosis. European Journal of Radiology, 84(11), 2287–2295.

    PubMed  Google Scholar 

  • Chen, H. J., Zhang, L., Jiang, L. F., et al. (2016). Identifying minimal hepatic encephalopathy in cirrhotic patients by measuring spontaneous brain activity. Metabolic Brain Disease, 31(4), 761–769.

    PubMed  Google Scholar 

  • Chen, H. J., Lin, H. L., Chen, Q. F., et al. (2017a). Altered dynamic functional connectivity in the default mode network in patients with cirrhosis and minimal hepatic encephalopathy. Neuroradiology, 59(9), 905–914.

    PubMed  Google Scholar 

  • Chen, H. J., Liu, P. F., Chen, Q. F., et al. (2017b). Brain microstructural abnormalities in patients with cirrhosis without overt hepatic encephalopathy: A voxel-based diffusion kurtosis imaging study. AJR American Journal of Roentgenology, 209(5), 1128–1135.

    PubMed  Google Scholar 

  • Cheng, Y., Zhang, G., Shen, W., et al. (2018). Impact of previous episodes of hepatic encephalopathy on short-term brain function recovery after liver transplantation: A functional connectivity strength study. Metabolic Brain Disease, 33(1), 237–249.

    PubMed  Google Scholar 

  • Cheng, Y., Zhang, G., Zhang, X., et al. (2021). Identification of minimal hepatic encephalopathy based on dynamic functional connectivity. Brain Imaging and Behavior, 15(5), 2637–2645.

    PubMed  Google Scholar 

  • Das, A., Dhiman, R. K., Saraswat, V. A., et al. (2001). Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. Journal of Gastroenterology and Hepatology, 16(5), 531–535.

    CAS  PubMed  Google Scholar 

  • Deco, G., Jirsa, V. K., & McIntosh, A. R. (2011). Emerging concepts for the dynamical organization of resting-state activity in the brain. Nature Reviews Neuroscience, 12(1), 43–56.

    CAS  PubMed  Google Scholar 

  • Dehaene, S., Lau, H., & Kouider, S. (2017). What is consciousness, and could machines have it? Science (New York, N.Y.), 358(6362), 486–492.

    CAS  Google Scholar 

  • Du, Y., Pearlson, G. D., Yu, Q., et al. (2016). Interaction among subsystems within default mode network diminished in schizophrenia patients: A dynamic connectivity approach. Schizophrenia Research, 170(1), 55–65.

    PubMed  Google Scholar 

  • Garcia-Garcia, R., Cruz-Gomez, A. J., Mangas-Losada, A., et al. (2017). Reduced resting state connectivity and gray matter volume correlate with cognitive impairment in minimal hepatic encephalopathy. PLoS One, 12(10), e0186463.

    PubMed  PubMed Central  Google Scholar 

  • Gong, L., Xu, R., Liu, D., et al. (2020). Abnormal functional connectivity density in patients with major depressive disorder with comorbid insomnia. Journal of Affective Disorders, 266, 417–423.

    PubMed  Google Scholar 

  • Heilbronner, S. R., & Platt, M. L. (2013). Causal evidence of performance monitoring by neurons in posterior cingulate cortex during learning. Neuron, 80(6), 1384–1391.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herlin, B., Navarro, V., & Dupont, S. (2021). The temporal pole: From anatomy to function-a literature appraisal. Journal of Chemical Neuroanatomy, 113, 101925.

    PubMed  Google Scholar 

  • Hutchison, R. M., Womelsdorf, T., Allen, E. A., et al. (2013). Dynamic functional connectivity: Promise, issues, and interpretations. NeuroImage, 80, 360–378.

    PubMed  Google Scholar 

  • Jones, D. T., Vemuri, P., Murphy, M. C., et al. (2012). Non-stationarity in the "resting brain's" modular architecture. PLoS One, 7(6), e39731.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kucyi, A., & Davis, K. D. (2014). Dynamic functional connectivity of the default mode network tracks daydreaming. Neuroimage, 100, 471–480.

    PubMed  Google Scholar 

  • Lerner, Y., Honey, C. J., Silbert, L. J., et al. (2011). Topographic mapping of a hierarchy of temporal receptive windows using a narrated story. The Journal of Neuroscience, 31(8), 2906–2915.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li, L., Lu, B., & Yan, C. G. (2020). Stability of dynamic functional architecture differs between brain networks and states. NeuroImage, 216, 116230.

    PubMed  Google Scholar 

  • Li, X., Zhang, Y., Meng, C., et al. (2021). Functional stability predicts depressive and cognitive improvement in major depressive disorder: A longitudinal functional MRI study. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 111, 110396.

    Google Scholar 

  • Margulies, D. S., & Uddin, L. Q. (2019). Network convergence zones in the anterior midcingulate cortex. Handbook of Clinical Neurology, 166, 103–111.

    PubMed  Google Scholar 

  • Mina, A., Moran, S., Ortiz-Olvera, N., et al. (2014). Prevalence of minimal hepatic encephalopathy and quality of life in patients with decompensated cirrhosis. Hepatology Research : The Official Journal of the Japan Society of Hepatology, 44(10), E92–E99.

    Google Scholar 

  • Montoliu, C., Gonzalez-Escamilla, G., Atienza, M., et al. (2012). Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy. Neuroimage, 61(4), 1165–1175.

    PubMed  Google Scholar 

  • Mueller, S., Wang, D., Fox, M. D., et al. (2015). Reliability correction for functional connectivity: Theory and implementation. Human Brain Mapping, 36(11), 4664–4680.

    PubMed  PubMed Central  Google Scholar 

  • Nguyen, T. T., Kovacevic, S., Dev, S. I., et al. (2017). Dynamic functional connectivity in bipolar disorder is associated with executive function and processing speed: A preliminary study. Neuropsychology, 31(1), 73–83.

    PubMed  Google Scholar 

  • Nickel, J., & Seitz, R. J. (2005). Functional clusters in the human parietal cortex as revealed by an observer-independent meta-analysis of functional activation studies. Anatomy and Embryology, 210(5–6), 463–472.

    PubMed  Google Scholar 

  • Nikolaou, F., Orphanidou, C., Papakyriakou, P., et al. (2016). Spontaneous physiological variability modulates dynamic functional connectivity in resting-state functional magnetic resonance imaging. Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences, 374(2067), 20150183.

  • Noble, S., Spann, M. N., Tokoglu, F., et al. (2017). Influences on the test-retest reliability of functional connectivity MRI and its relationship with behavioral utility. Cerebral Cortex (New York, NY : 1991), 27(11), 5415–5429.

    Google Scholar 

  • Prasad, S., Dhiman, R. K., Duseja, A., et al. (2007). Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology (Baltimore, Md), 45(3), 549–559.

    Google Scholar 

  • Qi, R., Zhang, L. J., Chen, H. J., et al. (2015). Role of local and distant functional connectivity density in the development of minimal hepatic encephalopathy. Scientific Reports, 5, 13720.

    PubMed  PubMed Central  Google Scholar 

  • Rikkers, L., Jenko, P., Rudman, D., et al. (1978). Subclinical hepatic encephalopathy: Detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology, 75(3), 462–469.

    CAS  PubMed  Google Scholar 

  • Roland, P. E., Gulyás, B., Seitz, R. J., et al. (1990). Functional anatomy of storage, recall, and recognition of a visual pattern in man. Neuroreport, 1(1), 53–56.

    CAS  PubMed  Google Scholar 

  • Schomerus, H., & Schreiegg, J. (1993). Prevalence of latent portasystemic encephalopathy in an unselected population of patients with liver cirrhosis in general practice. Zeitschrift für Gastroenterologie, 31(4), 231–234.

    CAS  PubMed  Google Scholar 

  • Shehzad, Z., Kelly, A. M., Reiss, P. T., et al. (2009). The resting brain: Unconstrained yet reliable. Cerebral Cortex (New York, NY : 1991), 19(10), 2209–2229.

    Google Scholar 

  • Singh, J., Sharma, B. C., Maharshi, S., et al. (2016). Spectral electroencephalogram in liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy. Journal of Gastroenterology and Hepatology, 31(6), 1203–1209.

    CAS  PubMed  Google Scholar 

  • Small, D. M., Gitelman, D. R., Gregory, M. D., et al. (2003). The posterior cingulate and medial prefrontal cortex mediate the anticipatory allocation of spatial attention. Neuroimage, 18(3), 633–641.

    CAS  PubMed  Google Scholar 

  • Tarter, R. E., Hegedus, A. M., Van Thiel, D. H., et al. (1984). Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology, 86(6), 1421–1427.

    CAS  PubMed  Google Scholar 

  • Teng, C., Zhou, J., Ma, H., et al. (2018). Abnormal resting state activity of left middle occipital gyrus and its functional connectivity in female patients with major depressive disorder. BMC Psychiatry, 18(1), 370.

    PubMed  PubMed Central  Google Scholar 

  • Tomasi, D., & Volkow, N. D. (2010). Functional connectivity density mapping. Proceedings of the National Academy of Sciences of the United States of America, 107(21), 9885–9890.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vilstrup, H., Amodio, P., Bajaj, J., et al. (2014). Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the liver. Hepatology (Baltimore, Md), 60(2), 715–735.

    Google Scholar 

  • Wang, Y., Li, J., Wang, Z., et al. (2021). Spontaneous activity in primary visual cortex relates to visual creativity. Frontiers in Human Neuroscience, 15, 625888.

    PubMed  PubMed Central  Google Scholar 

  • Xu, H., Su, J., Qin, J., et al. (2018). Impact of global signal regression on characterizing dynamic functional connectivity and brain states. NeuroImage, 173, 127–145.

    PubMed  Google Scholar 

  • Yang, Y., Cui, Q., Pang, Y., et al. (2021). Frequency-specific alteration of functional connectivity density in bipolar disorder depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 104, 110026.

    CAS  Google Scholar 

  • Zafiris, O., Kircheis, G., Rood, H. A., et al. (2004). Neural mechanism underlying impaired visual judgement in the dysmetabolic brain: An fMRI study. Neuroimage, 22(2), 541–552.

    PubMed  Google Scholar 

  • Zhang, L. J., Zheng, G., Zhang, L., et al. (2014). Disrupted small world networks in patients without overt hepatic encephalopathy: A resting state fMRI study. European Journal of Radiology, 83(10), 1890–1899.

    PubMed  Google Scholar 

  • Zhang, G., Cheng, Y., Shen, W., et al. (2018). Brain regional homogeneity changes in cirrhotic patients with or without hepatic encephalopathy revealed by multi-frequency bands analysis based on resting-state functional MRI. Korean Journal of Radiology, 19(3), 452–462.

    PubMed  PubMed Central  Google Scholar 

  • Zhu, J., Zhang, S., Cai, H., et al. (2020). Common and distinct functional stability abnormalities across three major psychiatric disorders. NeuroImage Clinical, 27, 102352.

    PubMed  PubMed Central  Google Scholar 

  • Zhuo, C., Zhu, J., Qin, W., et al. (2014). Functional connectivity density alterations in schizophrenia. Frontiers in Behavioral Neuroscience, 8, 404.

    PubMed  PubMed Central  Google Scholar 

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Funding

This research was supported by grants from the National Natural Science Foundation of China (no. 82071900), Fujian Province Natural Science Foundation (nos. 2021 J01754, 2022J01254, and 2021 J01759), and Fujian Province Joint Funds for the Innovation of Science and Technology (no. 2019Y9067).

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Author notes

  1. Li-Min Cai, Jia-Yan Shi, Qiu-Yi Dong and Jin Wei contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China

    Li-Min Cai, Jia-Yan Shi, Qiu-Yi Dong, Jin Wei & Hua-Jun Chen

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  1. Li-Min Cai
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  3. Qiu-Yi Dong
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Contributions

LMC collected and analyzed the clinical and MRI data and was a major contributor in writing the manuscript. JYS and QYD performed the MRI scanning and the analysis regarding medical imaging data. JW performed the MRI scanning. HJC processed the resting state fMRI data and was a major contributor in the conceptualization, project administration, and writing the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hua-Jun Chen.

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All of the authors have no conflicts of interest to report.

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The Research Ethics Committee of the Fujian Medical University Union Hospital, China approved this study.

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Supplementary information

Supplementary Fig. 1

The effects of the global signal regression (GSR) on the functional stability analysis. The main findings in the analysis of variance (ANOVA) are similar when the analyses of functional stability without (A) and with (B) GSR are performed, indicating that GSR does not significantly influence the results. (PNG 1839 kb)

High resolution image (TIF 2766 kb)

Supplementary Fig. 2

The effects of different sliding-window parameters on the functional stability analysis. The sliding-window approach was used to analyze the dynamic functional connectivity with the following parameters: (A) window size = 64 s, sliding step = 4 s, and rectangular window type; (B) window size = 32 s, sliding step = 4 s, and rectangular window type; (C) window size = 48 s, sliding step = 4 s, and rectangular window type; (D) window size = 80 s, sliding step = 4 s, and rectangular window type; (E) window size = 64 s, sliding step = 2 s, and rectangular window type; and (F) window size = 64 s, sliding step = 4 s, and Hamming window type. The primary findings in the analysis of variance (ANOVA) can be replicated by performing the analyses of functional stability according to different window lengths (= 32 s, 48 s, 64 s, and 80 s), sliding steps (= 2 s and 4 s), and window types (including the rectangular and Hamming window types). This indicates that varying sliding-window parameters have no significant influence on the results. (PNG 576 kb)

High resolution image (TIF 8182 kb)

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Cai, LM., Shi, JY., Dong, QY. et al. Aberrant stability of brain functional architecture in cirrhotic patients with minimal hepatic encephalopathy. Brain Imaging and Behavior 16, 2258–2267 (2022). https://doi.org/10.1007/s11682-022-00696-9

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