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Hippocampal atrophy and functional connectivity disruption in cirrhotic patients with minimal hepatic encephalopathy

Metabolic Brain Disease volume 34, pages 1519–1529 (2019)Cite this article

Abstract

The hippocampus is a crucial pathological node for minimal hepatic encephalopathy (MHE) and it is associated with various cognitive impairments. Investigations on alterations involving hippocampal morphology and functional connectivity (FC) in MHE are limited. This study aimed to simultaneously evaluate hippocampal volume and FC alterations and their association with cognitive decline in MHE. Twenty-two cirrhotic patients with MHE, 31 cirrhotic patients without MHE (NHE), and 43 healthy controls underwent high-resolution T1-weighted imaging, resting-state functional magnetic resonance imaging, and cognition assessment based on Psychometric Hepatic Encephalopathy Score (PHES). The structural images were preprocessed using a voxel-based morphometry method, during which hippocampal volume was measured. The hippocampal connectivity network was identified using seed-based correlation analysis. Hippocampal volume and FC strength were compared across the three groups and correlated against the PHES results of the cirrhotic patients. Compared to the controls, MHE patients exhibited a significantly lower bilateral hippocampal volume. A slight decrease in hippocampal volume was obtained from NHE to MHE, but it did not reach statistically significance. In addition, the average FC strength of the bilateral hippocampal connectivity network was significantly lower in the MHE patients. In particular, the MHE patients showed a decrease in FC involving the left hippocampus to bilateral posterior cingulate gyrus and left angular gyrus. The MHE patients also showed FC reduction between the right hippocampus and bilateral medial frontal cortex. A progressive reduction in hippocampal FC from NHE to MHE was also observed. The bilateral hippocampal FC strength (but not hippocampal volume) was positively correlated with the PHES results of the cirrhotic patients. Our assessment of MHE patients revealed decreased hippocampal volume, which suggests regional atrophy, and reduced hippocampal connectivity with regions that are primarily involved in the default-mode network, thereby suggesting a functional disconnection syndrome. These alterations reveal the mechanisms underlying cognitive deterioration with disease progression.

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Abbreviations

MHE:

minimal hepatic encephalopathy

HE:

hepatic encephalopathy

FC:

functional connectivity

PHES:

Psychometric Hepatic Encephalopathy Score

DMN:

default-mode network

References

  • Agrawal S, Umapathy S, Dhiman RK (2015) Minimal hepatic encephalopathy impairs quality of life. J Clin Exp Hepatol 5:S42–S48

    PubMed  Google Scholar 

  • Ampuero J, Simon M, Montoliu C, Jover R, Serra MA, Cordoba J, Romero-Gomez M (2015) Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis. Gastroenterology. 149:1483–1489

    PubMed  Google Scholar 

  • Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage. 38:95–113

    PubMed  Google Scholar 

  • Bai F, Xie C, Watson DR, Shi Y, Yuan Y, Wang Y, Yue C, Teng Y, Wu D, Zhang Z (2011) Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study. PLoS One 6:e29288

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bajaj JS, Hafeezullah M, Hoffmann RG, Varma RR, Franco J, Binion DG, Hammeke TA, Saeian K (2008) Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy. Hepatology. 47:596–604

    PubMed  Google Scholar 

  • Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, Franco J, Varma RR, Gibson DP, Hoffmann RG, Stravitz RT, Heuman DM, Sterling RK, Shiffman M, Topaz A, Boyett S, Bell D, Sanyal AJ (2009) Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology. 50:1175–1183

    PubMed  PubMed Central  Google Scholar 

  • Bird CM (2017) The role of the hippocampus in recognition memory. Cortex 93:155–165

    PubMed  Google Scholar 

  • Blankenship SL, Redcay E, Dougherty LR, Riggins T (2017) Development of hippocampal functional connectivity during childhood. Hum Brain Mapp 38:182–201

    PubMed  Google Scholar 

  • Brueggen K, Kasper E, Dyrba M, Bruno D, Pomara N, Ewers M, Duering M, Burger K, Teipel SJ (2016) The primacy effect in amnestic mild cognitive impairment: associations with hippocampal functional connectivity. Front Aging Neurosci 8:244

    PubMed  PubMed Central  Google Scholar 

  • Cao X, Liu Z, Xu C, Li J, Gao Q, Sun N, Xu Y, Ren Y, Yang C, Zhang K (2012) Disrupted resting-state functional connectivity of the hippocampus in medication-naive patients with major depressive disorder. J Affect Disord 141:194–203

    PubMed  Google Scholar 

  • Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology. 46:514–519

    CAS  PubMed  Google Scholar 

  • Chen HJ, Wang Y, Zhu XQ, Cui Y, Chen YC, Teng GJ (2012a) White matter abnormalities correlate with neurocognitive performance in patients with HBV-related cirrhosis. J Neurol Sci 321:65–72

    PubMed  Google Scholar 

  • Chen HJ, Zhu XQ, Shu H, Yang M, Zhang Y, Ding J, Wang Y, Teng GJ (2012b) Structural and functional cerebral impairments in cirrhotic patients with a history of overt hepatic encephalopathy. Eur J Radiol 81:2463–2469

    PubMed  Google Scholar 

  • Chen HJ, Jiao Y, Zhu XQ, Zhang HY, Liu JC, Wen S, Teng GJ (2013) Brain dysfunction primarily related to previous overt hepatic encephalopathy compared with minimal hepatic encephalopathy: resting-state functional MR imaging demonstration. Radiology. 266:261–270

    PubMed  Google Scholar 

  • Chen HJ, Wang Y, Zhu XQ, Li PC, Teng GJ (2014a) Classification of cirrhotic patients with or without minimal hepatic encephalopathy and healthy subjects using resting-state attention-related network analysis. PLoS One 9:e89684

    PubMed  PubMed Central  Google Scholar 

  • Chen JR, Wang BN, Tseng GF, Wang YJ, Huang YS, Wang TJ (2014b) Morphological changes of cortical pyramidal neurons in hepatic encephalopathy. BMC Neurosci 15:15

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen HJ, Jiang LF, Sun T, Liu J, Chen QF, Shi HB (2015) Resting-state functional connectivity abnormalities correlate with psychometric hepatic encephalopathy score in cirrhosis. Eur J Radiol 84:2287–2295

    PubMed  Google Scholar 

  • Chen HJ, Chen QF, Liu J, Shi HB (2016) Aberrant salience network and its functional coupling with default and executive networks in minimal hepatic encephalopathy: a resting-state fMRI study. Sci Rep 6:27092

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen HJ, Liu PF, Chen QF, Shi HB (2017) Brain microstructural abnormalities in patients with cirrhosis without overt hepatic encephalopathy: a voxel-based diffusion kurtosis imaging study. AJR Am J Roentgenol 209:1128–1135

    PubMed  Google Scholar 

  • Ciecko-Michalska I, Wojcik J, Senderecka M, Wyczesany M, Binder M, Szewczyk J, Dziedzic T, Slowik A, Mach T (2013) Cognitive functions in patients with liver cirrhosis: a tendency to commit more memory errors. Med Sci Monit 19:283–288

    PubMed  PubMed Central  Google Scholar 

  • Deshpande G, Hu X (2012) Investigating effective brain connectivity from fMRI data: past findings and current issues with reference to granger causality analysis. Brain connect 2:235–245

    PubMed  PubMed Central  Google Scholar 

  • Dhanda S, Sunkaria A, Halder A, Sandhir R (2018) Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy. Metab Brain Dis 33:209–223

    CAS  PubMed  Google Scholar 

  • Eichenbaum H, Cohen NJ (2014) Can we reconcile the declarative memory and spatial navigation views on hippocampal function? Neuron. 83:764–770

    CAS  PubMed  PubMed Central  Google Scholar 

  • Erceg S, Monfort P, Hernandez-Viadel M, Rodrigo R, Montoliu C, Felipo V (2005) Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology. 41:299–306

    CAS  PubMed  Google Scholar 

  • Galland F, Negri E, Da Re C, Froes F, Strapazzon L, Guerra MC, Tortorelli LS, Goncalves CA, Leite MC (2017) Hyperammonemia compromises glutamate metabolism and reduces BDNF in the rat hippocampus. Neurotoxicology. 62:46–55

    CAS  PubMed  Google Scholar 

  • Guevara M, Baccaro ME, Gomez-Anson B, Frisoni G, Testa C, Torre A, Molinuevo JL, Rami L, Pereira G, Sotil EU, Cordoba J, Arroyo V, Gines P (2011) Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy. J Hepatol 55:564–573

    PubMed  Google Scholar 

  • Hiba OE, Elgot A, Ahboucha S, Gamrani H (2016) Differential regional responsiveness of astroglia in mild hepatic encephalopathy: an Immunohistochemical approach in bile duct ligated rat. Acta Histochem 118:338–346

    PubMed  Google Scholar 

  • Hsu TW, Wu CW, Cheng YF, Chen HL, Lu CH, Cho KH, Lin WC, Lin CP (2012) Impaired small-world network efficiency and dynamic functional distribution in patients with cirrhosis. PLoS One 7:e35266

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jao T, Schroter M, Chen CL, Cheng YF, Lo CZ, Chou KH, Patel AX, Lin WC, Lin CP, Bullmore ET (2015) Functional brain network changes associated with clinical and biochemical measures of the severity of hepatic encephalopathy. NeuroImage. 122:332–344

    PubMed  Google Scholar 

  • Kong X, Luo S, Wu JR, Wu S, De Cecco CN, Schoepf UJ, Spandorfer AJ, Wang CY, Tian Y, Chen HJ, Lu GM, Yang GF, Zhang LJ (2016) (18)F-DPA-714 PET imaging for detecting Neuroinflammation in rats with chronic hepatic encephalopathy. Theranostics. 6:1220–1231

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee Y, Kim C, Suk KT, Choi HC, Bang CS, Yoon JH, Baik GH, Kim DJ, Jang MU, Sohn JH (2016) Differences in cognitive function between patients with viral and alcoholic compensated liver cirrhosis. Metab Brain Dis 31:369–376

    PubMed  Google Scholar 

  • Lisman J, Buzsaki G, Eichenbaum H, Nadel L, Ranganath C, Redish AD (2017) Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci 20:1434–1447

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maguire EA, Burgess N, O'Keefe J (1999) Human spatial navigation: cognitive maps, sexual dimorphism, and neural substrates. Curr Opin Neurobiol 9:171–177

    CAS  PubMed  Google Scholar 

  • Montoliu C, Urios A, Forn C, Garcia-Panach J, Avila C, Gimenez-Garzo C, Wassel A, Serra MA, Giner-Duran R, Gonzalez O, Aliaga R, Belloch V, Felipo V (2013). Reduced white matter microstructural integrity correlates with cognitive deficits in minimal hepatic encephalopathy. Gut

  • Ortiz M, Cordoba J, Jacas C, Flavia M, Esteban R, Guardia J (2006) Neuropsychological abnormalities in cirrhosis include learning impairment. J Hepatol 44:104–110

    PubMed  Google Scholar 

  • Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (2007) Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 45:549–559

    PubMed  Google Scholar 

  • Qi R, Zhang LJ, Zhong J, Zhang Z, Ni L, Jiao Q, Liao W, Zheng G, Lu G (2013a) Altered effective connectivity network of the basal ganglia in low-grade hepatic encephalopathy: a resting-state fMRI study with granger causality analysis. PLoS One 8:e53677

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qi R, Zhang LJ, Zhong J, Zhang Z, Ni L, Zheng G, Lu GM (2013b) Disrupted thalamic resting-state functional connectivity in patients with minimal hepatic encephalopathy. Eur J Radiol 82:850–856

    PubMed  Google Scholar 

  • Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, Felipo V (2010) Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology. 139:675–684

    CAS  PubMed  Google Scholar 

  • Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar-Reina J (2001) Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 96:2718–2723

    CAS  PubMed  Google Scholar 

  • Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254

    CAS  PubMed  Google Scholar 

  • Sherrill KR, Erdem UM, Ross RS, Brown TI, Hasselmo ME, Stern CE (2013) Hippocampus and retrosplenial cortex combine path integration signals for successful navigation. J Neurosci 33:19304–19313

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shu H, Yuan Y, Xie C, Bai F, You J, Li L, Li SJ, Zhang Z (2014) Imbalanced hippocampal functional networks associated with remitted geriatric depression and apolipoprotein E epsilon4 allele in nondemented elderly: a preliminary study. J Affect Disord 164:5–13

    CAS  PubMed  PubMed Central  Google Scholar 

  • Srivastava A, Yadav SK, Yachha SK, Thomas MA, Saraswat VA, Gupta RK (2011) Pro-inflammatory cytokines are raised in extrahepatic portal venous obstruction, with minimal hepatic encephalopathy. J Gastroenterol Hepatol 26:979–986

    CAS  PubMed  Google Scholar 

  • Szczepanski SM, Knight RT (2014) Insights into human behavior from lesions to the prefrontal cortex. Neuron. 83:1002–1018

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thielen JW, Hong D, Rohani Rankouhi S, Wiltfang J, Fernandez G, Norris DG, Tendolkar I (2018) The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal-thalamus-hippocampus network. Hum Brain Mapp 39:2381–2390

    PubMed  PubMed Central  Google Scholar 

  • Zarei M, Beckmann CF, Binnewijzend MA, Schoonheim MM, Oghabian MA, Sanz-Arigita EJ, Scheltens P, Matthews PM, Barkhof F (2013) Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease. NeuroImage. 66:28–35

    PubMed  Google Scholar 

  • Zeidman P, Maguire EA (2016) Anterior hippocampus: the anatomy of perception, imagination and episodic memory. Nat Rev Neurosci 17:173–182

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XD, Zhang LJ (2018) Multimodal MR imaging in hepatic encephalopathy: state of the art. Metab Brain Dis 33:661–671

    PubMed  Google Scholar 

  • Zhang LJ, Qi R, Zhong J, Ni L, Zheng G, Xu J, Lu GM (2013) Disrupted functional connectivity of the anterior cingulate cortex in cirrhotic patients without overt hepatic encephalopathy: a resting state fMRI study. PLoS One 8:e53206

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Liu X, Zhang Y, Song L, Hou J, Chen B, He M, Cai P, Lii H (2014) Disrupted functional connectivity of the hippocampus in patients with hyperthyroidism: evidence from resting-state fMRI. Eur J Radiol 83:1907–1913

    PubMed  Google Scholar 

  • Zhang G, Cheng Y, Liu B (2017) Abnormalities of voxel-based whole-brain functional connectivity patterns predict the progression of hepatic encephalopathy. Brain Imaging and Behav 11(3):784–796

    CAS  Google Scholar 

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Funding

This study was funded by the grants from the National Natural Science Foundation of China (No.81501450), Fujian Provincial Science Fund for Distinguished Young Scholars (No. 2018 J06023), Fujian Provincial Program for Distinguished Young Scholars (No.2017B023), Startup Fund for scientific research, Fujian Medical University (Grant number: 2018QH1034), and Fujian Provincial Health Commission Project for Scientific Research Talents (No.2018-ZQN-28).

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Author notes

  1. Weiwen Lin, Xuhui Chen and Yong-Qing Gao contributed equally to this work.

Affiliations

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

    Weiwen Lin, Xuhui Chen, Zhe-Ting Yang & Hua-Jun Chen

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

    Weizhu Yang

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  1. Weiwen Lin
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  2. Xuhui Chen
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Correspondence to Weizhu Yang or Hua-Jun Chen.

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Supplementary Figure 1
figure 7

Differences in gray matter volume between cirrhotic patients without overt hepatic encephalopathy (n = 53) and healthy controls (n = 43), as revealed by voxel-based morphology analysis. The statistical threshold was set at P < 0.01 (FDR correction), with a cluster size >350 voxels. The yellow and blue colors indicate regions with decreased and increased volume in patients, respectively. Notably, the bilateral hippocampus shows a significant reduction in regional volume. The letters “L” and “R” respectively indicate the left and right sides of the brain. (PNG 1039 kb)

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Lin, W., Chen, X., Gao, YQ. et al. Hippocampal atrophy and functional connectivity disruption in cirrhotic patients with minimal hepatic encephalopathy. Metab Brain Dis 34, 1519–1529 (2019). https://doi.org/10.1007/s11011-019-00457-6

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Keywords

  • Minimal hepatic encephalopathy
  • Functional connectivity
  • Hippocampus
  • Atrophy
  • Resting state functional magnetic resonance imaging