Top

Published in:

01-12-2019 | Hepatic Encephalopathy | Original Article

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

Authors: Weiwen Lin, Xuhui Chen, Yong-Qing Gao, Zhe-Ting Yang, Weizhu Yang, Hua-Jun Chen

Published in: Metabolic Brain Disease | Issue 6/2019

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.

Available only for authorised users

Agrawal S, Umapathy S, Dhiman RK (2015) Minimal hepatic encephalopathy impairs quality of life. J Clin Exp Hepatol 5:S42–S48PubMed

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. 149:1483–1489PubMed

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

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:e29288PubMedPubMedCentral

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. 47:596–604PubMed

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. 50:1175–1183PubMedPubMedCentral

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

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

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 8:244PubMedPubMedCentral

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 141:194–203PubMed

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. 46:514–519PubMed

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 321:65–72PubMed

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 81:2463–2469PubMed

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. 266:261–270PubMed

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:e89684PubMedPubMedCentral

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

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 84:2287–2295PubMed

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 6:27092PubMedPubMedCentral

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 209:1128–1135PubMed

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 19:283–288PubMedPubMedCentral

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 2:235–245PubMedPubMedCentral

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

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

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. 41:299–306PubMed

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. 62:46–55PubMed

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 55:564–573PubMed

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 118:338–346PubMed

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:e35266PubMedPubMedCentral

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. 122:332–344PubMed

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. 6:1220–1231PubMedPubMedCentral

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 31:369–376PubMed

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 20:1434–1447PubMedPubMedCentral

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

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 44:104–110PubMed

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. 45:549–559PubMed

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:e53677PubMedPubMedCentral

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 82:850–856PubMed

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. 139:675–684PubMed

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 96:2718–2723PubMed

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

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 33:19304–19313PubMedPubMedCentral

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 164:5–13PubMedPubMedCentral

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 26:979–986PubMed

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

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 39:2381–2390PubMedPubMedCentral

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. 66:28–35PubMed

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

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

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:e53206PubMedPubMedCentral

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 83:1907–1913PubMed

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

Title: Hippocampal atrophy and functional connectivity disruption in cirrhotic patients with minimal hepatic encephalopathy
Authors: Weiwen Lin
Xuhui Chen
Yong-Qing Gao
Zhe-Ting Yang
Weizhu Yang
Hua-Jun Chen
Publication date: 01-12-2019
Publisher: Springer US
Keywords: Hepatic Encephalopathy
Magnetic Resonance Imaging
Magnetic Resonance Imaging
Hepatic Encephalopathy
Published in: Metabolic Brain Disease / Issue 6/2019
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-019-00457-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2019

The effects of Cinnamaldehyde on early brain injury and cerebral vasospasm following experimental subarachnoid hemorrhage in rabbits

Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy

Acylpeptide hydrolase (APEH) sequence variants with potential impact on the metabolism of the antiepileptic drug valproic acid

High fat-low protein diet induces metabolic alterations and cognitive dysfunction in female rats

Creatine plus pyruvate supplementation prevents oxidative stress and phosphotransfer network disturbances in the brain of rats subjected to chemically-induced phenylketonuria

Calotropis procera attenuates chronic unpredictable mild stress-induced depression in experimental animals