Advertisement

Metabolic Brain Disease

, Volume 31, Issue 5, pp 1065–1070 | Cite as

Intracortical inhibitory and excitatory circuits in subjects with minimal hepatic encephalopathy: a TMS study

  • Raffaele Nardone
  • Pierpaolo De Blasi
  • Yvonne Höller
  • Francesco Brigo
  • Stefan Golaszewski
  • Vanessa N. Frey
  • Andrea Orioli
  • Eugen Trinka
Original Article

Abstract

Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy (HE) and affects up to 80 % of patients with liver cirrhosis. By definition, MHE is characterized by psychomotor slowing and subtle cognitive deficits,  but obvious clinical manifestations are lacking. Given its covert nature, MHE is often underdiagnosed. This study was aimed at detecting neurophysiological changes, as assessed by means of transcranial magnetic stimulation (TMS), involved in the early pathogenesis of the HE. We investigated motor cortex excitability in 15 patients with MHE and in 15 age-matched age-matched cirrhotic patients without MHE; the resting motor threshold, the short-interval intracortical inhibition (SICI) and the intracortical facilitation (ICF) were examined. Paired-pulse TMS revealed significant increased SICI and reduced ICF in the patients with MHE. These findings may reflect abnormalities in intrinsic brain activity and altered organization of functional connectivity networks. In particular, the results suggest a shift in the balance between intracortical inhibitory and excitatory mechanisms towards a net increase of inhibitory neurotransmission. Together with other neurophysiological (in particular EEG) and neuroimaging techniques, TMS may thus provide early markers of cerebral dysfunction in cirrhotic patients with MHE.

Keywords

Transcranial magnetic stimulation Minimal hepatic encephalopathy Short-latency intracortical inhibition Intracortical facilitation Electroencephalography Magnetic resonance imaging 

Notes

Acknowledgments

None.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

References

  1. Albrecht J, Jones EA (1999) Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J Neurol Sci 170:138–146CrossRefPubMedGoogle Scholar
  2. Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 19:253–267CrossRefPubMedGoogle Scholar
  3. Amodio P, Valenti P, Del Piccolo F, Pellegrini A, Schiff S, Angeli P, Poci C, Mapelli D, Iannizzi P, Gatta A (2005) P300 latency for the diagnosis of minimal hepatic encephalopathy: evidence that spectral EEG analysis and psychometric tests are enough. Dig Liver Dis 37:861–868CrossRefPubMedGoogle Scholar
  4. Amodio P, Campagna F, Olianas S, Iannizzi P, Mapelli D, Penzo M, Angeli P, Gatta A (2008) Detection of minimal hepatic encephalopathy: normalization and optimization of the psychometric hepatic encephalopathy score. A neuropsychological and quantified EEG study. J Hepatol 49:346–353CrossRefPubMedGoogle Scholar
  5. Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, Morgan MY (2011) The design of clinical trials in hepatic encephalopathy—an international society for hepatic encephalopathy and nitrogen metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther 33:739–747CrossRefPubMedPubMedCentralGoogle Scholar
  6. Benardo LS (1995) N-Methyl-D-aspartate transmission modulates GABAB-mediated inhibition of rat hippocampal pyramidal neurons in vitro. Neuroscience 68:637–643CrossRefPubMedGoogle Scholar
  7. Cauli O, Rodrigo R, Llansola M, Montoliu C, Monfort P, Piedrafita B, El Mlili N, Boix J, Agustí A, Felipo V (2009) Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metab Brain Dis 24:69–80CrossRefPubMedGoogle Scholar
  8. 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 266:261–270CrossRefPubMedGoogle Scholar
  9. Ciancio A, Marchet A, Saracco G, Carucci P, Lavezzo B, Leotta D, Capellero B, Nobili M, Smedile A, Rizzetto M (2002) Spectral electroencephalogram analysis in hepatic encephalopathy and liver transplantation. Liver Transpl 8:630–635CrossRefPubMedGoogle Scholar
  10. Dharel N, Bajaj JS (2015) Definition and nomenclature of hepatic encephalopathy. J Clin Exp Hepatol S37–41Google Scholar
  11. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT (2002) Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th world congresses of gastroenterology, Vienna, 1998. Hepatology 35:716–721CrossRefPubMedGoogle Scholar
  12. Hallett M (2000) Transcranial magnetic stimulation and the human brain. Nature 406:147–150Google Scholar
  13. Kimiskidis VK, Papagiannopoulos S, Kazis DA, Sotirakoglou K, Vasiliadis G, Zara F, Kazis A, Mills KR (2006) Lorazepam-induced effects on silent period and corticomotor excitability. Exp Brain Res 173:603–611CrossRefPubMedGoogle Scholar
  14. Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Häussinger D (2002) Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 35:357–366CrossRefPubMedGoogle Scholar
  15. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519CrossRefPubMedPubMedCentralGoogle Scholar
  16. Martino ME, Fernández-Lorente J, Romero-Vives M, Bárcena R, Gaztelu JM (2014) Brain oscillatory activity during sleep shows unknown dysfunctions in early encephalopathy. J Physiol Biochem 70:821–835CrossRefPubMedGoogle Scholar
  17. Montoliu C, Gonzalez-Escamilla G, Atienza M, Urios A, Gonzalez O, Wassel A, Aliaga R, Giner-Duran R, Serra MA, Rodrigo JM, Belloch V, Felipo V, Cantero JL (2012) Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy. Neuroimage 61:1165–1175CrossRefPubMedGoogle Scholar
  18. Morgan MY, Amodio P, Cook NA, Jackson CD, Kircheis G, Lauridsen MM, Montagnese S, Schiff S, Weissenborn K (2015) Qualifying and quantifying minimal hepatic encephalopathy. Metab Brain Dis 2015Google Scholar
  19. Nolano M, Guardascione MA, Amitrano L, Perretti A, Fiorillo F, Ascione A, Santoro L, Caruso G (1997) Cortico-spinal pathways and inhibitory mechanisms in hepatic encephalopathy. Electroencephalogr Clin Neurophysiol 105:72–78CrossRefPubMedGoogle Scholar
  20. Paulus W, Classen J, Cohen LG, Large CH, Di Lazzaro V, Nitsche M, Pascual-Leone A, Rosenow F, Rothwell JC, Ziemann U (2008) State of the art: pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul 1:151–163CrossRefPubMedGoogle Scholar
  21. Poordad FF (2007) The burden of hepatic encephalopathy. Aliment Pharmacol Ther 25(Suppl 1):3–9CrossRefPubMedGoogle Scholar
  22. Qi R, Zhang L, Wu S, Zhong J, Zhang Z, Zhong Y, Ni L, Zhang Z, Li K, Jiao Q, Wu X, Fan X, Liu Y, Lu G (2012) Altered resting-state brain activity at functional MR imaging during the progression of hepatic encephalopathy. Radiology 264:187–195CrossRefPubMedGoogle Scholar
  23. Qi R, Zhang LJ, Zhong J, Zhu T, Zhang Z, Xu C, Zheng G, Lu GM (2013) Grey and white matter abnormalities in minimal hepatic encephalopathy: a study combining voxel-based morphometry and tract-based spatial statistics. Eur Radiol 23:3370–3378CrossRefPubMedGoogle Scholar
  24. Qi R, Zhang LJ, Luo S, Ke J, Kong X, Xu Q, Liu C, Lu H, Lu GM (2014) Default mode network functional connectivity: a promising biomarker for diagnosing minimal hepatic encephalopathy: CONSORT-compliant article. Medicine (Baltimore) 93, e227CrossRefGoogle Scholar
  25. Randolph C, Hilsabeck R, Kato A, Kharbanda P, Li YY, Mapelli D, Ravdin LD, Romero-Gomez M, Stracciari A, Weissenborn K, International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) (2009) Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. International society for hepatic encephalopathy and nitrogen metabolism (ISHEN). Liver Int 29:629–635CrossRefPubMedGoogle Scholar
  26. Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U (2015) Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol 126:1071–1107CrossRefPubMedGoogle Scholar
  27. Sanger TD, Garg RR, Chen R (2001) Interaction between two different inhibitory systems in the human motor cortex. J Physiol 530:307–317CrossRefPubMedPubMedCentralGoogle Scholar
  28. Sharma P, Sharma BC, Puri V, Sarin SK (2007) Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 47:67–73CrossRefPubMedGoogle Scholar
  29. Stinton LM, Jayakumar S (2013) Minimal hepatic encephalopathy. Can J Gastroenterol 27:572–574CrossRefPubMedPubMedCentralGoogle Scholar
  30. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P (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 60:715–735CrossRefPubMedGoogle Scholar
  31. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J (1999) Differential effects on motocortical inhibition induced by blockade of GABA uptake in humans. J Physiol 517:591–597CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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, e53206CrossRefPubMedPubMedCentralGoogle Scholar
  33. Ziemann U, Paulus W, Nitsche MA, Pascual-Leone A, Byblow WD, Berardelli A, Siebner HR, Classen J, Cohen LG, Rothwell JC (2008) Consensus: motor cortex plasticity protocols. Brain Stimul 1:164–182CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Raffaele Nardone
    • 1
    • 2
  • Pierpaolo De Blasi
    • 3
  • Yvonne Höller
    • 1
  • Francesco Brigo
    • 2
    • 4
  • Stefan Golaszewski
    • 1
  • Vanessa N. Frey
    • 1
  • Andrea Orioli
    • 2
  • Eugen Trinka
    • 1
  1. 1.Department of Neurology, Christian Doppler KlinikParacelsus Medical UniversitySalzburgAustria
  2. 2.Department of NeurologyFranz Tappeiner HospitalMeranoItaly
  3. 3.University of Torino and Collegio Carlo AlbertoTorinoItaly
  4. 4.Department of Neurological and Movement Sciences, Section of Clinical NeurologyUniversity of VeronaVeronaItaly

Personalised recommendations