, 198:323 | Cite as

Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer’s disease

  • Lorena R. R. GianottiEmail author
  • Gabriella Künig
  • Pascal L. Faber
  • Dietrich Lehmann
  • Roberto D. Pascual-Marqui
  • Kieko Kochi
  • Ursula Schreiter-Gasser
Original Investigation



The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer’s disease patients.

Materials and methods

Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer’s Disease were collected before and 3 months after the onset of rivastigmine medication.


Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards ‘normalization’. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula.


The results point to a ‘normalization’ of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer’s disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517–3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease.


Alzheimer’s disease Rivastigmine Cholinesterase inhibitors EEG Spectral analysis Source localization LORETA functional imaging 



The authors thank Mr. M. Manske and Mr. P. Lirgg for technical collaboration. The authors declare that this work was in part supported by NOVARTIS foundation (Grant no. CENA713IN01). PLF declares that in 2005 has received a 5% time compensation from NOVARTIS foundation, the manufacturer of rivastigmine, besides the 60% time income received from his primary employer.


  1. Adler G, Brassen S (2001) Short-term rivastigmine treatment reduces EEG Slow-wave power in Alzheimer patients. Neuropsychobiology 43:273–276PubMedCrossRefGoogle Scholar
  2. Adler G, Brassen S, Chwalek K, Dieter B, Teufel M (2004) Prediction of treatment response to rivastigmine in Alzheimer’s dementia. J Neurol Neurosur Ps 75:292–294Google Scholar
  3. Almkvist O, Darreh-Shori T, Stefanova E, Spiegel R, Nordberg A (2004) Preserved cognitive function after 12 months of treatment with rivastigmine in mild Alzheimer’s disease in comparison with untreated AD and MCI patients. Eur J Neurol 11:253–261PubMedCrossRefGoogle Scholar
  4. Almkvist O, Jelic V, Amberla K, Hellström-Lindahl E, Meurling L, Nordberg A (2001) Responder characteristics to a single oral dose of cholinesterase inhibitor: a double-blind placebo-controlled study with tacrine in Alzheimer patients. Dement Geriatr Cogn Disord 12:22–32Google Scholar
  5. Babiloni C, Binetti G, Cassetta E, Dal Forno G, Del Percio C, Ferreri F, Ferri R, Frisoni G, Hirata K, Lanuzza B, Miniussi C, Moretti DV, Nobili F, Rodriguez G, Romani GL, Salinari S, Rossini PM (2006a) Sources of cortical rhythms change as a function of cognitive impairment in pathological aging a multicenter study. Clin Neurophysiol 117:252–268PubMedCrossRefGoogle Scholar
  6. Babiloni C, Cassetta E, Dal Forno G, Del Percio C, Ferreri F, Ferri R, Lanuzza B, Miniussi C, Moretti DV, Nobili F, Pascual-Marqui RD, Rodriguez G, Romani GL, Salinari S, Zanetti O, Rossini PM (2006b) Donepezil effects on sources of cortical rhythms in mild Alzheimer’s disease: responders vs. nonresponders. Neuroimage 31:1650–1665PubMedCrossRefGoogle Scholar
  7. Babiloni C, Cassetta E, Binetti G, Tombini M, Del Percio C, Ferreri F, Ferri R, Frisoni G, Lanuzza B, Nobili F, Parisi L, Rodriguez G, Frigerio L, Gurzi M, Presia A, Vernieri F, Eusebi F, Rossini PM (2007) Resting EEG sources correlate with attentional span in mild cognitive impairment and Alzheimer’s disease. Eur J Neurosci 25:3742–3757PubMedCrossRefGoogle Scholar
  8. Balkan S, Yaraş N, Mihçi E, Dora B, Ağar A, Yargiçoğlu P (2003) Effect of denepezil on EEG spectral analysis in Alzheimer’s disease. Acta Neurol Belg 103:164–169PubMedGoogle Scholar
  9. Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA, Meltzer CC, Constantine G, Davis JG, Mathis CA, DeKosky ST, Moore RY (2005) Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosur Ps 76:315–319CrossRefGoogle Scholar
  10. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  11. Bradley KM, O’Sullivan VT, Soper NDW, Nagy Z, King EM-F, Smith AD, Shepstone BJ (2002) Cerebral perfusion SPECT correlated with Braak pathological stage in Alzheimer’s disease. Brain 125:1772–1781PubMedCrossRefGoogle Scholar
  12. Brassen S, Adler G (2003) Short-term effects of acetylcholinesterase inhibitor treatment on EEG and memory performance in Alzheimer patients: an open, controlled trial. Pharmacopsychiatry 36:304–308PubMedCrossRefGoogle Scholar
  13. Buchan RJ, Nagata K, Yokoyama E, Langman P, Yuya H, Hirata Y, Hatazawa J, Kanno I (1997) Regional correlations between the EEG and oxygen metabolism in dementia of Alzheimer’s type. Electroenceph Clin Neurophysiol 103:409–417PubMedCrossRefGoogle Scholar
  14. Bullock R, Dengiz A (2005) Cognitive performance in patients with Alzheimer’s disease receiving cholinesterase inhibitors for up to 5 years. Int J Clin Pract 59:817–822PubMedCrossRefGoogle Scholar
  15. Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL, DePeau K, Rentz DM, Selkoe DJ, Blacker D, Albert MS, Sperling RA (2006) Alterations in memory networks in mild cognitive impairment and Alzheimer’ disease: An independent component analysis. J Neurosci 26:10222–10231PubMedCrossRefGoogle Scholar
  16. Ceravolo R, Volterrani D, Tognoni G, Dell’gnello G, Manca G, Kiferle L, Rossi Logi C, Strauss HW, Mariani G, Murri L (2004) Cerebral perfusional effects of cholinesterase inhibitors in Alzheimer disease. Clin Neuropharmacol 27:166–170PubMedCrossRefGoogle Scholar
  17. Collins DL, Neelin P, Peters TM, Evans AC (1994) Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr 18:192–205PubMedCrossRefGoogle Scholar
  18. Crouzier D, Baubichon D, Bourbon F, Testylier G (2006) Acetylcholine release, EEG spectral analysis, sleep staging and body temperature studies: a multiparametric approach on freely moving rats. J Neurosci Methods 151:159–167PubMedCrossRefGoogle Scholar
  19. Dickson J, Drury H, Van Essen DC (2001) ‘The surface management system’ (SuMS) database: A surface-based database to aid cortical surface reconstruction, visualization and analysis. Philos T Roy Soc B 356:1277–1292CrossRefGoogle Scholar
  20. Dierks T, Vesna J, Pascual-Marqui RD, Wahlund LO, Julin P, Linden DEJ, Maurer K, Winblad B, Nordberg A (2000) Spatial pattern of cerebral glucose metabolism (PET) correlates with localization of intracerebral EEG-generators in Alzheimer’s disease. Clin Neurophysiol 111:1817–1824PubMedCrossRefGoogle Scholar
  21. Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, Mohs RC, Thal LJ, Whitehouse PJ, DeKosky ST, Cummings JL (2001) Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 56:1154–1166PubMedGoogle Scholar
  22. Farlow M, Anand R, Messin J Jr, Hartman R, Veach J (2000) A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’ disease. Eur Neurol 44:236–241PubMedCrossRefGoogle Scholar
  23. Feldman HH, Lane R (2007) Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 78:1056–1063PubMedCrossRefGoogle Scholar
  24. Folstein MF, Folstein SE, McHugh PR (1975) ‘Mini’-mental state. A practical method for grading the cognitive state of patients’ for the clinician. J Psychiat Res 12:189–198PubMedCrossRefGoogle Scholar
  25. Foundas AL, Leonard CM, Mahoney SM, Agee OF, Heilman KM (1997) Atrophy of the hippocampus, parietal cortex, and insula in Alzheimer’s disease: a volumetric magnetic resonance imaging study. Neuropsychiatry Neuropsychol Behav Neurol 10:81–89PubMedGoogle Scholar
  26. Frei E, Gamma A, Pascual-Marqui R, Lehmann D, Hell D, Vollenweider FX (2001) Localization of MDMA-induced brain activity in healthy volunteers using low resolution brain electromagnetic tomography (LORETA). Hum Brain Mapp 4:152–165CrossRefGoogle Scholar
  27. Friston KJ, Frith CD, Liddle PF, Dolan RJ, Lammertsma AA, Frackowiak KS (1990) The relationship between global and local changes in PET scans. J Cerebr Blood-Flow Metab 10:458–466Google Scholar
  28. Gasser T, Bacher P, Mocks J (1982) Transformations towards the normal distribution of broad band spectral parameters of the EEG. Electroenceph Clin Neurophysiol 53:119–124PubMedCrossRefGoogle Scholar
  29. Geula C (1998) Abnormalities of neural circuitry in Alzheimer’ disease: hippocampus and cortical cholinergic innervation. Neurology 51:18–29Google Scholar
  30. Gianotti LRR, Künig G, Lehmann D, Faber PL, Pascual-Marqui RD, Kochi K, Schreiter-Gasser U (2007) Correlation between disease severity and brain electric LORETA tomography in Alzheimer’s disease. Clin Neurophysiol 118:186–196PubMedCrossRefGoogle Scholar
  31. Grasby PM, Frith CD, Friston KJ, Simpson J, Fletcher PC, Frackowiak RS, Dolan RJ (1994) A graded task approach to the functional mapping of brain areas implicated in auditory–verbal memory. Brain 117:1271–1282PubMedCrossRefGoogle Scholar
  32. Gusnard DA, Raichle ME (2001) Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2:685–694PubMedCrossRefGoogle Scholar
  33. Hartikainen P, Soininen H, Partanen J, Helkala EL, Riekkinen P (1992) Aging and spectral analysis of EEG in normal subjects: a link to memory and CSF AChE. Acta Neurol Scand 86:148–155PubMedGoogle Scholar
  34. Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168–1170PubMedCrossRefGoogle Scholar
  35. Jagust WJ, Eberling JL, Reed BR, Mathis CA, Budinger TF (1997) Clinical studies of cerebral blood flow in Alzheimer’s disease. Ann NY Acad Sci 826:254–262PubMedCrossRefGoogle Scholar
  36. Jelic V, Dierks T, Amberla K, Almkvist O, Winblad B, Nordberg A (1998) Longitudinal changes in quantitative EEG during long-term tacrine treatment of patients with Alzheimer’s disease. Neurosci Lett 254:85–88PubMedCrossRefGoogle Scholar
  37. Keita MS, Frankel-Kohn L, Bertrand N, Lecanu L, Monmaura P (2000) Acetylcholine release in the hippocampus of the urethane anaesthetised rat positively correlates with both peak theta frequency and relative power in the theta band. Brain Res 887:323–334PubMedCrossRefGoogle Scholar
  38. Kogan EA, Korczyn AD, Virchovsky RG, Klimovizky SS, Treves TA, Neufeld MY (2001) EEG changes during long-term treatment with donepezil in Alzheimer’ disease patients. J Neural Transm 108:1167–1173PubMedCrossRefGoogle Scholar
  39. Kubicki S, Herrmann WM, Fichte K, Freund G (1979) Reflections on the topics: EEG frequency bands and regulation of vigilance. Pharmakopsychiatr Neuropsychopharmacol 12:237–245Google Scholar
  40. Lehmann D, Skrandies W (1980) Reference-free identification of components of checkerboard-evoked multichannel potential fields. Electroenceph Clin Neurophysiol 48:609–621PubMedCrossRefGoogle Scholar
  41. Machulda MM, Ward HA, Borowski B, Gunter JL, Cha RH, O’Brien PC, Petersen C, Boeve BF, Knopman D, Tang-Wai DF, Ivnik RJ, Smith GE, Tangalos EG, Jack CR Jr. (2003) Comparison of memory fMRI response among normal, MCI, and Alzheimer’s patients. Neurology 61:500–506PubMedGoogle Scholar
  42. Manes F, Springer J, Jorge R, Robinson RG (1999) Verbal memory impairment after left insular cortex infarction. J Neurol Neurosur Ps 67:532–534CrossRefGoogle Scholar
  43. Matsuda H (2001) Cerebral blood flow and metabolic abnormalities in Alzheimers disease. Ann Nucl Med 15:85–92PubMedGoogle Scholar
  44. McKahnn G, Drachmann D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health an Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944Google Scholar
  45. Mega MS, Cummings JL, O’Connor SM, Dinov ID, Reback E, Felix J, Masterman DL, Phelps ME, Small GW, Toga AW (2001) Cognitive and metabolic responses to Metrifonate therapy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol 14:63–68PubMedGoogle Scholar
  46. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’ disease. Ann Neurol 42:85–94PubMedCrossRefGoogle Scholar
  47. Mulert C, Jäger L, Schmitt R, Bussfeld P, Pogarell O, Möller H-J, Juckel G, Hegerl U (2004) Integration of fMRI and simultaneous EEG: towards a comprehensive understanding of localization and time-course of brain activity in target detection. NeuroImage 22:83–94PubMedCrossRefGoogle Scholar
  48. Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1–25PubMedCrossRefGoogle Scholar
  49. Nuwer MR, Comi G, Emerson R, Fuglsang-Frederiksen A, Guerit J-M, Hinrichs H, Ikeda A, Luccas FJ, Rappelsburger P (1998) IFCN standards for digital recording of clinical EEG. Electroenceph Clin Neurophysiol 106:259–261PubMedCrossRefGoogle Scholar
  50. Oakes TR, Pizzagalli DA, Hendrick AM, Horras KA, Larson CL, Abercrombie HC, Schaefer SM, Koger JV, Davidson RJ (2004) Functional coupling of simultaneous electrical and metabolic activity in the human brain. Hum Brain Mapp 21:257–270PubMedCrossRefGoogle Scholar
  51. Pascual-Marqui RD, Michel CM, Lehmann D (1994) Low resolution electromagnetic tomography: A new method for localizing electrical activity in the brain. Int J Psychophysiol 7:49–65CrossRefGoogle Scholar
  52. Pascual-Marqui RD, Lehmann D, Koenig T, Kochi K, Merlo MCG, Hell D, Koukkou M (1999) Functional imaging in acute, neuroleptic-naive, first-episode, productive schizophrenia. Psychiatr Res-Neuroim 90:169–179CrossRefGoogle Scholar
  53. Paulesu E, Frith CD, Frackowiak RSJ (1993) The neural correlates of the verbal component of working memory. Nature 362:342–345PubMedCrossRefGoogle Scholar
  54. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL (2001) A default mode of brain function. P Natl Acad Sci USA 98:676–682CrossRefGoogle Scholar
  55. Riekkinen P, Buzsaki G, Riekkinen Jr P, Soininen H, Partanen J (1991) The cholinergic system and EEG slow waves. Electroencephalogr Clin Neurophysiol 78:89–96PubMedCrossRefGoogle Scholar
  56. Shelley BP, Trimble MR (2004) The insular lobe of Reil—its anatamico-functional, behavioural and neuropsychiatric attributes in humans—review. World J Biol Psychiatry 5:176–200PubMedCrossRefGoogle Scholar
  57. Schreiter-Gasser U, Gasser T, Ziegler P (1993) Quantitative EEG analysis in early onset Alzheimer’s disease: a controlled study. Electroencephalogr Clin Neurophysiol 86:15–22PubMedCrossRefGoogle Scholar
  58. Schreiter-Gasser U, Gasser T, Ziegler P (1994) Quantitative EEG analysis in early onset Alzheimer’s disease: correlations with severity, clinical characteristics, visual EEG and CCT. Electroencephalogr Clin Neurophysiol 90:267–272PubMedCrossRefGoogle Scholar
  59. Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y (1999) Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Ann Neurol 45:466–472PubMedCrossRefGoogle Scholar
  60. Stefanova E, Wall A, Almkvist O, Nilsson A, Forsberg A, Långström B, Nordberg A (2006) Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer’s disease. J Neural Transm 113:205–218PubMedCrossRefGoogle Scholar
  61. Talairach J, Tournoux P (1988) Co-Planar Stereotaxic Atlas of the Human Brain. Stuttgart: ThiemeGoogle Scholar
  62. Towle VL, Bolanos J, Suarez D, Tan K, Grzeszczuk R, Levin D, Cakmur R, Frank SA, Spire JP (1993) The spatial location of EEG electrodes: Locating the best-fitting sphere relative to cortical anatomy. Electroencephalogr Clin Neurophysiol 86:1–6PubMedCrossRefGoogle Scholar
  63. Vincent JL, Snyder AZ, Fox MD, Shannon BJ, Andrews JR, Raichle ME, Buckner RN (2006) Coherent spontaneous activity identifies a hippocampal-parietal memory network. J Neurophysiol 96:3517–3531PubMedCrossRefGoogle Scholar
  64. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126PubMedCrossRefGoogle Scholar
  65. WHO (1993) The ICD-10 Classification of mental and behavioral disorders: diagnostic criteria for research. World Health Organization, Geneva, SwitzerlandGoogle Scholar
  66. Worrell GA, Lagerlund TD, Sharbrough FW, Brinkmann BH, Busacker NE, Cicora KM, O’Brien TJ (2000) Localization of the epileptic focus by low-resolution electromagnetic tomography in patients with a lesion demonstrated by MRI. Brain Topogr 12:273–282PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Lorena R. R. Gianotti
    • 1
    Email author
  • Gabriella Künig
    • 2
  • Pascal L. Faber
    • 1
  • Dietrich Lehmann
    • 1
  • Roberto D. Pascual-Marqui
    • 1
  • Kieko Kochi
    • 1
  • Ursula Schreiter-Gasser
    • 3
  1. 1.The KEY Institute for Brain-Mind ResearchUniversity Hospital of Psychiatry, University of ZurichZurichSwitzerland
  2. 2.Department of Psychiatry, Division of Geriatric PsychiatryUniversity of ZurichZurichSwitzerland
  3. 3.Praxis für Psychiatrie RehalpZurichSwitzerland

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