Abstract
Rationale
Daytime fatigue, which at the neurophysiological level is due to vigilance decrements, is a frequent complaint in postmenopausal women.
Objectives
In a three-arm, 2-month, parallel group-design study, vigilance-promoting effects of a novel continuous combination (=Climodien 2/3) of estradiol valerate (EV; 2 mg) and dienogest (DNG; 3 mg) were compared with the effects of both EV alone and placebo in 55 insomniac, postmenopausal syndrome patients.
Methods
Low-resolution brain electromagnetic tomography (LORETA) was undertaken to identify the cerebral target regions of hormone replacement therapy.
Results
An omnibus significance test revealed Climodien to increase activity in 882 of 2,394 voxels in the alpha-2 band, followed by 733, 706, and 664 voxels in the beta-2, beta-1, and beta-3 bands, and 509 voxels in the delta band, whereas 2 mg EV alone did not produce a significant suprathreshold activity. Current density increased predominantly in the right hemisphere, which had already been described in the literature as the center of the vigilance system. In the fast alpha range, which plays a major role in the context of vigilance, increased activity was found in the right prefrontal, temporal, and superior parietal cortices, i.e., those brain areas of the right-sided fronto-parietal neuronal network that are responsible for sustained attention. A further activity increase was seen in the anterior cingulate gyrus associated with attentional control and conflict monitoring. The right temporal lobe showed increased current density in all frequency bands.
Conclusions
Electroencephalographic tomography (LORETA) identified the right-hemispheric vigilance system as the target region of Climodien.
Similar content being viewed by others
References
Abt K (1991) Planning controlled clinical trials on the basis of descriptive data analysis. Stat Med 10:777–795
Anderer P, Saletu B, Kinsperger K, Semlitsch H (1987) Topographic brain mapping of EEG in neuropsychopharmacology—part I. Methodological aspects. Methods Find Exp Clin Pharmacol 9:371–384
Anderer P, Semlitsch H, Saletu B, Barbanoj M (1992) Artifact processing in topographic mapping of electroencephalic activity in neuropsychopharmacology. Psychiatry Res 45:79–93
Anderer P, Barbanoj MJ, Saletu B, Semlitsch HV (1993) Restriction to a limited set of EEG-target variables may lead to misinterpretation of pharmaco-EEG results. Neuropsychobiology 27:112–116
Anderer P, Saletu B, Pascual-Marqui RD (1998) Retest reliability of 3D-LORETA estimates of neural generators of classical frequency bands and changes after 5HTA-agonists (alnespirone and buspirone). Brain Topography. J Funct Neurophysiol 11(1):72
Anderer P, Saletu B, Pascual-Marqui RD (2000) Effect of the 5-HT1A partial agonist buspirone on regional brain electrical activity in man: a functional neuroimaging study using low-resolution electromagnetic tomography (LORETA). Psychiatry Res Neuroimaging 100:81–96
Anderer P, Semlitsch HV, Saletu B, Saletu-Zyhlarz G, Gruber D, Metka M, Huber J, Gräser T, Oettel M (2003) Effects of hormone replacement therapy on perceptual and cognitive event-related potentials in menopausal insomnia. Psychoneuroendocrinology 28:419–445
Anderer P, Saletu B, Saletu-Zyhlarz G, Gruber D, Metka M, Huber J, Pascual-Marqui RD (2004) Brain regions activated during an auditory discrimination task in insomniac postmenopausal patients before and after hormone replacement therapy: low-resolution brain electromagnetic tomography applied to event-related potentials. Neuropsychobiology 49:134–153
Arruda JE, Walker KA, Weiler MD, Valentino DA (1999) Validation of a right hemisphere vigilance system as measured by principal component and factor analyzed quantitative electroencephalogram. Int J Psychophysiol 32(2):119–128
Ary JP, Klein SA, Fender DH (1981) Location of sources of evoked scalp potentials: corrections for skull and scalp thickness. IEEE Trans Biomed Eng 28:447–452
Baumgartner A, Dietzel M, Saletu B, Wolf R, Campos-Barros A, Gräf K-J, Kürten I, Mannsmann U (1993) Influence of partial sleep deprivation on the secretion of thyrotropin, thyroid hormones, growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone and estradiol in healthy young women. Psychiatry Res 48:153–178
Bench CJ, Frith CD, Grasby PM, Friston KJ, Paulesu E, Frackowiak RSJ, Dolan RJ (1993) Investigations of the functional anatomy of attention using the Stroop test. Neuropsychologia 31(9):907–922
Bente D (1977) Vigilanz: Psychophysiologische Aspekte. Verh Dtsch Ges Inn Med 83:945–952
Berman KF, Weinberger DR (1990) Lateralisation of cortical function during cognitive tasks: regional cerebral blood flow studies of normal individuals and patients with schizophrenia. J Neurol Neurosurg Psychiatry 53(2):150–160
Conboy L, Domar A, O’Connell E (2001) Women at midlife: symptoms, attitudes and choices, an internet-based survey. Maturitas 38:129–136
Coull JT, Frackowiak RSJ, Frith CD (1998) Monitoring for target objects: activation of right frontal and parietal cortices with increasing time on task. Neuropsychologia 36(12):1325–1334
Cross EM, Chaffin WW (1982) Use of the binomial theorem in interpreting results of multiple tests of significance. Educ Psychol Meas 42:25–34
Ferber G, Abt K, Fichte K, Luthringer R (1999) IPEG guideline on statistical design and analysis for pharmacodynamic trials. Neuropsychobiology 39:92–100
Friston KJ (1996) Statistical parametric mapping and other analyses of functional imaging data. In: Toga AW, Mazziotta JC (eds) Brain mapping. Academic, San Diego, pp 363–386
Friston KJ, Frith CD, Liddle PF, Frackowiak RSJ (1991) Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab 11:690–699
Gasser T, Bacher P, Steinberg H (1985) Test-retest reliability of spectral parameters of the EEG. Electroencephalogr Clin Neurophysiol 60(4):312–319
Gräser T, Müller A, Mellinger U, Mück AO, Lippert TH, Oettel M (2000a) Continuous-combined treatment of the menopause with combinations of oestradiol valerate and dienogest—a dose ranging study. Maturitas 35:253–265
Gräser T, Koytchev R, Müller A, Oettel M (2000b) Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest® for continuous combined hormone replacement therapy in postmenopausal women. Climacteric 3:109–118
Head H (1923) The conception of nervous and mental energy. II. Vigilance: a physiological state of the nervous system. Br J Psychol 14:125–147
Hildebrandt H, Schwendemann G (2001) Tonic and phasic alertness—one or two right hemispheric cortico-subcortical networks? Aktuel Neurol 28(5):219–227
Kubicki S, Herrmann WM, Fichte K, Freund G (1979) Reflections on the topics: EEG frequency bands and regulation of vigilance. Pharmacopsychiatry 12:237–245
Kupperman HS, Wetchler BB, Blatt MHG (1959) Contemporary therapy of the menopausal syndrome. JAMA 171(12):1627–1637
Lancester JL, Rainey LH, Summerlin JL et al (1997) Automated labeling of the human brain—a preliminary report on the development and evaluation of a forward transform method. Hum Brain Mapp 5:238–242
Lewin JS, Friedman L, Wu D, Miller DA, Thompson LA, Klein SK, Wise AL, Hedera P, Buckley P, Meltzer H, Friedland RP, Duerk JL (1996) Cortical localization of human sustained attention: Detection with functional MR using a visual vigilance paradigm. J Comput Assist Tomogr 20(5):695–701
Linzmayer L, Semlitsch HV, Saletu B, Böck G, Saletu-Zyhlarz G, Zoghlami A, Gruber D, Metka M, Huber J, Oettel M, Gräser T, Grünberger J (2001) Double-blind, placebo-controlled psychometric studies on the effects of a combined estrogen–progestin regimen versus estrogen alone on performance, mood and personality of menopausal syndrome patients. Arzneimittelforschung/Drug Res 51(I):238–245
Luks TL, Simpson GV, Feiwell RJ, Miller WL (2002) Evidence for anterior cingulate cortex involvement in monitoring preparatory attentional set. Neuroimage 17(2):792–802
Meißner-Pöthig D, Zimmermann T, Domhardt R, Bitterlich N, Grässler A, Schmidt-Pich J, Foth D, Michalak U, Schulz J, Schicke B (2003) Die Gesundheit der Frau: Klimakterium, Vitalität und Hormonsubstitution—Ergebnisse einer funktionsdiagnostischen Pilotstudie. J Menopause 10(3):20–27
Menendez RGD, Andino SLG (2000) Discussing the capabilities of Laplacian minimization. Brain Topogr 13:97–104
Oettel M, Carol W, Elger W, Kaufmann G, Moore C, Römer W, Klinger G, Schneider B, Schröder J, Sobek L, Walter F, Zimmermann H (1995) A 19-norprogeston without an ethinyl group II: dienogest from a pharmacodynamic point of view. Drugs Today 31:517–536
Pardo JV, Fox PT, Raichle ME (1991) Localization of a human system for sustained attention by positron emission tomography. Nature 349(6304):61–64
Pascual-Marqui RD (1994) Low resolution electromagnetic tomography. Brain Topogr 7:180
Pascual-Marqui RD (1995) LORETA in 3D solution space. In: Skrandies W (ed) Source localization: continuing discussion of the inverse problem. ISBET Newslett 6:16–28
Pascual-Marqui RD (1999) Review of methods for solving the EEG inverse problem. Int J Bioelectromagnetism 1:75–86
Pascual-Marqui RD (2002) Standardized low resolution brain electromagnetic tomography (sLORETA): technical details. Methods Find Exp Clin Pharmacol 24(Suppl D):5–12
Pascual-Marqui RD, Michel CM (1994) LORETA (low resolution electromagnetic tomography): new authentic 3D functional images of the brain. In: Skrandies W (ed) Source localization: discussing the inverse problem. ISBET Newslett 5:4–8
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 18:49–65
Pascual-Marqui RD, Lehmann D, Koenig T, Kochi K, Merlo MCG, Hell D, Koukkou M (1999) Low resolution brain electromagnetic tomography (LORETA) functional imaging in acute, neuroleptic-naïve, first-episode, productive schizophrenia. Psychiatry Res Neuroimaging 90:169–179
Pascual-Marqui RD, Esslen M, Kochi K, Lehmann D (2002) Functional imaging with low resolution brain electromagnetic tomography (LORETA): review, new comparisons, and new validation. Jpn J Clin Neurophysiol 30:81–94
Paus T, Zatorre RJ, Hofle N, Caramanos Z, Gotman J, Petrides M, Evans AC (1997) Time-related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task. J Cogn Neurosci 9(3):392–408
Phillips C, Rugg MD, Friston KJ (2000a) Anatomically informed basis functions for EEG source localization: combining functional and anatomical constraints. NeuroImage 16:678–695
Phillips C, Rugg MD, Friston KJ (2000b) Systematic regularization of linear inverse solutions of the EEG source localization problem. NeuroImage 17:287–301
Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass MLS, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D for the WHIMS Investigators (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women. The women’s health initiative memory study: a randomized controlled trial. JAMA 289(20):2663–2672
Rechtschaffen A, Kales A (1968) A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Brain Information Service/Brain Research Institute, University of California, Los Angeles
Saletu B (1976) Psychopharmaka, Gehirntätigkeit und Schlaf. Karger, Basel
Saletu B, Brandstätter N, Metka M, Stamenkovic M, Anderer P, Semlitsch HV, Heytmanek G, Huber J, Grünberger J, Linzmayer L, Kurz C, Decker K, Binder G, Knogler W, Koll B (1995) Double-blind, placebo-controlled, hormonal, syndromal and EEG mapping studies with transdermal oestradiol therapy in menopausal depression. Psychopharmacology 122:321–329
Saletu B, Anderer P, Saletu-Zyhlarz GM, Arnold O, Pascual-Marqui RD (2002a) Classification and evaluation of the pharmacodynamics of psychotropic drugs by single-lead pharmaco-EEG, EEG mapping and tomography (LORETA). Methods Find Exp Clin Pharmacol 24(Suppl C):97–120
Saletu B, Anderer P, Gruber D, Metka M, Huber J, Saletu-Zyhlarz GM (2002b) Hormone replacement therapy and vigilance. Double-blind, placebo-controlled EEG-mapping studies with an estrogen–progestogen combination (Climodien®, Lafamme®) versus estrogen alone in menopausal syndrome patients. Maturitas 43:165–181
Saletu M, Anderer P, Saletu-Zyhlarz GM, Mandl M, Arnold O, Zeitlhofer J, Saletu B (2004) EEG-tomographic studies with LORETA on vigilance differences between narcolepsy patients and controls and subsequent double-blind, placebo-controlled studies with modafinil. J Neurol (in press)
Saletu-Zyhlarz G, Anderer P, Gruber G, Mandl M, Gruber D, Metka M, Huber J, Oettel M, Gräser T, Hassan Abu-Bakr M, Grätzhofer E, Saletu B (2003) Insomnia related to postmenopausal syndrome and hormone replacement therapy: sleep laboratory studies on baseline differences between patients and controls and double-blind, placebo-controlled investigations on the effects of a novel estrogen–progestogen combination (Climodien®, Lafamme®) versus estrogen alone. J Sleep Res 12:239–254
Schneider HP (2000) The role of antiandrogens in hormone replacement therapy. Climacteric 3:221–227
Short M (2003) Menopause, mood and management. Climacteric 6(Suppl 2):33–36
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller J for the WHIMS Investigators (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women’s health initiative memory study: a randomized controlled trial. JAMA 289(20):2651–2662
Skrandies W (1994) Source localization: discussing the inverse problem. ISBET Newslett 5:3–25
Skrandies W (1995) Source localization: continuing discussion of the inverse problem. ISBET Newslett 6:1–28
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Thieme, Stuttgart
Towle VL, Bolanos J, Suarez D et al (1993) The spatial location of EEG electrodes: locating the best-fitting sphere relative to cortical anatomy. Electroencephalogr Clin Neurophysiol 86:1–6
Van Veen V, Cohen JD, Botvinick MM, Stenger VA, Carter CS (2001) Anterior cingulate cortex, conflict monitoring, and levels of processing. NeuroImage 14(6):1302–1308
Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ for the WHI Investigators (2003) Effect of estrogen plus progestin on stroke in postmenopausal women. The women’s health initiative: a randomized trial. JAMA 289(20):2673–2684
Weinberg WA, Harper CR (1993) Vigilance and its disorders. Neurol Clin 11(1):59–78
Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 288:321–333
Yao D, He B (2001) A self-coherence enhancement algorithm and its application to enhancing three-dimensional source estimation from EEGs. Ann Biomed Eng 29:1019–1027
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Saletu, B., Anderer, P., Saletu-Zyhlarz, G.M. et al. Identifying target regions for vigilance improvement under hormone replacement therapy in postmenopausal syndrome patients by means of electroencephalographic tomography (LORETA). Psychopharmacology 178, 389–399 (2005). https://doi.org/10.1007/s00213-004-2029-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-004-2029-x