Abstract
Rationale
Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, an anesthetic agent, and a treatment for neuropsychiatric disorders. In previous electroencephalography (EEG) studies, GHB was shown to induce an electrophysiological pattern of “paradoxical EEG-behavioral dissociation” characterized by increased delta and theta oscillations usually associated with sleep during awake states. However, no detailed source localization of these alterations and no connectivity analyses have been performed yet.
Objectives and methods
We tested the effects of GHB (20 and 35 mg/kg, p.o.) on current source density (CSD), lagged phase synchronization (LPS), and global omega complexity (GOC) of neuronal oscillations in a randomized, double-blind, placebo-controlled, balanced cross-over study in 19 healthy, male participants using exact low-resolution electromagnetic tomography (eLORETA) of resting-state high-density EEG recordings.
Results
Compared to placebo, GHB increased CSD of theta oscillations (5–7 Hz) in the posterior cingulate cortex (PCC) and alpha1 (8–10 Hz) oscillations in the anterior cingulate cortex. Higher blood plasma values were associated with higher LPS values of delta (2–4 Hz) oscillations between the PCC and the right inferior parietal lobulus. Additionally, GHB decreased GOC of alpha1 oscillations.
Conclusion
These findings indicate that alterations in neuronal oscillations in the PCC mediate the psychotropic effects of GHB. Theta oscillations emerging from the PCC in combination with stability of functional connectivity within the default mode network might explain the GHB-related “paradoxical EEG-behavioral dissociation.” Our findings related to GOC suggest a reduced number of relatively independent neuronal processes, an effect that has also been demonstrated for other anesthetic agents.
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References
Abanades S, Farré M, Segura M, Pichini S, Barral D, Pacifici R et al (2006) Gamma-hydroxybutyrate (GHB) in humans: pharmacodynamics and pharmacokinetics. Ann N Y Acad Sci 1074:559–576. doi:10.1196/annals.1369.065
Appleton P, Burn J (1968) A neuroinhibitory substance: gamma hydroxybutyric acid. Preliminary report of first clinical trial in Britain. Anesth Analg 47(2):164–170
Babiloni C, Lizio R, Carducci F, Vecchio F, Redolfi A, Marino S et al (2011) Resting state cortical electroencephalographic rhythms and white matter vascular lesions in subjects with Alzheimer’s disease: an Italian multicenter study. J Alzheimers Dis 26(2):331–346. doi:10.3233/JAD-2011-101710
Borgen LA, Okerholm RA, Lai A, Scharf MB (2004) The pharmacokinetics of sodium oxybate oral solution following acute and chronic administration to narcoleptic patients. J Clin Pharmacol 44(3):253–257. doi:10.1177/0091270003262795
Bosch OG, Quednow BB, Seifritz E, Wetter TC (2012) Reconsidering GHB: orphan drug or new model antidepressant? J Psychopharmacol 26(5):618–628
Bosch OG, Rihm JS, Scheidegger M, Landolt H-P, Stampfli P, Brakowski J et al (2013) Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans. Proc Natl Acad Sci U S A 110(48):19597–19602. doi:10.1073/pnas.1317010110
Bosch OG, Eisenegger C, Gertsch J, von Rotz R, Dornbierer D, Gachet MS et al (2015) Gamma-hydroxybutyrate enhances mood and prosocial behavior without affecting plasma oxytocin and testosterone. Psychoneuroendocrinology 62:1–10. doi:10.1016/j.psyneuen.2015.07.167
Brenneisen R, ElSohly MA, Murphy TP, Passarelli J, Russmann S, Salamone SJ, Watson DE (2004) Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects. J Anal Toxicol 28(8):625–630. doi:10.1093/jat/28.8.625
Buzsáki G, Draguhn A (2004) Neuronal oscillations in cortical networks. Science 304(5679):1926–1929. doi:10.1126/science.1099745
Canuet L, Ishii R, Pascual-Marqui RD, Iwase M, Kurimoto R, Aoki Y et al (2011) Resting-state EEG source localization and functional connectivity in schizophrenia-like psychosis of epilepsy. PLoS One 6(11):e27863. doi:10.1371/journal.pone.0027863
Carhart-Harris RL, Leech R, Hellyer PJ, Shanahan M, Feilding A, Tagliazucchi E et al (2014) The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci 8:20. doi:10.3389/fnhum.2014.00020
de Havas JA, Parimal S, Soon CS, Chee MWL (2012) Sleep deprivation reduces default mode network connectivity and anti-correlation during rest and task performance. NeuroImage 59(2):1745–1751. doi:10.1016/j.neuroimage.2011.08.026
De Ridder D, Vanneste S, Kovacs S, Sunaert S, Dom G (2011) Transient alcohol craving suppression by rTMS of dorsal anterior cingulate: an fMRI and LORETA EEG study. Neurosci Lett 496(1):5–10
Ducloux B, Guieu J, Krivosic-Horber R (1989) Effects éléctroencéphalographiques (EEG) de l’induction par gammahydroxybutyrate de sodium (G-OH) chez l’enfant. Cah Anesthesiol 37(8):559–564
Entholzner E, Mielke L, Pichlmeier R, Weber F, Schneck H (1995) EEG-Veränderungen unter Sedierung mit gamma-hydroxybuttersäure (GHB). Anaesthesist 44(5):345–350. doi:10.1007/s001010050163
Ferrara SD, Zotti S, Tedeschi L, Frison G, Castagna F, Gallimberti L et al (1992) Pharmacokinetics of gamma hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses. Br J Clin Pharmacol 34(3):231–235
Friston KJ, Tononi G, Sporns O, Edelman GM (1995) Characterising the complexity of neuronal interactions. Hum Brain Mapp 3(4):302–314. doi:10.1002/hbm.460030405
Fuller DE, Hornfeldt CS, Kelloway JS, Stahl PJ, Anderson TF (2003) The Xyrem® risk management program. Drug Saf 27(5):293–306. doi:10.2165/00002018-200427050-00002
Galloway G, Frederick-Osborne S, Seymour R, Contini SE, Smith DE (2000) Abuse and therapeutic potential of gamma-hydroxybutyric acid. Alcohol 20(3):263–269. doi:10.1016/S0741-8329(99)00090-7
Grove-White IG, Kelman GR (1971) Effect of methohexitone, diazepam and sodium 4- hydroxybutyrate on short term memory. Br J Anaesth 43(2):113–116. doi:10.1093/bja/43.2.113
Harmony T (2013) The functional significance of delta oscillations in cognitive processing. Front Integr Neurosci 7:83. doi:10.3389/fnint.2013.00083
Hilty L, Langer N, Pascual-Marqui R, Boutellier U, Lutz K (2011) Fatigue-induced increase in intracortical communication between mid/anterior insular and motor cortex during cycling exercise. Eur J Neurosci 34(12):2035–2042. doi:10.1111/j.1460-9568.2011.07909.x
Hochberg Y, Benjamini Y (1990) More powerful procedures for multiple significance testing. Stat Med 9(7):811–818. doi:10.1002/sim.4780090710
Holm S (1979) A simple sequential rejective multiple test procedure. Scand J Stat 6(2):65–70
Horacek J, Brunovsky M, Novak T, Skrdlantova L, Klirova M, Bubenikova-Valesova V et al (2007) Effect of low-frequency rTMS on electromagnetic tomography (LORETA) and regional brain metabolism (PET) in schizophrenia patients with auditory hallucinations. Neuropsychobiology 55(3–4):132–142. doi:10.1159/000106055
Horovitz SG, Braun AR, Carr WS, Picchioni D, Balkin TJ, Fukunaga M, Duyn JH (2009) Decoupling of the brain’s default mode network during deep sleep. Proc Natl Acad Sci U S A 106(27):11376–11381. doi:10.1073/pnas.0901435106
Huber R, Ghilardi MF, Massimini M, Ferrarelli F, Riedner BA, Peterson MJ, Tononi G (2006) Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity. Nat Neurosci 9(9):1169–1176. doi:10.1038/nn1758
Jatoi MA, Kamel N, Malik AS, Faye I, Begum T (2014) A survey of methods used for source localization using EEG signals. Biomedical Signal Processing and Control 11:42–52. doi:10.1016/j.bspc.2014.01.009
Jenney EH, Murphree HB, Goldstein L, Pfeifer CC (1962) Behavioral and EEG effects of gamma-butyrolactone and gamma-hydroxybutyric acid in man. Pharmacologist 4:166
Jimenez F, Lopez TF, Nodal C, Arrigain S (1982) Neurophysiological study of the effects of gamma-OH at several doses in normal subjects [Estudio neurofisiologico de los efectos del gamma-OH a diferentes dosis, en sujetos normales]. Arch Neurobiol 45(1):3–28
Jordan D, Stockmanns G, Kochs EF, Pilge S, Schneider G (2008) Electroencephalographic order pattern analysis for the separation of consciousness and unconsciousness: an analysis of approximate entropy, permutation entropy, recurrence rate, and phase coupling of order recurrence plots. Anesthesiology 109(6):1014–1022. doi:10.1097/ALN.0b013e31818d6c55
Kim U, Sanchez-Vives MV, McCormick DA (1997) Functional dynamics of GABAergic inhibition in the thalamus. Science 278(5335):130–134. doi:10.1126/science.278.5335.130
Knyazev GG (2007) Motivation, emotion, and their inhibitory control mirrored in brain oscillations. Neurosci Biobehav Rev 31(3):377–395. doi:10.1016/j.neubiorev.2006.10.004
Kometer M, Pokorny T, Seifritz E, Volleinweider FX (2015) Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. Psychopharmacology 232(19):3663–3676. doi:10.1007/s00213-015-4026-7
Kondakor I, Michel CM, Wackermann J, Koenig T, Tanaka H, Peuvot J, Lehmann D (1999) Single-dose piracetam effects on global complexity measures of human spontaneous multichannel EEG. Int J Psychophysiol 34(1):81–87. doi:10.1016/S0167-8760(99)00044-6
Konopacki J, Gołȩbiewski H, Eckersdorf B, Błaszczyk M, Grabowski R (1997) Theta-like activity in hippocampal formation slices: the effect of strong disinhibition of GABAA and GABAB receptors. Brain Res 775(1–2):91–98. doi:10.1016/S0006-8993(97)00919-0
Kühnis J, Elmer S, Jäncke L (2014) Auditory evoked responses in musicians during passive vowel listening are modulated by functional connectivity between bilateral auditory-related brain regions. J Cogn Neurosci 26(12):2750–2761. doi:10.1162/jocn_a_00674
Laborit H (1964) Sodium 4-hydroxybutyrate. International Journal of Neuropharmacology 3(4):433–IN8. doi:10.1016/0028-3908(64)90074-7
Lakatos P, Karmos G, Mehta AD, Ulbert I, Schroeder CE (2008) Entrainment of neuronal oscillations as a mechanism of attentional selection. Science (New York, NY) 320(5872):110–113. doi:10.1126/science.1154735
Lapierre O, Montplaisir J, Lamarre M, Bedard MA (1990) The effect of gamma-hydroxybutyrate on nocturnal and diurnal sleep of normal subjects: further considerations on REM sleep-triggering mechanisms. Sleep 13(1):24–30
Leech R, Braga R, Sharp DJ (2012) Echoes of the brain within the posterior cingulate cortex. J Neurosci 32(1):215–222. doi:10.1523/JNEUROSCI.3689-11.2012
Lehmann D, Ozaki H, Pal I (1987) EEG alpha map series: brain micro-states by space-oriented adaptive segmentation. Electroencephalogr Clin Neurophysiol 67(3):271–288. doi:10.1016/0013-4694(87)90025-3
Leung LS, Shen B (2007) GABAB receptor blockade enhances theta and gamma rhythms in the hippocampus of behaving rats. Hippocampus 17(4):281–291. doi:10.1002/hipo.20267
Liechti ME, Quednow BB, Liakoni E, Dornbierer D, von Rotz R, Gachet MS, Gertsch J, Seifritz E, Bosch OG (2016) Pharmacokinetics and pharmacodynamics of γ-hydroxybutyrate in healthy subjects. Br J Clin Pharmacol 81:980–988. doi:10.1111/bcp.12863
Maitre M (1997) The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog Neurobiol 51(3):337–361
Mamelak M, Escriu JM, Stokan O (1977) The effects of gamma-hydroxybutyrate on sleep. Biol Psychiatry 12(2):273–288
Metcalf DR, Emde RN, Stripe JT (1966) An EEG-behavioral study of sodium hydroxybutyrate in humans. Electroencephalogr Clin Neurophysiol 20(5):506–512. doi:10.1016/0013-4694(66)90107-6
Meyer MR, Weber AA, Maurer HH (2011) A validated GC-MS procedure for fast, simple, and cost-effective quantification of glycols and GHB in human plasma and their identification in urine and plasma developed for emergency toxicology. Anal Bioanal Chem 400(2):411–414. doi:10.1007/s00216-011-4760-6
Miyashita T, Rockland KS (2007) GABAergic projections from the hippocampus to the retrosplenial cortex in the rat. Eur J Neurosci 26(5):1193–1204
Mölle M, Pietrowsky R, Fehm HL, Born J (1997) Regulation of human thought by neuropetpide ACTH 4-10: an analysis of the EEG’s dimensional complexity. Neuroreport 8(12):2715–2720
Mulert C, Jäger L, Propp S, Karch S, Störmann S, Pogarell O et al (2005) Sound level dependence of the primary auditory cortex: simultaneous measurement with 61-channel EEG and fMRI. NeuroImage 28(1):49–58. doi:10.1016/j.neuroimage.2005.05.041
Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15(1):1–25
Nissbrandt H, Engberg G (1993) The GABA B-receptor antagonist, CGP 35348, antagonises γ-hydroxybutyrate- and baclofen-induced alterations in locomotor activity and forebrain dopamine levels in mice. J Neural Transm 103(11):1255–1263. doi:10.1007/BF01271186
Olbrich S, Mulert C, Karch S, Trenner M, Leicht G, Pogarell O, Hegerl U (2009) EEG-vigilance and BOLD effect during simultaneous EEG/fMRI measurement. NeuroImage 45(2):319–332. doi:10.1016/j.neuroimage.2008.11.014
Olofsen E, Sleigh JW, Dahan A (2008) Permutation entropy of the electroencephalogram: a measure of anaesthetic drug effect. Br J Anaesth 101(6):810–821. doi:10.1093/bja/aen290
Orioli G, Cipriani G, Gambi D, Lugaresi E (1966) The electroencephalographic changes induced by gamma OH in normal subjects. Minerva Anestesiol 32(6):299–305
Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, Orlando R et al (1993) Dose- dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol 45(4):353–356. doi:10.1007/BF00265954
Pascual-Marqui RD (2007) Discrete, 3D distributed, linear imaging methods of electric neuronal activity. Part 1: exact, zero error localization. arXiv:0710.3341
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(1):49–65. doi:10.1016/0167-8760(84)90014-X
Pascual-Marqui RD, Lehmann D, Koukkou M, Kochi K, Anderer P, Saletu B et al (2011) Assessing interactions in the brain with exact low-resolution electromagnetic tomography. Philosophical transactions Series A, Mathematical, physical, and engineering sciences 369(1952):3768–3784. doi:10.1098/rsta.2011.0081
Pizzagalli DA, Oakes TR, Fox AS, Chung MK, Larson CL, Abercrombie HC et al (2004) Functional but not structural subgenual prefrontal cortex abnormalities in melancholia. Mol Psychiatry 9(4):325, 393–325, 405. doi:10.1038/sj.mp.4001469
Posner MI, Rothbart MK (1998) Attention, self-regulation and consciousness. Philos Trans R Soc Lond Ser B Biol Sci 353(1377):1915–1927. doi:10.1098/rstb.1998.0344
Purdon PL, Pierce ET, Mukamel EA, Prerau MJ, Walsh JL, Wong KFK et al (2013) Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proc Natl Acad Sci U S A 110(12):E1142–E1151. doi:10.1073/pnas.1221180110
Raichle ME (2015) The brain’s default mode network. Annu Rev Neurosci 38:433–447. doi:10.1146/annurev-neuro-071013-014030
Ramyead A, Kometer M, Studerus E, Koranyi S, Ittig S, Gschwandtner U et al (2015) Aberrant current source-density and lagged phase synchronization of neural oscillations as markers for emerging psychosis. Schizophr Bull 41(4):919–929. doi:10.1093/schbul/sbu134
Rinaldi F, Puca FM, Mastrosimone F, Memoli G (1967) On the use of gamma-hydroxybutyrate of sodium in psychiatric therapy [Sull’impiego del gamma-idrossibutirrato di sodio in terapia psichiatica]. Acta neurologica 22(1):21–41
Saito N, Kuginuki T, Yagyu T, Kinoshita T, Koenig T, Pascual-Marqui RD et al (1998) Global, regional, and local measures of complexity of multichannel electroencephalography in acute, neuroleptic-naive, first-break schizophrenics. Biol Psychiatry 43(11):794–802. doi:10.1016/S0006-3223(97)00547-7
Sämann PG, Wehrle R, Hoehn D, Spoormaker VI, Peters H, Tully C et al (2011) Development of the brain’s default mode network from wakefulness to slow wave sleep. Cerebral cortex (New York, NY : 1991) 21(9):2082–2093. doi:10.1093/cercor/bhq295
Schneider J, Thomalske G, Trautmann P, Smolarz R, Sabbagh R (1963) Le comportement EEG de l’homme et de l’animal soumis a l’action progressive du 4-hydroxybutyrate de sodium. Agressologie 4(1):55–70
Snead OC (2000) Evidence for a G protein-coupled γ-hydroxybutyric acid receptor. J Neurochem 75(5):1986–1996. doi:10.1046/j.1471-4159.2000.0751986.x
Stamatakis EA, Adapa RM, Absalom AR, Menon DK (2010) Changes in resting neural connectivity during propofol sedation. PLoS One 5(12):e14224. doi:10.1371/journal.pone.0014224
Szelenberger W, Wackermann J, Skalski M, Niemcewicz S, Drojewski J (1995) Analysis of complexity of EEG during sleep. Acta Neurobiol Exp 56(1):165–169
Talk A, Kang E, Gabriel M (2004) Independent generation of theta rhythm in the hippocampus and posterior cingulate cortex. Brain Res 1015(1–2):15–24. doi:10.1016/j.brainres.2004.04.051
Thatcher RW, North DM, Biver CJ (2012) Diffusion spectral imaging modules correlate with EEG LORETA neuroimaging modules. Hum Brain Mapp 33(5):1062–1075. doi:10.1002/hbm.21271
Tononi G, Edelman GM (1998) Consciousness and complexity. Science 282(5395):1846–1851. doi:10.1126/science.282.5395.1846
Toth M, Faludi B, Wackermann J, Czopf J, Kondakor I (2009) Characteristic changes in brain electrical activity due to chronic hypoxia in patients with obstructive sleep apnea syndrome (OSAS): a combined EEG study using LORETA and omega complexity. Brain Topogr 22(3):185–190. doi:10.1007/s10548-009-0110-9
Toth M, Faludi B, Kondakor I (2012) Effects of CPAP-therapy on brain electrical activity in obstructive sleep apneic patients: a combined EEG study using LORETA and omega complexity. Brain Topogr 25(4):450–460. doi:10.1007/s10548-012-0243-0
Towle VL, Bolaños J, Suarez D, Tan K, Grzeszczuk R, Levin DN et al (1993) The spatial location of EEG electrodes: locating the best-fitting sphere relative to cortical anatomy. Electroencephalogr Clin Neurophysiol 86(1):1–6. doi:10.1016/0013-4694(93)90061-Y
Uhlhaas PJ, Singer W (2010) Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci 11(2):100–113. doi:10.1038/nrn2774
Varela F, Lachaux JP, Rodriguez E, Martinerie J (2001) The brainweb: phase synchronization and large-scale integration. Nat Rev Neurosci 2(4):229–239. doi:10.1038/35067550
Vayer P, Mandel P, Maitre M (1987) Gamma-hydroxybutyrate, a possible neurotransmitter. Life Sci 41(13):1547–1557. doi:10.1016/0024-3205(87)90721-1
Vecchio F, Miraglia F, Curcio G, Altavilla R, Scrascia F, Giambattistelli F et al (2015) Cortical brain connectivity evaluated by graph theory in dementia: a correlation study between functional and structural data. Journal of Alzheimer’s disease : JAD 45(3):745–756. doi:10.3233/JAD-142484
Vogt BA, Laureys S (2005) Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness. In: Laureys S (Ed.), Progress in Brain Research: v. 150. The boundaries of consciousness. Neurobiology and neuropathology / edited by Steven Laureys (Vol. 150, pp. 205–217). Elsevier, Amsterdam, Oxford. doi:10.1016/S0079–6123(05)50015-3
Wackermann J (1996) Beyond mapping: estimating complexity of multichannel EEG recordings. Acta Neurobiol Exp 1(56):197–208
Williams SR, Turner JP, Crunelli V (1995) Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GABAB receptor-mediated hyperpolarization. Neuroscience 66(1):133–141. doi:10.1016/0306-4522(94)00604-4
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We especially would like to thank David Cole for his critical comments to the manuscript and Matthias Vonmoos for the technical support.
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All authors report no biomedical financial interests or potential conflicts of interest. Boris B. Quednow was supported by grants from the Swiss National Science Foundation (SNSF; grant no. PP00P1-123,516/1 and PP00P1-146,326/1). Robin von Rotz had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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von Rotz, R., Kometer, M., Dornbierer, D. et al. Neuronal oscillations and synchronicity associated with gamma-hydroxybutyrate during resting-state in healthy male volunteers. Psychopharmacology 234, 1957–1968 (2017). https://doi.org/10.1007/s00213-017-4603-z
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DOI: https://doi.org/10.1007/s00213-017-4603-z