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Localization of MDMA-Induced Brain Activity in Healthy Volunteers Using

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Localization of MDMA-Induced Brain Activity in Healthy Volunteers Using ᭜HumanBrainMapping14:152–165(2001)᭜ LocalizationofMDMA-InducedBrainActivityin HealthyVolunteersUsingLowResolutionBrain ElectromagneticTomography(LORETA) EdiFrei,1 AlexGamma,1 RobertoPascual-Marqui,2 DietrichLehmann,2 DanielHell,1 andFranzX.Vollenweider1* 1UniversityHospitalofPsychiatry,Zurich,Switzerland 2KEYInstituteforBrain-MindResearch,UniversityHospitalofPsychiatry,Zurich,Switzerland ᭜ ᭜ Abstract:3,4-Methylenedioxymethamphetamine(MDMA;’Ecstasy’)isapsychostimulantdrugproducing heightenedmoodandfacilitatedsocialcommunication.Inanimalstudies,MDMAeffectsareprimarily mediatedbyserotonin(5-HT),butalsobydopamine(DA)andpossiblynoradrenaline(NA).Inhumans, however,theneurochemicalandneurophysiologicalbasisofacuteMDMAeffectsremainsunknown.The distributionofactiveneuronalpopulationsafteradministrationofasingledoseofMDMA(1.7mg/kg) orplacebowasstudiedin16healthy,MDMA-na¨ı vevolunteers.Thirty-one-channelscalpEEGsduring restingwithopenandclosedeyeswasanalyzedinthedifferentEEGfrequencybands.Scalpmapsof powershowedsignificant,globaldifferencesbetweenMDMAandplaceboinbotheyeconditionsandall frequencybands.Lowresolutionbrainelectromagnetictomography(LORETA)wasusedtocompute3D, functionalimagesofelectricneuronalactivityfromthescalpEEGdata.MDMAproducedawidespread decreaseofslowandmediumfrequencyactivityandanincreaseoffastfrequencyactivityintheanterior temporalandposteriororbitalcortex,concomitantwithamarkedenhancementofmood,emotional arousalandincreasedextraversion.Thisactivationoffrontotemporalareasindicatesthattheobserved enhancementofmoodandpossiblytheincreasedextroversionrelyonmodulationoflimbicorbitofrontal andanterotemporalstructuresknowntobeinvolvedinemotionalprocesses.ComparisonoftheMDMA- specificEEGpatternwiththatofvarious5-HT,DA,andNAagonistsindicatesthatserotonin,noradren- aline,and,toalesserdegree,dopamine,contributetotheeffectsofMDMAonEEG,andpossiblyalsoon moodandbehavior.Hum.BrainMapping14:152–165,2001. ©2001Wiley-Liss,Inc. Keywords:3,4-methylenedioxymethamphetamine(MDMA);EEG;LORETA;powerspectrum;Ecstasy; serotonin;mood;emotion;human ᭜ ᭜ INTRODUCTION 3,4-Methylenedioxymethamphetamine(MDMA) isarecreationaldrugfrequentlyusedbyyoung Contractgrantsponsor:UBSScienceFoundation;Contractgrantnum- adults.Itssubjectiveeffectsarecharacterizedbya ber:ANGS-MRYGrant;Contractgrantsponsor:SwissFederalHealth markedenhancementofmoodandsocialinteraction Office;Contractgrantnumber:0686;Contractgrantsponsor:Markart andanincreaseinsensoryawareness[Greerand Foundation,Zurich;Contractgrantsponsor:HeffterResearchInstitute. Tolbert,1986;Vollenweideretal.,1998].MDMAis *Correspondenceto:Dr.F.X.Vollenweider,UniversityHospitalof Psychiatry,Zurich,POBox68,CH-8029Zurich,Switzerland. alsoreportedtoincreasepsychomotordrive[So- E-mail:[email protected] lowijetal.,1992],asitisknownfromstimulant Receivedforpublication11May1999;accepted21June2001 drugsoftheamphetaminetype.Inanimals,itsmain ©2001Wiley-Liss,Inc. ᭜ Electromagnetic Tomography of MDMA Effects ᭜ neurochemical mechanism of action is the enhanced MATERIALS AND METHODS release and inhibited uptake of central serotonin (5-HT) [Green et al., 1996], but dopamine (DA) and Subjects noradrenaline (NA) were found or implicated in the mediation of MDMA effects [Battaglia et al., 1988]. It Sixteen MDMA-naı¨ve healthy subjects (6 women ϭ ϭ is unclear, however, to what extent the 5-HT, DA and 10 men; mean age 26.0 years, SD 2.5 years) and NA systems contribute to the effects of MDMA without a history of drug abuse were recruited from and how MDMA affects neurophysiological, partic- university students and hospital staff. Before admis- ularly electrophysiological brain processes in hu- sion to the study all subjects were carefully screened mans. The aim of this study was to characterize by psychiatric interview to assure that they had nei- acute MDMA effects in terms of regional cerebral ther personal nor family histories of major psychiatric disorders in first-degree relatives. Subjects were changes in brain electric (EEG) activity compared to healthy according to physical examination, electrocar- placebo. Furthermore, by comparing the MDMA- diogram and blood and urine analysis. Written in- specific EEG pattern with that of various 5-HT, DA formed consent was obtained from all subjects. The and NA agonists reported in the literature, we at- study was approved by the Ethics Committee of the tempted to clarify the relative contributions of these University Hospital of Psychiatry, Zurich, and the use transmitter systems to the effects of MDMA. of 3,4-methylenedioxymethamphetamine (MDMA) Conventional analysis of surface EEG recordings by was approved by the Swiss Federal Health Office, dipole modeling provides only limited information on Department of Pharmacology and Narcotics, Bern. the neural generators because it disregards their intra- cerebral distribution. The spatial distribution is partic- Procedure and material ularly important in the case of higher brain functions that are commonly assumed to engage widely distrib- Thirty-one Grass electrodes were applied to the sub- uted regions [Mesulam, 1990]. Low resolution electro- jects’ heads following the international 10/20 system magnetic tomography (LORETA) [Pascual-Marqui et (FP1/2, FPZ, F3/4, F7/8, FZ, FT9/10, FC5/6, T3/4, al., 1994; Pascual-Marqui, 1999], permits direct, true T5/6, TP9/TP10, C3/4, CZ, CP5/6, P3/4, PZ, PO9/10, 3D functional imaging of brain electric activity based O1/2, OZ). A further electrode below the left eye on the constraint of maximal smoothness of the solu- recorded eye movements for later artifact recognition. tion. LORETA, unlike dipole modeling, does not need Both F3 and F4 served as common recording reference a priori knowledge about the putative number of dis- electrodes. After electrode application, subjects re- cernible source regions. With this method, the high ceived MDMA (1.7 mg/kg body weight) or placebo time resolution of the brain electric data can be fully (double blind application). There were two recording exploited for functional imaging of brain activities of sessions for each subject, one with MDMA and the different qualities, because brain electric activity can other with placebo; the sequence was pseudo-ran- be analyzed separately for the different EEG fre- domly assigned. Two hours after ingestion of MDMA quency bands that have different functional signifi- or placebo, respectively, subjects lay down. Their rest- ing EEG was recorded during eyes closed and eyes cances. This property has been exploited successfully open, each for at least 3 min (Neurofile System, Nihon in applications that validated LORETA with MRI and Kohden 32-channel headbox, 256 samples/sec, 1–50 PET findings [Anderer et al., 2000; Pascual-Marqui et Hz bandpass filter). al., 1999; Pizzagalli et al., 2001; Worrell et al., 2000]. Off-line, the EEG data were carefully reviewed for We used LORETA to assess acute MDMA-in- eye, muscle, movement, and technical artifacts. Two- duced changes of the cortical distribution of electric second epochs of artifact free EEG were used for fur- activity in the different spectral frequency bands in ther analyses. If three or fewer EEG channels con- healthy, MDMA-naı¨ve volunteers. We hypothesized tained artifacts, they were interpolated, otherwise the that, due to its well established role in mood regu- epoch was rejected. If fewer than 10 sec of EEG within lation, activity changes in the limbic system should one recording session were acceptable, the subject was be observed after MDMA-induced mood enhance- omitted from further analysis. The final sample con- ment. Based on animal data, we further expected sisted of EEG data, for placebo as well as the MDMA that MDMA would have some electrophysiological session, from 14 subjects recorded with eyes closed effects in common primarily with 5-HT, but also and from 12 subjects recorded with eyes open. For all with DA and NA agonists. these subjects, MDMA and placebo EEG data were ᭜ 153 ᭜ ᭜ Frei et al. ᭜ available. On the average across subjects, 36.3 Ϯ 14.4 by Towle et al. [1993]. The LORETA solution space sec of data for EO/MDMA, 39.2 Ϯ 19.6 sec of data for was restricted to the cortical gray matter and hip- EO/placebo, 39.4 Ϯ 8.2 sec of data for EC/MDMA, pocampus in the Talairach atlas as defined by the and 56.1 Ϯ 12.7 sec of data for EC/placebo were corresponding digitized Probability Atlas available available for analysis. from the Brain Imaging Center, Montreal Neurologic Spatial DC offset was removed (average reference Institute. A total of 2,394 voxels at 7 mm spatial reso- recomputation). Because EEG spectral frequency lution were produced under this neuroanatomical bands are known to reflect different functions and constraint. behave statistically independent, the analysis was LORETA images corresponding to the estimated done separately in the following seven bands [Kubicki neuronal generators of brain activity within a given et al., 1979]: Delta (1.5–6 Hz), Theta (6.5–8 Hz), Al- frequency band are defined as follows. For a given ⌽ pha1 (8.5–10 Hz), Alpha2 (10.5–12 Hz), Beta1 (12.5–18 subject, let i,t denote a vector comprised of the scalp Hz), Beta2 (18.5–21 Hz), and Beta3 (21.5–30 Hz). electric potentials measured at each scalp electrode (any reference electrode is allowed), at time instant t ϭ ϭ ⌽⍀ Scalp maps of spectral power (t 1…N␶), and for EEG epoch i (i 1…N⑀). Let i,t denote the band filtered EEG, where ⍀ denotes the All available epochs were submitted to FFT. For frequency band of interest. The instantaneous current each medication condition, recording condition,
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