Purpose: Neuroimaging, neurocognitive: to assess cortical activation during neurocognitive performance and to see whether altered neurocognitive performance in Ecstasy users was associated with altered cortical activation, assessed with functional magnetic resonance imaging (fMRI). Specific hypotheses tested - that Ecstasy users would have lower scores on a working memory task than non-user controls, and that low working memory performance in Ecstasy users would be associated with alterations in "underlying cortical networks." (p. 480)

Design: Retrospective (non-experimental) between-subjects design, with Ecstasy use (no use, moderate use or heavy use) serving as between-subjects variable, and with all participants performing a working memory task while simultaneously undergoing fMRI.

Subjects: 11 heavy Ecstasy users, 11 moderate Ecstasy users and 11 non-user controls probably residing in or near Aachen (Germany) and recruited directly from the dance event "scene" or community via word of mouth. Matching - Groups matched on gender, approximately on age and education. Criteria for Inclusion - Ecstasy Users - Reporting use of Ecstasy at least twice a month for 6 months or on at least 20 occasions, no regular use of other psychotropic drugs, meaning no more than once a month or more within six months or longer for the last two years, no heavy alcohol use, defined as severe drunkenness occurring twice per month or more. Heavy Ecstasy users (decided on median split) - Lifetime consumption of more than 80 tablets. Moderate Ecstasy Users (decided on median split) - Lifetime consumption of up to 80 tablets. Non-Users - Never reported use of Ecstasy, and no regular use of other psychotropic drugs as defined above, hence infrequent or irregular use of other drugs permitted. All groups - Absence of current or previous Axis 1 psychiatric disorders (except for drug abuse in the two user groups), no organic brain disorder or relevant disorder requiring pharmacological treatment, not pregnant, no metallic objects in body and negative urinary drug screen (except for cannabis) on study day. All participants were required to abstain from psychoactive substances save cannabis for 7 days prior to study day, with abstinence verified through urinary analysis, and all participants were required to abstain from cannabis on the study day, with abstinence verified through self-report only (though urinary screen did assess cannabis).

Drug Use Parameters - Heavy ecstasy users reported having used 258.18 +/- 220.25 tablets, and an average dose per use of 1.91 +/- 0.94 tablets. Heavy Ecstasy users reported an average duration of regular Ecstasy use of 53.18 +/- 29.09 months, and an average frequency of use (in days per month) of 2.78 +/- 3.59 times per month. Heavy Ecstasy users' time since last use, in days, was 89.27 +/- 210.48 days. Heavy users' age of onset for use was 21.27 +/- 3.77 years, and all defined themselves as "regular" rather than "sporadic" Ecstasy users. Moderate Ecstasy users reported a lifetime use of 27.36 +/- 5.61 tablets, and an average dose per use of 1.57 +/- 0.75 tablets. Moderate Ecstasy users reported an average duration of regular Ecstasy use of 16.2 +/- 13.28 months, and average frequency of use (per month) as 1.8 +/- 1.38 times per month. Moderate users' time since last use until study day, in days, was 330.09 +/- 520.65 days. Average age of onset of first use in moderate Ecstasy users was 20.18 +/- 2.79 years, and 10 were "regular" users while one was a "sporadic" user. Other drugs - All data in heavy and moderate Ecstasy users only. Amphetamine was used by 7/11 heavy Ecstasy users, reporting lifetime consumption of 14.56 +/- 16.75 g, with average dose per use of 190.1 +/- 188.17 mg. Duration of amphetamine use in heavy Ecstasy users was 19.91 +/- 28.08 months, with a frequency of 4.33 +/- 3.67 times per month, and time elapsed since last use, 204.25 +/- 313.45 days. Heavy Ecstasy users first used amphetamine when 21.13 +/- 2.9 years, and 1 of 7 considered him/herself a "sporadic" amphetamine user. Amphetamine was used by 5/11 moderate Ecstasy users, reporting lifetime consumption of 7.91 +/- 15.20 g, with average dose per use of 122.73 +/- 180.79 mg. Duration of amphetamine use in moderate Ecstasy users was 12 +/- 21.30 months, with a frequency of 1.64 +/- 2.63 times per month, and time elapsed since last use, 67.40 +/- 97 days. Moderate Ecstasy users first used amphetamine when 17.8 +/- 2.2.28 years, and none of 5 considered themselves "sporadic" amphetamine users. Cannabis - No lifetime cannabis use reported for either heavy or moderate users. Cannabis used by 6/11 heavy Ecstasy users, with average dose per use of 287.82 +/- 245.43 mg, duration of cannabis use in heavy Ecstasy users was 52.26 +/- 54.27 months, with a frequency of 9 +/- 11.65 times per month, and time elapsed since last use was 3.17 +/- 2.99 days. Heavy Ecstasy users first used cannabis when 15.17 +/- 1.6 years, and none considered themselves to be "sporadic" users. Cannabis used by 7/11 moderate Ecstasy users, with average dose per use of 424.18 +/- 417.44 mg, duration of cannabis use was 36 +/- 29.39 months, with a frequency of 13.23 +/- 13.93 times per month, and time elapsed since last use was 4.25 +/- 3.24 days. Heavy Ecstasy users first used cannabis when 16.5 +/- 2.2 years, and none considered themselves to be "sporadic" users.

Group Demographics and Matched Variables - All groups matched on gender; groups approximately matched on age and education. Gender, as M/F Ratio - Heavy Ecstasy users, 8/3, moderate Ecstasy users, 8/3, non-users, 8/3. Age - (as sample average) - Heavy Ecstasy users, 27 +/- 3.92 years, moderate users, 23.27 +/- 2.49 years, non-users, 25.64 +/- 2.34 years. Education - (Indicated in terms of attaining "intermediate school" versus "at least pre-university") - Heavy users, approximately 12.18 years (3 "intermediate school only", 8 "at least pre-university"), moderate users, = approximately 12.72 years (1 "intermediate school only" and 10 "at least pre-university"), non-users = approximately 12.18 years (3 "intermediate school only," 8 "at least pre-university). Other variable - Average body weight, in kg: Heavy users = 67.36 +/- 9.63 kg, moderate users = 73.27 +/- 14.16 kg, non-users = 70 +/- 10.10 kg.

Measures: Working Memory - Assessed via "n-back" task, wherein participants attend to a series of sequentially presented targets and respond to a target, either upon presentation ("0-back"), or after 1 or 2 non-targets follow target presentation (1-back and 2-back conditions, respectively). All participants were allowed a practice session before entering the scanner. Performance measured through response time (RT) and number of correct responses (CR).

Imaging - All participants' blood oxygenation level-dependent (BOLD) contrast fMRI imaging assessed regional brain activation with a standard 1.5 T scanner. Scanning was performed during task performance and interspersed "rest" periods.

Analyses: Working memory task - A random-effects analysis compared task performance between groups, with drug-use (heavy user, moderate user and non-user) serving as the between-groups variable, and each task difficulty level (0-back, 1-back and 2-back) treated as levels of one variable (working memory). Three analyses of variance were also performed, one set at p = 0.05 but corrected for possible Type 1 error, one uncorrected for Type 1error, but at p = 0.001, and another uncorrected comparison at p = 0.0. (Type 1 error = falsely concluding the presence of an effect when it is in fact absent). Imaging - Regional blood flow determined through application of general linear model to each voxel, and separate analyses performed for 0-back, 1-back and 2-back conditions.

Other analyses - Analyses of covariance examined patterns of brain activation using task performance, but were not described in detail. Correlational analyses using drug use parameters were performed but not described in detail.

Results - Significant Differences Found: Working memory - Longer RT and lower numbers of correct responses were seen in the more difficult task conditions than in the easier conditions. (There was a trend for heavy Ecstasy users to have lower RTs on the2-back task only, but this did not reach significance).

Imaging - As predicted on the basis of previous research with n-back tasks, participants in all groups showed brain activation changed in pre-frontal, parietal, occipital cortex and cingulate, with these areas not activated during rest periods. The following differences only found in the "liberal" analyses, uncorrected for possible Type 1 error. (For p = 0.001) Moderate Ecstasy users performing 1-back task had greater right parietal activation than non-users. (For p = 0.01) Both heavy and moderate Ecstasy users had greater R parietal activity during 1-back task than non-users, and there was more lateralization (rightward activation) in moderate than in heavy users. (P = 0.001) Heavy users had less activation in the left superior temporal lobe during 2-back task than non-user controls. (p. = 0.01). Both moderate and heavy Ecstasy users had greater right parietal activation during 2-back task than non-users. Heavy Ecstasy users showed greater activation of Brodmann area 40 during 2-back task, and it was apparently below the area activated in moderate users, and included an area of left superior temporal gyrus not activated in non-users. Lower activation (apparently in both Ecstasy user groups) appeared in the left superior frontal gyrus, anterior cingulate, and heavy Ecstasy users lower activation of left-lateralized frontal areas during 2-back task. Other analyses - Neither the analysis of covariance using task performance nor the correlational analyses yielded significant differences or findings.

Results - No Significant Differences: Working memory - Except for the trend described above (longer RT in heavy users on 2-back task), heavy Ecstasy users, moderate Ecstasy users and non-users performed similarly on all levels of the n-back task, from the easiest to the most difficult condition, both in terms of RT and number of correct responses.

Imaging - Structural MRI was normal for all three groups (heavy and moderate Ecstasy users, non-user controls). When examined with conservative analyses, no differences in brain activation during n-back task were seen to occur across heavy Ecstasy users, moderate Ecstasy users and non-user controls. Other analyses - Applying task performance as a covariate did not alter results of analyses of brain activation during n-back task. In other words, there were still no differences between groups, even when accounting for task performance in all conditions. Analyses using drug use parameters (presumably including frequency, duration and time since last use of Ecstasy, and perhaps amphetamine and cannabis as well) also found no differences in task performance or brain activation associated with any drug use variable.

Overall Effects: Gender-matched samples of moderate Ecstasy users, heavy Ecstasy users and non-drug user controls recruited from among dance event attendees performed similarly on a measure of working memory, the "n-back" task. There was a trend for heavy Ecstasy users respond more slowly when performing the most difficult 2-back level of the task, but this difference did not reach statistical significance. The researchers failed to find any significant differences in brain activation across any of the groups during task performance, with non-users, moderate users and heavy users showing similar patterns of brain activation in prefrontal, parietal, occipital and cingulate areas during the working memory task. Differences between brain activation during n-back task in Ecstasy users and controls were only detected when applying less stringent criteria (meaning, more likely to find differences where none really exist). Under these less stringent significance criteria, both moderate and heavy ecstasy users showed greater activation in the right parietal area when performing the 1-back and 2-back tasks, with greatest activation over the supramarginal gyrus. The difference was more pronounced in moderate users than in heavy users. Comparisons using relaxed tests of significance also found greater activation in Brodmann area 40 and less activation in left superior temporal lobe in heavy ecstasy users when compared with controls performing the most difficult ("2-back") level of the task. The authors found no association between extent of previous ecstasy use and brain activation during the "n-back" task. Specific hypotheses were not confirmed; there were no differences between groups on task performance, and differences in brain activation (present but not statistically significant) could not be associated with differences in task performance.

Comments: To date, this is the first comparison of brain activity in Ecstasy users and controls using fMRI imaging. This study is also one of the few that deliberately sought participants from the same population (the dance event community) and strove to exclude heavy polydrug users, including heavy drinkers. This is one of a growing number of studies that have failed to find impaired memory in Ecstasy users (Simon et al. 2002), or at least in current Ecstasy users (Thomasius et al. 2003). It seems that careful selection and matching for drug use is associated with a reduction in detectable neurocognitive differences between Ecstasy users and controls. The authors acknowledge that evidence for impaired working memory has remained inconclusive across studies, as differences were found in some studies (Gouzoulis-Mayfrank et al. 2000; McCann et al. 1999) and not others (Dafters et al. 1999). The significance of slight differences in brain activation remain unclear and may represent a case of Type 1 error, but if confirmed, they may suggest that Ecstasy users rely on slightly different strategies during task performance. Since fMRI is a relatively new area of research, a better understanding of study findings may await further developments in fMRI research as relates to neurocognitive task performance. Study limitations include retrospective study design, between-group differences in use of other drugs (such as amphetamine) and reporting study findings derived from less stringent analyses. It is also possible that differentiating Ecstasy users groups via median split reduced the ability to detect drug-use related differences by forcing Ecstasy use into discrete drug use variables rather than a continuous drug-use variable. (That is, there might still be an association only detectable if Ecstasy use were treated as a continuous variable). However, failure to detect any relationships between drug-use parameters and either outcome variable (task performance or brain activation) suggests that lack of significant findings is not due to defining groups by median split. The authors propose that future research rely on longitudinal rather than retrospective designs.