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Official websites use. Share sensitive information only on official, secure websites. Correspondence , Rebecca C. Email: rebecca. Although such memory deficits have been repeatedly reported, their neurofunctional origin remains elusive. Therefore, we here investigate the neuronal basis of altered declarative memory in recurrent MDMA users at the level of brain connectivity. We examined a group of 44 chronic MDMA users and 41 demographically matched controls. Declarative memory performance was assessed by the Rey Auditory Verbal Learning Test and a visual associative learning test. Recent MDMA use was confirmed by hair analyses. MVPA revealed a large cluster located in the left postcentral gyrus of global connectivity differences between groups. In addition, hyperconnectivity in regions of a cognitive control network might indicate compensation for degraded sensory processing. The cognitive profile of MDMA users is characterized by deficits in declarative memory which includes semantic and episodic memory Kalechstein et al. At the molecular level, memory formation is characterized by functional strengthening of existing synapses and de novo synaptogenesis Radwanska et al. Consequently, the administration of MDMA in rodents has profound impacts on gene expression patterns and induces lasting synaptic reorganization within brain regions associated with learning and memory Hemmerle et al. One examination found decreased cortical glucose metabolism in recurrent MDMA users, which was correlated to verbal memory performance in bilateral frontal and parietal regions Bosch et al. Working memory was related to reduced activity in the cingulate cortex and temporal lobe, increased activity in the frontal cortex, and altered activity in the parietal lobe Daumann et al. Episodic and prospective memory were associated with reduced left hippocampal activity Daumann et al. Semantic encoding was associated with greater activity in somatosensory areas, the supramarginal gyrus, and the angular gyrus Watkins et al. It allows the study of complex networks that are required for cognition in general and memory in particular Suri et al. Here, we aimed to investigate whether functional networks and network interactions are impaired in MDMA users and how they relate to declarative memory tests. Specifically, we predict FC differences in areas such as the medial temporal lobe, the hippocampus, or in neocortical processing regions, as these together form ensembles for storing newly formed declarative memories Horner et al. Diffusion tensor imaging, quantitative susceptibility mapping, and substance use data from this sample have been published before Zimmermann et al. The groups were matched regarding age, sex, verbal intelligence, years of education, and smoking status. Further excluded were control participants' reporting more than 15 lifetime occasions of illegal substance use, except for cannabis. Compliance with these instructions was verified by urine drug testing. The study adhered to the principles of the Declaration of Helsinki and all participants' provided written informed consent prior to their participation. Subjective history of current and lifetime substance consumption was inquired with a structured and standardized Interview for Psychotropic Drug Consumption Quednow et al. Amounts and frequency of present and past consumption of all known psychotropic substances were quantified on this basis. For additional assessments of depressive symptoms and sleep disturbances the Center for Epidemiologic Studies Depression Scale Eaton et al. The RAVLT consists of a list of 15 noun words list A read aloud to participants' a total of five times in the same order encoding phase, trials 1—5. Word recognition was measured at both delayed recall timepoints by a list of words containing 35 distractor words and the 15 learned noun words Bean, This task was developed for assessing visual associative learning and memory functions, piloted, and published before Schneider et al. In total, four such clips were presented to each participant. While one animal lingered in the hiding place, other animals could enter the scene and the hiding place, thus some animals encountered each other in the hiding place and others did not. The movies were shown twice in a row. Participants' were recruited by online advertisement and underwent an examination on two consecutive days at the Psychiatric University Hospital, Zurich. First, participants' were informed about the study and their right to withdraw at any time before they signed the consent form. Next, a comprehensive screening and clinical assessment was carried out, followed by the hair sample collection. Afterward, the first part of the two memory tests was presented see above. Drug abstinence was monitored by urine drug testing at the beginning of both test days. Participants' were compensated after completing all tasks with a monetary reward. Preprocessing steps included motion correction Jenkinson et al. We have taken the more conservative nonaggressive approach for FIX cleanup, to avoid removing variance of interest from the data Griffanti et al. In addition, 16 motion parameters Friston et al. These noise components were removed separately for each voxel and each subject by application of Ordinary Least Squares regression. The dimensions of these multivariate patterns were then reduced with a principal component analysis extracting 64 components separately for each subject. The number of components was chosen following conventions from previous investigations Thompson et al. The analysis was again controlled for age and handedness. The same analysis, with age as covariate, was performed within the user group only to define the association between past and current MDMA consumption and FC strength. To map clusters resulting from post hoc seed based connectivity analyses to functional networks, we used the network atlas from Smith Smith et al. Linear mixed effect LME models were used to analyze repeated recalls in memory tests lme4 package, v. Graphics were produced with the ggplot2 package v. The demographic comparisons revealed close matching between the groups regarding age, years of school, verbal IQ, and current nicotine use except lifetime cigarettes. The groups were relatively similar in the extent of alcohol consumption, except that MDMA users drank more per occasion and had a higher lifetime amount. However, the groups differed in the amounts of cannabis, cocaine, and amphetamine use Table 1. Groups did not differ regarding ADHD and depressive symptoms, as well as sleep quality measurements Supplementary Table 1. Mean for t test, median for Mann—Whitney U test is shown. Standard deviation is shown in parentheses. Used during lft. Amount lft. Occasion lft. In the first analysis, two separate linear mixed models were conducted, one for the learning trials trials 1—5 and one for the free recall trials trials 6—8. The second model trials 6—8 examined differences between groups after the interference list and the delayed recalls. For each summarized score, an ANCOVA was conducted to examine differences between groups after controlling for age and years of education Figure 1. Therefore, a Wilcox test without control variables is additionally reported for each. Octahedron represents group mean. This score included the number of the pairs of animals that had been remembered correctly twice, at immediate retrieval and delayed recall. We considered the pairs that had been known twice as truly learned animal pairs correctly encoded and correctly remembered. Also, memory performance in the animals movie task was not significantly different between sexes Supplementary Table 2. The MVPA revealed two clusters of connectivity differences between groups. Details of clusters are reported in Table 2 and are depicted in Figure 2. Note : Cluster coordinates are in MNI space. Details are shown in Figure 3 and tabulated in Table 3. Green : seed region. Blue : clusters showing less correlation with seed region in MDMA users compared to controls. Red : clusters showing more correlation with seed region. A : right side view. B : left side view. C : superior view. D : anterior view. E : posterior view. Age and years of education were controlled for in the partial correlation analysis Figure 4 , Supplementary Table 4 and Supplementary Figure 2. Seed : left postcentral gyrus LPCG. Age and years of education are controlled for. Blue : positive correlation with memory performance. Red : negative correlation with memory performance. Results are not corrected for multiple comparisons. This indicates that stronger FC between those two regions was associated with better memory performance. We used partial Spearman rank correlations within the MDMA user group only to assess the relationship between FC scores and the four calculated scores, since variables were not normally distributed Supplementary Figure 3. Except for cluster e , all FC scores were negatively correlated, indicating greater anticorrelation between the LPCG and the target cluster with more MDMA intake and vice versa for cluster e. No further significant correlations with other FC scores were found. The aim of the current study was to investigate the neuronal correlates of memory impairments in MDMA users. Thus, our results are consistent with a large body of existing evidence. On a network level, the PCG was identified as a heteromodal connector hub, linking control and processing networks. On one hand, the PCG regulated dorsal attention network activity Bagarinao et al. Hypoconnected clusters were located in the bilateral temporal lobe and to a small extent, in the inferior part of the posterior supramarginal gyrus. All clusters combined correlated mostly with the auditory network Smith et al. The PCG is not part of any core memory network Rottschy et al. Instead, its most eminent role is the sensory representation of the face and body, and the in integration of somatosensory stimuli. Nevertheless, evidence found the PCG to participate in language and verbal working memory Emch et al. Recognition was related to the extent of FC differences between the LPCG and the left planum temporale Wernicke's area , which plays a role in the temporal integration of auditory events Mustovic et al. Language and verbal memory are closely related entities MacDonald, ; Roger et al. Accordingly, memory storage occurs within a network of specialized cortical processing modules, and the same areas are also recruited during perception, encoding and retrieval of the relevant information Weinberger, Since Kandel's research in Brunelli et al. Since deficits included early performance indices, such as recall consistency, early processes during the formation of a memory trace may already be affected Wamsley, Notably, delayed recall of the RAVLT was previously associated with altered glucose metabolism in this same region Bosch et al. Recall consistency was negatively related with increased FC between the LPCG and regions in the ipsilateral superior parietal lobe. Further, the increased FC between the LPCG and ipsilateral parts of the middle frontal gyrus and the precentral gyrus were correlated with lifetime MDMA intake, yet not with any memory performance score. Previous investigations in recurrent MDMA users found reduced activation during a semantic task in these regions Raj et al. Moreover, acute MDMA administration was demonstrated to affect middle frontal gyrus processes resulting in impoverished memory encoding Kuypers et al. As such, hyperconnectivity within the dorsal attention network might reflect a compensatory effort in MDMA users to maintain performance Hartwigsen, Parietal hyperactivation has also been suggested as a marker of cognitive deficits in cases of substance use Lees et al. The present study has some limitations that should be acknowledged. Second, hair analyses only allowed for objective detection of substances consumed in the past months. So we cannot exclude that other substance use may have biased our results. Rebecca C. Coray: Conceptualization, methodology, formal analysis, investigation, data curation, writing — original draft, visualization. Josua Zimmermann: Conceptualization, investigation, writing — review and editing. Amelie Haugg: Methodology, formal analysis, writing — review and editing. Markus R. Baumgartner: Toxicological hair analysis. Andrea E. Steuer: Toxicological hair analysis. Erich Seifritz: Funding acquisition. Christian Beste: Funding acquisition, Writing — review and editing. David M. Cole: Conceptualization, investigation, writing — review and editing. Boris B. Quednow: Conceptualization, methodology, writing — original draft, funding acquisition. The authors sincerely thank Prof. Katharina Henke for providing the Animal Movie Task. Coray, R. Human Brain Mapping, 44 15 , — The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Hum Brain Mapp. Find articles by Rebecca C Coray. Find articles by Josua Zimmermann. Find articles by Amelie Haugg. Find articles by Markus R Baumgartner. Find articles by Andrea E Steuer. Find articles by Erich Seifritz. Find articles by Christian Beste. Find articles by David M Cole. Find articles by Boris B Quednow. Open in a new tab. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Amount g per occasion. Max amount per week g lft. Days since last intake. THC hair conc.