Modafinil enhances cognitive, but not emotional conflict processing via enhanced inferior frontal gyrus activation and its communication with the dorsomedial prefrontal cortex.

Cognitive control regulates cognitive and emotional systems to facilitate goal-directed behavior in the context of task-irrelevant distractors. Cognitive control deficits contribute to residual functional impairments across psychiatric disorders and represent a promising novel treatment target. Translational evidence suggests that modafinil may enhance performance in executive functions; however, differential effects on regulatory control in cognitive and emotional domains have not been examined. The present pre-registered randomized-controlled pharmacological fMRI trial examined differential effects of modafinil (single-dose, 200 mg) on cognitive and emotional conflict processing. To further separate objective cognitive enhancing effects from subjective performance perception, a metacognitive paradigm was employed. Results indicated that modafinil specifically enhanced cognitive conflict performance and concomitantly increased activation in the inferior frontal gyrus and its functional communication with the dorsomedial prefrontal cortex. Exploratory analysis further revealed modafinil-enhanced basolateral amygdala reactivity to cognitive conflict, with stronger reactivity being associated with higher cognitive conflict performance. Whereas modafinil enhanced cognitive performance in the metacognitive paradigm, confidence indices remained unaffected. Overall, the present results suggest that modafinil has the potential to enhance cognitive conflict processing while leaving emotional conflict processing unaffected. On the neural level modafinil enhanced the recruitment of a network engaged in general conflict and regulatory control processes, whereas effects on the amygdala may reflect improved arousal-mediated attention processes for conflicting information. The pattern of cognitive enhancing effects in the absence of effects on affective processing suggests a promising potential to enhance cognitive control in clinical populations.

Inhibition of return (IOR) in patients with schizophrenia and cannabis use.

Research concerning the spatial orientation in patients with schizophrenia has demonstrated a state independent deficit in inhibition of return (IOR), which has been discussed as a vulnerability marker for schizophrenia. Other recent investigations on brain structure and cognitive processing have revealed less deficits in schizophrenia patients with comorbid cannabis use (SCH + CUD) compared to abstinent schizophrenia patients (SCH). It was hypothesized that these results may reflect a premorbid lower vulnerability in at least a subgroup of comorbid patients. The aim of the present study is to extend previous work by investigating IOR functioning in patients with schizophrenia and cannabis use. This in turn should supplement the existing studies on the vulnerability of this patient group. Therefore, we compared IOR functioning in four groups: 62 patients with schizophrenia and 46 healthy controls, both with and without cannabis use. Participants underwent a covert orienting of attention task (COVAT) with peripheral cues and three stimulus onset asynchronies (SOAs: 200 ms, 400 ms and 800 ms). Both schizophrenia groups displayed delayed IOR with a more pronounced IOR effect in SCH + CUD compared to SCH. In healthy controls, IOR did not seem to be significantly affected by cannabis use. Significant IOR-differences between groups were only seen between SCH patients without cannabis use and both healthy groups at SOA 400 ms. Patterns of cannabis use as well as clinical parameters of psychoses did not affect IOR. Our results may support the hypothesis of IOR as a vulnerability marker for schizophrenia and of a lower biological vulnerability in at least a subgroup of SCH + CUD.

Motor Improvement and Emotional Stabilization in Patients With Tourette Syndrome After Deep Brain Stimulation of the Ventral Anterior and Ventrolateral Motor Part of the Thalamus.

BACKGROUND: Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS. METHODS: In this prospective open-label trial, eight patients (three female, five male) 19-56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset. RESULTS: Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome. CONCLUSIONS: Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS.

Trans-Sector Integrated Treatment in Psychosis and Addiction.

BACKGROUND: Patients with psychosis often develop comorbid addiction, with a lifetime prevalence of ca. 50%. Dual diagnoses are considered hard to treat. Long-term integrated treatment programs might improve such patients' outcomes, at least to a moderate extent, but they have not yet been adequately studied or implemented in Germany to date. METHODS: 100 dual diagnosis patients participated in a single-center, randomized, controlled trial under standard hospital treatment conditions. They were randomly allotted to two groups. Patients in the intervention group were admitted to a specialized open hospital ward, where they were given integrated treatment, including disorder-specific group therapy. Their treatment was continued with further disorder-specific group therapy in the outpatient setting. Patients in the control group were admitted to an open general psychiatric ward and received treatment as usual, but no disorder-specific treatment either during their hospitalization or in the subsequent outpatient phase. Follow-up examinations were performed three, six, and twelve months after inclusion. The primary outcome was defined as the changes in substance use and abstinence motivation. The secondary outcome consisted of the patients' satisfaction with treatment and with life in general, retention rate, psychopathology, rehospitalizations, and global level of functioning. RESULTS: The patients in the intervention group developed higher abstinence motivation than those in the control group (p = 0.009) and transiently reduced their substance use to a greater extent (p = 0.039 at three months). They were also more satisfied with their treatment (group effect: p = 0.011). Their global level of functioning and their retention rate were also higher, but these differences did not reach statistical significance. CONCLUSION: Low-threshold, motivational, integrated treatment programs with psycho-educative and behavioral therapeutic elements may be helpful in the treatment of dual diagnosis patients and should be more extensively implemented as part of standard hospital treatment. Larger-scale, methodologically more complex studies will be needed to identify subgroups of patients that respond to such treatments in different ways.

Ziprasidone versus clozapine in the treatment of dually diagnosed (DD) patients with schizophrenia and cannabis use disorders: a randomized study.

BACKGROUND AND OBJECTIVES: Clozapine is considered to be particularly effective in the treatment of dually diagnosed (DD) patients with psychosis and substance use disorders. However, its use is restricted by potentially severe side effects. The aim of the present pilot study was to compare the effects of clozapine with the newer second generation antipsychotic (SGA) ziprasidone in DD-patients. METHODS: Thirty (n = 30) patients with schizophrenia and cannabis abuse/dependence were randomized to ziprasidone or clozapine and were followed up for up to 12 months. RESULTS: Cannabis use was reduced in both groups during follow-up. Clozapine treatment was associated with less positive symptoms of schizophrenia, more side effects and poorer compliance with treatment. CONCLUSIONS: Results from this small pilot RCT suggest beneficial effects of both clozapine and ziprasidone in the treatment of cannabis use disorders in psychotic patients. Larger-scale RCTs are needed in order to assess advantages and disadvantages of the different SGAs in dually diagnosed populations.

Memory-related hippocampal functioning in ecstasy and amphetamine users: a prospective fMRI study.

RATIONALE: Recreational use of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) has been associated with memory impairments. Functional neuroimaging studies with cross-sectional designs reported altered memory-related hippocampal functioning in ecstasy-polydrug users. However, differences might be pre-existing or related to the concomitant use of amphetamine. OBJECTIVE: To prospectively investigate the specific effects of ecstasy on memory-related hippocampal functioning. METHODS: We used an associative memory task and functional magnetic resonance imaging (fMRI) in 40 ecstasy and/or amphetamine users at baseline (t1) and after 12 months (t2). At t1, all subjects had very limited amphetamine and/or ecstasy experience (less than 5 units lifetime dose). Based on the reported drug use at t2, subjects with continued ecstasy and/or amphetamine use (n = 17) were compared to subjects who stopped use after t1 (n = 12). RESULTS: Analysis of repeated measures revealed that encoding-related activity in the left parahippocampal gyrus changed differentially between the groups. Activity in this region increased in abstinent subjects from t1 to t2, however, decreased in subjects with continued use. Decreases within the left parahippocampal gyrus were associated with the use of ecstasy, but not amphetamine, during the follow-up period. However, there were no significant differences in memory performance. CONCLUSIONS: The current findings suggest specific effects of ecstasy use on memory-related hippocampal functioning. However, alternative explanations such as (sub-)acute cannabis effects are conceivable.

Contributions of experimental psychiatry to research on the psychosis prodrome.

In the recent decades, a paradigmatic change in psychosis research and treatment shifted attention toward the early and particularly the prodromal stages of illness. Despite substantial progress with regard to the neuronal underpinnings of psychosis development, the crucial biological mechanisms leading to manifest illness are yet insufficiently understood. Until today, one significant approach to elucidate the neurobiology of psychosis has been the modeling of psychotic symptoms by psychedelic substances in healthy individuals. These models bear the opportunity to evoke particular neuronal aberrations and the respective psychotic symptoms in a controlled experimental setting. In the present paper, we hypothesize that experimental psychiatry bears unique opportunities in elucidating the biological mechanisms of the prodromal stages of psychosis. Psychosis risk symptoms are attenuated, transient, and often only retrospectively reported. The respective neuronal aberrations are thought being dynamic. The correlation of unstable psychopathology with observed neurofunctional disturbances is thus yet largely unclear. In modeling psychosis, the experimental setting allows not only for evoking particular symptoms, but for the concomitant assessment of psychopathology, neurophysiology, and neuropsychology. Herein, the glutamatergic model will be highlighted exemplarily, with special emphasis on its potential contribution to the elucidation of psychosis development. This model of psychosis appears as candidate for modeling the prodrome by inducing psychotic-like symptoms in healthy individuals. Furthermore, it alters pre-attentive processing like the Mismatch Negativity, an electrophysiological component which has recently been identified as a potential predictive marker of psychosis development. In summary, experimental psychiatry bears the potential to further elucidate the biological mechanisms of the psychosis prodrome. A better understanding of the respective pathophysiology might assist in the identification of predictive markers, and the development of preventive treatments.

Increased gray matter density in patients with schizophrenia and cannabis use: a voxel-based morphometric study using DARTEL.

Alterations in gray matter density as well as cognitive impairments are commonly described in patients with schizophrenia (SCH patients). Both gray matter deficits and cognitive impairments have recently been discussed to represent vulnerability markers of schizophrenia. The counterintuitive finding of better cognitive performance in patients with schizophrenia and cannabis use (SCH+CAN patients) compared to cannabis naïve patients is discussed as a reflection of lower vulnerability for schizophrenia in at least one subgroup of SCH+CAN patients. We hypothesized that SCH+CAN patients would display fewer gray matter deficits compared to SCH patients reflecting their presumed lower vulnerability. We therefore compared gray matter density in 30 first episode SCH+CAN and 24 first episode SCH patients using a fast diffeomorphic registration algorithm (DARTEL) and voxel-based morphometry (VBM). We found less severe cognitive impairments and middle frontal gray matter deficits in the SCH+CAN patients. In the pooled sample gray matter density was positively associated with cognitive functioning. Results may support the hypothesis of a lower biological vulnerability in at least one subgroup of SCH+CAN patients.

Medial prefrontal gray matter volume reductions in users of amphetamine-type stimulants revealed by combined tract-based spatial statistics and voxel-based morphometry.

Amphetamine-type stimulants (ATS) refer to a group of drugs whose principal members include amphetamine, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Worldwide, ATS are among the most common illicit drugs. Therefore, understanding whether and to what extent ATS exposure affects brain structure and functioning in recreational users has become a critical public health issue. We studied gray and white matter densities in 20 experienced users of ATS (more than 100 units MDMA and/or 50 g of amphetamine lifetime dose), 42 low exposure users with very limited ATS experience (less than 5 units lifetime dose) and 16 drug-naive controls. A tract-based spatial statistics (TBSS) analysis of fractional anisotropy images was applied to diffusion magnetic resonance imaging (MRI) data. Furthermore, alignment invariant white matter tract representations acquired from the TBSS analysis were used as a reference for inter-subject brain registrations in a voxel-based morphometry (VBM) analysis of gray matter volume, reducing characteristic alignment inaccuracies associated with this voxel-wise gray matter investigation approach. Between-group white matter comparison revealed no significant results. However, compared to low exposure users, experienced users showed several regions of lower gray matter volume in medial frontal regions, in particular the orbital and medial frontal cortex. Differences are likely to reflect effects of repeated ATS exposure even in recreational users. However, differences in pre-existing or confounding factors might also account for between-group differences.

Interactions between specific parameters of cannabis use and verbal memory.

Recently, the impact of different parameters of cannabis use, including the age of first use, the average frequency of use, the cumulative lifetime dose, the average dose per occasion, and the duration of regular use upon cognitive functions has been discussed. However, to date no study has systematically investigated the interactions of these parameters with regard to cognitive performance. To determine whether these interactions exist, 142 healthy young adult cannabis users participated in a neuropsychological assessment study with a German version of the Rey Auditory Verbal Learning Test (RAVLT). In line with previous studies on cannabis use and verbal memory, significant associations between certain components of verbal memory and frequency of use, cumulative lifetime dose and duration of regular use respectively were found. Remarkably, a multivariate analysis solely revealed a significant main effect of the duration of cannabis use with regard to immediate recall and recall after interference. Moreover, the findings suggest that age of first use, duration of use and frequency of cannabis use interact with regard to their impact on different measures of verbal memory. The findings of the present study provide first evidence that particular parameters of cannabis use interact with regard to their impact on cognitive functions in unintoxicated cannabis users. This finding might deliver more insight into the complex mechanisms underlying the impaired memory functions observed in cannabis users.

The impact of early-onset cannabis use on functional brain correlates of working memory.

Cannabis is the most commonly used illicit drug. Prevalence rates are particularly high among adolescents. Neuropsychological studies have identified cannabis-associated memory deficits, particularly linked to an early onset of use. However, it remains unclear, whether the age of onset accounts for altered cortical activation patterns usually observed in cannabis users. Functional magnetic resonance imaging was used to examine cortical activation during verbal working memory challenge in (1) early-onset (onset before the age of sixteen; n=26) and (2) late-onset cannabis users (age at onset at least sixteen; n=17). Early-onset users showed increased activation in the left superior parietal lobe. Correlational analyses confirmed the association between an earlier start of use and increased activity. Contrariwise neither cumulative dose, frequency nor time since last use was significantly associated with cortical activity. Our findings suggest that an early start of cannabis use is associated with increased cortical activation in adult cannabis users, possibly reflecting suboptimal cortical efficiency during cognitive challenge. The maturing brain might be more vulnerable to the harmful effects of cannabis use. However, due to a lack of a non-using control group we cannot exclude alternative interpretations.

Altered parahippocampal functioning in cannabis users is related to the frequency of use.

RATIONALE: Converging lines of evidence suggest an association between cannabis use and impaired episodic memory as well as related associative learning. These deficits have been associated with the duration, frequency, and age of onset of cannabis use. However, it remains unclear whether these parameters of use differently impact memory-related hippocampal functioning. METHODS: Forty-two cannabis users were examined by means of functional magnetic resonance imaging while they encoded and retrieved face-profession associations. Region of interest analysis was subsequently used to compare (para-)hippocampal functioning in users with (1) a longer and shorter duration of use, (2) a higher and lower frequency of use, and (3) an earlier and later onset. To further separate the effects of these parameters of use on performance and (para-)hippocampal activity, linear regression analysis was applied. RESULTS: Compared to low-frequency users, high-frequency users displayed stronger blood oxygenation level-dependent response during encoding in the left parahippocampal gyrus. No differences were obvious for the groups separated according to duration of use or an earlier and later onset of use. Linear regression analysis confirmed the association between a higher frequency of use and increased activity in the left parahippocampal gyrus. CONCLUSIONS: Our findings suggest that the frequency of use might have a particular critical impact on intact parahippocampal functioning in cannabis users. Increased activity within the encoding-related network might reflect functional compensation to maintain cognitive functioning.

The role of cannabis in cognitive functioning of patients with schizophrenia.

RATIONALE: Cognitive deficits are commonly found both in patients with schizophrenia (SCH) and in people with cannabis use disorders (CUD). Surprisingly, some small recent studies reported better cognitive performance in SCH patients with comorbid cannabis use disorders (SCH + CUD) compared to other SCH patients. OBJECTIVES: The aim of the present study was to investigate the residual impact of CUD and specific patterns of consumption on cognition in a larger sample of SCH + CUD patients. METHODS: We administered a cognitive test battery to 34 SCH and 35 currently abstinent SCH + CUD patients. We explored the association between patterns of cannabis consumption and cognitive performance. Potential confounds with influence on cognitive ability were assessed and controlled for. RESULTS: SCH + CUD patients had poorer academic achievements and lower vocabulary scores, but they performed better in tests of verbal and working memory, visuomotor speed and executive function (p < .05). More frequent cannabis use was associated with better performance in attention and working memory tasks. CONCLUSIONS: Although our findings might be interpreted as beneficial effect of cannabis use on cognition in patients with schizophrenia, we favorise an alternative interpretation: in our view, the better cognitive functioning of SCH + CUD patients may rather reflect a relatively lower vulnerability to psychosis compared to the SCH group. Lower vulnerability may correspond to a higher level of functioning such as cognitive ability. This conclusion is consistent with the view of cannabis playing a critical role in the manifestation of psychosis in at least some of the SCH + CUD patients.

Correlation of passivity symptoms and dysfunctional visuomotor action monitoring in psychosis.

Passivity experiences are hallmark symptoms of schizophrenia that can be characterized by the belief that one's thoughts or actions are controlled by an external agent. It has recently been suggested that these psychotic experiences result from defective monitoring of one's own actions, i.e. disturbed comparison of actions and perceived outcomes. In this study, we examined the function of the previously characterized action monitoring network of the inferior parietal lobule (IPL), medial (mPFC) and lateral prefrontal cortices in patients with different levels of passivity symptoms with an fMRI task. The visuomotor fMRI task demanded control of visually perceived object movements by alternating button presses with the left and the right index finger. In the monitoring condition of this task subjects stopped their actions whenever they detected visuomotor incongruence. fMRI and behavioural data from 15 patients were tested for correlation with passivity symptoms using standardized Scale for Assessment of Positive Symptoms (SAPS)- and AMDP- passivity symptom ratings. Both types of data were tested for differences between the patients group and 15 healthy controls. In the patient group we found the expected correlation of passivity symptoms and visuomotor monitoring performance. There was a significant positive correlation of passivity symptoms with increased latency of incongruence detection and a negative correlation of SAPS-passivity with the number of detected events. fMRI data revealed correlations of passivity symptoms with activation in bilateral IPL, primary motor and sensory cortices in the action monitoring condition. A correlation of passivity symptoms with the main experimental effect (actions with -- actions without monitoring) was found in the posterior cingulate cortex (PCC) and in the left IPL. No group differences or group by task interactions were found within the visuomotor-action-monitoring network. Our results demonstrate the association between passivity symptoms and the dysfunction of visuomotor action monitoring and support the idea that psychotic passivity experiences result from dysfunctions of central action monitoring mechanisms: According to pre-existing concepts of parietal cortex function, IPL-hyperactivation may represent an increase in false detections of visuomotor incongruence while the correlation between passivity and the differential effect of monitoring on PCC-activation assumedly represents greater self-monitoring effort in passivity experiences.

Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis.

RATIONALE: Attentional deficits are common symptoms in schizophrenia. Recent evidence suggests that schizophrenic patients show abnormalities in spatial orienting of attention, particularly a deficit of inhibition of return (IOR). IOR is mostly thought to reflect an automatic, inhibitory mechanism protecting the organism from redirecting attention to previously scanned, insignificant locations. Pharmacologic challenges with hallucinogens have been used as models for psychosis. OBJECTIVES: The aim of this study was to investigate the neural correlates underlying orienting of attention in the human N-methyl-D-aspartic acid antagonist and 5-HT2A agonist models of psychosis. MATERIALS AND METHODS: Fourteen healthy volunteers participated in a randomized, double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. We administered a covert orienting of attention task with nonpredictive peripheral cues, and we scanned the subjects on two separate days at least 14 days apart with a placebo and a verum condition on each day. RESULTS: DMT, but not S-ketamine, slowed down reaction times significantly. IOR was blunted after DMT, but not after S-ketamine. Relative to placebo, S-ketamine increased activation in the IOR condition in the right superior frontal gyrus, left superior temporal gyrus, and right midfrontal frontal gyrus. CONCLUSIONS: The discrepancy between the behavioral and functional imaging outcome indicates that pharmacological fMRI might be a sensitive tool to detect drug-modulated blood oxygenation level-dependent signal changes in the absence of behavioral abnormalities. Our findings might help to further clarify the contradictory findings of IOR in schizophrenic patients and might, thus, shed more light on possible differential pathomechanisms of schizophrenic symptoms.

Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis.

RATIONALE: Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-D-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model). OBJECTIVES: The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design. MATERIALS AND METHODS: Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation. RESULTS: Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN. CONCLUSIONS: The NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.

An fMRI approach to particularize the frontoparietal network for visuomotor action monitoring: Detection of incongruence between test subjects' actions and resulting perceptions.

Contemporary theories of motor control assume that motor actions underlie a supervisory control system which utilizes reafferent sensory feedbacks of actions for comparison with the original motor programs. The functional network of visuomotor action monitoring is considered to include inferior parietal, lateral and medial prefrontal cortices. To study both sustained monitoring for visuomotor incongruence and the actual detection of incongruence, we used a hybrid fMRI epoch-/event-related design. The basic experimental task was a continuous motor task, comprising a simple racing game. Within certain blocks of this task, incongruence was artificially generated by intermittent takeover of control over the car by the computer. Fifteen male subjects were instructed to monitor for incongruence between their own and the observed actions in order to abstain from their own action whenever the computer took over control. As a result of both sustained monitoring and actual detection of visuomotor incongruence, the rostral inferior parietal lobule displayed a BOLD signal increase. In contrast, the prefrontal cortex (PFC) exhibited two different activation patterns. Dorsolateral (BA 9/46) and medial/cingulate (BA 8, BA 32) areas of the PFC displayed a greater increase of activation in sustained monitoring, while ventrolateral PFC showed greater event-related activation for the actual detection of visuomotor incongruence. Our results suggest that the rostral inferior parietal lobule is specifically involved in the reafferent comparison of the test subjects' own actions and visually perceived actions. Different activation patterns of the PFC may reflect different frontoparietal networks for sustained action monitoring and actual detection of reafferent incongruence.

The confounding problem of polydrug use in recreational ecstasy/MDMA users: a brief overview.

The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine -- MDMA) is neurotoxic upon central serotonergic neurons in laboratory animals and possibly also in humans. In recent years, several studies reported alterations of serotonergic transmission and neuropsychiatric abnormalities in ecstasy users which might be related to MDMA-induced neurotoxic brain damage. To date, the most consistent findings associate subtle cognitive, particularly memory, deficits with heavy ecstasy use. However, most studies have important inherent methodological problems. One of the most serious confounds is the widespread pattern of polydrug use which makes it dif.cult to relate the findings in user populations to one specific drug. The present paper represents a brief overview on this issue. The most commonly co-used substances are alcohol, cannabis and stimulants (amphetamines and cocaine). Stimulants are also neurotoxic upon both serotonergic and dopaminergic neurons. Hence, they may act synergistically with MDMA and enhance its long-term adverse effects. The interactions between MDMA and cannabis use may be more complex: cannabis use is a well-recognized risk factor for neuropsychiatric disorders and it was shown to contribute to psychological problems and cognitive failures in ecstasy users. However, at the cellular level, cannabinoids have neuroprotective actions and they were shown to (partially) block MDMA-induced neurotoxicity in laboratory animals. In future, longitudinal and prospective research designs should hopefully lead to a better understanding of the relation between drug use and subclinical psychological symptoms or neurocognitive failures and, also, of questions around interactions between the various substances of abuse.

Intensity dependence of auditory evoked dipole source activity in polydrug ecstasy users: evidence from an 18 months longitudinal study.

Numerous animal studies have been able to demonstrate neurotoxic damage to central serotonergic systems after exposure to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). It has been suggested that a high loudness dependence of auditory evoked potentials (LDAEP) and, particularly, of the tangential N1/P2 source activity is associated with a low functioning of serotonergic activity. Therefore, the LDAEP may be used as a non-invasive indicator for a possible neurotoxic damage caused by the long-term use of ecstasy in recreational users. We recorded auditory evoked potentials (AEP) with a passive listening paradigm in 18 polydrug ecstasy users at baseline (t1) and after 18 months (t2). Several aspects of ecstasy use, such as frequency of use, cumulative lifetime dose or period of abstinence were associated with the LDAEP for several tangential dipoles at both measuring times. However, we failed to demonstrate any significant relationship between drug use reported at follow-up and AEP changes from baseline to follow-up. Despite some incertitude these data suggest, yet do not unambiguously con.rm, the hypothesis that abstinent ecstasy users present with diminished central serotonergic activity. This feature of information processing is potentially related to the neurotoxic potential of ecstasy. However, alternative interpretations of these data refer to possible preexisting traits and the potential impact of other illicit drugs, particularly amphetamine, since ecstasy users typically exhibit polydrug use patterns. Thus, further research with larger sample sizes and prospective study designs are needed to definitively establish a causative link between ecstasy use and neurotoxicity-related dysfunctions in sensory processing.

Memory-related hippocampal dysfunction in poly-drug ecstasy (3,4-methylenedioxymethamphetamine) users.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is neurotoxic in animal studies and its use has been associated with cognitive impairments in humans. OBJECTIVE: To study hippocampal activation during the retrieval from episodic memory in polyvalent users of ecstasy. METHODS: Twelve polyvalent ecstasy users and twelve matched controls were examined by means of functional magnetic resonance imaging (fMRI) while they retrieved face-profession associations from episodic memory. RESULTS: Ecstasy users had a normal structural MRI scan without focal brain lesions or anatomical abnormalities. They exhibited equal retrieval accuracy during memory retrieval to that of the matched controls. Yet, their retrieval-related activity was lower and more spatially restricted in the left anterior hippocampus than that of the controls. CONCLUSIONS: These results provide evidence for abnormal hippocampal functioning in MDMA users even at the presence of normal memory performance. This finding may be linked to MDMA-induced neurotoxicity and suggests that diminished hippocampal activation during memory retrieval might be a more sensitive or earlier index of MDMA-related neurotoxicity than neuropsychological performance.