Joerg Daumann

Unilateral deep brain stimulation of the nucleus accumbens in patients with treatment-resistant obsessive-compulsive disorder: Outcomes after one year.

OBJECTIVE To investigate the effects of unilateral deep brain stimulation (DBS) in the right nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Predominantly bilateral stimulation of the anterior limb of the internal capsule was utilized. METHODS The study was designed as a double-blind sham-controlled crossover study. Patients received 3 months of deep brain stimulation followed by 3 months of sham stimulation, or vice versa. Subsequently, stimulation was continued unblinded for all patients. The primary outcome measure was the severity level of OCD, measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Secondary outcome measures were depressive symptoms, anxiety, psychological symptom severity, global functioning, quality of life, and cognitive function. RESULTS The mean Y-BOCS scores decreased significantly from 32.2 (+/-4.0) at baseline to 25.4 (+/-6.7) after 12 months (p=0.012). Five out of ten patients showed a decrease of more than 25%, indicating at least a partial response. One patient showed a decrease in Y-BOCS severity greater than 35%. Similarly, depression, global functioning and quality of life improved within one year. In contrast, anxiety, global symptom severity and cognitive function showed no significant changes. In general, DBS was well-tolerated. CONCLUSIONS DBS of the unilateral right nucleus accumbens showed encouraging results in patients with treatment-resistant OCD. Five out of ten patients reached at least a partial response after the first year.

A prospective study of learning, memory, and executive function in new MDMA users.

AIMS It is still unclear if cognitive abnormalities in human 3,4-methylenedioxymeth-amphetamine (MDMA) users existed before the beginning of use or if other confounders could explain the deficits. The present study was conducted in order to assess the relationship between beginning MDMA use and subsequent cognitive performance and to overcome previous methodological shortcomings. DESIGN A prospective cohort study in new MDMA users between 2006 and 2009 with a follow-up duration of 12 months. SETTING AND PARTICIPANTS Of the 149 almost MDMA-naive subjects examined at the initial assessment, 109 subjects participated again after 1 year. During this period, 43 subjects did not use any other illicit substance apart from cannabis; 23 subjects used more than 10 pills MDMA (mean = 33.6). These groups then were compared by means of multivariate analyses of variance. MEASUREMENTS Change scores between the initial examination and follow-up on a neuropsychological test battery including measures of learning, memory, and frontal executive functions [Auditiv-Verbaler Lerntest (AVLT), Lern- und Gedächtnistest (LGT) 3, digit span test, digit symbol test, Stroop task, Trail-making test]. In addition, a comprehensive number of possibly relevant confounders including age, general intelligence, cannabis use, alcohol use, cigarette use, medical treatment, participation in sports, nutrition, sleep patterns and subjective wellbeing was assessed. FINDINGS Groups did not differ in any of the potential confounders. However, significant effects of immediate and delayed recall of a visual paired associates learning task between MDMA users and controls were found (respectively, F ((1,64)) = 11.43, P = 0.001, η(2) = 0.136 and F ((1,64)) = 11.08, P = 0.002, η(2) = 0.144). No significant differences on the other neuropsychological tests were found. CONCLUSIONS MDMA appears to impair visual paired associates learning in new users, suggesting serotonergic dysfunction in hippocampal regions as a consequence of MDMA use.

Inhibition of Return in the Human 5HT2A Agonist and NMDA Antagonist Model of Psychosis

Patients with schizophrenia exhibit disturbances of orienting of attention. However, findings have been inconsistent. Pharmacologic challenges with hallucinogens have been used as models for psychosis. The NMDA antagonist state (PCP, ketamine) resembles undifferentiated psychoses with positive and negative symptoms, while the 5-HT2A agonist state (LSD, dimethyltryptamine (DMT)) is thought to be an appropriate model for psychoses with prominent positive symptoms. The aim of this study was to investigate orienting of attention in the human NMDA antagonist and 5-HT2A agonist models of psychosis. A total of 15 healthy volunteers participated in a randomized, double-blind, crossover study with a low and a high dose of DMT and S-ketamine, which elicited subtle ‘prepsychotic’ or full-blown psychotic symptoms (low and high dose, respectively). Nine subjects completed both experimental days with the two doses of both drugs. Overall, both hallucinogens slowed down reaction times dose dependently (DMT >S-ketamine) and DMT diminished the general response facilitating (alerting) effect of spatially neutral cues. Inhibition of Return (IOR), that is, the normal reaction time disadvantage for validly cued trials with exogenous cues and long cue target intervals, was blunted after both doses of DMT and the low dose of S-ketamine. IOR reflects an automatic, inhibitory mechanism of attention, which is thought to protect the organism from redundant, distracting sensory information. In conclusion, our data suggest a deficit of IOR in both hallucinogen models of psychosis, with the effect being clearer in the serotonin model. Blunted IOR may underlie or predispose to different psychotic manifestations, but particularly to those with prominent positive symptoms.

Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis.

Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients. Alertness is a nonselective attention component that refers to a state of general readiness that improves stimulus processing and response initiation. The main goal of the present study was to investigate cerebral correlates of alertness in the human 5HT2A agonist and N-methyl-D-aspartic acid (NMDA) antagonist model of psychosis. 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. A target detection task with cued and uncued trials in both the visual and the auditory modality was used. Administration of DMT led to decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in extrastriate regions during visual alerting and in temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. The results of the present study might deliver more insight into potential differences and overlapping pathomechanisms in schizophrenia. These conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modality-specific alertness tasks.

Orienting of attention in unmedicated patients with schizophrenia, prodromal subjects and healthy relatives

In typical orienting of attention tasks subjects have to respond as fast as possible to targets which appear in the periphery of the visual field and are preceded by spatial cues (e.g. brightening of a peripheral box where the target may subsequently appear). Reaction times (RT) are facilitated when cue and target appear at the same location (valid cueing) and the cue target interval is short (<250 ms). However, RTs slow down again when the target follows a valid cue after an interval of 250 ms and longer. This latter phenomenon is called Inhibition of Return (IOR) and is thought to reflect an automatic, inhibitory mechanism to protect the organism from redundant and distracting stimuli. Deficits of IOR were repeatedly reported in patients with schizophrenia. However, the role of medications and the nature of the deficit (trait or vulnerability indicator?) were unclear. In the present study we examined 15 unmedicated patients with schizophrenia (age: 31.2+/-11.1, m/f: 11/4, global scores SAPS: 48.33+/-33.09, SANS: 19.22+/-26.16), 29 subjects who were putatively in a prodromal state of psychosis, 30 first-degree relatives, another 8 first-degree relatives who had one child and at least one more relative with schizophrenia, and 50 healthy controls. We found an impairment of IOR only in the unmedicated patient group. In conclusion, blunted IOR in schizophrenia is not secondary to medications. According to this and previous studies blunted IOR may be most probably viewed as a trait cognitive feature of the schizophrenic disorder.

Decision-making in Polydrug Amphetamine-type Stimulant Users: an fMRI Study

Qualitative poor decision-making and associated altered neuronal activation patterns have been described for the users of several drugs, amongst others for stimulants like amphetamine and MDMA. Deficits in decision-making might be caused by an augmented attraction to short-term rewarding properties despite negative long-term consequences, leading to rigid stimulus–response patterns. In the present imaging study, we investigated decision-making and associated neuronal activation in three groups differing in their exposure to amphetamine and MDMA. An established paradigm on risky choices was used to evaluate decision-making performance and corresponding functional magnet resonance imaging (fMRI) activation. Subjects could choose between a low-risk control gamble and an experimental gamble, which always differed in the probability of winning or losing, as well as the magnitudes of monetary gain or loss. Experienced users (EU), users with low exposure to stimulants and drug-naive controls, did not differ from each other in behavioral performance. In accordance with our hypotheses, the anticipation of reward led to an activation of primarily the frontal cortex and the striatum in low-exposure users and drug-naive controls. In contrast, frontal and parietal activation was observed in all groups when the actual outcome of an experimental gamble was presented. EU displayed more activation compared to both control groups when there was a high probability of winning. The study at hand supports the hypothesis that neuronal activation patterns might even differ between drug users and healthy controls when no behavioral deficits are apparent. In EU, the probability of the occurrence of an event has more influence on neuronal activation than on the actual magnitude of reinforcing properties of this event.

Learning, Memory, and Executive Function in New MDMA Users: A 2-Year Follow-Up Study

3,4-Methylenedioxymethamphetamine (MDMA) is associated with changes in neurocognitive performance. Recent studies in laboratory animals have provided additional support for the neurodegeneration hypothesis. However, results from animal research need to be applied to humans with caution. Moreover, several of the studies that examine MDMA users suffer from methodological shortcomings. Therefore, a prospective cohort study was designed in order to overcome these previous methodological shortcomings and to assess the relationship between the continuing use of MDMA and cognitive performance in incipient MDMA users. It was hypothesized that, depending on the amount of MDMA taken, the continued use of MDMA over a 2-year period would lead to further decreases in cognitive performance, especially in visual paired association learning tasks. Ninety-six subjects were assessed, at the second follow-up assessment: 31 of these were non-users, 55 moderate-users, and 10 heavy-users. Separate repeated measures analyses of variance were conducted for each cognitive domain, including attention and information processing speed, episodic memory, and executive functioning. Furthermore, possible confounders including age, general intelligence, cannabis use, alcohol use, use of other concomitant substances, recent medical treatment, participation in sports, level of nutrition, sleep patterns, and subjective well-being were assessed. The Repeated measures analysis of variance (rANOVA) revealed that a marginally significant change in immediate and delayed recall test performances of visual paired associates learning had taken place within the follow-up period of 2 years. No further deterioration in continuing MDMA-users was observed in the second follow-up period. No significant differences with the other neuropsychological tests were noted. It seems that MDMA use can impair visual paired associates learning in new users. However, the groups differed in their use of concomitant use of illicit drugs. Therefore, performance differences between the groups cannot completely ascribed to the use of MDMA.

Interactions between specific parameters of MDMA use and cognitive and psychopathological measures

The aim of the present study was to investigate the relevance of different parameters of 3,4-methylenedioxymethamphetamine (MDMA) use, including age of first use, cumulative lifetime dose and highest daily dose for predicting cognitive performance and self-reported psychopathology. Moreover, interactions between those parameters were examined. Ninety-six new MDMA users were interviewed to assess their drug use, and they completed a battery of cognitive tests concerning attention and information processing speed, episodic memory and executive functioning and self-reported psychopathology. Subjects participated again after 1year to provide follow-up data. Significant associations between age of first use and cumulative lifetime dose have been found for attention and information processing speed. Furthermore, the results showed a significant effect of age of first use on the recognition performance of the episodic memory. The findings of the current study provide a first estimation of the interactions between different MDMA use parameters. Future research should focus upon additional parameters of drug use and concentrate on consequent follow-up effects.

A Longitudinal Study of Self-Reported Psychopathology in Beginning Ecstasy and Amphetamine Users: A Third Follow-up Evaluation

ABSTRACT Background: It is still unknown whether psychopathological symptoms found in ecstasy and amphetamine users were apparent before the first use or developed subsequent to its use. Objectives: The present study presents the third follow-up evaluation of a longitudinal study to assess the nature of the relationship between ecstasy, amphetamine (AMPH) and psychopathology. Methods: In this sample, 69 beginning ecstasy and AMPH users were followed over a period of 4 years. To explore different psychopathological dimensions, the Symptom Checklist-90-Revised was applied. Use of ecstasy, AMPH, cannabis and was gathered by structured interviews and use of cigarettes by a questionnaire. First, linear mixed models for repeated measures (unstructured covariance matrix) on the nine primary symptoms of the SCL-90-R with a separate model for each symptom category were performed. Second, linear regression analyses with the nine primary symptom categories of the baseline assessment (T0) as predictors and with ecstasy and AMPH use as dependent variables were fitted. Results: No significant associations between ecstasy, AMPH, and psychopathology were evident. However, a significant two-way interaction between ecstasy and cigarette use at the baseline assessment, as well as a three-way interaction effect between ecstasy, cigarette use, and time on obsessive-compulsive symptoms, were found. Conclusions: This study suggests that nicotine may moderate the effect of ecstasy on obsessive-compulsive symptoms. However, no associations between ecstasy, AMPH, and psychopathology have been found. This is one of the few studies, which highlights the role of nicotine in the study of psychopathology in beginning ecstasy and AMPH users.

Neuropsychologie des Ecstasy-Abusus

Der Begriff Ecstasy wird meistens synonym fur 3,4- Methylendioxymethamphetamin (MDMA) verwandt. MDMA ist die verbreiteteste Jugenddroge nach Cannabis und in der Regel auch der einzige Inhaltsstoff der Ecstasypillen. Nur gelegentlich werden chemische Analoga wie 3,4-Methylendioxyamphetamin und 3,4-Methylendioxyethylamphetamin, die hinsichtlich ihrer Wirkungen kaum vom MDMA zu unterscheiden sind, als Ecstasy verkauft. Deutlich seltener beinhalten die Ecstasypillen andere Substanzen wie Amphetaminstimulanzien, Koffein u. a. Vereinfachend werden im Folgenden die Begriffe Ecstasy und MDMA synonym verwandt.