Neurometabolic profile of the amygdala in smokers assessed with 1H-magnetic resonance spectroscopy.

Tobacco smoking is one of the main causes of premature death worldwide and quitting success remains low, highlighting the need to understand the neurobiological mechanisms underlying relapse. Preclinical models have shown that the amygdala and glutamate play an important role in nicotine addiction. The aims of this study were to compare glutamate and other metabolites in the amygdala between smokers and controls, and between different smoking states. Furthermore, associations between amygdalar metabolite levels and smoking characteristics were explored. A novel non-water-suppressed proton magnetic resonance spectroscopy protocol was applied to quantify neurometabolites in 28 male smokers (≥15 cigarettes/day) and 21 non-smoking controls, matched in age, education, verbal IQ, and weekly alcohol consumption. Controls were measured once (baseline) and smokers were measured in a baseline state (1-3 h abstinence), during withdrawal (24 h abstinence) and in a satiation state (directly after smoking). Baseline spectroscopy data were compared between groups by independent t-tests or Mann-Whitney-U tests. Smoking state differences were investigated by repeated-measures analyses of variance (ANOVAs). Associations between spectroscopy data and smoking characteristics were explored using Spearman correlations. Good spectral quality, high anatomical specificity (98% mean gray matter) and reliable quantification of most metabolites of interest were achieved in the amygdala. Metabolite levels did not differ between groups, but smokers showed significantly higher glutamine levels at baseline than satiation. Glx levels were negatively associated with pack-years and smoking duration. In summary, this study provides first insights into the neurometabolic profile of the amygdala in smokers with high anatomical specificity. By applying proton magnetic resonance spectroscopy, neurometabolites in smokers during different smoking states and non-smoking controls were quantified reliably. A significant shift in glutamine levels between smoking states was detected, with lower concentrations in satiation than baseline. The negative association between Glx levels and smoking quantity and duration may imply altered glutamate homeostasis with more severe nicotine addiction.

Accumbal-thalamic connectivity and associated glutamate alterations in human cocaine craving: A state-dependent rs-fMRI and 1H-MRS study.

Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9.4 × 18.8 × 8.4 mm3) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans.

Cannabis Consumers' View of Regulated Access to Recreational Cannabis: A Multisite Survey in Switzerland.

INTRODUCTION: There is considerable effort in legalizing recreational use of cannabis globally. The successful implementation of a program of regulated access to recreational cannabis (PRAC) depends on the consumers' engagement. The aim of this study was to examine the acceptability of twelve different regulatory aspects by cannabis users including those obtaining cannabis from the illicit market and vulnerable populations such as young adults and problematic users. METHODS: The current study is a multisite online survey conducted in Switzerland. A total of 3,132 adult Swiss residents who consumed cannabis within the previous 30 days represented the studied population. Mean age was 30.5 years, 80.5% were men, and 64.2% of the participants stated that they always or often obtain cannabis from the illicit market. We described consumers' acceptability of twelve regulatory aspects concerning THC content control, disclosure of sensitive personal data, security aspects, and follow-up procedures by applying descriptive statistics and multiple regression models. RESULTS: THC content regulation showed most discrepancy with 89.4% of the participants stating to engage in a PRAC if five different THC contents were available as compared to 54% if only 12% THC was available. The least accepted regulatory aspect was disposal of contact details with an acceptability rate of 18.1%. Consumers mainly obtaining cannabis from the illicit market, young adults, and problematic users showed similar acceptability patterns. Participants obtaining cannabis from the illicit market were more likely to engage in a PRAC if five different THC contents were available as compared to participants obtaining cannabis from other sources (OR 1.94, 95% CI: 1.53-2.46). CONCLUSION: A carefully designed PRAC that takes into account the consumers' perspective is likely to transfer them to the regulated market and to engage vulnerable populations. We cannot recommend the distribution of cannabis with only 12% THC content as this is unlikely to engage the target population.

Transdiagnostic brain correlates of self-reported trait impulsivity: A dimensional structure-symptom investigation.

Impulsivity transcends psychiatric diagnoses and is often related to anhedonia. This ad hoc cross-sectional investigation explored 1) whether self-reported trait impulsivity mapped onto a common structural brain substrate across healthy controls (HCs) and psychiatric patients, and 2) in a more exploratory fashion, whether impulsivity and anhedonia were related to each other and shared overlapping brain correlates. Structural magnetic resonance imaging (sMRI) datasets from 234 participants including HCs (n = 109) and patients with opioid use disorder (OUD, n = 22), cocaine use disorder (CUD, n = 43), borderline personality disorder (BPD, n = 45) and schizophrenia (SZ, n = 15) were included. Trait impulsivity was measured with the Barratt Impulsiveness Scale (BIS-11) and anhedonia with a subscore of the Beck Depression Inventory (BDI). BIS-11 global score data were available for the entire sample, while data on the BIS-11 2nd order factors attentional, motor and non-planning were additionally in hand for a subsample consisting of HCs, OUD and BPD patients (n = 116). Voxel-based morphometry analyses were conducted for identifying dimensional associations between grey matter volume and impulsivity/anhedonia. Partial correlations were further performed to exploratory test the relationships between impulsivity and anhedonia and their corresponding volumetric brain substrates. Volume of the left opercular part of the inferior frontal gyrus (IFG) was negatively related to global impulsivity across the entire sample and specifically to motor impulsivity in the subsample of HCs, OUD and BPD patients. Across patients anhedonia expression was negatively correlated with left putamen volume. Although there was no relationship between global impulsivity and anhedonia across all patients, only across OUD and BPD patients anhedonia was positively associated with attentional impulsivity. Finally, also across OUD and BPD patients, motor impulsivity associated left IFG volume was positively linked with anhedonia-associated volume in the left putamen. Our findings suggest a critical role of left IFG volume in self-reported global impulsivity across healthy participants and patients with substance use disorder, BPD and SZ. Preliminary findings in OUD and BPD patients further suggests associations between impulsivity and anhedonia that are related to grey matter reductions in the left IFG and putamen.

Thalamic volume and functional connectivity are associated with nicotine dependence severity and craving.

Tobacco smoking is associated with deleterious health outcomes. Most smokers want to quit smoking, yet relapse rates are high. Understanding neural differences associated with tobacco use may help generate novel treatment options. Several animal studies have recently highlighted the central role of the thalamus in substance use disorders, but this research focus has been understudied in human smokers. Here, we investigated associations between structural and functional magnetic resonance imaging measures of the thalamus and its subnuclei to distinct smoking characteristics. We acquired anatomical scans of 32 smokers as well as functional resting-state scans before and after a cue-reactivity task. Thalamic functional connectivity was associated with craving and dependence severity, whereas the volume of the thalamus was associated with dependence severity only. Craving, which fluctuates rapidly, was best characterized by differences in brain function, whereas the rather persistent syndrome of dependence severity was associated with both brain structural differences and function. Our study supports the notion that functional versus structural measures tend to be associated with behavioural measures that evolve at faster versus slower temporal scales, respectively. It confirms the importance of the thalamus to understand mechanisms of addiction and highlights it as a potential target for brain-based interventions to support smoking cessation, such as brain stimulation and neurofeedback.

Negative symptoms in alcohol use disorder: A pilot study applying the two-factor model of negative symptoms to patients with alcohol use disorder.

Background and aims: Alcohol Use Disorder (AUD) is characterized by a reduction in goal-directed behavior, with alcohol use taking precedence over other areas of life. These features in AUD resemble negative symptoms in schizophrenia, especially the reduction in motivation and pleasure (MAP). Given the clinical similarities of negative symptoms across diagnostic categories, it comes as a surprise that there are few investigations on negative symptoms in alcohol and other substance use disorders. To our knowledge, our study is the first to assess negative symptoms in AUD based on a two-factorial approach, and to investigate the interrelation of these dimensions with the severity of AUD, and alcohol craving. Materials and methods: We examined a sample of 42 patients with AUD at the Psychiatric University Hospital in Zurich. Participants provided self-report and interview-based measures of the severity of AUD, negative symptoms, and alcohol craving. Finally, we used data from the electronic health records of the patients. Results: Patients with AUD show negative symptoms to a similar extent as patients with schizophrenia or bipolar disorder. We found a positive correlation between the extent of impairment within the MAP factor and overall severity of AUD. Furthermore, MAP negative symptoms were correlated with alcohol craving. In a linear regression, negative symptoms predicted alcohol craving whereas depression did not. Summary: Negative symptoms as conceptualized for schizophrenia are prevalent in patients with AUD and associated with the severity of AUD. More specifically, severity of AUD correlates with diminished motivation and pleasure, highlighting the importance of disturbances in motivational functions in AUD. This is further supported by the correlation between negative symptoms and craving, a hallmark of AUD. Taken together, our findings suggest that negative symptoms might be a highly relevant but hitherto often neglected therapeutic target in AUD.

Analysis of individual differences in neurofeedback training illuminates successful self-regulation of the dopaminergic midbrain.

The dopaminergic midbrain is associated with reinforcement learning, motivation and decision-making - functions often disturbed in neuropsychiatric disorders. Previous research has shown that dopaminergic midbrain activity can be endogenously modulated via neurofeedback. However, the robustness of endogenous modulation, a requirement for clinical translation, is unclear. Here, we examine whether the activation of particular brain regions associates with successful regulation transfer when feedback is no longer available. Moreover, to elucidate mechanisms underlying effective self-regulation, we study the relation of successful transfer with learning (temporal difference coding) outside the midbrain during neurofeedback training and with individual reward sensitivity in a monetary incentive delay (MID) task. Fifty-nine participants underwent neurofeedback training either in standard (Study 1 N = 15, Study 2 N = 28) or control feedback group (Study 1, N = 16). We find that successful self-regulation is associated with prefrontal reward sensitivity in the MID task (N = 25), with a decreasing relation between prefrontal activity and midbrain learning signals during neurofeedback training and with increased activity within cognitive control areas during transfer. The association between midbrain self-regulation and prefrontal temporal difference and reward sensitivity suggests that reinforcement learning contributes to successful self-regulation. Our findings provide insights in the control of midbrain activity and may facilitate individually tailoring neurofeedback training.

Aberrant striatal coupling with default mode and central executive network relates to self-reported avolition and anhedonia in schizophrenia.

BACKGROUND: Avolition and anhedonia are common symptoms in schizophrenia and are related to poor long-term prognosis. There is evidence for aberrant cortico-striatal function and connectivity as neural substrate of avolition and anhedonia. However, it remains unclear how both relate to shared or distinct striatal coupling with large-scale intrinsic networks. Using resting state functional magnetic resonance imaging (rs-fMRI) this study investigated the association of large-scale cortico-striatal functional connectivity with self-reported and clinician-rated avolition and anhedonia in subjects with schizophrenia. METHODS: Seventeen subjects with schizophrenia (SZ) and 28 healthy controls (HC) underwent rs-fMRI. Using Independent Component Analysis (ICA), we assessed Independent Components (ICs) reflecting intrinsic connectivity networks (ICNs), intra intrinsic functional connectivity within the ICs (intra-iFC), and intrinsic functional connectivity between different ICs (inter-iFC). Avolition and anhedonia were assessed using the Self Evaluation Scale for Negative Symptoms and the Brief Negative Symptom Scale. RESULTS: ICA revealed three striatal components and six cortical ICNs. Both self-rated avolition and anhedonia correlated with increased inter-iFC between the caudate and posterior Default Mode Network (pDMN) and between the caudate and Central Executive Network (CEN). In contrast, clinician-rated avolition and anhedonia were not correlated with cortico-striatal connectivity. Group comparison revealed trend-wise decreased inter-iFC between the caudate and Salience Network (SN) in schizophrenia patients compared to HC. DISCUSSION: Self-rated, but not clinician-rated, avolition and anhedonia was associated with aberrant striatal coupling with the default mode and the central executive network. These findings suggest that self-reported and clinician-rated scores might capture different aspects of motivational and hedonic deficits in schizophrenia and therefore relate to different cortico-striatal functional abnormalities.

Disentangling craving- and valence-related brain responses to smoking cues in individuals with nicotine use disorder.

Tobacco smoking is one of the leading causes of preventable death and disease worldwide. Most smokers want to quit, but relapse rates are high. To improve current smoking cessation treatments, a better understanding of the underlying mechanisms of nicotine dependence and related craving behaviour is needed. Studies on cue-driven cigarette craving have been a particularly useful tool for investigating the neural mechanisms of drug craving. Here, functional neuroimaging studies in humans have identified a core network of craving-related brain responses to smoking cues that comprises of amygdala, anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex and ventral striatum. However, most functional Magnetic Resonance Imaging (fMRI) cue-reactivity studies do not adjust their stimuli for emotional valence, a factor assumed to confound craving-related brain responses to smoking cues. Here, we investigated the influence of emotional valence on key addiction brain areas by disentangling craving- and valence-related brain responses with parametric modulators in 32 smokers. For one of the suggested key regions for addiction, the amygdala, we observed significantly stronger brain responses to the valence aspect of the presented images than to the craving aspect. Our results emphasize the need for carefully selecting stimulus material for cue-reactivity paradigms, in particular with respect to emotional valence. Further, they can help designing future research on teasing apart the diverse psychological dimensions that comprise nicotine dependence and, therefore, can lead to a more precise mapping of craving-associated brain areas, an important step towards more tailored smoking cessation treatments.

Psychedelic-Assisted Therapy for Substance Use Disorders and Potential Mechanisms of Action.

Substance use disorders (SUD) represent a significant public health issue with a high need for novel and efficacious treatment options. In light of this high unmet need, recent results reporting beneficial outcomes of psychedelic-assisted therapy in SUD are particularly relevant. However, several questions remain with regard to this treatment approach. The clinical mechanisms of action of psychedelic substances in the treatment of SUD are not well understood. Closing this knowledge gap is critical to inform and optimize the psychotherapeutic embedding of the acute substance administration. In this chapter, we discuss potential mechanisms that have implications on psychotherapeutic approaches including induced neuroplasticity, alterations in brain network connectivity, reward and emotion processing, social connectedness, insight, and mystical experiences. Furthermore, we outline considerations and approaches that leverage these mechanisms in order to optimize the therapeutic embedding by maximizing synergy between substance effects and psychotherapy. Understanding the mechanisms of action, developing psychotherapeutic approaches accordingly, and evaluating their synergistic efficacy in scientific studies will be critical to advance the framework of psychedelic-assisted therapy for addiction, create evidence-based approaches, and achieve the best treatment outcome for patients with SUD.

Neural mapping of anhedonia across psychiatric diagnoses: A transdiagnostic neuroimaging analysis.

Anhedonia has been associated with abnormal reward-related striatal dopamine functioning in patients with different psychiatric disorders. Here, we tested whether anhedonia expression mapped onto striatal volume across several psychiatric diagnoses. T1-weighted images from 313 participants including 89 healthy controls (HC), 22 patients with opioid use disorder (OUD), 50 patients with major depressive disorder (MDD), 45 patients with borderline personality disorder (BPD), 49 patients with first-episode psychosis (FEP), 43 patients with cocaine use disorder (CUD) and 15 patients with schizophrenia (SZ) were included. Anhedonia was assessed with subscores of the Beck Depression Inventory (BDI) and/or the Scale for the Assessment of Negative Symptoms (SANS). Voxel-based morphometry (VBM) was conducted for identifying dimensional symptom-structure associations using region of interest (ROI, dorsal and ventral striatum) and whole-brain analyses, as well as for group comparisons of striatal volume. ROI analyses revealed significant negative relationships between putamen volume and BDI and SANS anhedonia scores across OUD, MDD, BPD, CUD and SZ patients (n = 175) and MDD, FEP and SZ patients (n = 114), respectively. Whole-brain VBM analyses confirmed these associations and further showed negative relationships between anhedonia severity and volume of the bilateral cerebellum. There were group differences in right accumbens volume, which however were not related to anhedonia expression across the different diagnoses. Our findings indicate volumetric abnormalities in the putamen and cerebellum as a common neural substrate of anhedonia severity that cut across psychiatric entities.

Predictors of real-time fMRI neurofeedback performance and improvement - A machine learning mega-analysis.

Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.

Neurometabolic alterations in the nucleus accumbens of smokers assessed with 1 H magnetic resonance spectroscopy: The role of glutamate and neuroinflammation.

Tobacco use is one of the leading causes of premature death and morbidity worldwide. For smokers trying to quit, relapse rates are high, even after prolonged periods of abstinence. Recent findings in animal models highlight the role of alterations in glutamatergic projections from the prefrontal cortex onto the nucleus accumbens (NAc) in relapse vulnerability. Moreover, inflammatory responses in the NAc have been reported during withdrawal. A novel proton magnetic resonance spectroscopy (1 H-MRS) protocol was applied in humans to measure molar concentrations for glutamate, its sum with glutamine (Glx), and myoinositol plus glycine (mI + Gly) in the NAc (19 smokers, 20 matched controls). Smokers were measured at baseline and during withdrawal and satiation. No difference between groups or smoking states was found for glutamate or Glx, but, in smokers, stronger craving and more severe nicotine dependence were associated with lower baseline glutamate and Glx levels, respectively. Interestingly, mI + Gly concentrations were higher during withdrawal than baseline and correlated negatively with nicotine dependence severity and pack years of smoking. The lack of glutamatergic changes between groups and smoking states may imply that glutamate homeostasis is not significantly altered in smokers or that changes are too small for detection by 1 H-MRS. Moreover, the observed increase in mI + Gly may imply that neuroinflammatory processes occur in the NAc during nicotine withdrawal. These findings shed light on neurobiological relapse mechanisms in smokers and may provide the opportunity to develop more effective treatment options targeting the glutamate and neuroinflammation system.

Use of psychotropic substances among elite athletes - a narrative review.

BACKGROUND AND AIMS: Elite athletes may use psychotropic substances for recreational reasons, (perceived) performance enhancement or self-medication. Causes can overlap. For athletes, substance use may be associated with various medical and social risks. Psychoactive substances include alcohol and nicotine, illicit and various prescription drugs, which all have a potential for abuse and dependence. This paper reviews the existing literature on the use of psychoactive substances and associated substance use disorders among elite athletes in terms of prevalence, patterns of use, as well as underlying causes and risk factors. METHODS: Due to the heterogeneous and partially fragmentary study data, a narrative approach with selection of applicable publications of a Medline search was chosen. RESULTS: The most commonly used psychoactive substances among elite athletes were alcohol, nicotine, cannabis, stimulants and (prescription) opioids. Overall consumption rates are lower in professional sports than in the general population, but use of several substances (smokeless tobacco products, prescription opioids, stimulants) have high prevalence in specific sports and athlete groups. Substance use is subject to multiple risk factors and varies by substance class, sport discipline, country and gender, among other factors. CONCLUSION: Knowledge on the underlying causes and patterns of substance use, as well as the prevalence of substance use disorders in professional sports, is still limited. High prevalence of various substances (i.e., nicotine, prescription opioids) may indicate potentially harmful patterns of use, requiring further research. Specific preventive and therapeutic concepts for the treatment of substance use disorders in elite athletes should be developed.

SmoCuDa: A Validated Smoking Cue Database to Reliably Induce Craving in Tobacco Use Disorder.

BACKGROUND: Cue-reactivity paradigms provide valuable insights into the underlying mechanisms of nicotine craving in nicotine-dependent subjects. In order to study cue-driven nicotine craving, robust and validated stimulus datasets are essential. OBJECTIVES: The aim of this study was to generate and validate a large set of individually rated smoking-related cues that allow for assessment of different stimulus intensities along the dimensions craving, valence, and arousal. METHODS: The image database consisted of 330 visual cues. Two hundred fifty smoking-associated pictures (Creative Commons license) were chosen from online databases and showed a widespread variety of smoking-associated content. Eighty pictures from previously published databases were included for cross-validation. Forty volunteers with tobacco use disorder rated "urge-to-smoke," "valence," and "arousal" for all images on a 100-point visual analogue scale. Pictures were also labelled according to 18 categories such as lit/unlit cigarettes in mouth, cigarette end, and cigarette in ashtray. RESULTS: Ratings (mean ± SD) were as follows: urge to smoke, 44.9 ± 13.2; valence, 51.2 ± 7.6; and arousal, 54.6 ± 7.1. All ratings, particularly "urge to smoke," were widely distributed along the whole scale spectrum. CONCLUSIONS: We present a novel image library of well-described smoking-related cues, which were rated on a continuous scale along the dimensions craving, valence, and arousal that accounts for inter-individual differences. The rating software, image database, and their ratings are publicly available at https://smocuda.github.io.

Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction.

Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in the nucleus accumbens to underlie addiction-like behavior. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared with healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared with baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on 2 days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalized medicine approach in addiction.

Can we predict real-time fMRI neurofeedback learning success from pretraining brain activity?

Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning.

Concomitant Heroin and Cocaine Use among Opioid-Dependent Patients during Methadone, Buprenorphine or Morphine Opioid Agonist Therapy.

BACKGROUND: Among all the treatment methods developed so far, opioid agonist treatment (OAT) is the most effective therapy for opioid dependence. While methadone (MTD) is the most commonly used, fewer data are available on alternative opioid agonist. The aim of this study was to assess the efficacy of buprenorphine (BUP) and slow-released morphine compared to MTD with regard to the reduction of concomitant heroin and cocaine use. METHODS: This cross-sectional study included 105 patients receiving MTD, BUP, or slow-release morphine as opioid agonist therapy at the Psychiatric Hospital of Zurich. Illicit drug use was assessed using a retrospective 3-month hair toxicology analysis to quantify concentrations of heroin degradation products and metabolites, as well as cocaine and cocaine metabolites. We have also collected self-reports, but in the data of the study, only the results of the hair analysis were considered. RESULTS: BUP-treated patients showed lower rates of illicit opiate consumption in comparison to the group treated with MTD or slow-released morphine (p < 0.05). The proportion of heroin-positive hair samples associated with slow-release morphine treatment was similar to the proportion associated with MTD treatment. Neither the MTD vs. slow-released morphine groups nor the BUP vs. MTD groups showed significant differences in the number of patients consuming cocaine although patients in the BUP group had significantly lower concentrations of cocaine in hair testing compared to the patients in the MTD group. Prevalence of cocaine consumption was also significantly lower in the BUP group compared to patients in the slow-release morphine group (p < 0.05). CONCLUSION: This study suggests that BUP OAT is associated with reduced additional opiate co-use.

Cannabis use in Switzerland 2015-2045: A population survey based model.

BACKGROUND: Alternative cannabis regulation models are discussed and implemented worldwide. A baseline scenario under the assumption of no policy or market changes may prove useful to forecast cannabis use and treatment demand and evaluate changes in legislation. METHODS: Based on data of the Continuous Rolling Survey of Addictive Behaviours and Related Risks on cannabis use, age, gender and nationality from 2011 to 2015, we used general estimating equation analysis to model lifetime and 30-days prevalence from 2015 to 2045 in Switzerland accounting for demographic trends. RESULTS: Lifetime prevalence of cannabis use is projected to grow from 28.3% (CI 95% 27.8-28.8) in 2015 to 42.0% (CI 95% 41.0-43.0) in 2045. 30-days prevalence would increase slightly from 2.70% (CI 95% 2.53-2.88) to 3.39% (CI 95% 3.11-3.66). Due to population growth, absolute numbers with past 30-day cannabis use are estimated to increase from 202,784 (CI 95% 189,534-216,035) to 314,302 (CI 95% 288,504-340,100). Among those aged under 30 years no substantial change in lifetime and 30-days prevalence of cannabis use is projected. Larger changes are estimated to occur in the age group 30+. The mean age of past 30-day cannabis users would increase for men with Swiss nationality from 30.3 to 38.7 years. DISCUSSION: Population-based survey data and demographic projections can be used to develop baseline scenarios of future cannabis use. Assuming no changes in cannabis legislation, growing absolute numbers of users will likely increase treatment demand. Cannabis use is estimated to increase among the group aged >30 years, which is currently underrepresented in clinical treatment and research. Our findings highlight the need for prospective baseline scenarios to evaluate the impact of legislative changes on cannabis use. Moreover, in Switzerland effective prevention and treatment interventions for cannabis use disorders are required even if cannabis legislation remains unchanged.

Subtle white matter alterations in schizophrenia identified with a new measure of fiber density.

Altered cerebral connectivity is one of the core pathophysiological mechanism underlying the development and progression of information-processing deficits in schizophrenia. To date, most diffusion tensor imaging (DTI) studies used fractional anisotropy (FA) to investigate disrupted white matter connections. However, a quantitative interpretation of FA changes is often impeded by the inherent limitations of the underlying tensor model. A more fine-grained measure of white matter alterations could be achieved by measuring fiber density (FD) - a novel non-tensor-derived diffusion marker. This study investigates, for the first time, FD alterations in schizophrenia patients. FD and FA maps were derived from diffusion data of 25 healthy controls (HC) and 21 patients with schizophrenia (SZ). Using tract-based spatial statistics (TBSS), group differences in FD and FA were investigated across the entire white matter. Furthermore, we performed a region of interest (ROI) analysis of frontal fasciculi to detect potential correlations between FD and positive symptoms. As a result, whole brain TBSS analysis revealed reduced FD in SZ patients compared to HC in several white matter tracts including the left and right thalamic radiation (TR), superior longitudinal fasciculus (SLF), corpus callosum (CC), and corticospinal tract (CST). In contrast, there were no significant FA differences between groups. Further, FD values in the TR were negatively correlated with the severity of positive symptoms and medication dose in SZ patients. In summary, a novel diffusion-weighted data analysis approach enabled us to identify widespread FD changes in SZ patients with most prominent white matter alterations in the frontal and subcortical regions. Our findings suggest that the new FD measure may be more sensitive to subtle changes in the white matter microstructure compared to FA, particularly in the given population. Therefore, investigating FD may be a promising approach to detect subtle changes in the white matter microstructure of altered connectivity in schizophrenia.