The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Mismatch of Biological and Social Time in Cocaine-Addicted Men.

INTRODUCTION: Chronotype describes a person's preferential activity pattern during a 24-hour period, which may not be in line with their social lifestyle. A mismatch between biological and social time is known as "social jetlag," which has negative effects on wellbeing. Cocaine influences a person's activity levels, but very little is known about possible changes in chronotype of patients with cocaine use disorder (CUD). Here, we aimed to shed light on self-reported changes in chronotype in patients with CUD and the clinical implications. METHODS: A total of 90 men from the local community were recruited; about half of the sample met the criteria for CUD, while the other half were healthy without a personal history of substance use disorder. Participants completed the Munich Chronotype Questionnaire along with questionnaires about mental health, daily fatigue, and drug/alcohol use. RESULTS: Half of the CUD patients fell into the category of late chronotype - a significantly larger proportion than their healthy peers. Late "night owls" tended to have started using cocaine at an earlier age than other chronotypes; a finding that was not observed with tobacco, cannabis, or alcohol. Drug use severity in CUD patients did not differ across chronotypes. CUD patients (52%) did not have a preferred time of day to use cocaine. The mismatch between social and biological time was significantly greater in CUD patients and unrelated to drug use or mental health status. CONCLUSION: CUD appears to be associated with disruptions in chronotype which are, contrary to a widely held view, not reflected by using patterns or addiction severity.

Evidence of Hypothalamic-Pituitary-Adrenal and -Gonadal Dysfunction in Cocaine-Addicted Men.

INTRODUCTION: Regular cocaine use has been associated with hormonal dysfunction including hypogonadism, which can lead to fatigue, reduced stamina, sexual dysfunction, and impaired quality of life. However, cocaine's endocrine effects are largely under-reported in the scientific addiction literature and, in many cases, are not addressed within treatment services. The low profile of these adverse effects might be attributable to a lack of awareness and linkage with cocaine use, such that they are recognized only when an acute/emergency problem arises. METHODS: We assessed endocrine diurnal function (adrenocorticotrophic hormone [ACTH], cortisol, and testosterone) in 26 healthy and 27 cocaine-dependent men and examined changes in hormone levels in response to a single 40 mg dose of the noradrenaline re-uptake inhibitor atomoxetine in a double-blind, placebo-controlled experimental medicine study. RESULTS: When compared with healthy controls, diurnal and atomoxetine-induced changes in ACTH and cortisol showed greater variability in cocaine-dependent men. Interestingly, despite an exaggerated rise in ACTH following atomoxetine, an attenuated cortisol response was observed, and one-third of cocaine-dependent men had subnormal testosterone levels. CONCLUSION: Our findings point to a potential disconnection between the pituitary and adrenal responses in cocaine-dependent men, a higher rate of hypogonadism, and a pressing need for more research into the endocrine effects of cocaine and their clinical implications.

[Stimulants : Current insights into the principles, diagnostics and treatment]. / Stimulanzien : Aktuelle Erkenntnisse zu Grundlagen, Diagnostik und Therapie.

BACKGROUND: Consumption of stimulant drugs, a heterogeneous group of addictive substances, has significantly increased in recent years with rising numbers of stimulant-associated intoxication and deaths. OBJECTIVE: To provide an overview of recent scientific evidence of the diagnosis and treatment of stimulant use disorders. MATERIAL AND METHODS: A literature review of the neuropathology, clinical presentation, diagnostic criteria and evidence-based treatment for stimulant use disorders. RESULTS: The chronic use of stimulant drugs is associated with significant physical (e.g., hypertension, tachycardia and dyspnoea) and psychological harm (e.g., dependence, psychotic disorders and affective disorders). Despite major advances in the research of the neuropathology of stimulant use disorder and the refinement of diagnostic criteria, the disorder still presents a challenge, not least because of the lack of effective treatments. There are currently no approved pharmacotherapeutic interventions for stimulant use disorder and meta-analyses show that the efficacy of behavioural interventions is low to moderate, similar to cognitive behavioural treatment. CONCLUSION: Despite growing insights into the neuropathology associated with stimulant use disorder, treatment remains a challenge. The lack of effective interventions makes it difficult to give clear recommendations for the clinical practice. Further scientific research is thus warranted.

Brain networks underlying vulnerability and resilience to drug addiction.

Regular drug use can lead to addiction, but not everyone who takes drugs makes this transition. How exactly drugs of abuse interact with individual vulnerability is not fully understood, nor is it clear how individuals defy the risks associated with drugs or addiction vulnerability. We used resting-state functional MRI (fMRI) in 162 participants to characterize risk- and resilience-related changes in corticostriatal functional circuits in individuals exposed to stimulant drugs both with and without clinically diagnosed drug addiction, siblings of addicted individuals, and control volunteers. The likelihood of developing addiction, whether due to familial vulnerability or drug use, was associated with significant hypoconnectivity in orbitofrontal and ventromedial prefrontal cortical-striatal circuits-pathways critically implicated in goal-directed decision-making. By contrast, resilience against a diagnosis of substance use disorder was associated with hyperconnectivity in two networks involving 1) the lateral prefrontal cortex and medial caudate nucleus and 2) the supplementary motor area, superior medial frontal cortex, and putamen-brain circuits respectively implicated in top-down inhibitory control and the regulation of habits. These findings point toward a predisposing vulnerability in the causation of addiction, related to impaired goal-directed actions, as well as countervailing resilience systems implicated in behavioral regulation, and may inform novel strategies for therapeutic and preventative interventions.

Impaired Learning From Negative Feedback in Stimulant Use Disorder: Dopaminergic Modulation.

BACKGROUND: Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. METHODS: We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. RESULTS: Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. CONCLUSION: Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.

Network failures: When incentives trigger impulsive responses.

Adequate control of impulsive urges to act is demanded in everyday life but is impaired in neuropsychiatric conditions such as stimulant use disorder. Despite intensive research it remains unclear whether failures in impulse control are caused by impaired suppression of behavior or by the over invigoration of behavior by stimuli associated with salient incentives such as drugs, food, and money. We investigated failures in impulse control using functional magnetic resonance imaging (fMRI) to map the neural correlates of premature (impulsive) responses during the anticipation phase of the Monetary Incentive Delay (MID) task in healthy controls (HC), stimulant-dependent individuals (SDIs), and their unaffected first-degree siblings (SIB). We combined task-based fMRI analyses with dynamic causal modeling to show that failures of impulse control were associated with interactions between cingulo-opercular and dorsal striatal networks regardless of group status and incentive type. We further report that group-specific incentive salience plays a critical role in modulating impulsivity in SDIs since drug-related incentives specifically increased premature responding and shifted task modulation away from the dorsal striatal network to the cingulo-opercular network. Our findings thus indicate that impulsive actions are elicited by salient personally-relevant incentive stimuli and those such slips of action recruit a distinct fronto-striatal network.

Goal-Directed and Habitual Control in Smokers.

INTRODUCTION: Harmful behavior such as smoking may reflect a disturbance in the balance of goal-directed and habitual control. Animal models suggest that habitual control develops after prolonged substance use. In this study, we investigated whether smokers (N = 49) differ from controls (N = 46) in the regulation of goal-directed and habitual behavior. It was also investigated whether individual differences in nicotine dependence levels were associated with habitual responding. METHODS: We used two different multistage instrumental learning tasks that consist of an instrumental learning phase, subsequent outcome devaluation, and a testing phase to measure the balance between goal-directed and habitual responding. The testing phases of these tasks occurred after either appetitive versus avoidance instrumental learning. The appetitive versus aversive instrumental learning stages in the two different tasks modeled positive versus negative reinforcement, respectively. RESULTS: Smokers and nonsmoking controls did not differ on habitual versus goal-directed control in either task. Individual differences in nicotine dependence within the group of smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. CONCLUSIONS: The current finding highlights the importance of individual differences within smokers. For future research, neuroimaging studies are suggested to further unravel the nature of the imbalance between goal-directed versus habitual control in severely dependent smokers by directly measuring activity in the corresponding brain systems. IMPLICATIONS: Goal-directed versus habitual behavior in substance use and addiction is highly debated. This study investigated goal-directed versus habitual control in smokers. The findings suggest that smokers do not differ from controls in goal-directed versus habitual control. Individual differences in nicotine dependence within smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. These findings add to the ongoing debate on habitual versus goal-directed control in addiction and emphasize the importance of individual differences within smokers.

Determination of atomoxetine or escitalopram in human plasma by HPLC: Applications in neuroscience research studies
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BACKGROUND: Atomoxetine and escitalopram are potent and selective drugs approved for noradrenergic or serotonergic modulation of neuronal networks in attention-deficit hyperactivity disorder (ADHD) or depression, respectively. High-performance liquid chromatography (HPLC) methods still play an important role in the therapeutic drug monitoring (TDM) of psychopharmacological drugs, and coupled with tandem mass spectrometry are the gold standard for the quantification of drugs in biological matrices, but not available everywhere. The aim of this work was to develop and validate a HPLC method for neuroscientific studies using atomoxetine or escitalopram as a test drug. MATERIALS AND METHODS: A HPLC method from routine TDM determination of atomoxetine or citalopram in plasma was adapted and validated for use in neuroscientific research. Using photo diode array detection with UV absorption at 205 nm, the variation of internal standard within one chromatographic method enables separate drug monitoring for concentration-controlled explorative studies in healthy humans and patients with Parkinson's disease. RESULTS: The method described here was found to be linear in the range of 0.002 - 1.4 mg/L for atomoxetine and 0.0012 - 0.197 mg/L for escitalopram, with overall mean intra-day and inter-day imprecision and accuracy bias < 10% for both drugs. The method was successfully applied in concentration-controlled neuroimaging studies in populations of healthy humans and patients with Parkinson's disease. CONCLUSION: A simple, sensitive, robust HPLC method capable of monitoring escitalopram and atomoxetine is presented and validated, as a useful tool for drug monitoring and the study of pharmacokinetics in neuroscientific study applications.

Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol-dependent and polysubstance-dependent individuals.

Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance-dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened 'top-down' control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no-go (GNG) task, we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent polysubstance-dependent (poly-SUD) individuals and controls during a randomised double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly-SUD groups respectively. Self-reported trait impulsivity in the poly-SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly-SUD groups, which are predicted by trait impulsivity in the poly-SUD group.

BMI-related cortical morphometry changes are associated with altered white matter structure.

BACKGROUND: While gross measures of brain structure have shown alterations with increasing body mass index (BMI), the extent and nature of such changes has varied substantially across studies. Here, we sought to determine whether small-scale morphometric measures might prove more sensitive and reliable than larger scale measures and whether they might offer a valuable opportunity to link cortical changes to underlying white matter changes. To examine this, we explored the association of BMI with millimetre-scale Gaussian curvature, in addition to standard measures of morphometry such as cortical thickness, surface area and mean curvature. We also assessed the volume and integrity of the white matter, using white matter signal intensity and fractional anisotropy (FA). We hypothesised that BMI would be linked to small-scale changes in Gaussian curvature and that this phenomenon would be mediated by changes in the integrity of the underlying white matter. METHODS: The association of global measures of T1-weighted cortical morphometry with BMI was examined using linear regression and mediation analyses in two independent groups of healthy young to middle aged human subjects (n1 = 52, n2 = 202). In a third dataset of (n3 = 897), which included diffusion tensor images, we sought to replicate the significant associations established in the first two datasets, and examine the potential mechanistic link between BMI-associated cortical changes and global FA. RESULTS: Gaussian curvature of the white matter surface showed a significant, positive association with BMI across all three independent datasets. This effect was mediated by a negative association between the integrity of the white matter and BMI. CONCLUSIONS: Increasing BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults. Our results are consistent with a model whereby BMI-linked cortical changes are mediated by the effects of BMI on white matter microstructure.

Impulsivity and compulsivity are differentially associated with automaticity and routine on the Creature of Habit Scale.

Habits may develop when meaningful action patterns are frequently repeated in a stable environment. We measured the differing tendencies of people to form habits in a population sample of n = 533 using the Creature of Habit Scale (COHS). We confirmed the high reliability of the two latent factors measured by the COHS, automaticity and routines. Whilst automatic behaviours are triggered by context and do not serve a particular purpose or goal, routines often have purpose, and because they have been performed so often in a given context, they become automatic only after their action sequence has been activated. We found that both types of habitual behaviours are influenced by the frequency of their occurrence and they are differentially influenced by personality traits. Compulsive personality is associated with an increase in both aspects of habitual tendency, whereas impulsivity is linked with increased automaticity, but reduced routine behaviours. Our findings provide further evidence that the COHS is a useful tool for understanding habitual tendencies in the general population and may inform the development of therapeutic strategies that capitalise on functional habits and help to treat dysfunctional ones.

Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

Acute naltrexone does not remediate fronto-striatal disturbances in alcoholic and alcoholic polysubstance-dependent populations during a monetary incentive delay task.

There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and 'missed' rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence.

Creature of Habit: A self-report measure of habitual routines and automatic tendencies in everyday life.

Our daily lives involve high levels of repetition of activities within similar contexts. We buy the same foods from the same grocery store, cook with the same spices, and typically sit at the same place at the dinner table. However, when questioned about these routine activities, most of us barely remember the details of our actions. Habits are automatically triggered behaviours in which we engage without conscious awareness or deliberate control. Although habits help us to operate efficiently, breaking them requires great effort. We have developed a 27-item questionnaire to measure individual differences in habitual responding in everyday life. The Creature of Habit Scale (COHS) incorporates two aspects of the general concept of habits, namely routine behaviour and automatic responses. Both aspects of habitual behaviour were weakly correlated with underlying anxiety levels, but showed a more substantial difference in relation to goal-oriented motivation. We also observed that experiences of adversity during childhood increased self-reported automaticity, and this effect was further amplified in participants who also reported exposure to stimulant drugs. The COHS is a valid and reliable self-report measure of habits, which may prove useful in a number of contexts where discerning individuals' propensity for habit is beneficial.

Signing below the dotted line: signature position as a marker of vulnerability for visuospatial processing difficulties.

Almost one-third of the participants in a neuropsychological study signed the consent form below the given line. The relationship between a signature position on or below the line and participants' cognitive function was investigated. Fifty drug-dependent individuals, 50 of their siblings, and 50 unrelated control participants completed a battery of neuropsychological tests using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Individuals signing below, rather than on, the line performed more poorly on tests of visuospatial memory, but no differently on other cognitive tests. Signature positioning may be a soft sign for impairment of the mechanisms involved in visuospatial memory.

Overlapping decline in orbitofrontal gray matter volume related to cocaine use and body mass index.

Loss of control over hedonically motivated actions is a defining component of impulse control disorders, such as drug dependence and the proposed 'food addiction' model of obesity. Devolution from goal-directed to compulsively maintained behaviors is partially attributed to abnormalities in the orbitofrontal cortex, an area critical in reward valuation. In the current study, overlapping reductions in orbitofrontal gray matter volume relating to body mass index were seen in healthy control and cocaine-dependent individuals, as well as in relation to duration of cocaine abuse, providing support for a shared neuropathology between the two conditions potentially related to dysfunctional reward-seeking behavior.

Cocaine's appetite for fat and the consequences on body weight.

For many individuals in treatment for cocaine dependence, weight gain is a substantial problem during recovery. This weight gain causes significant distress and seems to increase the risk of relapse. The mechanisms underlying cocaine's effects on weight remain elusive. It is widely assumed that this weight gain reflects a metabolic or behavioural compensatory response to the cessation of cocaine use. Here we challenge this assumption and outline potential mechanisms by which chronic cocaine use produces disturbances in the regulation of fat intake and storage, through its effects on the central and peripheral nervous systems, specifically the sympathetic nervous system. We hypothesize that the cocaine-induced alteration in fat regulation results in cocaine users developing a pronounced appetite for fatty food but keeps their fat mass low. This altered fat appetite subsequently leads to excessive weight gain when individuals enter treatment and stop using cocaine. Our aim is to shed light on the neurobiological mechanisms that may underlie the alterations in eating and fat regulation in cocaine-dependent individuals, to open up potential new avenues to support these individuals in recovery.

A wavelet method for modeling and despiking motion artifacts from resting-state fMRI time series.

The impact of in-scanner head movement on functional magnetic resonance imaging (fMRI) signals has long been established as undesirable. These effects have been traditionally corrected by methods such as linear regression of head movement parameters. However, a number of recent independent studies have demonstrated that these techniques are insufficient to remove motion confounds, and that even small movements can spuriously bias estimates of functional connectivity. Here we propose a new data-driven, spatially-adaptive, wavelet-based method for identifying, modeling, and removing non-stationary events in fMRI time series, caused by head movement, without the need for data scrubbing. This method involves the addition of just one extra step, the Wavelet Despike, in standard pre-processing pipelines. With this method, we demonstrate robust removal of a range of different motion artifacts and motion-related biases including distance-dependent connectivity artifacts, at a group and single-subject level, using a range of previously published and new diagnostic measures. The Wavelet Despike is able to accommodate the substantial spatial and temporal heterogeneity of motion artifacts and can consequently remove a range of high and low frequency artifacts from fMRI time series, that may be linearly or non-linearly related to physical movements. Our methods are demonstrated by the analysis of three cohorts of resting-state fMRI data, including two high-motion datasets: a previously published dataset on children (N=22) and a new dataset on adults with stimulant drug dependence (N=40). We conclude that there is a real risk of motion-related bias in connectivity analysis of fMRI data, but that this risk is generally manageable, by effective time series denoising strategies designed to attenuate synchronized signal transients induced by abrupt head movements. The Wavelet Despiking software described in this article is freely available for download at www.brainwavelet.org.