Evaluation of heroin-assisted treatment in Norway: protocol for a mixed methods study.

BACKGROUND: Opioid agonist treatment (OAT) for patients with opioid use disorder (OUD) has a convincing evidence base, although variable retention rates suggest that it may not be beneficial for all. One of the options to include more patients is the introduction of heroin-assisted treatment (HAT), which involves the prescribing of pharmaceutical heroin in a clinical supervised setting. Clinical trials suggest that HAT positively affects illicit drug use, criminal behavior, quality of life, and health. The results are less clear for longer-term outcomes such as mortality, level of function and social integration. This protocol describes a longitudinal evaluation of the introduction of HAT into the OAT services in Norway over a 5-year period. The main aim of the project is to study the individual, organizational and societal effects of implementing HAT in the specialized healthcare services for OUD. METHODS: The project adopts a multidisciplinary approach, where the primary cohort for analysis will consist of approximately 250 patients in Norway, observed during the period of 2022-2026. Cohorts for comparative analysis will include all HAT-patients in Denmark from 2010 to 2022 (N = 500) and all Norwegian patients in conventional OAT (N = 8300). Data comes from individual in-depth and semi-structured interviews, self-report questionnaires, clinical records, and national registries, collected at several time points throughout patients' courses of treatment. Qualitative analyses will use a flexible inductive thematic approach. Quantitative analyses will employ a wide array of methods including bi-variate parametric and non-parametric tests, and various forms of multivariate modeling. DISCUSSION: The project's primary strength lies in its comprehensive and longitudinal approach. It has the potential to reveal new insights on whether pharmaceutical heroin should be an integral part of integrated conventional OAT services to individually tailor treatments for patients with OUD. This could affect considerations about drug treatment even beyond HAT-specific topics, where an expanded understanding of why some do not succeed with conventional OAT will strengthen the knowledge base for drug treatment in general. Results will be disseminated to the scientific community, clinicians, and policy makers. TRIAL REGISTRATION: The study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics (REK), ref.nr.:195733.

Neural fingerprints of gambling disorder using diffusion tensor imaging.

Gambling disorder (GD) is a behavioral addiction associated with personal, social and occupational consequences. Thus, examining GD's clinical relationship with its neural substrates is critical. We compared neural fingerprints using diffusion tensor imaging (DTI) in GD subjects undergoing treatment relative to healthy volunteers (HV). Fifty-three (25 GD, 28 age-matched HV) males were scanned with structural magnetic resonance imaging (MRI) and DTI. We applied probabilistic tractography based on DTI scanning data, preprocessed and analyzed using permutation testing of individual connectivity weights between regions for group comparison. Permutation-based comparisons between group-averaged connectomes highlighted significant structural differences. The GD group demonstrated increased connectivity, and striatal network reorganisation, contrasted by reduced connectivity within and to frontal lobe nodes. Modularity analysis revealed that the GD group had fewer hubs integrating information across the brain. We highlight GD neural changes involved in controlling risk-seeking behaviors. The observed striatal restructuring converges with previous research, and the increased connectivity affects subnetworks highly active in gambling situations, although these findings are not significant when correcting for multiple comparisons. Modularity analysis underlines that, despite connectivity increases, the GD connectome loses hubs, impeding its neuronal network coherence. Together, these results demonstrate the feasibility of using whole-brain computational modeling in assessing GD.

Doubting the double-blind: Introducing a questionnaire for awareness of experimental purposes in neurofeedback studies.

Double-blinding subjects to the experiment's purpose is an important standard in neurofeedback studies. However, it is difficult to provide evidence that humans are entirely unaware of certain information. This study used insights from consciousness studies and neurophenomenology to develop a contingency awareness questionnaire for neurofeedback. We assessed whether participants had an awareness of experimental purposes to manipulate their attention and multisensory perception. A subset of subjects (5 out of 20) gained a degree of awareness of experimental purposes as evidenced by their correct guess about the purposes of the experiment to affect their attention and multisensory perceptions specific to their double-blinded group assignment. The results warrant replication before they are applied to clinical neurofeedback studies, given the considerable time taken to perform the questionnaire (∼25 min). We discuss the strengths and limitations of our contingency awareness questionnaire and the growing appeal of the double-blinded standard in clinical neurofeedback studies.

Can neurofeedback provide evidence of direct brain-behavior causality?

Neurofeedback is a procedure that measures brain activity in real-time and presents it as feedback to an individual, thus allowing them to self-regulate brain activity with effects on cognitive processes inferred from behavior. One common argument is that neurofeedback studies can reveal how the measured brain activity causes a particular cognitive process. The causal claim is often made regarding the measured brain activity being manipulated as an independent variable, similar to brain stimulation studies. However, this causal inference is vulnerable to the argument that other upstream brain activities change concurrently and cause changes in the brain activity from which feedback is derived. In this paper, we outline the inference that neurofeedback may causally affect cognition by indirect means. We further argue that researchers should remain open to the idea that the trained brain activity could be part of a "causal network" that collectively affects cognition rather than being necessarily causally primary. This particular inference may provide a better translation of evidence from neurofeedback studies to the rest of neuroscience. We argue that the recent advent of multivariate pattern analysis, when combined with implicit neurofeedback, currently comprises the strongest case for causality. Our perspective is that although the burden of inferring direct causality is difficult, it may be triangulated using a collection of various methods in neuroscience. Finally, we argue that the neurofeedback methodology provides unique advantages compared to other methods for revealing changes in the brain and cognitive processes but that researchers should remain mindful of indirect causal effects.

Neurofeedback Modulation of the Sound-induced Flash Illusion Using Parietal Cortex Alpha Oscillations Reveals Dependency on Prior Multisensory Congruency.

Spontaneous neural oscillations are key predictors of perceptual decisions to bind multisensory signals into a unified percept. Research links decreased alpha power in the posterior cortices to attention and audiovisual binding in the sound-induced flash illusion (SIFI) paradigm. This suggests that controlling alpha oscillations would be a way of controlling audiovisual binding. In the present feasibility study we used MEG-neurofeedback to train one group of subjects to increase left/right and another to increase right/left alpha power ratios in the parietal cortex. We tested for changes in audiovisual binding in a SIFI paradigm where flashes appeared in both hemifields. Results showed that the neurofeedback induced a significant asymmetry in alpha power for the left/right group, not seen for the right/left group. Corresponding asymmetry changes in audiovisual binding in illusion trials (with 2, 3, and 4 beeps paired with 1 flash) were not apparent. Exploratory analyses showed that neurofeedback training effects were present for illusion trials with the lowest numeric disparity (i.e., 2 beeps and 1 flash trials) only if the previous trial had high congruency (2 beeps and 2 flashes). Our data suggest that the relation between parietal alpha power (an index of attention) and its effect on audiovisual binding is dependent on the learned causal structure in the previous stimulus. The present results suggests that low alpha power biases observers towards audiovisual binding when they have learned that audiovisual signals originate from a common origin, consistent with a Bayesian causal inference account of multisensory perception.

A bias towards natural rewards away from gambling cues in gamblers undergoing active treatment.

BACKGROUND: Disorders of substance and behavioral addiction are believed to be associated with a myopic bias towards the incentive salience of addiction-related cues away from general rewards in the environment. In non-treatment seeking gambling disorder patients, neural activity to anticipation of monetary rewards is enhanced relative to erotic rewards. Here we focus on the balance between anticipation of reward types in active treatment gamblers relative to healthy volunteers. METHODS: Fifty-three (25 gambling disorder males, 28 age-matched male healthy volunteers) were scanned with fMRI performing a Monetary Incentive Delay task with monetary and erotic outcomes. RESULTS: During reward anticipation, gambling disorder was associated with greater left orbitofrontal cortex and ventral striatal activity to erotic relative to monetary reward anticipation compared to healthy volunteers. Lower impulsivity correlated with greater activity in the dorsal striatum and dorsal anterior cingulate cortex to erotic anticipation in gambling disorder subjects. In the outcome phase, gambling disorder subjects showed greater activity in the ventral striatum, ventromedial and dorsolateral prefrontal cortex and anterior cingulate cortex to both reward types relative to healthy volunteers. CONCLUSIONS: These findings contrast directly with previous findings in non-treatment seeking gambling disorder. Our observations highlight the role of treatment state in active treatment gambling disorder, emphasizing a potential influence of treatment status, gambling abstinence or cognitive behavioral therapy on increasing the salience of general rewards beyond that of gambling-related cues. These findings support a potential therapeutic role for targeting the salience of non-gambling related rewards and potential biomarkers for treatment efficacy.

Incentives and voluntary stopping: The intentional hand task.

Intentional inhibition, the endogenous decision to stop or cancel an action, is arguably a more ecologically valid process than automatized, reactive, inhibition which occurs in response to an external stop signal without active decision making at the moment of inhibition. Choosing to stop an act of opening the fridge door, or of reaching for a bottle of alcohol may therefore extend beyond a reactive inhibitory process, e.g. stopping at a red traffic light. Existing paradigms of intentional inhibition focus on the proportions of intentional stops. Here we developed the Intentional Hand Task, which provides stop response times for intentional and instructed trials. Participants move a cursor by initiating an arm movement, after which a Go, Stop or Choice trial occurs. In Go trials, participants are instructed to make a speeded continuation of their arm movement towards a target whereas in the Stop trials participants are instructed to rapidly stop the already initiated movement. In Choice trials, participants chose whether to continue or stop the movement. By comparing response times when movement was stopped, we found that intentionally stopping took significantly longer than externally instructed stopping. We further investigated the influence of reward incentives, by cueing trials with either the prospect of No, Low or High reward for correctly continuing in Go trials, stopping in Stop trials or achieving a random balance of intentional Go and Stops in Choice trials. Reward incentives led to greater approach behaviours, indicated by significantly higher Go accuracy in instructed Go trials and faster response times across both Go trial types. The presence of reward incentives led to significantly fewer intentional stop choices. Our findings suggest intentional inhibition of an ongoing action may require a further decisional process. Furthermore, monetary incentives may implicitly trigger an appetitive system thus facilitating approach rather than intentional inhibitory behaviour. These findings are particularly relevant to cue-related relapse in disorders of addiction where cues may facilitate approach behaviours to the detriment of intentional inhibitory control.

The role of dopaminergic and serotonergic transmission in the processing of primary and monetary reward.

Natural rewards such as erotic stimuli activate common neural pathways with monetary rewards. In human studies, the manipulation of dopamine and serotonin play an important role in the processing of monetary rewards with less understood on its role on erotic stimuli. In this study, we investigate the neuromodulatory effects of dopaminergic and serotonergic transmission in the processing of erotic versus monetary visual stimuli. We scanned one hundred and two (N = 102) healthy volunteers using functional magnetic resonance imaging while performing a modified version of the well-validated monetary incentive delay task consisting of erotic, monetary and neutral visual stimuli. We show a role for enhanced central dopamine and lowered central serotonin levels in increasing activity in the right caudate and left anterior insula during anticipation of erotic relative to monetary rewards in healthy controls. We further show differential activation in the anticipation of natural versus monetary rewards with the former associated with ventromesial and dorsomesial activity and the latter with dorsal cingulate, striatal and anterior insular activity. These findings are consistent with preclinical and clinical findings of a role for dopaminergic and serotonergic mechanisms in the processing of natural rewards. Our study provides further insights into the neural substrates underlying reward processing for natural primary erotic rewards and yields importance for the neurochemical systems of addictive disorders including gambling disorder.

Pilot study: Improving attention bias modification of alcohol cues through concealed gaze-contingent feedback in alcohol dependence.

In an attempt to improve attention bias modification (ABM), we tested whether an attentional training protocol which featured monetary operant conditioning of eye-gaze to avoid alcohol stimuli in alcohol-dependent patients could reduce attention, craving and relapse to alcohol. We employed a pilot randomized control trial (RCT) with 21 detoxified alcohol dependent patients (48.9 ±â€¯10 years of age, 9 male) from an inpatient and outpatient treatment centre. The novel concealed operant conditioning paradigm provided monetary reinforcements or punishments respective to eye-gaze patterns towards neutral or towards alcohol stimuli along with an 80% probability of a to-be-detected probe appearing following neutral stimuli (ET-ABM group). Patients in the control-group received random monetary feedback and a 50/50 ABM contingency. We compared AB on trained and untrained stimuli and addiction severity measures of obsessive thoughts and desires to alcohol following training. We further assessed addiction severity and relapse outcome at a 3-month follow-up. Results indicate that this attentional retraining only worked for the trained stimuli and did not generalize to untrained stimuli or to addiction severity measures or relapse outcome. Potential explanations for lack of generalization include the low sample size and imbalances on important prognostic variables between the active-group and control-group. We discuss progress and challenges for further research on cognitive training using gaze-contingent feedback.

The myeloarchitecture of impulsivity: premature responding in youth is associated with decreased myelination of ventral putamen.

Impulsivity has been suggested as a neurocognitive endophenotype conferring risk across a number of neuropsychiatric conditions, including substance and behavioural addictions, eating disorders, and attention deficit/hyperactivity disorder. We used a paradigm with interspecies translation validity (the four-choice serial reaction time task, 4CSRTT) to assess 'waiting' impulsivity in a youth sample (N = 99, aged 16-26 years). We collected magnetization prepared two rapid acquisition gradient echo (MP2RAGE) scans, which enabled us to measure R1, the longitudinal relaxation rate, a parameter closely related to tissue myelin content, as well as quantify grey matter volume. We also assessed inhibitory control (commission errors) on a Go/NoGo task and measured decisional impulsivity (delay discounting) using the Monetary Choice Questionnaire (MCQ). We found R1 of the bilateral ventral putamen was negatively correlated with premature responding, the index of waiting impulsivity on the 4CSRTT. Heightened impulsivity in youth was significantly and specifically associated with lower levels of myelination in the ventral putamen. Impulsivity was not associated with grey matter volume. The association with myelination was specific to waiting impulsivity: R1 was not associated with decisional impulsivity on the MCQ or inhibitory control on the Go/NoGo task. We report that heightened waiting impulsivity, measured as premature responding on the 4CSRTT, is specifically associated with lower levels of ventral putaminal myelination, measured using R1. This may represent a neural signature of vulnerability to diseases associated with excessive impulsivity and demonstrates the added explanatory power of quantifying the mesoscopic organization of the human brain, over and above macroscopic volumetric measurements.

Pupillary reactivity to alcohol cues as a predictive biomarker of alcohol relapse following treatment in a pilot study.

RATIONALE: Identifying the predictors of relapse in detoxified alcohol-dependent patients is crucial for effective surveillance procedures and the optimization of treatment. Physiological measures such as functional MRI activity and heart rate variability have been shown as potential markers of relapse prediction. OBJECTIVES: Our aim was to assess differential pupillary reactions to alcohol-related cues as an objective physiological candidate predictor of relapse. METHODS: We examined the relationship between cue-elicited pupillary reactions to alcohol stimuli and luminance-controlled neutral stimuli in 21 detoxified alcohol-dependent patients and subsequent relapse outcome at a 4-month follow-up. RESULTS: Differential pupillary dilation to alcohol stimuli as compared to neutral stimuli at 150 to 250 ms after stimulus onset substantially improved the model prediction of relapse outcome (additional 27% of variance) beyond that achieved from five standardized questionnaires on alcohol craving, alcohol use, problematic use severity, depressive tendencies, and duration of abstinence (47% of variance). In contrast, alcohol craving did not improve relapse model prediction. CONCLUSIONS: This pilot study shows that alcohol-dependent patients with greater pupillary dilation to alcohol stimuli are more vulnerable to relapse, and that pupillometry presents as an important tool for addiction science.

Compulsive sexual behavior: Prefrontal and limbic volume and interactions.

BACKGROUND: Compulsive sexual behaviors (CSB) are relatively common and associated with significant personal and social dysfunction. The underlying neurobiology is still poorly understood. The present study examines brain volumes and resting state functional connectivity in CSB compared with matched healthy volunteers (HV). METHODS: Structural MRI (MPRAGE) data were collected in 92 subjects (23 CSB males and 69 age-matched male HV) and analyzed using voxel-based morphometry. Resting state functional MRI data using multi-echo planar sequence and independent components analysis (ME-ICA) were collected in 68 subjects (23 CSB subjects and 45 age-matched HV). RESULTS: CSB subjects showed greater left amygdala gray matter volumes (small volume corrected, Bonferroni adjusted P < 0.01) and reduced resting state functional connectivity between the left amygdala seed and bilateral dorsolateral prefrontal cortex (whole brain, cluster corrected FWE P < 0.05) compared with HV. CONCLUSIONS: CSB is associated with elevated volumes in limbic regions relevant to motivational salience and emotion processing, and impaired functional connectivity between prefrontal control regulatory and limbic regions. Future studies should aim to assess longitudinal measures to investigate whether these findings are risk factors that predate the onset of the behaviors or are consequences of the behaviors. Hum Brain Mapp 38:1182-1190, 2017. © 2016 Wiley Periodicals, Inc.

Sexually dimorphic brain volume interaction in college-aged binge drinkers.

BACKGROUND: Binge consumption of alcohol is a major societal problem associated with important cognitive, physiological and neurotoxic consequences. Converging evidence highlights the need to assess binge drinking (BD) and its effects on the developing brain while taking into account gender differences. Here, we compared the brain volumetric differences between genders in college-aged binge drinkers and healthy volunteers. METHOD: T1-weighted magnetic resonance imaging (MRI) images of 30 binge drinkers (18 males) and 46 matched healthy volunteers (23 males) were examined using voxel-based morphometry. The anatomical scans were covaried with Alcohol Use Disorders Identification Test (AUDIT) scores. Whole brain voxel-wise group comparisons were performed using a cluster extent threshold correction. RESULTS: Several large clusters qualified with group-by-gender interactions were observed in prefrontal, striatal and medial temporal areas, whereby BD females had more volume than non-BD females, while males showed the inverse pattern of decreased volume in BD males and increased volume in non-BD males. AUDIT scores negatively correlated with volume in the right superior frontal cortex and precentral gyrus. CONCLUSIONS: These findings dovetail with previous studies reporting that a state effect of BD in college-aged drinkers and the severity of alcohol use are associated with volumetric alterations in the cortical and subcortical areas of the brain. Our study indicates that these widespread volumetric changes vary differentially by gender, suggesting either sexual dimorphic endophenotypic risk factors, or differential neurotoxic sensitivities for males and females.