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.

Reactivation strength during cued recall is modulated by graph distance within cognitive maps.

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8 min consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms, with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps.

The truth is in there: Belief processes in the human brain.

Belief, defined by William James as the mental state or function of cognizing reality, is a core psychological function with strong influence on emotion and behavior. Furthermore, strong and aberrant beliefs about the world and oneself play important roles in mental disorders. The underlying processes of belief have been the matter of a long debate in philosophy and psychology, and modern neuroimaging techniques can provide insight into the underlying neural processes. Here, we conducted a functional magnetic resonance imaging study with N = 30 healthy participants in which we presented statements about facts, politics, religion, conspiracy theories, and superstition. Participants judged whether they considered them as true (belief) or not (disbelief) and reported their certainty in the decision. We found belief-associated activations in bilateral dorsolateral prefrontal cortex, left superior parietal cortex, and left lateral frontopolar cortex. Disbelief-associated activations were found in an anterior temporal cluster extending into the amygdala. We found a larger deactivation for disbelief than belief in the ventromedial prefrontal cortex that was most pronounced during decisions, suggesting a role of the vmPFC in belief-related decision-making. As a category-specific effect, we found disbelief-associated activation in retrosplenial cortex and parahippocampal gyrus for conspiracy theory statements. Exploratory analyses identified networks centered at anterior cingulate cortex for certainty, and dorsomedial prefrontal cortex for uncertainty. The uncertainty effect identifies a neural substrate for Alexander Bain's notion from 1859 of uncertainty as the real opposite of belief. Taken together, our results suggest a two-factor neural process model of belief with falsehood/veracity and uncertainty/certainty factors.

Cue-exposure treatment influences resting-state functional connectivity-a randomized controlled fMRI study in alcohol use disorder.

RATIONALE: Cue-exposure therapy (CET) consists of exposing patients to the cause of their affliction in a controlled environment and after psychological preparation. Ever since it was conceived, it has been suggested as a treatment for different types of behavioural impairments, from anxiety disorders to substance abuse. In the field of addictive behaviour, many different findings have been shown regarding the effectiveness of this therapy. OBJECTIVES: This study aims to examine the underlying neurobiological mechanisms of the effects of CET in patients with alcohol use disorder using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: In a randomized, controlled study, we examined patients after inpatient detoxification as well as healthy controls. Patients underwent nine sessions of CET spaced over 3 weeks. Rs-fMRI was conducted before treatment and 3 weeks after treatment onset in patients, healthy controls received only one rs-fMRI measurement. The final participant sample with complete data included 35 patients in the CET group, 17 patients in the treatment-as-usual group, and 43 HCs. RESULTS: Our results show differences in the Salience Network when comparing the CET group to the treatment-as-usual group (TAU). Functional connectivity between the anterior cingulate Cortex (ACC) and the insula was increased after CET, whereas it was decreased from ACC to the putamen and globus pallidus. Further, increased connectivity with the precuneus was found in the dorsal attention network after cue exposure treatment. CONCLUSIONS: These findings suggest that cue exposure therapy changes the resting-state brain connectivity with additional effects to the standard psychotherapy treatment. Hence, our study results suggest why including CET in standard therapies might improve the preparation of patients in front of daily situations.

No evidence from a negative mood induction fMRI task for frontal functional asymmetry as a suitable neurofeedback target.

Frontal functional asymmetry (FA) has been proposed as a potential target for neurofeedback (NFB) training for mental disorders but most FA NFB studies used electroencephalography while the investigations of FA NFB in functional magnetic resonance imaging (fMRI) are rather limited. In this study, we aimed at identifying functional asymmetry effects in fMRI and exploring its potential as a target for fMRI NFB studies by re-analyzing an existing data set containing a resting state measurement and a sad mood induction task of n = 30 participants with remitted major depressive disorder and n = 30 matched healthy controls. We applied low-frequency fluctuations (ALFF), fractional ALFF, and regional homogeneity and estimated functional asymmetry in both a voxel-wise and regional manner. We assessed functional asymmetry during rest and negative mood induction as well as functional asymmetry changes between the phases, and associated the induced mood change with the change in functional asymmetry. Analyses were conducted within as well as between groups. Despite extensive analyses, we identified only very limited effects. While some tests showed nominal significance, our results did not contain any clear identifiable patterns of effects that would be expected if a true underlying effect would be present. In conclusion, we do not find evidence for FA effects related to negative mood in fMRI, which questions the usefulness of FA measures for real-time fMRI neurofeedback as a treatment approach for affective disorders.

Neural responses to instructed positive couple interaction: an fMRI study on compliment sharing.

Love is probably the most fascinating feeling that a person ever experiences. However, little is known about what is happening in the brains of a romantic couple-the central and most salient relationship during adult age-while they are particularly tender and exchanging loving words with one another. To gain insight into nearly natural couple interaction, we collected data from N = 84 individuals (including N = 43 heterosexual couples) simultaneously in two functional magnetic resonance imaging scanners, while they sent and received compliments, i.e. short messages about what they liked about each other and their relationship. Activation patterns during compliment sharing in the individuals revealed a broad pattern of activated brain areas known to be involved in empathy and reward processing. Notably, the ventral striatum, including parts of the putamen, was activated particularly when selecting messages for the partner. This provides initial evidence that giving a verbal treat to a romantic partner seems to involve neural reward circuitry in the basal ganglia. These results can have important implications for the neurobiological mechanisms protecting and stabilizing romantic relationships, which build a highly relevant aspect of human life and health.

Decoding fMRI alcohol cue reactivity and its association with drinking behaviour.

BACKGROUND: Cue reactivity, the enhanced sensitivity to conditioned cues, is associated with habitual and compulsive alcohol consumption. However, most previous studies in alcohol use disorder (AUD) compared brain activity between alcohol and neutral conditions, solely as cue-triggered neural reactivity. OBJECTIVE: This study aims to find the neural subprocesses during the processing of visual alcohol cues in AUD individuals, and how these neural patterns are predictive for relapse. METHODS: Using cue reactivity and rating tasks, we separately modelled the patterns decoding the processes of visual object recognition and reward appraisal of alcohol cues with representational similarity analysis, and compared the decoding involvements (ie, distance between neural responses and hypothesised decoding models) between AUD and healthy individuals. We further explored connectivity between the identified neural systems and the whole brain and predicted relapse within 6 months using decoding involvements of the neural patterns. FINDINGS: AUD individuals, compared with healthy individuals, showed higher involvement of motor-related brain regions in decoding visual features, and their reward, habit and executive networks were more engaged in appraising reward values. Connectivity analyses showed the involved neural systems were widely connected with higher cognitive networks during alcohol cue processing in AUD individuals, and decoding involvements of frontal eye fields and dorsolateral prefrontal cortex could contribute to relapse prediction. CONCLUSIONS: These findings provide insight into how AUD individuals differently decode alcohol cues compared with healthy participants, from the componential processes of visual object recognition and reward appraisal. CLINICAL IMPLICATIONS: The identified patterns are suggested as biomarkers and potential therapeutic targets in AUD.

Association between iron accumulation in the dorsal striatum and compulsive drinking in alcohol use disorder.

RATIONALE: Brain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration. OBJECTIVES: In this study, we used quantitative susceptibility mapping (QSM), an emerging MRI technique developed for quantifying tissue magnetic susceptibility, to examine brain iron accumulation in individuals with alcohol use disorder (AUD) and its relation to compulsive drinking. METHODS: Based on our previous projects, QSM was performed as a secondary analysis with gradient echo sequence images, in 186 individuals with AUD and 274 healthy participants. Whole-brain susceptibility values were calculated with morphology-enabled dipole inversion and referenced to the cerebrospinal fluid. Then, the susceptibility maps were compared between AUD individuals and healthy participants. The relationship between drinking patterns and susceptibility was explored. RESULTS: Whole-brain analyses showed that the susceptibility in the dorsal striatum (putamen and caudate) among AUD individuals was higher than healthy participants and was positively related to the Obsessive Compulsive Drinking Scale (OCDS) scores and the amount of drinking in the past three months. CONCLUSIONS: Increased susceptibility suggests higher iron accumulation in the dorsal striatum in AUD. This surrogate for the brain iron level was linearly associated with the compulsive drinking pattern and the recent amount of drinking, which provides us a new clinical perspective in relation to brain iron accumulation, and also might indicate an association of AUD with neuroinflammation as a consequence of brain iron accumulation. The iron accumulation in the striatum is further relevant for functional imaging studies in AUD by potentially producing signal dropout and artefacts in fMRI images.

Choice matters: Pupils' stress regulation, brain development and brain function in an outdoor education project.

BACKGROUND: Education outside the classroom (EOtC) is considered beneficial to children's physical and mental health. Especially, stress resilience has been linked to nature experience. AIMS: This study experimentally explored the effects of pupils' autonomy support (AUT) and physical activity (PA) on their biological stress responses and brain development in EOtC. SAMPLE: The study comprised 48 fifth and sixth graders. METHODS: The intervention consisted of one day/week taught in a forest over one school year. Structural magnetic resonance imaging (MRI) was conducted at the beginning and the end of the school year, functional MRI under a stress condition at the end. Regions of interest were amygdala, hippocampus and the anterior cingulate cortex (ACC). All other measures were obtained at the beginning, at mid-term and at the end of the school year. PA was measured using accelerometry. Cortisol levels were obtained three times during the examined school days. AUT was measured with a paper-based survey. Data were analysed using Bayesian multivariate models. RESULTS: EOtC students exhibit more efficient regulation of biological stress-reactivity and show a reduction of cortisol over the day associated with light PA in the forest. Cortisol is further associated with amygdala activation in the stress condition. Cerebral structural change is best explained by age; however, AUT has a positive direct effect on the maturation of the ACC, which is stronger in EOtC. CONCLUSIONS: Our results support the idea that autonomy supportive teaching fosters cerebral maturation and that EOtC can have a positive effect on biological stress regulation.

Neural cue reactivity is not stronger in male than in female patients with alcohol use disorder.

Background: Males consume more alcohol than females, and alcohol use disorder (AUD) is more prevalent in males than females. However, females progress faster to AUD. Sex differences in neural alcohol cue reactivity were previously observed in young social drinkers, indicating a role of hypersensitivity to alcohol-related cues in very early stages of addiction. To our knowledge, this is the first study on patients diagnosed with AUD to test sex differences in neural reactivity to alcohol cues in order to widen previous findings. Methods: We analyzed data from previous studies, using a well-established functional magnetic resonance imaging (fMRI) paradigm to compare neural reactivity to alcohol cues between 42 female and 124 male patients with AUD (mean age 45 and 46 years) in predefined regions of interest that were implicated by previous studies (ventral and dorsal striatum as well as caudate, putamen, amygdala, hippocampus, insula, anterior cingulate cortex, and medial prefrontal cortex) using independent samples t-tests. Post-hoc, effect size calculations were performed. Results: Throughout all nine regions of interest, we found no statistically significant sex differences in neural reactivity toward alcoholic pictures alone or in comparison to neutral pictures (p > 0.05, FDR-corrected). Post-hoc effect size estimates indicated a magnitude between 0.137 and 0.418 (Hedge's g) on alcohol reactivity to alcohol cues compared to neutral cues and indicate very small to less than medium effect sizes in the direction of higher cue reactivity in female patients. Conclusion: Previous studies showed sex differences in neural alcohol cue reactivity in younger social and problematic alcohol drinkers, i.e., stronger striatal cue-reactivity in males. After correction for multiple comparisons, we did not observe significant sex differences in a cohort of middle-aged females and males with AUD. Sex differences that are present during early phases of addiction development might disappear at later stages of AUD and might thus be considered as clinically less relevant in patients with more severe AUD.

Striatal hub of dynamic and stabilized prediction coding in forebrain networks for olfactory reinforcement learning.

Identifying the circuits responsible for cognition and understanding their embedded computations is a challenge for neuroscience. We establish here a hierarchical cross-scale approach, from behavioral modeling and fMRI in task-performing mice to cellular recordings, in order to disentangle local network contributions to olfactory reinforcement learning. At mesoscale, fMRI identifies a functional olfactory-striatal network interacting dynamically with higher-order cortices. While primary olfactory cortices respectively contribute only some value components, the downstream olfactory tubercle of the ventral striatum expresses comprehensively reward prediction, its dynamic updating, and prediction error components. In the tubercle, recordings reveal two underlying neuronal populations with non-redundant reward prediction coding schemes. One population collectively produces stabilized predictions as distributed activity across neurons; in the other, neurons encode value individually and dynamically integrate the recent history of uncertain outcomes. These findings validate a cross-scale approach to mechanistic investigations of higher cognitive functions in rodents.

In search of systems consolidation.

Systems consolidation solves the stability-plasticity-dilemma and is a persuasive theory within the neuroscience of memory. The study by Tallman et al. (this issue) adds to the current literature showing that brain activity changes over time follow a power function in some neocortical areas but not in the hippocampus. In our comment, we suggest that a power function may, however, not be the only model that needs to be considered for such an analysis. We also highlight that reasoning by the absence of statistical significance should be replaced by appropriate statistics (e.g., using superiority or equivalence tests).

Feasibility of training the dorsolateral prefrontal-striatal network by real-time fMRI neurofeedback.

Real-time fMRI neurofeedback (rt-fMRI NF) is a promising non-invasive technique that enables volitional control of usually covert brain processes. While most rt-fMRI NF studies so far have demonstrated the ability of the method to evoke changes in brain activity and improve symptoms of mental disorders, a recently evolving field is network-based functional connectivity (FC) rt-fMRI NF. However, FC rt-fMRI NF has methodological challenges such as respirational artefacts that could potentially bias the training if not controlled. In this randomized, double-blind, yoke-controlled, pre-registered FC rt-fMRI NF study with healthy participants (N = 40) studied over three training days, we tested the feasibility of an FC rt-fMRI NF approach with online global signal regression (GSR) to control for physiological artefacts for up-regulation of connectivity in the dorsolateral prefrontal-striatal network. While our pre-registered null hypothesis significance tests failed to reach criterion, we estimated the FC training effect at a medium effect size at the end of the third training day after rigorous control of physiological artefacts in the offline data. This hints at the potential of FC rt-fMRI NF for the development of innovative transdiagnostic circuit-specific interventional approaches for mental disorders and the effect should now be confirmed in a well-powered study.

Brain-wide inferiority and equivalence tests in fMRI group analyses: Selected applications.

Null hypothesis significance testing is the major statistical procedure in fMRI, but provides only a rather limited picture of the effects in a data set. When sample size and power is low relying only on strict significance testing may lead to a host of false negative findings. In contrast, with very large data sets virtually every voxel might become significant. It is thus desirable to complement significance testing with procedures like inferiority and equivalence tests that allow to formally compare effect sizes within and between data sets and offer novel approaches to obtain insight into fMRI data. The major component of these tests are estimates of standardized effect sizes and their confidence intervals. Here, we show how Hedges' g, the bias corrected version of Cohen's d, and its confidence interval can be obtained from SPM t maps. We then demonstrate how these values can be used to evaluate whether nonsignificant effects are really statistically smaller than significant effects to obtain "regions of undecidability" within a data set, and to test for the replicability and lateralization of effects. This method allows the analysis of fMRI data beyond point estimates enabling researchers to take measurement uncertainty into account when interpreting their findings.

Dynamic frontostriatal functional peak connectivity (in alcohol use disorder).

Alcohol use disorder (AUD) is associated with changes in frontostriatal connectivity, but functional magnetic resonance imaging (fMRI) functional connectivity (FC) approaches are usually not adapted to these circuits. We developed a circuit-specific fMRI analysis approach to detect dynamic changes in frontostriatal FC inspired by medial-ventral-rostral to lateral-dorsal-caudal frontostriatal gradients originally identified in nonhuman primate tract-tracing data. In our PeaCoG ("peak connectivity on a gradient") approach we use information about the location of strongest FC on empirical frontostriatal connectivity gradients. We have recently described a basic PeaCoG version with conventional FC, and now developed a dynamic PeaCoG approach with sliding-window FC. In resting state data of n = 66 AUD participants and n = 40 healthy controls we continue here the analyses that we began with the basic version. Our former result of an AUD-associated ventral shift in right orbitofrontal cortex PeaCoG is consistently detected in the dynamic approach. Temporospatial variability of dynamic PeaCoG in the left dorsolateral prefrontal cortex is reduced in AUD and associated with self-efficacy to abstain and days of abstinence. Our method has the potential to provide insight into the dynamics of frontostriatal circuits, which has so far been relatively unexplored, and into their role in mental disorders and normal cognition.

Dynamic Causal Modeling for fMRI With Wilson-Cowan-Based Neuronal Equations.

Dynamic causal modeling (DCM) is an analysis technique that has been successfully used to infer about directed connectivity between brain regions based on imaging data such as functional magnetic resonance imaging (fMRI). Most variants of DCM for fMRI rely on a simple bilinear differential equation for neural activation, making it difficult to interpret the results in terms of local neural dynamics. In this work, we introduce a modification to DCM for fMRI by replacing the bilinear equation with a non-linear Wilson-Cowan based equation and use Bayesian Model Comparison (BMC) to show that this modification improves the model evidences. Improved model evidence of the non-linear model is shown for our empirical data (imitation of facial expressions) and validated by synthetic data as well as an empirical test dataset (attention to visual motion) used in previous foundational papers. For our empirical data, we conduct the analysis for a group of 42 healthy participants who performed an imitation task, activating regions putatively containing the human mirror neuron system (MNS). In this regard, we build 540 models as one family for comparing the standard bilinear with the modified Wilson-Cowan models on the family-level. Using this modification, we can interpret the sigmoid transfer function as an averaged f-I curve of many neurons in a single region with a sigmoidal format. In this way, we can make a direct inference from the macroscopic model to detailed microscopic models. The new DCM variant shows superior model evidence on all tested data sets.

Using mind control to modify cue-reactivity in AUD: the impact of mindfulness-based relapse prevention on real-time fMRI neurofeedback to modify cue-reactivity in alcohol use disorder: a randomized controlled trial.

BACKGROUND: Alcohol Use Disorder is a severe mental disorder affecting the individuals concerned, their family and friends and society as a whole. Despite its high prevalence, novel treatment options remain rather limited. Two innovative interventions used for treating severe disorders are the use of real-time functional magnetic resonance imaging neurofeedback that targets brain regions related to the disorder, and mindfulness-based treatments. In the context of the TRR SFB 265 C04 "Mindfulness-based relapse prevention as an addition to rtfMRI NFB intervention for patients with Alcohol Use Disorder (MiND)" study, both interventions will be combined to a state-of-the art intervention that will use mindfulness-based relapse prevention to improve the efficacy of a real-time neurofeedback intervention targeting the ventral striatum, which is a brain region centrally involved in cue-reactivity to alcohol-related stimuli. METHODS/DESIGN: After inclusion, N = 88 patients will be randomly assigned to one of four groups. Two of those groups will receive mindfulness-based relapse prevention. All groups will receive two fMRI sessions and three real-time neurofeedback sessions in a double-blind manner and will regulate either the ventral striatum or the auditory cortex as a control region. Two groups will additionally receive five sessions of mindfulness-based relapse prevention prior to the neurofeedback intervention. After the last fMRI session, the participants will be followed-up monthly for a period of 3 months for an assessment of the relapse rate and clinical effects of the intervention. DISCUSSION: The results of this study will give further insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback interventions for the treatment of Alcohol Use Disorder. Additionally, the study will provide further insight on neurobiological changes in the brain caused by the neurofeedback intervention as well as by the mindfulness-based relapse prevention. The outcome might be useful to develop new treatment approaches targeting mechanisms of Alcohol Use Disorder with the goal to reduce relapse rates after discharge from the hospital. TRIAL REGISTRATION: This trial is pre-registered at clinicaltrials.gov (trial identifier: NCT04366505; WHO Universal Trial Number (UTN): U1111-1250-2964). Registered 30 March 2020, published 29 April 2020.

Specific and segregated changes to the functional connectome evoked by the processing of emotional faces: A task-based connectome study.

The functional connectome is organized into several separable intrinsic connectivity networks (ICNs) that are thought to be the building blocks of the mind. However, it is currently not well understood how these networks are engaged by emotionally salient information, and how such engagement fits into emotion theories. The current study assessed how ICNs respond during the processing of angry and fearful faces in a large sample (N = 843) and examined how connectivity changes relate to the ICNs. All ICNs were modulated by emotional faces and showed functional interactions, a finding which is in line with the "theory of constructed emotions" that assumes that basic emotion do not arise from separable ICNs but from their interplay. We further identified a set of brain regions whose connectivity changes during the tasks suggest a special role as "affective hubs" in the brain. While hubs were located in all ICNs, we observed high selectivity for the amygdala within the subcortical network, a finding which also fits into "primary emotion" theory. The topology of hubs corresponded closely to a set of brain regions that has been implicated in anxiety disorders, pointing towards a clinical relevance of the present findings. The present data are the most comprehensive mapping of connectome-wide changes in functionally connectivity evoked by an affective processing task thus far and support two competing views on how emotions are represented in the brain, suggesting that the connectome paradigm might help with unifying the two ideas.