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.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

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.

Neural responses to acute stress predict chronic stress perception in daily life over 13 months.

The importance of amygdala, hippocampus, and medial prefrontal cortex (mPFC) for the integration of neural, endocrine, and affective stress processing was shown in healthy participants and patients with stress-related disorders. The present manuscript which reports on one study-arm of the LawSTRESS project, aimed at investigating the predictive value of acute stress responses in these regions for biopsychological consequences of chronic stress in daily life. The LawSTRESS project examined law students either in preparation for their first state examination (stress group [SG]) or in the mid-phase of their study program (control group [CG]) over 13 months. Ambulatory assessments comprising perceived stress measurements and the cortisol awakening response (CAR) were administered on six sampling points (t1 = - 1 year, t2 = - 3 months, t3 = - 1 week, t4 = exam, t5 = + 1 week, t6 = + 1 month). In a subsample of 124 participants (SG: 61; CG: 63), ScanSTRESS was applied at baseline. In the SG but not in the CG, amygdala, hippocampus, and (post-hoc analyzed) right mPFC activation changes during ScanSTRESS were significantly associated with the trajectory of perceived stress but not with the CAR. Consistent with our finding in the total LawSTRESS sample, a significant increase in perceived stress and a blunted CAR over time could be detected in the SG only. Our findings suggest that more pronounced activation decreases of amygdala, hippocampus, and mPFC in response to acute psychosocial stress at baseline were related to a more pronounced increase of stress in daily life over the following year.

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.

Effects of Rumination and Mindful Self-Focus Inductions During Daily Life in Patients With Remitted Depression: An Experimental Ambulatory Assessment Study.

Rumination has been proposed as an important risk factor for depression, whereas mindful attention is considered a protective form of self-focusing. Experimental studies have demonstrated differential effects of these modes when induced in the lab. However, their impact on daily life processes is poorly understood, particularly in individuals vulnerable to depressive relapses. The aim of our study was to examine short- and longer-term effects of repeated brief rumination and mindful self-focus inductions during daily life on momentary mood, cognitions, and cortisol in patients with remitted depression (rMDD) as well as in healthy individuals, and to identify their potential differential effects in these groups. The study involved repeated short ambulatory inductions of a ruminative or a mindful self-focus during daily life with additional assessments of momentary mood, rumination, self-acceptance, and cortisol over 4 consecutive days in a sample of patients with rMDD (n = 32, ≥2 lifetime episodes, age 19-55 years) and matched healthy controls (n = 32, age 21-54 years). Multilevel models revealed differential immediate effects of the two induction modes on all momentary mood and cognitive outcomes (all p's < .001), but not on cortisol. Detrimental effects of rumination over mindful self-focus inductions were particularly strong for cognitions in the patient group. Longer-term effects of the inductions over the day were lacking. This study underlines immediate deteriorating effects of an induced ruminative compared to a mindful self-focus on momentary mood and cognitions during daily life in patients with rMDD and in healthy individuals. The observed stronger rumination-related reactivity in patients suggests heightened cognitive vulnerability. Understanding rumination- and mindfulness-based mechanisms of action in real-life settings can help to establish mechanism-based treatment options for relapse prevention in depression.

Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence.

INTRODUCTION: Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology. Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

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.

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.

Comparing Discounting of Potentially Real Rewards and Losses by Means of Functional Magnetic Resonance Imaging.

Aim: Delay discounting (DD) has often been investigated in the context of decision making whereby individuals attribute decreasing value to rewards in the distant future. Less is known about DD in the context of negative consequences. The aim of this pilot study was to identify commonalities and differences between reward and loss discounting on the behavioral as well as the neural level by means of computational modeling and functional Magnetic Resonance Imaging (fMRI). We furthermore compared the neural activation between anticipation of rewards and losses. Method: We conducted a study combining an intertemporal choice task for potentially real rewards and losses (decision-making) with a monetary incentive/loss delay task (reward/loss anticipation). Thirty healthy participants (age 18-35, 14 female) completed the study. In each trial, participants had to choose between a smaller immediate loss/win and a larger loss/win at a fixed delay of two weeks. Task-related brain activation was measured with fMRI. Results: Hyperbolic discounting parameters of loss and reward conditions were correlated (r = 0.56). During decision-making, BOLD activation was observed in the parietal and prefrontal cortex, with no differences between reward and loss conditions. During reward and loss anticipation, dissociable activation was observed in the striatum, the anterior insula and the anterior cingulate cortex. Conclusion: We observed behavior concurrent with DD in both the reward and loss condition, with evidence for similar behavioral and neural patterns in the two conditions. Intertemporal decision-making recruited the fronto-parietal network, whilst reward and loss anticipation were related to activation in the salience network. The interpretation of these findings may be limited to short delays and small monetary outcomes.

A Model Guided Approach to Evoke Homogeneous Behavior During Temporal Reward and Loss Discounting.

Background: The tendency to devaluate future options as a function of time, known as delay discounting, is associated with various factors such as psychiatric illness and personality. Under identical experimental conditions, individuals may therefore strongly differ in the degree to which they discount future options. In delay discounting tasks, this inter-individual variability inevitably results in an unequal number of discounted trials per subject, generating difficulties in linking delay discounting to psychophysiological and neural correlates. Many studies have therefore focused on assessing delay discounting adaptively. Here, we extend these approaches by developing an adaptive paradigm which aims at inducing more comparable and homogeneous discounting frequencies across participants on a dimensional scale. Method: The proposed approach probabilistically links a (common) discounting function to behavior to obtain a probabilistic model, and then exploits the model to obtain a formal condition which defines how to construe experimental trials so as to induce any desired discounting probability. We first infer subject-level models on behavior on a non-adaptive delay discounting task and then use these models to generate adaptive trials designed to evoke graded relative discounting frequencies of 0.3, 0.5, and 0.7 in each participant. We further compare and evaluate common models in the field through out-of-sample prediction error estimates, to iteratively improve the trial-generating model and paradigm. Results: The developed paradigm successfully increases discounting behavior during both reward and loss discounting. Moreover, it evokes graded relative choice frequencies in line with model-based expectations (i.e., 0.3, 0.5, and 0.7) suggesting that we can successfully homogenize behavior. Our model comparison analyses indicate that hyperboloid models are superior in predicting unseen discounting behavior to more conventional hyperbolic and exponential models. We report out-of-sample error estimates as well as commonalities and differences between reward and loss discounting, demonstrating for instance lower discounting rates, as well as differences in delay perception in loss discounting. Conclusion: The present work proposes a model-based framework to evoke graded responses linked to cognitive function at a single subject level. Such a framework may be used in the future to measure cognitive functions on a dimensional rather than dichotomous scale.

Daily life stress and the cortisol awakening response over a 13-months stress period - Findings from the LawSTRESS project.

The LawSTRESS project is a controlled prospective-longitudinal study on psychological, endocrine, central nervous and genetic predictors of responses to long-lasting academic stress in a homogenous cohort. In this first project report, we focused on the association between daily life stress and the cortisol awakening response (CAR). The CAR, a distinct cortisol rise in the first 30-45 min after morning awakening, is a well-established marker of cortisol regulation in psychoneuroendocrinology. Law students from Bavarian universities (total n = 452) have been studied over a 13-months period at six sampling points starting 12 months prior exam. The stress group (SG) consisted of students experiencing a long-lasting and significant stress period, namely the preparation for the first state examination for law students. Law students assigned to the control group (CG) were studied over an equally long period without particular and sustained stress exposure. To investigate stress related alterations in the CAR, we examined a subsample of the LawSTRESS project consisting of 204 students with 97 participants from the SG (69.1% female, mean age = 22.84 ± 1.82) and 107 from the CG (78.5% female, mean age = 20.95 ± 1.93). At each sampling point, saliva samples for cortisol assessment were collected immediately upon awakening and 30 as well as 45 min later. Perceived stress in daily life was measured by repeated ambulatory assessments (about 100 queries over six sampling points). The time course of perceived stress levels in the two groups differed significantly, with the SG showing an increase in perceived stress until the exam and a decrease thereafter. Stress levels in the CG were relatively stable. The CAR was not significantly different between groups at baseline. However, a blunted CAR in the SG compared to the baseline measure and to the CG developed over the measurement timepoints and reached significance during the exam. Remarkably, this effect was neither associated with the increase in perceived stress nor with anxiety and depression symptoms, test anxiety and chronic stress at baseline. The present study successfully assessed multidimensional stress trajectories over 13 months and it documented the significant burden, law students preparing for the first state examination are exposed to. This period was related to a blunted CAR with presumed physiological consequences (e.g., on energy metabolism and immune function). Mean psychological stress levels as well as the CAR returned to baseline levels after the exam, suggesting a fast recovery in the majority of the participants.

Directed coupling in multi-brain networks underlies generalized synchrony during social exchange.

Advances in social neuroscience have made neural signatures of social exchange measurable simultaneously across people. This has identified brain regions differentially active during social interaction between human dyads, but the underlying systems-level mechanisms are incompletely understood. This paper introduces dynamic causal modeling and Bayesian model comparison to assess the causal and directed connectivity between two brains in the context of hyperscanning (h-DCM). In this setting, correlated neuronal responses become the data features that have to be explained by models with and without between-brain (effective) connections. Connections between brains can be understood in the context of generalized synchrony, which explains how dynamical systems become synchronized when they are coupled to each another. Under generalized synchrony, each brain state can be predicted by the other brain or a mixture of both. Our results show that effective connectivity between brains is not a feature within dyads per se but emerges selectively during social exchange. We demonstrate a causal impact of the sender's brain activity on the receiver of information, which explains previous reports of two-brain synchrony. We discuss the implications of this work; in particular, how characterizing generalized synchrony enables the discovery of between-brain connections in any social contact, and the advantage of h-DCM in studying brain function on the subject level, dyadic level, and group level within a directed model of (between) brain function.

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.

Increased network centrality of the anterior insula in early abstinence from alcohol.

Abnormal resting-state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph-theoretical analyses, enabling improved resolution and fine-grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large-scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region-specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular-supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment.

Model-based experimental manipulation of probabilistic behavior in interpretable behavioral latent variable models.

Introduction: Interpretable latent variable models that probabilistically link behavioral observations to an underlying latent process have increasingly been used to draw inferences on cognition from observed behavior. The latent process usually connects experimental variables to cognitive computation. While such models provide important insights into the latent processes generating behavior, one important aspect has often been overlooked. They may also be used to generate precise and falsifiable behavioral predictions as a function of the modeled experimental variables. In doing so, they pinpoint how experimental conditions must be designed to elicit desired behavior and generate adaptive experiments. Methods: These ideas are exemplified on the process of delay discounting (DD). After inferring DD models from behavior on a typical DD task, the models are leveraged to generate a second adaptive DD task. Experimental trials in this task are designed to elicit 9 graded behavioral discounting probabilities across participants. Models are then validated and contrasted to competing models in the field by assessing the ouf-of-sample prediction error. Results: The proposed framework induces discounting probabilities on nine levels. In contrast to several alternative models, the applied model exhibits high validity as indicated by a comparably low prediction error. We also report evidence for inter-individual differences with respect to the most suitable models underlying behavior. Finally, we outline how to adapt the proposed method to the investigation of other cognitive processes including reinforcement learning. Discussion: Inducing graded behavioral frequencies with the proposed framework may help to highly resolve the underlying cognitive construct and associated neuronal substrates.

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.

Sex-specific interaction between cortisol and striato-limbic responses to psychosocial stress.

Although women and men differ in psychological and endocrine stress responses as well as in the prevalence rates of stress-related disorders, knowledge on sex differences regarding stress regulation in the brain is scarce. Therefore, we performed an in-depth analysis of data from 67 healthy participants (31 women, taking oral contraceptives), who were exposed to the ScanSTRESS paradigm in a functional magnetic resonance imaging study. Changes in cortisol, affect, heart rate and neural activation in response to psychosocial stress were examined in women and men as well as potential sex-specific interactions between stress response domains. Stress exposure led to significant cortisol increases, with men exhibiting higher levels than women. Depending on sex, cortisol elevations were differently associated with stress-related responses in striato-limbic structures: higher increases were associated with activations in men but with deactivations in women. Regarding affect or heart rate responses, no sex differences emerged. Although women and men differ in their overall stress reactivity, our findings do not support the idea of distinct neural networks as the base of this difference. Instead, we found differential stress reactions for women and men in identical structures. We propose considering quantitative predictors such as sex-specific cortisol increases when exploring neural response differences of women and men.