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.

Effective connectivity during face processing in major depression - distinguishing markers of pathology, risk, and resilience.

BACKGROUND: Aberrant brain connectivity during emotional processing, especially within the fronto-limbic pathway, is one of the hallmarks of major depressive disorder (MDD). However, the methodological heterogeneity of previous studies made it difficult to determine the functional and etiological implications of specific alterations in brain connectivity. We previously reported alterations in psychophysiological interaction measures during emotional face processing, distinguishing depressive pathology from at-risk/resilient and healthy states. Here, we extended these findings by effective connectivity analyses in the same sample to establish a refined neural model of emotion processing in depression. METHODS: Thirty-seven patients with MDD, 45 first-degree relatives of patients with MDD and 97 healthy controls performed a face-matching task during functional magnetic resonance imaging. We used dynamic causal modeling to estimate task-dependent effective connectivity at the subject level. Parametric empirical Bayes was performed to quantify group differences in effective connectivity. RESULTS: MDD patients showed decreased effective connectivity from the left amygdala and left lateral prefrontal cortex to the fusiform gyrus compared to relatives and controls, whereas patients and relatives showed decreased connectivity from the right orbitofrontal cortex to the left insula and from the left orbitofrontal cortex to the right fusiform gyrus compared to controls. Relatives showed increased connectivity from the anterior cingulate cortex to the left dorsolateral prefrontal cortex compared to patients and controls. CONCLUSIONS: Our results suggest that the depressive state alters top-down control of higher visual regions during face processing. Alterations in connectivity within the cognitive control network present potential risk or resilience mechanisms.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

The Treatment of Substance Use Disorders: Recent Developments and New Perspectives.

Substance-related disorders are complex psychiatric disorders that are characterized by continued consumption in spite of harmful consequences. Addiction affects various brain networks critically involved in learning, reward, and motivation, as well as inhibitory control. Currently applied therapeutic approaches aim at modification of behavior that ultimately leads to decrease of consumption or abstinence in individuals with substance use disorders. However, traditional treatment methods might benefit from recent neurobiological and cognitive neuroscientific research findings. Novel cognitive-behavioral approaches in the treatment of addictive behavior aim at enhancement of strategies to cope with stressful conditions as well as craving-inducing cues and target erroneous learning mechanisms, including cognitive bias modification, reconsolidation-based interventions, mindfulness-based interventions, virtual-reality-based cue exposure therapy as well as pharmacological augmentation strategies. This review discusses therapeutic strategies that target dysregulated neurocognitive processes associated with the development and maintenance of disordered substance use and may hold promise as effective treatments for substance-related disorders.

Neural correlates of RDoC-specific cognitive processes in a high-functional autistic patient: a statistically validated case report.

The level of functioning of individuals with autism spectrum disorder (ASD) varies widely. To better understand the neurobiological mechanism associated with high-functioning ASD, we studied the rare case of a female patient with an exceptional professional career in the highly competitive academic field of Mathematics. According to the Research Domain Criteria (RDoC) approach, which proposes to describe the basic dimensions of functioning by integrating different levels of information, we conducted four fMRI experiments targeting the (1) social processes domain (Theory of mind (ToM) and face matching), (2) positive valence domain (reward processing), and (3) cognitive domain (N-back). Patient's data were compared to data of 14 healthy controls (HC). Additionally, we assessed the subjective experience of our case during the experiments. The patient showed increased response times during face matching and achieved a higher total gain in the Reward task, whereas her performance in N-back and ToM was similar to HC. Her brain function differed mainly in the positive valence and cognitive domains. During reward processing, she showed reduced activity in a left-hemispheric frontal network and cortical midline structures but increased connectivity within this network. During the working memory task patients' brain activity and connectivity in left-hemispheric temporo-frontal regions were elevated. In the ToM task, activity in posterior cingulate cortex and temporo-parietal junction was reduced. We suggest that the high level of functioning in our patient is rather related to the effects in brain connectivity than to local cortical information processing and that subjective report provides a fruitful framework for interpretation.

Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence.

Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2-94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0-21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.

Neural correlates of cue-induced changes in decision-making distinguish subjects with gambling disorder from healthy controls.

In addiction, there are few human studies on the neural basis of cue-induced changes in value-based decision making (Pavlovian-to-instrumental transfer, PIT). It is especially unclear whether neural alterations related to PIT are due to the physiological effects of substance abuse or rather related to learning processes and/or other etiological factors related to addiction. We have thus investigated whether neural activation patterns during a PIT task help to distinguish subjects with gambling disorder (GD), a nonsubstance-based addiction, from healthy controls (HCs). Thirty GD and 30 HC subjects completed an affective decision-making task in a functional magnetic resonance imaging (fMRI) scanner. Gambling-associated and other emotional cues were shown in the background during the task. Data collection and feature modeling focused on a network of nucleus accumbens (NAcc), amygdala, and orbitofrontal cortex (OFC) (derived from PIT and substance use disorder [SUD] studies). We built and tested a linear classifier based on these multivariate neural PIT signatures. GD subjects showed stronger PIT than HC subjects. Classification based on neural PIT signatures yielded a significant area under the receiver operating curve (AUC-ROC) (0.70, p = 0.013). GD subjects showed stronger PIT-related functional connectivity between NAcc and amygdala elicited by gambling cues, as well as between amygdala and OFC elicited by negative and positive cues. HC and GD subjects were thus distinguishable by PIT-related neural signatures including amygdala-NAcc-OFC functional connectivity. Neural PIT alterations in addictive disorders might not depend on the physiological effect of a substance of abuse but on related learning processes or even innate neural traits.

Amygdala functional connectivity in major depression - disentangling markers of pathology, risk and resilience.

BACKGROUND: Limbic-cortical imbalance is an established model for the neurobiology of major depressive disorder (MDD), but imaging genetics studies have been contradicting regarding potential risk and resilience mechanisms. Here, we re-assessed previously reported limbic-cortical alterations between MDD relatives and controls in combination with a newly acquired sample of MDD patients and controls, to disentangle pathology, risk, and resilience. METHODS: We analyzed functional magnetic resonance imaging data and negative affectivity (NA) of MDD patients (n = 48), unaffected first-degree relatives of MDD patients (n = 49) and controls (n = 109) who performed a faces matching task. Brain response and task-dependent amygdala functional connectivity (FC) were compared between groups and assessed for associations with NA. RESULTS: Groups did not differ in task-related brain activation but activation in the superior frontal gyrus (SFG) was inversely correlated with NA in patients and controls. Pathology was associated with task-independent decreases of amygdala FC with regions of the default mode network (DMN) and decreased amygdala FC with the medial frontal gyrus during faces matching, potentially reflecting a task-independent DMN predominance and a limbic-cortical disintegration during faces processing in MDD. Risk was associated with task-independent decreases of amygdala-FC with fronto-parietal regions and reduced faces-associated amygdala-fusiform gyrus FC. Resilience corresponded to task-independent increases in amygdala FC with the perigenual anterior cingulate cortex (pgACC) and increased FC between amygdala, pgACC, and SFG during faces matching. CONCLUSION: Our results encourage a refinement of the limbic-cortical imbalance model of depression. The validity of proposed risk and resilience markers needs to be tested in prospective studies. Further limitations are discussed.

Cue-induced effects on decision-making distinguish subjects with gambling disorder from healthy controls.

While an increased impact of cues on decision-making has been associated with substance dependence, it is yet unclear whether this is also a phenotype of non-substance-related addictive disorders, such as gambling disorder (GD). To better understand the basic mechanisms of impaired decision-making in addiction, we investigated whether cue-induced changes in decision-making could distinguish GD from healthy control (HC) subjects. We expected that cue-induced changes in gamble acceptance and specifically in loss aversion would distinguish GD from HC subjects. Thirty GD subjects and 30 matched HC subjects completed a mixed gambles task where gambling and other emotional cues were shown in the background. We used machine learning to carve out the importance of cue dependency of decision-making and of loss aversion for distinguishing GD from HC subjects. Cross-validated classification yielded an area under the receiver operating curve (AUC-ROC) of 68.9% (p = .002). Applying the classifier to an independent sample yielded an AUC-ROC of 65.0% (p = .047). As expected, the classifier used cue-induced changes in gamble acceptance to distinguish GD from HC. Especially, increased gambling during the presentation of gambling cues characterized GD subjects. However, cue-induced changes in loss aversion were irrelevant for distinguishing GD from HC subjects. To our knowledge, this is the first study to investigate the classificatory power of addiction-relevant behavioral task parameters when distinguishing GD from HC subjects. The results indicate that cue-induced changes in decision-making are a characteristic feature of addictive disorders, independent of a substance of abuse.

Addiction Research Consortium: Losing and regaining control over drug intake (ReCoDe)-From trajectories to mechanisms and interventions.

One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12-year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism-based interventions. These goals will be achieved by: (i) using mobile health (m-health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real-life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal-directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.

MAOA-VNTR genotype affects structural and functional connectivity in distributed brain networks.

Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA-L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico-limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219-284 across modalities) and network-based statistics (NBS) to probe the specificity of MAOA-L-related connectomic alterations to cortical-limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA-L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between-lobe ("anisocoupled") network links and showed a pronounced involvement of frontal-temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting-state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA-L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.

Substance Use and Prevention Programs in Berlin's Party Scene: Results of the SuPrA-Study.

BACKGROUND: Berlin is internationally known for its nightlife. In a nation-wide and Europe-wide comparison, the use of legal and illegal substances is comparatively higher in Berlin than in other similar cities. However, few data exist about the drug use in the party scene. OBJECTIVE: This study aims to assess the sociodemographic characteristics of Berlin's party scene and its patterns of substance use as well as expectations towards prevention in order to derive appropriate preventive measures. METHODS: Using questionnaires, both online (n = 674) and in the field (n = 203), a total of 877 people of the Berlin party scene were interviewed. The questionnaires ascertained the demographic information of the participants and patterns of substance use in the scene. It also collected the demand for consulting services and personal assessments on the usefulness of prospective and existing prevention programs and offers. RESULTS: The study participants were 29 years old (SD 7.5); 43% were female. Alcohol is the most common substance in the party scene, followed by cannabis, MDMA/Ecstasy, amphetamine, cocaine, and ketamine. In this particular cohort, methamphetamine and "legal highs" did not play a major role. The most demanded preventive measure was more education about drugs and the so called drug-checking. CONCLUSIONS: Prevention in this area is both needed and requested, and an expansion of the existing programs (e.g., by so far politically controversial drug-checking) should be considered.

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.

Dynamic reconfiguration of frontal brain networks during executive cognition in humans.

The brain is an inherently dynamic system, and executive cognition requires dynamically reconfiguring, highly evolving networks of brain regions that interact in complex and transient communication patterns. However, a precise characterization of these reconfiguration processes during cognitive function in humans remains elusive. Here, we use a series of techniques developed in the field of "dynamic network neuroscience" to investigate the dynamics of functional brain networks in 344 healthy subjects during a working-memory challenge (the "n-back" task). In contrast to a control condition, in which dynamic changes in cortical networks were spread evenly across systems, the effortful working-memory condition was characterized by a reconfiguration of frontoparietal and frontotemporal networks. This reconfiguration, which characterizes "network flexibility," employs transient and heterogeneous connectivity between frontal systems, which we refer to as "integration." Frontal integration predicted neuropsychological measures requiring working memory and executive cognition, suggesting that dynamic network reconfiguration between frontal systems supports those functions. Our results characterize dynamic reconfiguration of large-scale distributed neural circuits during executive cognition in humans and have implications for understanding impaired cognitive function in disorders affecting connectivity, such as schizophrenia or dementia.

Pathological gambling in Parkinson's disease: what are the risk factors and what is the role of impulsivity?

The incidence of pathological gambling in Parkinson's patients is significantly greater than in the general population. A correlation has been observed between dopamine agonist medication and the development of pathological gambling. However, scientists conjecture that the affected patients have underlying risk factors. Studies analysing Parkinson's patients have detected that patients who developed pathological gambling are younger, score higher on novelty-seeking tests, are more impulsive and are more likely to have a personal or family history of alcohol addiction. In addition, some genetic variations have been associated with the susceptibility of developing pathological gambling, which include mutations of DRD3, 5-HTTLPR and GRIN2B. Studies focusing on neurofunctional discrepancies between Parkinson's patients with and without pathological gambling have found increased functional activation and dopamine release in regions associated with the mesolimbic reward system. Furthermore, there is also evidence showing increased processing of reward and decreased activation elicited by punishment, suggesting altered learning processes. Furthermore, the role of deep brain stimulation of the nucleus subthalamicus (STN DBS) is controversial. In most Parkinson's patients, pathological gambling resolved after the initiation of the STN DBS, which might be explained by discontinuation or decrease in dopamine agonist medication. However, it has been also shown that some patients are more impulsive while the STN DBS is activated. These differences may depend on the DBS localization in the more limbic or motor part of the STN and their regulative effects on impulsivity. Further research is needed to clarify susceptibility factors for the development of pathological gambling in Parkinson's patients.

Decision-making in chronic ecstasy users: a systematic review.

Different cognitive impairments have been reported as a result of long-term MDMA/ecstasy use. Increased impulsivity and altered decision-making have been shown to be associated with the development and maintenance of addictive disorders pointing toward the necessity to understand a potential impairment of decision-making due to MDMA use. Thus, assessing the long-term effects of MDMA is crucial in order to evaluate its controversially discussed therapeutic use. The aim of this systematic review was to summarize the scientific literature on potential effects of chronic MDMA use on higher order decision-making processes in humans. Therefore, a systematic search for controlled trials relevant to the topic has been performed. Only studies using specific tasks on decision-making were included that involved subjects in the drug-free interval with drug-naïve, and/or polydrug control groups. A total of 12 studies could be identified that met the inclusion criteria, all of which were cross-sectional studies. The findings on decision-making disturbances in MDMA users were heterogeneous. Seven studies reported increased risky decisions, whereas five studies did not find MDMA-specific influences on decision-making. Increased impulsivity was observed both in MDMA groups and in (poly)drug control groups in almost all studies. Thus, the current state of research does not allow for the conclusion that long-term use of MDMA affects decision-making behavior in general. More detailed specifications as well as further investigations of the relevant processes are needed. Significant tendencies toward risky decision-making among long-term MDMA use have been observed, but need to be confirmed by studies using a longitudinal design.

Segregation of face sensitive areas within the fusiform gyrus using global signal regression? A study on amygdala resting-state functional connectivity.

The application of global signal regression (GSR) to resting-state functional magnetic resonance imaging data and its usefulness is a widely discussed topic. In this article, we report an observation of segregated distribution of amygdala resting-state functional connectivity (rs-FC) within the fusiform gyrus (FFG) as an effect of GSR in a multi-center-sample of 276 healthy subjects. Specifically, we observed that amygdala rs-FC was distributed within the FFG as distinct anterior versus posterior clusters delineated by positive versus negative rs-FC polarity when GSR was performed. To characterize this effect in more detail, post hoc analyses revealed the following: first, direct overlays of task-functional magnetic resonance imaging derived face sensitive areas and clusters of positive versus negative amygdala rs-FC showed that the positive amygdala rs-FC cluster corresponded best with the fusiform face area, whereas the occipital face area corresponded to the negative amygdala rs-FC cluster. Second, as expected from a hierarchical face perception model, these amygdala rs-FC defined clusters showed differential rs-FC with other regions of the visual stream. Third, dynamic connectivity analyses revealed that these amygdala rs-FC defined clusters also differed in their rs-FC variance across time to the amygdala. Furthermore, subsample analyses of three independent research sites confirmed reliability of the effect of GSR, as revealed by similar patterns of distinct amygdala rs-FC polarity within the FFG. In this article, we discuss the potential of GSR to segregate face sensitive areas within the FFG and furthermore discuss how our results may relate to the functional organization of the face-perception circuit.

Alterations in neural Theory of Mind processing in euthymic patients with bipolar disorder and unaffected relatives.

OBJECTIVES: Behavioral deficits in the Theory of Mind (ToM) have been robustly demonstrated in bipolar disorder. These deficits may represent an intermediate phenotype of the disease. The aim of this study was: (i) to investigate alterations in neural ToM processing in euthymic patients with bipolar disorder, and (ii) to examine whether similar effects are present in unaffected relatives of patients with bipolar disorder suggesting that ToM functional activation may be, in part, due to genetic risk for the disease. METHODS: A total of 24 euthymic patients with bipolar disorder, 21 unaffected first-degree relatives, and 81 healthy controls completed a ToM task while undergoing functional magnetic resonance imaging. RESULTS: We observed reduced bilateral activation of the temporoparietal junction (TPJ) and diminished functional fronto-temporoparietal connectivity in patients compared to controls. Relatives tended towards intermediate temporoparietal activity and functional coupling with medial prefrontal areas. There was also evidence for a potentially compensatory enhanced recruitment of the right middle temporal gyrus and stronger connectivity between this region and the medial prefrontal cortex in relatives. CONCLUSIONS: These findings provide further evidence of altered neural ToM processing in euthymic patients with bipolar disorder. Further, our findings in relatives lend support to the idea that altered ToM processing may act as an intermediate phenotype of the disorder.

Effects of an Innovative Psychotherapy Program for Surgical Patients: Bridging Intervention in Anesthesiology--A Randomized Controlled Trial.

BACKGROUND: The stepped care program Bridging Intervention in Anesthesiology (BRIA) aims at motivating and supporting surgical patients with comorbid mental disorders to engage in psychosocial mental healthcare options. This study examined the efficacy of BRIA. METHODS: This randomized, parallel-group, open-label, controlled trial was conducted in the preoperative anesthesiological assessment clinics and surgical wards of a large university hospital in Germany. A total of 220 surgical patients with comorbid mental disorders were randomized by using the computer-generated lists to one of two intervention groups: BRIA psychotherapy sessions up to 3 months postoperatively (BRIA) versus no psychotherapy/computerized brief written advice (BWA) only. Primary outcome was participation in psychosocial mental healthcare options at month 6. Secondary outcome was change of self-reported general psychological distress (Global Severity Index of the Brief Symptom Inventory) between baseline and month 6. RESULTS: At 6-month follow-up, the rate of patients who engaged in psychosocial mental healthcare options was 30% (33 of 110) in BRIA compared with 11.8% (13 of 110) in BWA (P = 0.001). Number needed to treat and relative risk reduction were 6 (95% CI, 4 to 13) and 0.21 (0.09 to 0.31), respectively. In BRIA, Global Severity Index decreased between baseline and month 6 (P < 0.001), whereas it did not change significantly in BWA (P = 0.197). CONCLUSIONS: Among surgical patients with comorbid mental disorders, BRIA results in an increased engagement in subsequent therapy options and a decrease of general psychological distress. These data suggest that it is reasonable to integrate innovative psychotherapy programs into the context of interdisciplinary surgical care.

Pathological gambling and alcohol dependence: neural disturbances in reward and loss avoidance processing.

Pathological gambling (PG) shares clinical characteristics such as craving and loss of control with substance use disorders and is thus considered a behavioral addiction. While functional alterations in the mesolimbic reward system have been correlated with craving and relapse in substance use disorders, only a few studies have examined this brain circuit in PG, and no direct comparison has been conducted so far. Thus, we investigated the neuronal correlates of reward processing in PG in contrast to alcohol-dependent (AD) patients and healthy subjects. Eighteen PG patients, 15 AD patients and 17 controls were investigated with a monetary incentive delay task, in which visual cues predict the consequence (monetary gain, avoidance of loss, none) of a fast response to a subsequent target stimulus. Functional magnetic resonance imaging data were analyzed to account for possible confounding factors such as local gray matter volume. Activity in the right ventral striatum during loss anticipation was increased in PG patients compared with controls and AD patients. Moreover, PG patients showed decreased activation in the right ventral striatum and right medial prefrontal cortex during successful loss avoidance compared with controls, which was inversely associated with severity of gambling behavior. Thus, despite neurobiological similarities to substance use disorders in reward processing, as reported by previous studies, we found relevant differences with respect to the anticipation of loss as well as its avoidance (negative reinforcement), which further contributes to the understanding of PG.