Effects of baclofen on insular gain anticipation in alcohol-dependent patients - a randomized, placebo-controlled, pharmaco-fMRI pilot trial.

RATIONALE: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION: Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.

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.

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.

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.

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study.

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work.

Risk profiles for heavy drinking in adolescence: differential effects of gender.

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi-domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross-sectional analyses on the large IMAGEN sample (N ≈ 1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19-for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19-year-olds' bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

Reduced loss aversion in pathological gambling and alcohol dependence is associated with differential alterations in amygdala and prefrontal functioning.

Diagnostic criteria for pathological gambling and alcohol dependence (AD) include repeated addictive behavior despite severe negative consequences. However, the concept of loss aversion (LA) as a facet of value-based decision making has not yet been used to directly compare these disorders. We hypothesized reduced LA in pathological gamblers (PG) and AD patients, correlation of LA with disorder severity, and reduced loss-related modulation of brain activity. 19 PG subjects, 15 AD patients and 17 healthy controls (HC) engaged in a LA task in a functional magnetic resonance imaging setting. Imaging analyses focused on neural gain and loss sensitivity in the meso-cortico-limbic network of the brain. Both PG and AD subjects showed reduced LA. AD subjects showed altered loss-related modulation of activity in lateral prefrontal regions. PG subjects showed indication of altered amygdala-prefrontal functional connectivity. Although we observed reduced LA in both a behavioral addiction and a substance-related disorder our neural findings might challenge the notion of complete neuro-behavioral congruence of substance-use disorders and behavioral addictions.

Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients.

CONTEXT: In alcohol-dependent patients, brain atrophy and functional brain activation elicited by alcohol-associated stimuli may predict relapse. However, to date, the interaction between both factors has not been studied. OBJECTIVE: To determine whether results from structural and functional magnetic resonance imaging are associated with relapse in detoxified alcohol-dependent patients. DESIGN: A cue-reactivity functional magnetic resonance experiment with alcohol-associated and neutral stimuli. After a follow-up period of 3 months, the group of 46 detoxified alcohol-dependent patients was subdivided into 16 abstainers and 30 relapsers. SETTING: Faculty for Clinical Medicine Mannheim at the University of Heidelberg, Germany. PARTICIPANTS: A total of 46 detoxified alcohol-dependent patients and 46 age- and sex-matched healthy control subjects MAIN OUTCOME MEASURES: Local gray matter volume, local stimulus-related functional magnetic resonance imaging activation, joint analyses of structural and functional data with Biological Parametric Mapping, and connectivity analyses adopting the psychophysiological interaction approach. RESULTS: Subsequent relapsers showed pronounced atrophy in the bilateral orbitofrontal cortex and in the right medial prefrontal and anterior cingulate cortex, compared with healthy controls and patients who remained abstinent. The local gray matter volume-corrected brain response elicited by alcohol-associated vs neutral stimuli in the left medial prefrontal cortex was enhanced for subsequent relapsers, whereas abstainers displayed an increased neural response in the midbrain (the ventral tegmental area extending into the subthalamic nucleus) and ventral striatum. For alcohol-associated vs neutral stimuli in abstainers compared with relapsers, the analyses of the psychophysiological interaction showed a stronger functional connectivity between the midbrain and the left amygdala and between the midbrain and the left orbitofrontal cortex. CONCLUSIONS: Subsequent relapsers displayed increased brain atrophy in brain areas associated with error monitoring and behavioral control. Correcting for gray matter reductions, we found that, in these patients, alcohol-related cues elicited increased activation in brain areas associated with attentional bias toward these cues and that, in patients who remained abstinent, increased activation and connectivity were observed in brain areas associated with processing of salient or aversive stimuli.