TY  - JOUR
A1  - Gleich, Tobias
A1  - Spitta, Gianna
A1  - Butler, Oisin
A1  - Zacharias, Kristin
A1  - Aydin, Semiha
A1  - Sebold, Miriam Hannah
A1  - Garbusow, Maria
A1  - Rapp, Michael A.
A1  - Schubert, Florian
A1  - Buchert, Ralph
A1  - Heinz, Andreas
A1  - Gallinat, Jürgen
T1  - Dopamine D2/3 receptor availability in alcohol use disorder and individuals at high risk
BT  - towards a dimensional approach
JF  - Addiction Biology
N2  - Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying F-18-fallypride positron emission tomography (F-18-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.
KW  - alcohol
KW  - D2/3 receptors
KW  - dependence
KW  - dopamine
KW  - high risk
KW  - PET
Y1  - 2020
U6  - https://doi.org/10.1111/adb.12915
SN  - 1369-1600
VL  - 26
IS  - 2
SP  - 1
EP  - 10
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Chen, Ke
A1  - Hollunder, Barbara
A1  - Garbusow, Maria
A1  - Sebold, Miriam Hannah
A1  - Heinz, Andreas
T1  - The physiological responses to acute stress in alcohol-dependent patients
BT  - a systematic review
JF  - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
N2  - Dysregulation of physiological stress reactivity plays a key role in the development and relapse risk of alcohol dependence. This article reviews studies investigating physiological responses to experimentally induced acute stress in patients with alcohol dependence. A systematic search from electronic databases resulted in 3641 articles found and after screening 62 articles were included in our review. Studies are analyzed based on stress types (i.e., social stress tasks and nonsocial stress tasks) and physiological markers (i.e., the nervous system, the endocrine system, somatic responses and the immune system). In studies applying nonsocial stress tasks, alcohol-dependent patients were reported to show a blunted stress response compared with healthy controls in the majority of studies applying markers of adrenocorticotropic hormone and cortisol. In studies applying social stress tasks, findings are inconsistent, with less than half of the studies reporting altered physiological stress responses in patients. We discuss the impact of duration of abstinence, comorbidities, baseline physiological arousal and intervention on the discrepancy of study findings. Furthermore, we review evidence for an associationbetween blunted physiological stress responses and the relapse risk among patients with alcohol dependence. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
KW  - acute stress
KW  - alcohol dependence
KW  - hypothalamic- pituitary-adrenal axis
KW  - physiological reactivity
Y1  - 2020
U6  - https://doi.org/10.1016/j.euroneuro.2020.09.003
SN  - 0924-977X
SN  - 1873-7862
VL  - 41
SP  - 1
EP  - 15
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Nebe, Stephan
A1  - Kroemer, Nils B.
A1  - Schad, Daniel
A1  - Bernhardt, Nadine
A1  - Sebold, Miriam Hannah
A1  - Mueller, Dirk K.
A1  - Scholl, Lucie
A1  - Kuitunen-Paul, Sören
A1  - Heinz, Andreas
A1  - Rapp, Michael A.
A1  - Huys, Quentin J. M.
A1  - Smolka, Michael N.
T1  - No association of goal-directed and habitual control with alcohol consumption in young adults
JF  - Addiction biology
N2  - Alcohol dependence is a mental disorder that has been associated with an imbalance in behavioral control favoring model-free habitual over model-based goal-directed strategies. It is as yet unknown, however, whether such an imbalance reflects a predisposing vulnerability or results as a consequence of repeated and/or excessive alcohol exposure. We, therefore, examined the association of alcohol consumption with model-based goal-directed and model-free habitual control in 188 18-year-old social drinkers in a two-step sequential decision-making task while undergoing functional magnetic resonance imaging before prolonged alcohol misuse could have led to severe neurobiological adaptations. Behaviorally, participants showed a mixture of model-free and model-based decision-making as observed previously. Measures of impulsivity were positively related to alcohol consumption. In contrast, neither model-free nor model-based decision weights nor the trade-off between them were associated with alcohol consumption. There were also no significant associations between alcohol consumption and neural correlates of model-free or model-based decision quantities in either ventral striatum or ventromedial prefrontal cortex. Exploratory whole-brain functional magnetic resonance imaging analyses with a lenient threshold revealed early onset of drinking to be associated with an enhanced representation of model-free reward prediction errors in the posterior putamen. These results suggest that an imbalance between model-based goal-directed and model-free habitual control might rather not be a trait marker of alcohol intake per se.
KW  - alcohol
KW  - goal-directed
KW  - reinforcement learning
Y1  - 2017
U6  - https://doi.org/10.1111/adb.12490
SN  - 1355-6215
SN  - 1369-1600
VL  - 23
IS  - 1
SP  - 379
EP  - 393
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Obst, Elisabeth
A1  - Schad, Daniel
A1  - Huys, Quentin J. M.
A1  - Sebold, Miriam Hannah
A1  - Nebe, Stephan
A1  - Sommer, Christian
A1  - Smolka, Michael N.
A1  - Zimmermann, Ulrich S.
T1  - Drunk decisions
BT  - Alcohol shifts choice from habitual towards goal-directed control in adolescent intermediate-risk drinkers
JF  - Journal of Psychopharmacology
N2  - Background: Studies in humans and animals suggest a shift from goal-directed to habitual decision-making in addiction. We therefore tested whether acute alcohol administration reduces goal-directed and promotes habitual decision-making, and whether these effects are moderated by self-reported drinking problems. Methods: Fifty-three socially drinking males completed the two-step task in a randomised crossover design while receiving an intravenous infusion of ethanol (blood alcohol level=80 mg%), or placebo. To minimise potential bias by long-standing heavy drinking and subsequent neuropsychological impairment, we tested 18- to 19-year-old adolescents. Results: Alcohol administration consistently reduced habitual, model-free decisions, while its effects on goal-directed, model-based behaviour varied as a function of drinking problems measured with the Alcohol Use Disorders Identification Test. While adolescents with low risk for drinking problems (scoring <8) exhibited an alcohol-induced numerical reduction in goal-directed choices, intermediate-risk drinkers showed a shift away from habitual towards goal-directed decision-making, such that alcohol possibly even improved their performance. Conclusions: We assume that alcohol disrupted basic cognitive functions underlying habitual and goal-directed decisions in low-risk drinkers, thereby enhancing hasty choices. Further, we speculate that intermediate-risk drinkers benefited from alcohol as a negative reinforcer that reduced unpleasant emotional states, possibly displaying a novel risk factor for drinking in adolescence.
KW  - Computer-assisted Alcohol Infusion System
KW  - habitual learning
KW  - model-free and model-based decision-making
KW  - two-stage Markov decision task
KW  - subjective response to ethanol
KW  - drinking problems
KW  - real-life drinking behaviour
Y1  - 2018
U6  - https://doi.org/10.1177/0269881118772454
SN  - 0269-8811
SN  - 1461-7285
VL  - 32
IS  - 8
SP  - 855
EP  - 866
PB  - Sage Publ.
CY  - London
ER  - 
TY  - JOUR
A1  - Schad, Daniel
A1  - Garbusow, Maria
A1  - Friedel, Eva
A1  - Sommer, Christian
A1  - Sebold, Miriam Hannah
A1  - Hägele, Claudia
A1  - Bernhardt, Nadine
A1  - Nebe, Stephan
A1  - Kuitunen-Paul, Sören
A1  - Liu, Shuyan
A1  - Eichmann, Uta
A1  - Beck, Anne
A1  - Wittchen, Hans-Ulrich
A1  - Walter, Henrik
A1  - Sterzer, Philipp
A1  - Zimmermann, Ulrich S.
A1  - Smolka, Michael N.
A1  - Schlagenhauf, Florian
A1  - Huys, Quentin J. M.
A1  - Heinz, Andreas
A1  - Rapp, Michael A.
T1  - Neural correlates of instrumental responding in the context of alcohol-related cues index disorder severity and relapse risk
JF  - European archives of psychiatry and clinical neuroscience : official organ of the German Society for Biological Psychiatry
N2  - The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = -3.86, p < .001), but not in healthy controls (t = -0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t((30)) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors.
KW  - Alcohol dependence
KW  - Human neuroimaging
KW  - Nucleus accumbens
KW  - Pavlovian-instrumental transfer
KW  - Relapse
Y1  - 2018
U6  - https://doi.org/10.1007/s00406-017-0860-4
SN  - 0940-1334
SN  - 1433-8491
VL  - 269
IS  - 3
SP  - 295
EP  - 308
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Garbusow, Maria
A1  - Nebe, Stephan
A1  - Sommer, Christian
A1  - Kuitunen-Paul, Sören
A1  - Sebold, Miriam Hannah
A1  - Schad, Daniel
A1  - Friedel, Eva
A1  - Veer, Ilya M.
A1  - Wittchen, Hans-Ulrich
A1  - Rapp, Michael A.
A1  - Ripke, Stephan
A1  - Walter, Henrik
A1  - Huys, Quentin J. M.
A1  - Schlagenhauf, Florian
A1  - Smolka, Michael N.
A1  - Heinz, Andreas
T1  - Pavlovian-To-Instrumental Transfer and Alcohol Consumption in Young Male Social Drinkers
BT  - Behavioral, Neural and Polygenic Correlates
JF  - Journal of Clinical Medicine
N2  - In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, p(SVC) = 0.04, x = 26, y = -6, z = -12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (r(s) = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.
KW  - Pavlovian-to-instrumental transfer
KW  - amygdala
KW  - alcohol
KW  - polygenic risk
KW  - high risk drinkers
Y1  - 2019
U6  - https://doi.org/10.3390/jcm8081188
SN  - 2077-0383
VL  - 8
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Sebold, Miriam Hannah
A1  - Garbusow, Maria
A1  - Jetzschmann, P.
A1  - Schad, Daniel
A1  - Nebe, S.
A1  - Schlagenhauf, Florian
A1  - Heinz, A.
A1  - Rapp, Michael A.
A1  - Romanczuk-Seiferth, Nina
T1  - Reward and avoidance learning in the context of aversive environments and possible implications for depressive symptoms
JF  - Psychopharmacology
N2  - Background Aversive stimuli in the environment influence human actions. This includes valence-dependent influences on action selection, e.g., increased avoidance but decreased approach behavior. However, it is yet unclear how aversive stimuli interact with complex learning and decision-making in the reward and avoidance domain. Moreover, the underlying computational mechanisms of these decision-making biases are unknown. Methods To elucidate these mechanisms, 54 healthy young male subjects performed a two-step sequential decision-making task, which allows to computationally model different aspects of learning, e.g., model-free, habitual, and model-based, goal-directed learning. We used a within-subject design, crossing task valence (reward vs. punishment learning) with emotional context (aversive vs. neutral background stimuli). We analyzed choice data, applied a computational model, and performed simulations. Results Whereas model-based learning was not affected, aversive stimuli interacted with model-free learning in a way that depended on task valence. Thus, aversive stimuli increased model-free avoidance learning but decreased model-free reward learning. The computational model confirmed this effect: the parameter lambda that indicates the influence of reward prediction errors on decision values was increased in the punishment condition but decreased in the reward condition when aversive stimuli were present. Further, by using the inferred computational parameters to simulate choice data, our effects were captured. Exploratory analyses revealed that the observed biases were associated with subclinical depressive symptoms. Conclusion Our data show that aversive environmental stimuli affect complex learning and decision-making, which depends on task valence. Further, we provide a model of the underlying computations of this affective modulation. Finally, our finding of increased decision-making biases in subjects reporting subclinical depressive symptoms matches recent reports of amplified Pavlovian influences on action selection in depression and suggests a potential vulnerability factor for mood disorders. We discuss our findings in the light of the involvement of the neuromodulators serotonin and dopamine.
KW  - Reward learning
KW  - Avoidance learning
KW  - Reinforcement learning
KW  - Computational psychiatry
KW  - Decision-making
KW  - Affective modulation
KW  - Depression symptoms
Y1  - 2019
U6  - https://doi.org/10.1007/s00213-019-05299-9
SN  - 0033-3158
SN  - 1432-2072
VL  - 236
IS  - 8
SP  - 2437
EP  - 2449
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Sebold, Miriam Hannah
A1  - Spitta, G.
A1  - Gleich, T.
A1  - Dembler-Stamm, T.
A1  - Butler, Oisin
A1  - Zacharias, Kristin
A1  - Aydin, S.
A1  - Garbusow, Maria
A1  - Rapp, Michael A.
A1  - Schubert, Florian
A1  - Buchert, Ralph
A1  - Gallinat, Jürgen
A1  - Heinz, A.
T1  - Stressful life events are associated with striatal dopamine receptor availability in alcohol dependence
JF  - Journal of neural transmission
N2  - Stress plays a key role in modulating addictive behavior and can cause relapse following periods of abstinence. Common effects of stress and alcohol on the dopaminergic system have been suggested, although the precise mechanisms are unclear. Here, we investigated 20 detoxified alcohol-dependent patients and 19 matched healthy controls and assessed striatal D2/D3 availability using [F-18]-fallypride positron emission tomography and stressful life events. We found a strong association between striatal D2/D3 availability and stress in patients, but not in healthy controls. Interestingly, we found increased D2/D3 receptor availability in patients with higher stress levels. This mirrors complex interactions between stress and alcohol intake in animal studies and emphasizes the importance to investigate stress exposure in neurobiological studies of addiction.
KW  - Stressful life events
KW  - Dopamine D2
KW  - D3 receptor
KW  - Positron emission tomography
KW  - Striatum
KW  - Alcohol dependence
Y1  - 2019
U6  - https://doi.org/10.1007/s00702-019-01985-2
SN  - 0300-9564
SN  - 1435-1463
VL  - 126
IS  - 9
SP  - 1127
EP  - 1134
PB  - Springer
CY  - Wien
ER  - 
TY  - JOUR
A1  - Sekutowicz, Maria
A1  - Guggenmos, Matthias
A1  - Kuitunen-Paul, Sören
A1  - Garbusow, Maria
A1  - Sebold, Miriam Hannah
A1  - Pelz, Patricia
A1  - Priller, Josef
A1  - Wittchen, Hans-Ulrich
A1  - Smolka, Michael N.
A1  - Zimmermann, Ulrich S.
A1  - Heinz, Andreas
A1  - Sterzer, Philipp
A1  - Schmack, Katharina
T1  - Neural Response Patterns During Pavlovian-to-Instrumental Transfer Predict Alcohol Relapse and Young Adult Drinking
JF  - Biological psychiatry : a journal of psychiatric neuroscience and therapeutics ; a publication of the Society of Biological Psychiatry
N2  - BACKGROUND: Pavlovian-to-instrumental transfer (PIT) describes the influence of conditioned stimuli on instrumental behaviors and is discussed as a key process underlying substance abuse. Here, we tested whether neural responses during alcohol-related PIT predict future relapse in alcohol-dependent patients and future drinking behavior in adolescents. METHODS: Recently detoxified alcohol-dependent patients (n = 52) and young adults without dependence (n = 136) underwent functional magnetic resonance imaging during an alcohol-related PIT paradigm, and their drinking behavior was assessed in a 12-month follow-up. To predict future drinking behavior from PIT activation patterns, we used a multivoxel classification scheme based on linear support vector machines. RESULTS: When training and testing the classification scheme in patients, PIT activation patterns predicted future relapse with 71.2% accuracy. Feature selection revealed that classification was exclusively based on activation patterns in medial prefrontal cortex. To probe the generalizability of this functional magnetic resonance imaging-based prediction of future drinking behavior, we applied the support vector machine classifier that had been trained on patients to PIT functional magnetic resonance imaging data from adolescents. An analysis of cross-classification predictions revealed that those young social drinkers who were classified as abstainers showed a greater reduction in alcohol consumption at 12-month follow-up than those classified as relapsers (Delta = -24.4 +/- 6.0 g vs. -5.7 +/- 3.6 g; p = .019). CONCLUSIONS: These results suggest that neural responses during PIT could constitute a generalized prognostic marker for future drinking behavior in established alcohol use disorder and in at-risk states.
KW  - Alcohol dependence
KW  - Future drinking behavior
KW  - Multivoxel classification
KW  - Pavlovian-to-instrumental transfer
KW  - Relapse
Y1  - 2019
U6  - https://doi.org/10.1016/j.biopsych.2019.06.028
SN  - 0006-3223
SN  - 1873-2402
VL  - 86
IS  - 11
SP  - 857
EP  - 863
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Wyckmans, Florent
A1  - Otto, A. Ross
A1  - Sebold, Miriam Hannah
A1  - Daw, Nathaniel
A1  - Bechara, Antoine
A1  - Saeremans, Mélanie
A1  - Kornreich, Charles
A1  - Chatard, Armand
A1  - Jaafari, Nemat
A1  - Noël, Xavier
T1  - Reduced model-based decision-making in gambling disorder
JF  - Scientific reports
N2  - Compulsive behaviors (e.g., addiction) can be viewed as an aberrant decision process where inflexible reactions automatically evoked by stimuli (habit) take control over decision making to the detriment of a more flexible (goal-oriented) behavioral learning system. These behaviors are thought to arise from learning algorithms known as "model-based" and "model-free" reinforcement learning. Gambling disorder, a form of addiction without the confound of neurotoxic effects of drugs, showed impaired goal-directed control but the way in which problem gamblers (PG) orchestrate model-based and model-free strategies has not been evaluated. Forty-nine PG and 33 healthy participants (CP) completed a two-step sequential choice task for which model-based and model-free learning have distinct and identifiable trial-by-trial learning signatures. The influence of common psychopathological comorbidities on those two forms of learning were investigated. PG showed impaired model-based learning, particularly after unrewarded outcomes. In addition, PG exhibited faster reaction times than CP following unrewarded decisions. Troubled mood, higher impulsivity (i.e., positive and negative urgency) and current and chronic stress reported via questionnaires did not account for those results. These findings demonstrate specific reinforcement learning and decision-making deficits in behavioral addiction that advances our understanding and may be important dimensions for designing effective interventions.
Y1  - 2019
U6  - https://doi.org/10.1038/s41598-019-56161-z
SN  - 2045-2322
VL  - 9
PB  - Nature Publ. Group
CY  - London
ER  -