mechanisms
Domain B: Behavioral and cognitive mechanisms and their molecular/neurobiological correlates underlying loss and regain of control
Domain B will elucidate the cognitive and neurobiological/molecular mechanisms that impair goal-directed decision making and executive control, and that influence behavior toward habitual drug use elicited by exposure to cues and stress. We will create computational models for specific learning mechanisms (such as Pavlovian mechanisms, including the 'Pavlovian-to-instrumental transfer' that activates perpetual craving for drugs), for goal-directed vs. habitual decision-making behavior, and for corticolimbic control mechanisms and their respective impact on future drug use. In laboratory experiments, the impact of triggers and modulating factors on the assumed learning and control mechanisms of people in Domain A recorded with an alcohol use disorder. These are compared to tobacco use disorder in order to generalize our conclusions. Closely related studies in humans and animals will capture the essential learning and control mechanisms and measure (I) their neurobiological and molecular correlates that contribute to a shift from goal-directed to habitual and eventually compulsive drug use, and (II) their potential re-regulations when purposeful control is regained.
B01: Moderators of habitual and goal-directed decision-making behavior in substance use disorders
The current project investigates habitual and goal-directed decision-making behaviour in individuals with alcohol use disorders using behavioural experiments and functional imaging (fMRI). The focus is on the question to what extent the extent of habitual and goal-directed behaviour is related to the loss of control over alcohol consumption. Different behavioural measures of habitual and goal-directed behavioural control will be used to a) predict clinical trajectories from the A01/S01 cohort, b) examine the influence of addiction-specific reinforcers on behavioural control, and c) compare mechanisms of habit formation and motor routines. Project management: Prof. Dr. Tanja Endrass, Technical University of Dresden Prof. Dr. Florian Schlagenhauf, Charité - University Medicine Berlin Project collaborators: Viktoria Arndt, Dresden University of Technology Julia Berghäuser, Dresden University of Technology Claudia Ebrahimi, Charité - University Medicine Berlin Sophie Tragert, Charité - University Medicine Berlin
B02: The importance of habit learning for alcohol addiction
Both habit formation and motor learning occur in two phases; initial acquisition and later consolidation, with neuron populations in the ventral and dorsal striatum and D1 and D2 dopamine receptors playing different roles. We hypothesise that the striatal mechanisms are similar in motor and habitual forms of learning and that they are altered in alcohol use disorders. By targeting neuronal circuits in genetically modified rodents, we aim to identify the pathophysiological mechanisms of habit formation and search for ways to influence them. Project leader: Dr. Anita C Hansson, Central Institute for Mental Health Mannheim Prof. Dr. Wolfgang H. Sommer, Central Institute of Mental Health Mannheim Project collaborators: Francesco Giannone, Central Institute of Mental Health Mannheim
B03: Stimulus-response effects in addictions in humans - Pavlovian instrumental transfer
This project will investigate whether acute and/or chronic stress exposure can exacerbate PIT effects and whether such effects influence the loss or regaining of control over substance use in currently non-detoxified, i.e. continuing users, with mild to moderate alcohol use disorder. Participants will be recruited from the A01/S01 cohort, providing the opportunity to track their substance use over one year. Currently active smokers with tobacco use disorder will also be studied using a general PIT paradigm to compare cognitive and neurobiological correlates in people with alcohol versus tobacco use disorder. Finally, a specific PIT paradigm for individuals with alcohol use disorder will be developed and its neurobiological correlates measured. Project management: Prof. Dr. Dr. Andreas Heinz, Charité - Universitätsmedizin Berlin PD Dr. Maximilian Pilhatsch, Technical University of Dresden Project collaborators: Matt Belanger, Dresden University of Technology Hao Chen, Dresden University of Technology Dr Claudia Ebrahimi, Charité - University Medicine Berlin Pascale Fischbach, Dresden University of Technology Dr. Maria Garbusow, Charité - University Medicine Berlin Angela Hentschel, Dresden University of Technology Carlotta Riemerschmid, Charité - University Medicine Berlin Prof. Dr. Michael N. Smolka, Dresden University of Technology
B04: Cue effects and targeted neuromodulation in the rat model of alcohol dependence
We will use the rat model of the alcohol withdrawal effect (ADE) to identify individual animals that develop alcohol dependence. To do this, we will identify individual differences in the tendency to attribute a particular value to stimuli that predict reward. We will investigate whether this predicts the development of alcohol dependence. We will investigate specific Pavlovian mechanisms, including PIT. Building on these studies, we will apply neuromodulatory interventions to influence the attribution of a special motivational value to alcohol stimuli and measure their molecular correlates. In a further step, we will investigate the preventive efficacy of neuromodulatory interventions against the development of dependent behaviour. Project management: Prof. Dr. Josef Priller, Charité - Universitätsmedizin Berlin Prof. Dr. Christine Winter, Charité - University Medicine Berlin Project staff: Dr. Chotima Böttcher, Charité - Universitätsmedizin Berlin Dr. Ravit Hadar, Charité - University Medicine Berlin Aileen Hakus, Charité - Universitätsmedizin Berlin
B05: Prefrontal control of emotion regulation and alternative reinforcers in tobacco use disorder
In order to obtain long-term data regarding the severity of TUD and the use of alternative reinforcers, we will conduct a 10-year follow-up survey of the well-characterised (including EEG, genetics, clinical phenotyping, neuropsychology), DFG-funded National Nicotine Cohort with almost 2400 individuals. We will contact all individuals included to date, collect current data (including smoking status, emotion regulation and use of alternative reinforcers) and use machine learning to identify predictors of progression. In addition, we will experimentally study a subset of the cohort (N=120) using EEG, simultaneous EEG/fMRI (Resting State) and fMRI (emotion regulation paradigms on negative affect and craving) to assess the neural basis of prefrontal control over reinforcer preference in TUD. Project leader: Prof. Dr. Dr. Henrik Walter, Charité - Universitätsmedizin Berlin Prof. Dr. Georg Winterer, Charité - University Medicine Berlin Project staff: Pablo Reinhardt, Charité - University Medicine Berlin Dr. Norman Zacharias, Charité - Universitätsmedizin Berlin
B07: Addiction-related changes in automatic S-R associations and their effects on cognitive control
The project investigates how differences in the formation of automatisms affect cognitive control (and vice versa) in adults with moderate alcohol use disorder vs. healthy control subjects. We investigate the relationship between individual differences in the speed and strength of automatic S-R associations and cognitive control deficits, record the interaction of control and automatisms, and identify functionally relevant brain regions using neurophysiological methods. Based on this, TMS in these brain regions will be combined with EEG to investigate whether experimentally induced reductions in automatic S-R associations improve cognitive control (and vice versa). Project leader: Prof. Dr. Christian Beste, Dresden University of Technology Dr. Ann-Kathrin Stock, Dresden University of Technology Project collaborators: Dr. Filippo Ghin, University Hospital Dresden
B08: Devaluation of aversive consequences in the behavioral control of addiction patients and in animal models
To date, devaluation of future vs. present reward but not punishment has been studied in addicted patients. Our hypothesis of increased temporal devaluation of negative consequences by patients with AUD will be tested with newly developed tests that allow reliable quantitative investigation of devaluation of future aversive consequences. The neurobiological mechanisms involved will be assessed using fMRI in humans and calcium signal microendoscopy in rats. Computational methods will be used to model the decision-making processes and formally parameterise the devaluation of aversive consequences at multiple levels of analysis. In the future, this information can be used to develop therapeutic approaches to strengthen cognitive control. Project management: Prof. Dr. Peter Kirsch, Central Institute of Mental Health Mannheim Dr. Georgia Koppe, Central Institute of Mental Health Mannheim Prof. Dr. Wolfgang Sommer, Central Institute of Mental Health Mannheim Project staff: Mathieu Pinger, Central Institute of Mental Health Mannheim
B09: Computational modeling of reduced control in addiction disorders
In the theoretical part of the project, we will develop a computational model of dependent behaviour that integrates Pavlovian mechanisms and the dynamic allocation of habitual and goal-directed control during forward planning. In the experimental part, we will test whether substance use disorders (alcohol and tobacco) are associated with (1) an increased tendency to habit formation and impaired forward planning, (2) an increased influence of Pavlovian stimuli on habitual and goal-directed control, and (3) whether such static and dynamic changes in habitual and goal-directed control are associated with the course of substance use. Project management: Prof. Dr. Stefan Kiebel, Dresden University of Technology Prof. Dr. Michael Smolka, Dresden University of Technology Project collaborators: Pascale Fischbach, Dresden University of Technology Sascha Frölich, Dresden University of Technology Philipp Neukam, Dresden University of Technology
B08: Devaluation of aversive consequences in the behavioral control of addiction patients and in animal models
To date, devaluation of future vs. present reward but not punishment has been studied in addicted patients. Our hypothesis of increased temporal devaluation of negative consequences by patients with AUD will be tested with newly developed tests that allow reliable quantitative investigation of devaluation of future aversive consequences. The neurobiological mechanisms involved will be assessed using fMRI in humans and calcium signal microendoscopy in rats. Computational methods will be used to model the decision-making processes and formally parameterise the devaluation of aversive consequences at multiple levels of analysis. In the future, this information can be used to develop therapeutic approaches to strengthen cognitive control. Project management: Prof. Dr. Peter Kirsch, Central Institute of Mental Health Mannheim Dr. Georgia Koppe, Central Institute of Mental Health Mannheim Prof. Dr. Wolfgang Sommer, Central Institute of Mental Health Mannheim Project staff: Mathieu Pinger, Central Institute of Mental Health Mannheim