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Domain B: Behavioral and cognitive mechanisms and their molecular/neurobiological correlates underlying losing and regaining control
Domain B will elucidate the cognitive and neurobiological/molecular mechanisms that impair goal-directed decision-making, executive control and that bias behavior towards habitual drug seeking and intake triggered by exposures to cues, stress, and priming drug doses. We will examine and build computational models for specific learning mechanisms (such as Pavlovian mechanisms including Pavlovian-to-Instrumental Transfer (PIT) that energizes ongoing drug-seeking), for goal-directed vs. habitual decision-making and for corticolimbic control mechanisms and their respective effect on prospective drug intake. The impact of triggers and modulating factors on the proposed learning and control mechanisms in subjects with alcohol use disorder in Domain A will be assessed in lab experiments and compared to tobacco use disorder in order to achieve generalizability of our conclusions. Closely linked human studies and animal experiments will assess key learning and control mechanisms and measure their neurobiological and molecular correlates that contribute to a shift from goal-directed to habitual and ultimately compulsive drug consumption, and their potential readjustment when regaining goal-directed control.
Project B01: Moderators of habitual versus goal-directed decision making in human addiction
The current project investigates habitual and goal-directed decision making in participants with alcohol use disorders by means of behavioral experiments and fMRI. Specifically, we will focus on how the balance between habitual and goal-directed behavior relates to the loss of control over alcohol intake. We will use different behavioral measures for habitual and goal-directed behavioral control with the following aims: a) to predict the clinical course of the A01/S01 cohort, b) to investigate the influence of addiction-specific reinforcers on behavioral control and c) to compare the mechanisms of habit formation and motor routines.
Principal Investigators:
Prof. Dr. Tanja Endrass, Technische Universität Dresden
Prof. Dr. Florian Schlagenhauf, Charité – Universitätsmedizin Berlin
Project members:
Viktoria Arndt, Technische Universität Dresden
Julia Berghäuser, Technische Universität Dresden
Claudia Ebrahimi, Charité - Universitätsmedizin Berlin
Sophie Tragert, Charité - Universitätsmedizin Berlin
Project B02: Habit formation and its relevance in alcohol addiction
Both habit formation and skill learning involve two principal steps, initial acquisition and subsequent consolidation, which are differentially controlled by ventral and dorsal striatal neurons, respectively, and their dopamine D1 and D2 receptors. These mechanisms are likely shared among different striatal learning paradigms and impacted by alcohol dependence. We will use advanced genetically modified rodent models that allow for spatial, temporal and circuit-specific control of neuronal activity to identify pathophysiological mechanisms underlying habit formation and to find ways to improve control over the behavior.
Principal Investigators:
Dr. Anita C. Hansson, Zentralinstitut für Seelische Gesundheit Mannheim
Prof. Dr. Wolfgang H. Sommer, Zentralinstitut für Seelische Gesundheit Mannheim
Project member:
Francesco Giannone, Zentralinstitut für Seelische Gesundheit Mannheim
Project B03: Cue effects in human addiction: Pavlovian-to-Instrumental Transfer
In B03, we will assess whether acute and/or chronic stress exposure increase general Pavlovian-to-Instrumental Transfer (PIT) effects and whether such effects predict losing versus regaining control in currently consuming subjects with mild to moderate alcohol use disorder. AUD subjects will be part of the Domain A01/S01 cohort and we will thus be able to follow up drug consumption over one year. We will also assess the cognitive and neurophysiological mechanisms associated with PIT processing in active smokers with tobacco use disorder and compare them with mechanisms in currently alcohol consuming patients with AUD. Finally, we will pilot a specific PIT paradigm for use in subjects with alcohol use disorder and healthy controls and assess its neurobiological correlates.
Principal Investigators:
Prof. Dr. Dr. Andreas Heinz, Charité – Universitätsmedizin Berlin
PD Dr. Maximilian Pilhatsch, Technische Universität Dresden
Project members:
Matt Belanger, Technische Universität Dresden
Hao Chen, Technische Universität Dresden
Dr. Claudia Ebrahimi, Charité - Universitätsmedizin Berlin
Pascale Fischbach, Technische Universität Dresden
Dr. Maria Garbusow, Charité - Universitätsmedizin Berlin
Angela Hentschel, Technische Universität Dresden
Carlotta Riemerschmid, Charité - Universitätsmedizin Berlin
Prof. Dr. Michael N. Smolka, Technische Universität Dresden
Project B04: Cue effects and targeted neuromodulation in animal models of human addiction
We will use the alcohol deprivation effect (ADE) rodent model to trace individual rats prone to have been from moderate alcohol consumption to alcohol addiction. We will probe the idiosyncratic tendency of rats to attribute additional value to stimuli predicting reward as a possible behavioral predictor of alcohol addiction. We will study specific Pavlovian mechanisms including PIT. Once predictors for alcohol addiction have been identified, we will apply targeted neuromodulation to affect the attribution of excessive motivational salience to alcohol-related cues, and molecular correlates will be measured. Finally, we will study the efficacy of neuromodulation targeting motivational trajectories as a preventive approach for alcohol addiction.
Principal Investigators:
Prof. Dr. Josef Priller, Charité – Universitätsmedizin Berlin
Prof. Dr. Christine Winter, Charité – Universitätsmedizin Berlin
Project members:
Dr. Chotima Böttcher, Charité - Universitätsmedizin Berlin
Dr. Ravit Hadar, Charité - Universitätsmedizin Berlin
Aileen Hakus, Charité - Universitätsmedizin Berlin
Project B05: Prefrontal control of emotion regulation and alternative reward in tobacco use disorder
To acquire long term data regarding severity of tobacco use disorder (TUD) and the use of alternative rewards, we will perform a 10 year follow-up study of the well characterized (e.g. EEG, genetics, clinical phenotyping, neuropsychology) National Nicotine Cohort study comprising nearly 2400 subjects. We will contact all of them, acquire new data (in particular smoking status, emotion regulation, use of alternative reward) and we will investigate the prediction of outcome using machine learning approaches. We will recall a subset of the participants (N=120), investigate them experimentally with EEG, simultaneous EEG/fMRI (resting state), and fMRI (emotion regulation paradigms regarding negative affect and craving) in order to elucidate mechanisms of prefrontal control regarding reward preference in TUD.
Principal Investigators:
Prof. Dr. Dr. Henrik Walter, Charité – Universitätsmedizin Berlin
Prof. Dr. Georg Winterer, Charité – Universitätsmedizin Berlin
Project members:
Pablo Reinhardt, Charité - Universitätsmedizin Berlin
Dr. Norman Zacharias, Charité - Universitätsmedizin Berlin
Project B07: Addiction-related changes in automatic S-R associations and their effects on cognitive control
The project investigates how differences in outcome-unrelated formation of automatisms/habits affect cognitive control (and vice versa) in adults with moderate alcohol use disorder vs. healthy matched controls. We will relate the speed and intensity of automatic S-R association formation to cognitive control deficits, investigate the interaction of control and automaticity, and identify functionally associated brain areas with the help of neurophysiological methods. In a second step, we will combine TMS to those brain regions with EEG to assess whether experimentally induced decreases in automatic S-R formation foster cognitive control capacities (and vice versa).
Principal Investigators:
Prof. Dr. Christian Beste, Technische Universität Dresden
Dr. Ann-Kathrin Stock, Technische Universität Dresden
Project member:
Dr. Filippo Ghin, Universitätsklinikum Dresden
Project B08: Aversion discounting in behavioral control in animal models and human addiction
To date, reward discounting but not aversion discounting was examined in SUD. Our working hypothesis of increased temporal aversion discounting in AUD patients will be tested by novel tasks for reliable and quantitative assessment of aversion discounting in humans and animal models. We will study the underlying neurobiology of aversion discounting by fMRI in humans and calcium imaging microendoscopy in rats. Computational analyses will be used to model the decision-making processes and deliver a detailed and formal parametrization of aversion discounting on multiple levels of analysis. In the future, such information can be used for the development of therapeutic approaches that strengthen self-regulation and cognitive control.
Principal Investigators:
Prof. Dr. Peter Kirsch, Zentralinstitut für Seelische Gesundheit Mannheim
Dr. Georgia Koppe, Zentralinstitut für Seelische Gesundheit Mannheim
Prof. Dr. Wolfgang Sommer, Zentralinstitut für Seelische Gesundheit Mannheim
Project member:
Mathieu Pinger, Zentralinstitut für Seelische Gesundheit Mannheim
Project B09: Computational modelling of impaired control in addiction
In the theoretical part of this project, we will develop a computational model of addictive behavior that integrates Pavlovian mechanisms and the dynamic allocation of habitual and goal-directed control during forward planning. In the experimental part of the project, we will test whether SUD (alcohol and tobacco) is associated with (1) an increased habitual tendency and impaired forward planning, (2) a stronger impact of Pavlovian cues on habitual and goal-directed control, and (3) whether static and dynamic alterations in habitual and goal-directed control are associated with substance use trajectories.
Principal Investigators:
Prof. Dr. Stefan Kiebel, Technische Universität Dresden
Prof. Dr. Michael Smolka, Technische Universität Dresden
Project members:
Pascale Fischbach, Technische Universität Dresden
Sascha Frölich, Technische Universität Dresden
Philipp Neukam, Technische Universität Dresden