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Projects: Addicitive Behaviour Medicine

DFG - Deutsche Forschungsgemeinschaft : Das Abhängigkeitspotenzial der E-Zigarette: Neurobiologische, soziologische und epidemiologische Perspektiven. 10/2020-09/2023.

Die Nachfrage nach E-Zigaretten ist in den letzten Jahren sprunghaft gestiegen. Während das Abhängigkeitspotenzial von Nikotin unbestritten ist, birgt die Vermarktung der E-Zigarette als „gesunde“ Alternative zum Tabak die Gefahr, dass Rauchen durch die Etablierung von E-Zigaretten als Lifestyle-Produkt verharmlost und Präventionsbemühungen untergraben werden. Bisher liegen jedoch kaum Studien zum Abhängigkeitspotenzial von nikotinhaltigen E-Zigaretten vor.Im vorliegenden Projekt soll diese Lücke nun geschlossen werden, um durch Kombination verschiedenener Untersuchungsmethoden und Betrachtungsebenen das Abhängigkeitspotenzial der E-Zigarette auf drei Ebenen zu untersuchen: (1) das neurobiologische Abhängigkeitspotenzial von E-Zigaretten, (2) das Erleben und Wahrnehmen von Abhängigkeitssymptomen bei Nutzern von E-Zigaretten im sozialen Kontext und (3) die epidemiologische Perspektive hinsichtlich Einflussfaktoren auf das Abhängigkeitspotenzial. Dabei werden Kernsymptome von Abhängigkeitserkrankungen wie das Ausmaß von Entzugssymptomen, Belohnungseffekte, Toleranzentwicklung und Verlangen nach der Substanz („Craving“) untersucht.Im ersten Studienteil liegt der Schwerpunkt auf der Untersuchung von Belohnungseffekten mittels neurobiologischer und neuropsychologischer Maße. Der zweite Studienteil fokussiert auf Selbstberichte von Konsumenten und deckt dabei ebenfalls psychologische, physiologische als auch behaviorale Aspekte von Abhängigkeitserkrankungen ab. Im dritten Studienteil werden Abhängigkeitssymptome im Längsschnitt mit einem Fokus auf Toleranzentwicklung sowie die Rolle von psychosozialen und Produkt-Faktoren hinsichtlich Transitionen in und aus dem E-Zigarettenkonsum untersucht.Die Ergebnisse des Projekts sind für die Entwicklung von Präventionsmaßnahmen und Behandlungsangeboten relevant. So sind nicht nur Schlussfolgerungen für Präventionsmaßnahmen aus den soziologischen und epidemiologischen Analysen möglich, sondern der neurobiologische Ansatz liefert ergänzend auch Implikationen für individualisierte Therapien durch Identifikation von Konsumentengruppen mit unterschiedlichen neuronalen Mustern.

Flor H, Vollstädt-Klein S. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project C01: Modification of the imbalance between goal-directed and habitual behavior in human addiction. 07/2019-06/2023.

In this study, we aim to assess the imbalance between goal-directed and habitual behavior, its neural basis and how it can be modified in treatment-seeking smokers, using two training interventions. The first intervention (cognitive remediation treatment focusing on improving inhibitory control and executive functions) is hypothesized to affect top-down processing, whereas the second intervention (a learning approach through implicit priming and contextual modulation) is suggested to modify bottom-up processes.

Hansson AC, Sommer WH. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project B02: Habit formation and its relevance in alcohol addiction. 07/2023-06/2023.

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.

Kiefer F, Kirsch P. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project C04: Modification of cue reactivity by neurofeedback in human addiction. 07/2019-06/2023.

This project will investigate the hypothesis that combining real time fMRI neurofeedback (fMRI-NF) with a mindfulness-based intervention will increase the ability of alcohol dependent patients to deliberately reduce ventral striatal cue reactivity to alcohol. To this end we study the efficiency of fMRI-NF in patients receiving mindfulness-based training vs. patients receiving treatment as usual. We expect that the combination of mindfulness-based training and neurofeedback will boost the ability to regain control over habitual responses to alcohol-associated stimuli.

Kiefer F. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project A03: Stress-related predictor profiles for craving and relapse in human addiction. 07/2019-06/2023.

This project will investigate stress- and alcohol cue-related physiological markers in a lab experiment to assess interactions between acute psychological vs. physical stress exposure and alcohol cue-exposure regarding their effects on (1) alcohol craving and related markers, (2) their predictive capacity for future alcohol intake in a real-life setting, and (3) the identification of their neural correlates in brain circuits of motivational, cognitive, and affective processing. Our long-term aim is the definition of a setup of mobile sensors and their integration in a mobile infrastructure that allows the prediction of stress related alcohol intake in an ambulatory setting.

Kirsch P, Koppe G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project B08: Aversion discounting in behavioral control in animal models and human addiction. 07/2019-06/2023.

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

Rietschel M. DFG - Deutsche Forschungsgemeinschaft : CRC TRR 265: Project S01: Central recruitment, imaging and biobanking. 07/2019-06/2023.

Project S01 will be responsible for the recruitment and support the basic characterization of the central cohort of 1050 subjects for projects A01-A04. S01 will coordinate the acquisition and quality assurance of a basic neurocognitive and neuroimaging battery (anatomical MRI, resting state MRI, fMRI during inhibitory control), and the biobanking of blood, as well as genome-wide genetic and epigenetic analyses. S01 will provide 15 subprojects of the CRC/TRR 265 with pre-processed psychometric-, MRI- and genetic data to be included in the outcome variable analyses.

Spanagel R. DFG - Deutsche Forschungsgemeinschaft SFB/Transregio 265: Teilprojekt B08: Aversion discounting in animal models and human addiction. 07/2019-06/2023.

Ruprecht-Karls-Universität Heidelberg GRK 2350/1: Der Einfluss von Traumatisierung im Kindes- und Jugendalter auf psychosoziale und somatische Erkrankungen über die Lebensspanne, Projekt B5 "Stress sensitivity, emotion processing and cue-reactivity in substance-related disorders: the influence of ACE". 04/2019-09/2022.

TRR/1 TP C01: Losing and Regaining Control: TP Modifcation of the imbalance between goal-directed and habitual behavior. 07/2019-06/2022.

In this study, we aim to assess the imbalance between goal-directed and habitual behavior, its neural basis and how it can be differentially modified in treatment-seeking smokers, using two training interventions. The first intervention is cognitive remediation treatment (CRT), also known as cognitive enhancement therapy, focusing on improving inhibitory control and executive functions. The second intervention, a computer-based habit-modifying training focusing on implicit drug seeking ("implicit computer-based habit-modifying Training", ICHT) uses a conditioning approach through implicit priming and contextual modulation. We hypothesize that both interventions change the balance between goal-directed and habitual behavior but by different mechanisms. Whereas CRT should directly increase cognitive control, in contrast, ICHT should affect the early processing and the emotional valence of smoking and smoking cues.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 031L0190A : Target-OXY - Towards Targeted Oxytocin Treatment in Alcohol Addiction. 06/2019-05/2022.

Worldwide two billion people drink regularly alcohol. A major health consequence is alcohol addiction that is characterized by chronic relapses. Preventing relapse is the main Treatment goal. Current pharmacological treatments have limited effectiveness and there is a large heterogeneity in the treatment response. Better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. In our e:Med funded SysMedAlcoholism consortium we have identified early warning signs and drinking profiles that predict future relapse behavior and treatment response of clinically used anti-relapse medications. We have also identified in a multi-omics approach alterations in the oxytocin (OXY) system in alcoholic patients suggesting OXY as a candidate medication to reduce relapse. Here our Goals are (i) to demonstrate the clinical applicability of OXY and (ii) to computationally predict elapse and identify treatment responsive individuals. For the demonstration of the clinical applicability of OXY, we propose a new module in the drug development process, namely a preclinical multicenter placebo controlled trial in rats with a step-wise translation into a naturalistic pilot trial with ambulatory assessment in alcoholic patients. As a comparator, we will use datasets from previous trials where we tested placebo vs acamprosate – which is a clinically effective medication. These data will be contrasted with a 3-arm design in male and female alcohol addicted rats where two doses of intranasally applied OXY will be tested against placebo in a well-validated rat model for alcohol addiction. From this preclinical trial we will obtain intensive longitudinal data (ILD) sets on drinking and activity. Using new in silico approaches we will then be able to identify early warnings signs and drinking clusters for relapse and OXY treatment responsive individuals. This preclinical work will guide our naturalistic Trial with ambulatory assessment in alcoholic patients.

Vollstädt-Klein S. DFG - Deutsche Forschungsgemeinschaft VO 2173/4-1: Investigating Neurobiological Mechanisms of Chess as an Add-On Treatment against Alcohol Use Disorder. 06/2019-05/2022.

The current project aims to investigate the potential mechanism of action of chess as a “cognitive remediation therapy” to reduce cognitive deficits in individuals with alcohol use disorder (AUD) seeking treatment using neurobiological and neuropsychological approaches. Furthermore, we will assess whether this chess intervention has a generalized positive effect on short-term abstinence. Interestingly, the functional domains and associated underlying neuronal networks observed to be affected in individuals with AUD overlap significantly with those that could be strengthened by chessbased cognitive training or formal chess. Specifically, strengthening of cortical control regions (dorsolateral prefrontal cortex, DLPFC) and brain areas relevant for decision-making (orbitofrontal cortex, OFC) could prevent future relapse. Therefore, chess as an add-on therapy to complement other standard treatments of AUD could lead to improved therapeutic outcomes.

EU - Europäische Union 668863: SyBil-AA System Biology of Alcohol Addiction. 01/2016-12/2019.

Alcohol addiction ranks among the primary global causes of preventable death and disabilities in human population, but treatment options are very limited. Rational strategies for design and development of novel, evidence based therapies for alcohol addiction are still missing. Alcohol dependence is characterized by cycles of excessive alcohol consumption, interspersed with intervals of abstinence, and frequent relapses. Relapse is a key element of this disease process and blocking relapse is therefore a key objective for the treatment of alcohol dependent patients. In this project we will provide a novel discovery strategy based on the principles of systems medicine that uses mathematical and network theoretical models to identify brain sites and functional networks that can be targeted specifically by therapeutic interventions. To build predictive models of the ‘relapse-prone’ state of brain networks we will use magnetic resonance imaging, electrophysiology and neurochemical data from patients and laboratory animals. The mathematical models will be rigorously tested through experimental procedures aimed to guide the network towards increased resilience against relapse. We expect to identify hubs that promote ‘relapse-proneness’ and to predict how aberrant network states could be normalized. Proof of concept experiments in animals will need to demonstrate this possibility by showing directed remodeling of functional brain networks by targeted interventions suggested by the theoretical models. Thus, our translational goal will be achieved by a theoretical and experimental framework for making predictions based on fMRI and mathematical modeling, which is verified in animals, and which can be transferred to humans. With our highly interdisciplinary EU consortium (PIs from seven European countries and Israel with outstanding expertise) it is expected that after having such a world-wide unique effort in place, new neurobiologically-defined treatment strategies will be delivered to our addicted patients and thus help to address a serious and widespread health problem in our European societies.

Kiefer F. BMBF - Bundesministerium für Bildung und Forschung 01EE1406C: Verbund AERIAL im Forschungsnetz für psychische Erkrankungen - Mechanismen von Suchterkrankungen: Sozialer Ausschluss, Vorhersage von Erkrankungsrisiken, Widerstandsfähigkeit und angepasste Theorien, Projekt 6. 01/2017-12/2019.

We will define the impact of social influences on drug consumption patterns across lifespan in the rat. In particular, social exclusion from peers during adolescence is suggested as an early risk factor for psychopathologies and social stressors in adolescent individuals facilitate drug abuse-related behaviors [1]. However, it is unclear how social exclusion during adolescence impacts on drug consumption patterns and the risk to develop SUD across the lifespan. By studying the impact of social exclusion in the adolescent rat we will provide essential epigenetic, transcriptomic, molecular and neurochemical information to Project 1 to better define neurobehavioral predictor profiles for SUD later in life. We will use our novel animal model of social exclusion [2] where inadequate playful interactions in adolescent rats produces life-long adverse consequences such as alterations in social behavior, emotional and pain-reactivity. Rats deriving from this model will be studied for gender-dependent alcohol consumption patterns, nicotine self-administration behavior and vulnerability to develop addictive behavior. Beside this behavioral characterization we will examine neurobiological alterations induced by social exclusion within the dopaminergic and the endocannabinoid systems by longitudinal translational PET studies and adjunct in vivo microdialysis, post mortem biochemical and immunohistochemistry experiments. In parallel, together with partners from Project 7 we will conduct genome-wide methylation and gene expression studies in socially excluded vs. non-excluded rats and will functionally study by virus-mediated gene transfer epigenetically altered genes in their role in later alcohol drinking, nicotine self-administration and addictive behavior. In a convergent approach our validated datasets will be merged with the databank of Project 1. Having defined genetic and neurobehavioral risk profiles we will manipulate in animals the genetic and neurobehavioral mechanisms identified in our corresponding animal and humans experiments. This approach aims to inform the identification of marker sets in humans as well as the development of targeted early interventions.

Kiefer F. Ministerium für Soziales und Integration Baden-Württemberg Az.: 55-5072.1: Evaluation und Definition des therapeutischen Interventionsbedarfs bei Patienten mit häufigen stationären Wiederaufnahmen bei Alkoholabhängigkeit. 08/2016-07/2019.

Um die Hypothese zu prüfen, ob unter den häufig wiederkehrenden Patienten („Heavy User“) in den Suchtkliniken von PZN und ZI ein erhöhter Anteil von Patienten mit komorbider Emotionaler Instabilität, adultem ADHS und Traumaerfahrung anzutreffen ist, soll den Patienten, die auf Grund des Krankheitsverlaufs als „Heavy User“ (mindestens 5 stationäre Aufnahmen in einem Jahr oder 10 stationäre Aufnahmen in den vergangenen 5 Jahren) identifiziert wurden, auf Basis spezifischer diagnostischer Testungen der drei genannten Krankheitsbilder mit Patienten verglichen werden, die in der Vergangenheit einen eher günstigeren Krankheitsverlauf zeigten (max. zwei Aufnahmen in den vergangenen 5 Jahren). Hierbei sollen diagnostische Instrumente zum Einsatz kommen, die nach Ende der Studie auch in die stationäre Routineversorgung integriert werden können.

Kiefer F. Universität Heidelberg : Marsilius-Kolleg. 04/2018-03/2019.

Schuster R. Bundesverwaltungsamt, Köln : Winter School 2019 der DG-Sucht Nachwuchsgruppe. 11/2018-01/2019.

Es handelt sich um einen Folgeantrag der DG-Sucht Nachwuchsgruppe. Im Rahmen des Pilotprojektes der im Januar 2017 geförderten und durchgeführten Winter School in Lübeck möchten wir diese nach Evaluation der Teilnehmer nun weiterentwickeln. Geplant ist eine Winter School 2019 in Mannheim. Ziel ist es, eine zweitägige Winter School für forschungsinteressierte Praktiker/innen und Nachwuchswissenschaftler/innen durchzuführen. Dabei steht sowohl die individuelle Weiterentwicklung von Projekten / Forschungsvorhaben als auch die Vernetzung zwischen Klinik / Forschung und Praxis im Vordergrund. Neben Impulsreferaten von ausgewählten Experten/innen aus Forschung und Praxis soll den Teilnehmern/innen in Workshops die Möglichkeit gegeben werden ihre Projekte in Kleingruppen vorzustellen und weiter zu entwickeln. Die Diskussion bzw. der Workshop soll jeweils von einer/m Experten/in geleitet werden. Dabei sollen die Teilnehmer/innen in thematisch passenden Gruppen eingeteilt werden (Praxisbezug /wissenschaftlicher Bezug). Die Winter School ist auf max. 20 Teilnehmer/innen begrenzt, um einen intensiven Austausch und eine hohe Betreuungsdichte der Teilnehmer/innen durch die Experten/innen zu gewährleisten. Angesprochen sind hierbei vor allem Kollegen/innen in den ersten 5 Jahren ihrer Berufstätigkeit. Weiterhin ist eine Veröffentlichung der Diskussionsergebnisse der Winter School 2019 in Bezug auf die Projekte der Teilnehmer/innen in der Zeitschrift SUCHT geplant.

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:Med II - SPs 3: Central Resource II: Transcriptomics platform. 01/2017-12/2018.

SP3 provides human post-mortem brain material from deceased alcoholics, iPSC lines from humanised mouse models and humans, and transcriptomic profiles of these biological materials to the consortium. In the first two years we have (i) enlarged our human brain bank through effective national and international collaborations, (ii) established the routine generation of iPSC lines from mouse and humans (almost 20 m/hiPSC lines have been generated), (iii) analyzed opioid and dopamine system adaptations at both transcriptional and protein levels in post-mortem brains from alcoholics and alcohol addicted rats (SP5) and developed a new molecular model of a hyper-dopaminergic state that drives alcohol craving (Hirth et al., 2015), and finally (iv) established with a collaborator from NIAAA, Bethesda USA, a database of brain miRNA profiles from the prefrontal cortices of abstinent alcohol dependent rats.

BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:Med II SPs10 - Functional Validation II: Neuroimaging x genetics. 01/2017-12/2018.

In SP10 neuroimaging x genetics predictions are studied (see Fig. 2). During the first two years data collection of neuroimaging, neuropsychology, psychometrics, genetics and epigenetics for the follow-up of the NGFN-plus sample was initiated. Recruitment for the follow-up assessments (alcohol addicted patients from the NGFNplus study, 1st degree relatives and healthy individuals) is in line with the initially proposed time plan. In the meantime we have performed data analysis from existing data (NGFNplus, IMAGEN) and reported on SNPs of genes coding for molecular components of the opioidergic and glutamatergic signaling and their association to neural cue reactivity, craving and relapse (Bach et al., 2015a, b).

DFG - Deutsche Forschungsgemeinschaft SFB 1134: TP B04: Untersuchung von verhaltensrelevanten raum-zeitlichen Aktivitätsmustern neuronaler Netzwerke im Präfrontalcortex der Ratte mit Hilfe der in vivo Weitfeldmikroendoskopie. 01/2015-12/2018.

Kiefer F. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: Alcohol Addiction-A Systems-Oriented Approach (SysMedAlcoholism); Teilprojekt 10: Functional Validation II: Neuroimaging X genetics. 01/2017-12/2018.

Das Teilprojekt 10 ist eine in Berlin und Mannheim durchgeführe Studie (SysMedAlcoholism – eMEDS), die mit Hilfe bildgebender Verfahren (fMRT= Kernspintomographie) bei alkoholabhängigen Patienten (N= 112) und ihren Angehörigen 1. Grades (n= 112), den Zusammenhang von genetischer Veranlagung zur Alkoholabhängigkeit, neuropsychologischen Maßen und strukturellen und funktionellen Veränderungen des Gehirns untersucht. Die Grundidee dabei ist, dass sich auf Gehirnebene schon Effekte genetischer „Risikovarianten“ nachweisen lassen, auch wenn Verhalten oder Klinik völlig unauffällig sind. Für die einzelne Person ist dieses genetische „Risiko“ aber so gering und klinisch unbedeutend, dass man solche Untersuchungen in größeren Gruppen durchführen muss, um klinisch relevante Aussagen zu machen, z.B. ob sich anhand solcher Gehirnveränderungen bzw. aus Kombination von Gehirnveränderung und Genetik (Imaging Genetics) die Wahrscheinlichkiet von Rückfällen oder Alkoholkonsum in einer Gruppe vorhersagen lassen. Deshalb werden neu erhobene Daten (SysMedAlcoholism) mit Daten aus anderen großen Untersuchungen (NGFNplus: Erwachsene, IMAGEN: Jugendliche), die ähnliche Fragestellungen verfolgen, und an denen die Projektleiter beteiligt sind, kombiniert, um eine bessere Aussagekraft zu erlangen und Befunde gegenseitig zu überprüfen (Kreuzvalidierung). The goal of the multicenter subproject 10 of the eMED Alcohol Addiction Consortium - A Systems-Oriented Approach is to study neuroimaging x genetics predictions in an existing sample (NGFNplus) of tightly endophenotyped and genome-wide genotyped alcohol dependent subjects (N=240) and controls (N=240); (ii) to translate the results of neuroimaging and genetic analyses from an adolescent risk sample (IMAGEN) to adult disease (NGFNplus sample) by examing related MRI-paradigms tagging the same functional brain systems in both samples (e.g. reward system, inhibitory control system, emotion processing, working memory); (iii) to conduct a follow-up neuroimaging study on the NGFNplus sample validating the neurobehavioral risk profiles predicitve for juvenile harmful alcohol use in adult patients with alcohol addiction, (iv) to expand the NGFNplus sample by including a new set of healthy subjects with high genetic risk (1st degree relatives of patients with alcohol addiction). We will do so by using elaborate imaging genetic methods that are already available and successfully used in other multicenter studies by our group (e.g. univariate analyses, functional and effective connectivity analyses, polygenetic scores, network topology) as well as by using complex computational algorithms and mathematical models, in particular advanced machine learning methods, developed in TP 6. Our approach aims in the long to to predict and characterize longitudinal outcomes in patients with alcohol addiction (5 years following our index session) and to complement the NGFN-sample with an add-on study with 1st degree relatives that will allow us to test the generalizability of the identified predicitive risk profiles for early risk identification.

Leménager T. DFG - Deutsche Forschungsgemeinschaft LE 2739/4-1: Internet gaming disorder: Microstructural brain alterations and their relation to functionally assessed correlates of reward processing, inhibitory control and the self-concept . 01/2016-12/2018.

Koopmann A. Oberberg Stiftung Matthias Gottschaldt : Der Effekt von „Trauma Informed Hatha Yoga“ auf die psychopathologische Symptombelastung und Lebensqualität bei Patienten/innen mit einer emotional instabilen Persönlichkeitsstörung vom Borderline Typ sowie einer komorbiden Suchterkrankung. 10/2016-09/2018.

Ziel der vorliegenden Studie ist es, zu untersuchen ob die psychopathologische Symptombelastung und das physiologische Stressniveau (gemessen anhand der Plasma- und Speichel- Cortisol Konzentration) bei Patienten/innen mit einer emotional instabilen Persönlichkeitsstörung vom Borderline-Typ sowie einer komorbiden Suchterkrankung durch wöchentliche 60- minütige „Trauma Informed Hatha Yoga“ Übungsstunden gesenkt werden kann. Die Studiendauer beträgt hierbei 12 Wochen. Die Studie erfolgt während des vollstationären Aufenthalts der Patienten/innen auf unserer Spezialstation für Dialektisch Behaviorale Therapie Sucht (DBT-S). Während der gesamten Studienzeit nehmen alle 48 Patienten/innen, die in die Studie eingeschlossen werden, an unserem regulären Psychotherapieprogramm im Rahmen der Dialektisch Behavioralen Therapie Sucht (DBT-S) teil, begleitend hierzu absolvieren die 24 Patienten/innen der Interventionsgruppe „Trauma Informed Hatha Yoga“ Übungsstunden. Bei der Kontrollgruppe (24 Patienten) entfällt diese Intervention ersatzlos.

Mann KF. Baden-Württemberg Stiftung gGmbH: Sucht im Alter 2. 01/2015-06/2018.

Die BW Stiftung hat sich im Rahmen eines Aktionsprogramms zur Suchtprävention zum Ziel gesetzt, u. a. die Problematik von Abhängigen im Alter erneut aufzugreifen und neue Asprekte einzubringen. Das Programm knüfpt an das zwischen 2009 und 2013 umgesetzte Programm "Sucht im Alter" an und entwickelt dieses auf Grundlage der dort gemachten Erfahrungen weiter. Sucht im Alter 2 legt den Schwerpunkt auf die Betroffenen, die von ihrer Altersstruktur gesehen im sogenannten aktiven Ruhestand zu finden sind. Das Projekt zielt auf Menschen im Alter von 55 bis etwa 80 Jahren mit problematischem Alkohol- und Medikamentenkonsum, die nicht mehr am Erwerbsleben teilnehmen aber auch (noch) keine Pflegebedürftigkeit aufweisen. Neben Struktur- und Prozessqualität der einzelnen Projekte verschiebt sich der Fokus auf die Lebensqualität. Von Interesse sind der einzelne Patient und seine individuelle Behandlung durch den Hausarzt, die klinische Ambulanz und das Suchthilfesystem in Hinblick auf sein Krankheitsbild. Es werden Instrumente angepasst und entwickelt die diesen individuellen Verlauf ebenso abbilden wie auch die Motivation der betroffenen Institutionen und deren Zusammenspiel erfasst.

ZIS Hamburg (Weiterleitungsvertrag BMG) : IMPELA (Implementierung und Evaluation der S3-Leitlinie zu Screening, Diagnose und Behandlung alkohol-bezogener Störungen) . 11/2017-02/2018.

Kiefer F, Kirsch P. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D06: Reward learning and extinction training in alcohol dependence: impact of. 01/2012-12/2015.

Preclinical studies support the critical role of learning and memory processes for the development and maintenance of addictive disorders. Particularly based on the importance of classical and instrumental conditioning in this context, cue-exposure-based extinction training (CET) of conditioned, drug-related responses has been introduced in the treatment of addiction. During the last funding period we gathered data suggestive for an effect of CET on mesolimbic cue-reactivity in abstinent alcohol dependent subjects. However, neuronal pathways involved, especially the role of functional and structural frontostriatal connectivity, remain to be explored. Therefore, we are now aiming to test to what extent extinction of fMRI cue-reactivity in chronic alcohol dependent patients following cue-exposure based training is modulated by frontal-striatal connectivity and reward sensitivity. This will be investigated by studying (a) structural connectivity (DTI) (b) trait like functional connectivity (resting state fMRI) and (c) effective functional connectivity during alcohol cue presentation (event related fMRI). Additionally, in a reward paradigm we will study the general responsivity of reward pathways and their frontal control in alcohol dependent patients prior to extinction training and compare it to healthy controls to identify alterations in reward sensitvity. We expect that these functional and structural measures contributes to a better understanding of neuronal pathways involved in reward extinction, and the definition of factors that predict efficacy of CET in alcohol-dependent subjects.

Mann KF, Ende G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D07: Neuroplasticity of brain glutamate and glutamine and treatment. 01/2012-12/2015.

The glutamate hypothesis of alcoholism posits that chronic alcohol intake leads to an enhanced activity of the glutamate system. As soon as alcohol is discontinued, withdrawal develops with marked brain hyperexcitability. Under abstinent conditions this hyperglutamatergic state could be reinstated by stress or alcohol cues and precipitate relapse. Anti-glutamatergic compounds are effective in preventing relapse and potentially also in alleviation of withdrawal. Effect sizes of this pharmacotherapy are moderate, a fact which may be accounted for by individual differences in the extent of neuroplastic changes of the glutamate system. Thus, we predict that antiglutamatergic medications work primarily in individuals who develop a pronounced hyperglutamatergic state, a condition that can be identified and monitored by magnetic resonance spectroscopy (MRS). We previously found that alcohol withdrawal is reflected by increased central glutamate levels. A new measure to be studied in the coming funding period is the glutamate/glutamine ratio which we now can also measure reliably in humans. This ratio will be tested as a potential biomarker for monitoring alcoholism, which may lay the grounds for a personalized treatment approach of this condition. We believe that a translational approach involving human patients and “alcohol dependent rats” serves the purpose of our research best. In both species prefrontal cortex changes in metabolite concentrations during acute withdrawal and into several weeks of abstinence are measured with and without pharmacological interference targeting the glutamatergic system. In the last funding period we developed methods for absolute quantification of metabolites in the human and rat brain. Under control conditions glutamate concentrations in the human anterior cingulate cortex (ACC) and the rat medial prefrontal cortex (mPFC) were highly similar. Thus, for the first time direct evidence for increased central glutamate levels during acute alcohol withdrawal in both species was provided. In the animal experiments, we will induce alcohol dependence through chronic, intermittent, ethanol-vapor exposure. Rats will be assessed repeatedly, over the course of acute alcohol withdrawal into abstinence, for neurometabolic changes in the medial-prefrontal cortex, using MRS at 9.4T. In the new funding period we shall concentrate on the effects of experimental pharmacotherapies for alcohol detoxification (glutamate modulators, such as acamprosate, memantine and lamotrigine) on neurometabolic profiles and on alcohol-related behaviors, comparing these therapies to standard treatments (GABAergic: diazepam). We will also compare neurometabolic profiles to in vivo, microdialysis measurements of extracellular glutamate release from parallel groups of rats. In the human study, we will continue to assess the effects of alcohol withdrawal. As a new element, alcohol cues and pharmacological intervention on levels of glutamate, glutamine and GABA in the prefrontal cortices of treatment-seeking alcoholics will be studied. Alcohol dependent inpatients (n=60) will undergo three combined measurements of MRS and fMRI cue reactivity. The first MR session will take place during acute withdrawal (without medication). The second group of measurements will be taken after five days of abstinence, in order to monitor the glutamate/glutamine ratio over time, and to what extent this ratio is affected by the diazepam that will at this point have been administered for withdrawal-symptom relief. The third MR session will take place on day 14 to monitor the effects of abstinence, both for patients under treatment with acamprosate (which will have been initiated as an open-label treatment following the second MR session) and for patients not being treated with medication. Relapse behavior will be monitored in follow-up assessments, and correlated to MRS metabolites. A control group of n=20 healthy subjects will undergo combined MRS and fMRI twice, two weeks apart.

Mann KF. DFG - Deutsche Forschungsgemeinschaft BO799/8-1: DeBraSTRA: Deep Brain Stimulation in Treatment Resistant Alcoholism. 01/2012-09/2015.

The main objective of this study is to assess the efficacy of bilateral deep brain stimulation (DBS) of the Nucleus accumbens (NAc) as a novel treatment in severe TRAA. To our knowledge, this will be the first clinical trial to assess DBS in TRAA worldwide. Prior to this study, our group treated 7 patients with severe TRAA with DBS on the basis of an off-label single patient use (5 patients in Magdeburg and 2 patients in Cologne). 4 out of the 7 patients remained completely abstinent (Follow-up up to 32 month), one patient had a short relapse after 16 months of abstinence and two patients showed a significant reduction of drinking days. Our hypothesis is based on these preliminary data and on the well-documented role of the NAc in alcoholism derived from animal models and neuroimaging studies in humans. We hypothesize that bilateral DBS of the NAc will result in a significant prolongation of time to first relapse and consequently in a substantial reduction of alcohol consumption. A total number of 30 patients with TRAA (10 each center) will be enrolled.

Leménager T, Mann KF. Ministerium für Arbeit und Sozialordnung, Familie, Frauen und Senioren 55-5072-7.1: Pathologischer Computer- und Internetgebrauch - eine Verhaltenssucht?. 03/2015-08/2015.

Ziele der Studie sind die Identifikation psychopathologischer, neuropsychologischer sowie neurobiologischer Mechanismen, die zur Entstehung und Aufrechterhaltung pathologischen Computer- und Internetgebrauchs beitragen. Dabei soll der Fokus auf Ähnlichkeiten und Unterschiede zu substanzbezogenen Abhängigkeitserkrankungen gelegt werden, um eine Verbesserung der diagnostischen Klassifikation zu erreichen. Auch soll der Frage nachgegangen werden, inwieweit erhöhte Impulsivität bzw. mangelnde Verhaltenskontrolle, soziale Ängstlichkeit sowie ein damit assoziiertes defizitäres Selbstkonzept mit der zunehmenden Flucht ins Internet (Eskapismus) bei pathologischen Computer- und Internetnutzern assoziiert sind. Die hieraus resultierenden Befunde sollen die Entwicklung eines Erklärungsmodells sowie die Ableitung wissenschaftlich fundierter Therapieansätze ermöglichen.

Leménager T. DFG - Deutsche Forschungsgemeinschaft BE 2248/10-1: STICA: Effects of a manualized Short-term Treatment of Internet and Computer game Addiction. 04/2012-10/2014.

Spanagel R. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg 32-731.0/92: Arbeitsgruppe Translationale Suchtforschung. 09/2011-08/2014.

Die Arbeitsgruppe „Translationale Suchtforschung“ soll als Schnittstelle zwischen präklinischer Forschung und klinischer Entwicklung dienen. Sie beschäftigt sich mit der Übersetzung von Befunden, die z.B. mit Hilfe von Tiermodellen gewonnen wurden, in die Anwendung am Menschen. Das hier vorgestellte Konzept basiert auf drei Säulen: die mit der Suchtklinik gemeinsame Erforschung neurobiologischer Grundprinzipen der Sucht, die Charakterisierung genetischer Risikoprofile und biologischer Konstrukte (Biomarker) von Suchterkrankungen, sowie die Entwicklung von neuen Behandlungsstrategien (pharmakologische Interventionen und Verhaltenstherapien).

Mann KF. DGPPN - Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde : Entwicklung einer S3 Praxisleitlinie in Psychiatrie und Psychotherapie, Behandlungsleitlinie Suchtmedizin - Substanzbezogene Störungen. 10/2010-06/2014.

Mann KF. BMBF - Bundesministerium für Bildung und Forschung 01EW1112: ERA-Net NEURON TRANSALC TP2: Multimodales Neuroimaging bei Patienten mit Alkoholsucht. 03/2011-02/2014.

Sommer WH. BMBF - Bundesministerium für Bildung und Forschung 01EW1112: ERA-Net NEURON TRANSALC TP1: Multimodales Neuroimaging in Tiermodellen des Alkoholismus. 03/2011-02/2014.

Sommer WH. BMBF - Bundesministerium für Bildung und Forschung 01EW1112: ERA-Net NEURON TRANSALC: Dysfunctional neuronal networks in alcoholism: Utilizing translational neuroimaging to identify altered brain connectivity and treatment efficacy predictors. 03/2011-02/2014.

Alcoholism is a common psychiatric disorder with largely unmet treatment needs. Excellent animal models for this disorder have put forward a number of promising molecular targets for medication development. Yet, clinical trials aimed at exploiting this potential often fall short of expectations. We aim to improve the predictive validity of animal tests by means of functional connectivity analysis using magnetic resonance imaging (MRI) to identify brain response patterns to pharmacotherapy that are comparable between patients and animal models of alcoholism. To this end we have formed an international consortium with highly complementary expertise in the field of alcoholism and neuroimaging research. This project will reveal alcoholism specific connectivity maps and knowledge of their modification by clinical reference compounds, i.e. acamprosate and naltrexone, in humans and animals. Based on this information we expect to predict better the effects of experimental drugs proposed for treatment of alcoholism in human patients.

Mann KF. Landesstiftung Baden-Württemberg gGmbH : Projektbegleitung Sucht im Alter. 11/2009-12/2013.

Die Landesstiftung Baden-Württemberg führt als eigenes Projekt das Programm „Sucht im Alter“ durch. Das Programm hat Modellcharakter in Baden-Württemberg. Die Landesstiftung hat sich zum Ziel gesetzt, eine wissenschaftliche Evaluation zu ihrem Programm durchzuführen. Die wissenschaftliche Evaluation wird vom Zentralinstitut für Seelische Gesundheit durchgeführt.

Ende G, Mann KF. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP14: Endophenotyping with soectroscopy: Genetic modulation and treatment response. 06/2011-05/2013.

Kiefer F. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC TP13: Endophenotyping with fMRI: genetic modulation and treatment response. 06/2011-05/2013.

Mann KF. EU - Europäische Union 223059: AMPHORA: Alcohol Measures for Public Health Research Alliance. 01/2009-12/2012.

AMPHORA is a Europe wide project involving researches and research institutions from 12 European countries, and counterparts and organizations from all 27 Member States, that will provide new scientific evidence for the best public health measures to reduce the harm done by alcohol through addressing social and cultural determinants, marketing and advertising, taxes and pricing, availability and access, early diagnosis and treatment of disease, interventions in drinking environments, and safer untaxed alcohol products. Cost effectiveness analyses will be undertaken in multiple settings, geographical regions, and for different gender and age groups to guide integrated policy making to reduce the harm done by alcohol. Using time series analysis, longitudinal intervention research, policy mapping, cost effectiveness analyses, and other policy relevant research methodologies, recent and current alcohol policy changes will be evaluated throughout European Member States. Current alcohol policy related infrastructures will be documented and their impact on effective policy development and implementation analyzed. The interaction between social and cultural determinants of alcohol policy and policy and preventive measures will be studied to determine the extent to which the implementation and impact of effective alcohol policies is culturally determined. Methodologies will be developed to allow tools for benchmarking and comparative analysis at the European level, advancing the state of the art in alcohol policy research and enhancing cooperation between researchers in Europe and other geographic regions to promote integration and excellence of European research in alcohol policy. AMPHORA will provide the evidence base to inform policy and decision makers at European, national and local levels to implement effective interventions to reduce the harm done by alcohol throughout a wide range of policies implemented in different sectors and settings.

Flor H, Mann KF. EU - Europäische Union 037286: IMAGEN WP6: Reinforcement-related behaviour in normal brain function and psychopathology: Neuroimaging adolescents. 02/2007-07/2012.

To acquire a large integrated structural and functional MRI dataset to allow analysis of the structural-functional correlations within the dataset. Analysis will be conducted in cooperation with WP 07. This data will be acquired in an identical fashion from multiple sites and will require explicit standardization with the input of WP 05. Participants will be recruited in conjunction with WP 04. To relate findings in this dataset to external measures of adolescent development, environmental exposure (WP 04) and current neuropsychological performance on tasks which relate to impulsivity (WP 02) To relate findings to genetic information in a coordinated hypothesis testing approach using candidate genes identified from strategies developed in WP 01, 03, 08. Activities in this workpackage are also linked to training activities coordinated in WP 10. Initially each site will implement a comparable pulse sequence for BOLD sensitive functional imaging, for diffusion weighted imaging and for structural T1 weighed imaging. In addition each site will implement the agreed battery of tasks for fMRI scanning and test this set of paradigms. On this basis each site will conduct functional, structural and diffusion weighted imaging at a rate of approximately 100 subjects per year. This data will be analysed individually and then correlated with personality and genetic markers.

Ministerium für Arbeit und Sozialordnung, Familie, Frauen und Senioren 53-5072-7.1: Glücksspielsucht und verwandte Störungen: Patientenzentrierte Erfassung des Risikos und Entwicklung von Frühinterventionen für Gefährdete. 03/2009-07/2012.

Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de