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Projects: Translational Addiction Research

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.

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.

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.

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.

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.

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).

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.

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.



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