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Prof. Dr. Falk Kiefer

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.

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.

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.

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.

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. 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.

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.

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).

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.

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.



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