Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01ZX2204A: COMMITMENT - Modellierung von Komorbiditäts-Prozessen durch integratives, maschinelles Transfer-Lernen für psychiatrische Erkrankungen - Entwicklung einer Informationstechnologielösung zur Anwendung von verteiltem maschinellem Lernen. 06/2023-05/2025.
Patient with schizophrenia experience an increased risk for somatic comorbidities that include type 2 diabetes and cardiovascular disease. Substantial evidence suggests that these comorbidities share biological illness mechanisms with schizophrenia. As patients are treated largely using a “one-fits-all” approach, an improved understanding of comorbidity-related processes may facilitate novel interventions, and lead to a reduction in mortality and morbidity. The COMorbidity Modeling via Integrative Transfer machine learning in MENTal illness (COMMITMENT) project addresses this challenge through the application of innovative machine learning tools that identify comorbidity-related signatures from multimodal data. During the first funding period, COMMITMENT has already made substantial advances in the development of an IT infrastructure for geographically distributed application for machine learning, and the encoding of mechanistic knowledge in the form of knowledge graphs for downstream application of artificial intelligence methods. Similarly, COMMITMENT implemented new algorithms for the identification of comorbidity-related effects in cross-sectional data, as well as across the lifespan. In the second funding phase, the core focus of COMMITMENT is to leverage large-scale data resources, in order to apply the developed tools and uncover comorbidity-related signatures, to characterize the associated biological mechanisms, and to explore the possibility to prospectively predict comorbidity-related clinical outcomes. With this, COMMITMENT may build the basis for the future development of novel therapeutic approaches, as well as of clinical tools that could aid in the management of mental illness and somatic comorbidities.
Gründer G. BMBF - Bundesministerium für Bildung und Forschung 01EN2006A: EPIsoDE - Efficacy and Safety of Psilocybin in Treatment-Resistant Depression. 03/2021-02/2024.
In addition to research from the 1950s and 60s, recent modern clinical studies suggest the efficacy and safety of psilocybin, a classical psychedelic, in the treatment of depression and other psychiatric diseases.
While these early results are promising, most of these studies have methodological weaknesses and shortcomings (e.g. small sample sizes), underlining the need for additional research. The proposed bicentric parallel-group study aims to investigate the safety and efficacy of oral psilocybin administered under supportive conditions in major depression in a controlled, randomized, double-blind design. Only such a study allows for firm conclusions on its efficacy, paving the way for future phase III studies.
In order to ensure an appropriate control condition, the trial will investigate the efficacy of a therapeutic/high oral dose of psilocybin (25 mg) versus a low/supposedly inactive control dose (5 mg) versus 100 mg nicotinamide. We expect significant and stable treatment responses (defined as a ≥ 50% drop in the Hamilton Rating Scale for Depression; HAM-D) after the therapeutic (25 mg psilocybin) oral dose of psilocybin in comparison to active placebo (100 mg nicotinamide) and the low dose (5 mg psilocybin), while provoking only mild and transient adverse events (AE). The primary aim of the study is to examine the superiority of the 25 mg psilocybin over 5 mg and the placebo condition six weeks after the first dose. In a second step, the timing of treatment response/remission, the relative (%) change from baseline in terms of the initial value on the HAM-D scale and the question whether a second therapeutic dose (25 mg) is superior to only one therapeutic dose will be investigated.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01KC2004A: AhEAD Preclinical Phase II Assessment of Exosomes in Alcohol Addiction. 11/2020-10/2023.
Worldwide two billion people drink alcohol regularly. 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 efficacy, thus better treatments and prediction approaches that can be easily translated into the clinical situation are warranted. One major hypothesis in alcohol research is that chronic alcohol intake leads to neuroinflammation that in turn triggers addictive behaviour. It has been shown that intranasal delivery of mesenchymal stem cell-derived exosomes reduces relapse behaviour in rats. Here we propose a multi-center placebo-controlled trial in rats as a preclinical confirmatory proof. We aim to confirm the hypothesis that treatment with exosomes will have long-lasting positive effects on relapse behaviour in animal models of alcohol addiction. The preclinical trial design will follow the guidelines on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA), will adhere to the standards proposed for confirmatory biomedical research (Dirnagl, 2016) for nonclinical laboratory studies, and publication of the results will follow the ARRIVE guidelines. An independent third-party company focusing on the evaluation of data quality and practice in biomedical research will ensure adequate quality management and monitoring of our preclinical trial at the best possible level.
Ebner-Priemer U. DFG - Deutsche Forschungsgemeinschaft : Project S02: Mobile infrastructure for daily life research. 07/2019-06/2023.
We will develop and implement a mobile research infrastructure combining longitudinal assessments (A01) with two high-intensity measurement bursts (A04). MovisensXS will be used as a platform to assess e-diary items and track smartphone usage. Connected additional devices will capture physical activity and heart rate variability. All data will be sent via encrypted transmission to a secured server ensuring compliance with GDPR. Real-time analyses on all acquired data will allocate information on compliance and probability of phase changes. We will provide hard- and software interfaces to enable integration of apps (A02) and sensors (A03), as well as extensive training, ongoing support and troubleshooting.
Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01EF1803A: RELATER - Removing language barriers in treating refugees. 03/2019-02/2023.
More than any other area of medicine, psychiatry and psychotherapy depend on successful communication. Given that most refugees arriving in Germany in the 2last years speak languages such as Arabic that are not understood by the resident therapeutic community, interpreters are scarce and not available around the clock or in emergency situations, and no financing for language services is available for many hospitals, this presents a critical obstacle in providing mental health care for
refugees. This consortium will leverage recent advances in machine learning, cross-lingual communication, portable communication technologies and crosscultural psychiatry to decisively address this problem. First, we will develop a portable, secure and extensible cross-lingual communication (including speech-tospeech,
speech-to-text and text-to-text translation) system, based on
smartphones, to be used on site during psychiatric diagnosis in Iraqi Arabic- and Levantine-speaking refugees. This will incorporate recent technological advances to enhance diagnosis of psychiatric disorders in refugees by characterizing stress levels and psychopathology through machine-learning based tools to characterize paralinguistic features (such as prosody and voice spectral analysis) and semantic features. Diagnostic assessment will be based on an electronic version of the
M.I.N.I. (International Neuropsychiatric Interview), an established structured diagnostic interview with an administration time of approximately 15 minutes that is employed in more than 100 countries. Second, we will validate this tool against the gold standard of expert diagnosis with a human translator present, establishing feasibility, reliability and validity of our approach first regionally and then nationally
through a network of health care systems delivering refugee services. Third, we will extend the use of the mobile platform through building a smartphone-based app to be used by the community for logging, therapist communication, and community building, and for monitoring client’s well-being outside the clinic using ecological momentary assessment (EMA). To ensure rapid and widespread implementation into clinical practice, we will produce the necessary information for BfARM approval as a medical device. Beyond the immediate goals, our approach
has potential to benefit a wide range of therapeutic and diagnostic initiatives in refugees that depend on successful communication.
Koch P, Ladewig J. BMBF - Bundesministerium für Bildung und Forschung : SysMedSUDs - WP2: A human brain Organoid-based addiction circuitry to investigate molecular changes associated with SUDs. 11/2019-10/2022.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1909A: SysMedSUDs - A systems-medicine approach towards distinct and shared resilience and pathological mecha-nisms of substance use disorders. 11/2019-10/2022.
According to the WHO, 2 billion people drink alcohol, 1.3 billion smoke, 182 million consume cannabis, and almost 250 million use illicit drugs. Many of those alcohol, tobacco and drug users become addicted. Substance use disorders (SUDs) generate the largest disease burden and are categorized by DSM-5 and ICD11. SUDs are defined by compulsive drug use, craving, and re-lapses that can occur even after years of abstinence. SUDs encompass several drug classes including alcohol, nicotine, cannabis, opioids, and stimulants. One fundamental question in psy-chiatric research is: “How distinct are the different SUDs and what are the shared pathological phenomena?” Here we aim to determine the extent to which alcohol, nicotine, heroin, cannabis, and cocaine use disorders share genetic, epigenetic, transcriptomic and neurochemical mecha-nisms. In a convergent approach, multiple system levels in SUDs will be studied concurrently in humans and rats. Large samples from SUDs patients from several consortia (e.g. PGC and UK biobank) together with post-mortem brain tissue of deceased patients will give us comparative insights into distinct and overlapping genetic, epigenetic, and transcriptomic signatures of SUDs. Comparative analysis of brain organoids derived from SUD patients will reveal drug-induced tran-scriptional changes on a single cell level. A novel in silico approach and spectroscopy in patients will reveal alterations in neurochemical connectomes in SUDs. Rat models for addiction provide great face, construct and predictive validity and will be used to examine the functional relevance of our multi-level analyses of human biomaterial and in silico driven predictions. In sum, our in-terdisciplinary consortium will lead to an understanding of distinct and shared resilience and pathomechanisms of SUDs. This will have implications for diagnosis, precision medicine, comor-bidities, addiction theories, and socio-political decisions such as legalization and taxation.
DFG - Deutsche Forschungsgemeinschaft GRK 2350 : B2 - ACE and Stress Sensitivity: the Modulatory of the Social Environment. 04/2018-09/2022.
ACE have enduring effects on human stress regulatory circuits and promotes alterations in stress sensitivity and emotion regulation in later life. The likelihood of the sensitized neural system to (de)compensate is thereby shaped by adverse and protective social influences in everyday life, but the examination is methodologically challenging. The planned doctoral projects will tackle this problem and interrogate data on prior ACE, alterations in stress sensitivity and emotion regulation and real-life social environmental exposures to identify the intermediate neural mechanisms
Schmahl C. Ruprecht-Karls-Universität Heidelberg GRK 2350/1: Graduertenkolleg "Der Einfluss von Traumatisierung im Kindes- und Jugendalter auf psychosoziale und somatische Erkrankungen über die Lebensspanne". 04/2018-09/2022.
Das geplante Graduiertenkolleg (GRK) untersucht die neurobiologischen, somatischen und psychosozialen Folgen von traumatischen Kindheitserfahrungen (bis 18 Jahre; adverse childhood experiences, ACE). Eingebunden in die zentralen Forschungsschwerpunkte des Zentralinstituts für Seelische Gesundheit
und beider Medizinischen Fakultäten der Universität Heidelberg, profitiert das GRK inhaltlich von bestehenden Forschungsverbünden zum Thema ACE und existierenden Kohorten sowie strukturell von langjähriger Erfahrung mit Graduiertenprogrammen. ACE wie z.B. sexueller und körperlicher Missbrauch oder Vernachlässigung stellen massive Stressoren dar, die auf vulnerable Phasen der somato-psychischen Entwicklung treffen und damit sowohl kurz- als auch langfristig erhebliche Auswirkungen auf die psychische und körperliche Gesundheit haben. Weder die kausalen Zusammenhänge
noch vermittelnde Mechanismen dieser Schädigungen sind ausreichend verstanden.
Dies liegt zum einen an der großen Varianz bezüglich Art, Zeitpunkt, und Intensität der Traumatisierung sowie an einer Vielzahl möglicher protektiver Faktoren. Auf der anderen Seite manifestieren
sich die Folgen von ACE in sehr diversen psychosozialen und somatischen Problemen wie etwa dysfunktionaler Stressreaktivität oder Emotionalität, zwischenmenschlichen Problemen, Depression,
Sucht, chronischen Schmerzen oder inflammatorischen und metabolischen Erkrankungen. Die zentralen Ziele des GRK sind: (1) den Einfluss von Art, Zeitpunkt und Intensität von ACE sowie protektiver
Faktoren auf die Entstehung von psycho-somatischen Folgeerkrankungen zu untersuchen; (2) das Verständnis psychosozialer, neurobiologischer und epigenetischer Mechanismen von ACE-assoziierten psychischen und physischen Erkrankungen zu verbessern; (3) neue psychosoziale und pharmakologische Behandlungsansätze und Public Health Programme für die Folgen von ACE zu entwickeln.
Das geplante GRK wird Doktoranden der Fächer Medizin, Psychologie, Biologie und verwandter Naturwissenschaften sorgfältig auswählen und ausbilden. Neben der direkten wissenschaftlichen Betreuung in den beteiligten Arbeitsgruppen wird ein strukturiertes Betreuungs- und Qualifizierungskonzept – basierend auf der langjährigen Erfahrung in ähnlichen Programmen (SFB 636, KFO 256, weiteren Graduiertenschulen der Universität Heidelberg) – die bestehenden institutionellen Voraussetzungen für die Ausbildung international führender WissenschaftlerInnen optimieren. Das umfassende Lehrprogramm besteht aus Seminaren und Workshops mit ergänzender Sommerschule, Master Class, Symposien und nationalen oder internationalen Praktika. Diese vermitteln und trainieren relevante Inhalte und Methoden, Schlüsselqualifikationen und Soft Skills. Mentoring und Coaching optimieren die persönliche Weiterentwicklung.
Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01ZX1904A: COMMITMENT - COMorbidity Modeling via Integrative Transfer machine-learning in MENTal illness. 09/2019-08/2022.
Psychotic disorders, including schizophrenia and bipolar disorders, comprise some of the most severe mental illnesses that cause an enormous clinical and healthcare burden, costing close to €100 billion annually in Europe alone. The diagnostic delineation of these conditions is clinically defined and does not index appropriately the underlying biology. Patients are treated largely by a “one-fits-all” approach, despite substantial clinical heterogeneity in course, treatment response
and presence of somatic comorbidities that include type 2 diabetes, cardiovascular diseases and neurodegenerative processes. There is a strong need to identify biological means to stratify patients with psychotic disorders and identify the biological basis of somatic
comorbidity. This will allow improved clinical delineation of psychotic illnesses and facilitate novel intervention strategies targeted at the minimization of comorbidity risk, reducing mortality and morbidity. To address this, COMMITMENT will develop an innovative computational Framework for stratification of psychotic disorders and identification of biological domains shared with comorbidities. COMMITMENT builds on distributed machine learning that integrates mechanistic information mined from the literature. It extends approaches successfully used for oncological systems-medicine investigations, to optimally extract disease signatures from partially overlapping multi-OMICs data. We will use massive-scale genetic and neuroimaging data to explore the lifespan trajectories of stratification and comorbidity profiles, to identify age periods with pronounced comorbidity risk and to disentangle state- from trait-effects. We will explore the predictivity of comorbidity profiles for illness course, treatment response and occurrence of comorbidity
during early illness phases. With this, COMMITMENT will provide the basis for biologically-informed clinical tools for improved personalized care of patients with psychotic disorders.
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.
BMBF - Bundesministerium für Bildung und Forschung 01KU1905A: IMPLEMENT - Improved Personalized medicine through machine Learning in Mental disorders. 05/2019-04/2022.
Psychotic disorders are severe mental illnesses with early onset, frequently chronic course and often lifelong impairment. As a consequence, they cause an enormous healthcare burden, costing
close to €100 billion annually in Europe alone. The biology of these illnesses is insufficiently understood and no objective tools exist to aid in diagnosis or treatment selection. This leads to long periods of inadequate and ineffective treatment, significantly limiting the opportunity for achieving more optimal clinical outcomes. To address this, IMPLEMENT will develop a translational research framework that identifies biomarkers for treatment-relevant stratification of the most
severe psychotic disorder, schizophrenia. Building on known candidates, IMPLEMENT will use advanced machine learning on high-dimensional multi-OMICS and brain scans to identify illnessassociated profiles indexing patient subgroups. Using big data approaches (n > 60,000),
IMPLEMENT will explore the impact of genetic risk and neurodevelopmental processes on the formation of biological subgroups and use clinical studies of conventional antipsychotic treatment
and innovative treatment approaches to tune subgroup profiles towards clinical utility. The IMPLEMENT framework will incorporate preclinical validation to leverage neurobiological understanding and optimize biological subgroup profiles. The clinical utility of these profiles will be
validated in independent clinical samples and prospectively recruited subjects. IMPLEMENT will integrate these efforts with ICT development, to optimize the use of high-dimensional datasets across diverse repositories, to optimally harmonize data for personalized medicine investigations and safeguard patient privacy. Overall, IMPLEMENT will provide the basis for biologically-informed personalized medicine approaches in schizophrenia, addressing an enormous unmet medical Need in an area of medicine in which currently no robust clinical stratification tools exist.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01EW1908: PsiAlc - Preclinical Phase II Testing of Psilocybin in Alcohol Addiction and Epigenetic and Neuroimaging Studies on the Mode of Action. 05/2019-04/2022.
Alcohol use disorders create the largest health burden globally. Alcohol addiction in particular is a chronic disease characterized by dysfunctional behavior and impairment in quality of life, and thus represents a tremendous burden for the patient, health care services, and the general society. Current pharmacological treatment approaches have limited effectiveness. Due to the need for more efficacious treatments and encouraging safety and feasibility data, scientific interest in the potential clinical benefits of serotonergic hallucinogens such as psilocybin has recently returned, and here we wish to study the effects of psilocybin on alcohol relapse behavior and its underlying neurobiological mechanisms. Prior to time-intensive discussions with regulatory bodies, dose determination and finally cost-intensive phase II clinical testing for psilocybin in alcoholics, we propose for the first time with respect to mental disorders a preclinical multi-center placebo controlled trial in rats with a step-wise translation into alcoholic patients. Our preliminary experiment indicates that psilocybin reduces relapse behavior in rats and we hypothesize that a single administration of psilocybin will have long-lasting effects on relapse behavior. We will use a 4-arm design: placebo vs. acamprosate - a clinically effective medication used as a reference compound - vs. two doses of psilocybin will be tested in our DSM5-based rat model for alcohol addiction. The entire preclinical trial design will follow the guidelines on the development of medicinal products for the treatment of alcohol addiction provided by the European Medicines Agency (EMA) and will adhere to Good Laboratory Practice (GLP) for nonclinical laboratory studies. As preclinical and clinical evidence suggests that sex and gender influence disease trajectories and interventions in alcoholics, male and female rats will be studied in direct comparison in our 4-arm design. Therefore, the first aim of our proposal is to test the long-lasting efficacy of psilocybin in male and female subjects on relapse behavior. Many studies on psilocybin in humans describe very long-lasting positive effects on disease trajectories and quality of life. How can such long-lasting effects be explained and what is the mode of action of psilocybin? Epigenetic effects occur as one possible candidate mechanism, and at a higher systems level, restoration of normal network function in the diseased brain is another candidate. Here we propose to study genome-wide alterations in methylation and transcription in a longitudinal fashion in alcohol addicted rats and humans following a single application of psilocybin. We will also examine resting state activity longitudinally (using rs-fMRI) and subsequent alterations in reward processing in alcohol addicted rats and humans following a single application of psilocybin. Therefore, the second aim of our proposal is to provide translational information on the epigenetic, transcriptional, functional brain network, and behavioral levels to understand the neurobiological underpinnings and mode of action of psilocybin in the alcohol addicted brain.
Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01EE1407A: ESPRIT im Forschungsnetz für psychische Erkrankungen - Klinische Studie zur Wirksamkeit von Cannabidiol CR (Arvisol®) als Zusatztherapie zu einer Behandlung mit Olanzapin oder Amisulprid im Frühstadium einer Schizophrenie. 02/2015-01/2021.
We will conduct joint translational projects to test innovative interventions to (A) prevent conversion to schizophrenia in high-risk (HR) individuals, (B) enhance recovery in schizophrenia patients in the early phases of the illness, and (C) evaluate the outcome and efficacy of these interventions and implement them in clinical practice. (Aim A) For prevention of conversion in HR participants, we will conduct a randomized controlled trial (RCT) comparing two interventions with favorable risk-benefit ratios and clear translational rationale, a psychotherapy module aimed at improving social cognition, and a NMDA modulator/antioxidant (N-Acetyl Cysteine). (Aim B) To enhance recovery in patients after an acute episode, three harmonized RCTs will test the following add-on treatments: cannabidiol, mechanistically novel drug acting on the endocannabinoid system, actimetry-controlled physical exercise, and a psychotherapeutic intervention aiming at improving social cognition and social interaction. We will also perform a clinical experiment to test the hypothesis that transcranial direct current stimulation (tDCS) enhances the effects of cognitive training. (Aim C) We will evaluate treatment success for recovery, everyday function and stress reactivity, and quality of life. Using neuroimaging, we will examine neural systems related to gender and outcome. We provide costeffectiveness analyses both for experimental interventions and standardized inpatient treatment, and enhance transfer of successful results into practice.
Kirsch P. DFG - Deutsche Forschungsgemeinschaft KI 576/18-1: How culture shapes our brain: Neural correlates of cultural differences in social cognition. 09/2018-06/2020.
In times of globalization and increasing intercultural exchange, social understanding between cultures gains tremendously in importance. Recent studies, however, showed that people are better in understanding emotions and mental states of people from their own than from another culture.
The purpose of our project is to explore cultural differences in MNS responsivity with a new approach: CN. Specifically, we will study cultural differences in the response profiles of the MNS during social-cognitive and social-emotional processing. To this end, we will investigate the neural basis of imitation, as well as empathy for basic and social emotions, in two different cultures: individualism (Germany) and collectivism (China). Further, we will study the effect of social learning on cultural differences in social cognition with a cross-sectional approach by comparing participants from China and Germany who live abroad with those who never lived abroad.
BMBF - Bundesministerium für Bildung und Forschung 01EA1605: Verbund iCase: Induvidualisierte kognitive, affektive und soziale Verbesserungen durch Ernährungsinterventionen für ein langes, gesundes Leben.. 07/2016-06/2019.
Banaschewski T. BMBF - Bundesministerium für Bildung und Forschung 01EE1408E: ESCAbrain. 02/2015-01/2019.
Die Aufmerksamkeitsdefizit‐Hyperaktivitätsstörung (ADHS) ist eine sehr häufige und persistierende psychische Störung mit hohem Bedarf für individualisierte Behandlungen,welche altersübergreifend durch gestufte (stepped care) Behandlungen im VerbundvorhabenESCAlife untersucht werden. Da das inkonsistente Ansprechen von ADHS Patienten gerade auf nichtpharmakologische Behandlungen [1] ein andauerndes grosses Problem bei der individualisierten Behandlungsauswahl darstellt, sucht das ESCAbrainin den klinischen Studien des Verbundvorhabens gezielt nach biologischen Massen, welche das Ansprechen auf kostenintensive Behandlungen voraussagen können, und so eine effektivere personalisierte ADHS Behandlung ermöglichen. Zur Vorhersage nutzen wir neben psychosozialen Massen sich ergänzende, prädiktive Marker von Struktur, Konnektivität und Funktion des Gehirns, und kombinieren sie mit Verfahren zur multivariaten Musterklassierung. Der Fokus auf der biologischen Vorhersage in den klinischen Studien entspricht vollumfänglich den zentralen Zielen des Forschungsnetzes zu psychischen Erkrankungen, welches die Gesundheitsversorgung durch anwendungsorientierte Forschung und Transfer von Erkenntnissen aus der Grundlagenforschung in Deutschland verbessern will.
BMBF - Bundesministerium für Bildung und Forschung 01EE148E: ESCA-life - Vorhersage des Behandlungserfolges aus der Gehirmstruktur und -funktion bei evidenzbasierter. stufenweiser Versorung bei ADHS. 02/2015-01/2019.
Im Forschungsverbund ESCA-Life (Evidence-based, Stepped Care of ADHD along the life-span) werden neue Diagnose- und Behandlungsmöglichkeiten bei Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen erforscht. Diese Erkrankung beginnt zumeist bereits im Kindes- und Jugendalter. Oftmals wird ADHS aber auch in das Erwachsenenalter übertragen. Zur Therapie von ADHS sind medikamentöse und nicht-medikamentöse Verfahren verfügbar. Der Erfolg dieser Therapien ist aber individuell sehr unterschiedlich. Die Forschungsprojekte des ESCA-Life Verbundes verfolgen daher das Ziel, den Behandlungserfolg individuell zu verbessern. Hierzu sollen abgestufte Therapiekonzepte erforscht werden. Diese sehen unterschiedliche Optionen vor, die individuell angepasst werden. Die Behandlung beginnt mit einem sehr niederschwelligen Ansatz, etwa einer angeleiteten Selbsthilfe. Je nach Ansprechen wird die weitere Therapie dann entsprechend angepasst. In insgesamt vier klinischen Studien sollen abgestufte Therapieansätze an unterschiedlichen Zielgruppen erforscht werden: Vorschulkinder, Kinder im Schulalter, Jugendliche und Erwachsene. Parallel zu der eigentlichen Therapie sollen Parameter bestimmt werden, anhand derer sich der Behandlungserfolg vorab abschätzen lässt. Basierend auf den Ergebnissen der Studien wird eine Implementierung entsprechender Maßnahmen im Gesundheitswesen angestrebt. Der Behandlungserfolg nicht-pharmakologischer Therapien bei ADHS ist sehr heterogen. Patientinnen und Patienten sprechen individuell entweder besser oder schlechter auf eine bestimmte Behandlung an. Diese Unterschiede werden zunehmend anhand individueller Veränderungen der Gehirnstruktur und der Gehirnfunktion der Betroffenen interpretiert. In diesem Projekt, das vom ZI Mannheim geleitet wird, sollen diese Veränderungen daher näher untersucht werden. Ziel des Vorhabens ist es, anhand bestimmter Parameter den Behandlungserfolg einer spezifischen Therapie vorab besser einschätzen zu können. Die Arbeiten konzentrieren sich dabei speziell auf die Vorhersage des Behandlungserfolges bei Verhaltenstherapie und bei Neurofeedback. Hierzu werden Patientinnen und Patienten untersucht, die an den entsprechenden Modulen in den klinischen Studien des ESCA-Life Verbundprojektes teilnehmen. Es werden Merkmale der Funktion, der Struktur und der Konnektivität des Gehirns analysiert. Dies geschieht durch Bildgebungstechniken wie Elektroenzephalographie (EEG), Magnetresonanztomografie (MRT) oder transkranieller Sonographie (TCS). Durch die Arbeiten im Vorhaben sollen zukünftige Behandlungen gezielter und effizienter auf die individuellen Bedürfnisse angepasst werden können.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1611A: e:med II - Alcohol Addiction: A Systems-Oriented Approach . 01/2017-12/2018.
Our SP1 on coordination of the consortium was very productive in delivering (i) the consortium contract, (ii) a perspective article on systems medicine in alcoholism research with a description of our consortium in Addiction Biology (Spanagel et al., 2014; this article has already been cited 20 times), (iii) our website (www.sysmedalc.eu), (iv) meetings and reports (kick-off meeting, annual meetings, and method meetings) , (v) two press releases and public relation outreach involving radio and TV, and (vi) organization of the World Congress on Alcohol and Alcoholism in Berlin 2016 (www.isbra-esbra-2016.org) and co-organization of the Gordon Research Conference on Alcohol and the Nervous System (Galveston 2014).
DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP Z 2 Central Project 2 - Central Recruitment and Assessment. 08/2015-07/2018.
1 Work program
The Central Project is responsible for the coordination and administration of the entire CRU. This
comprises the following functions:
1. Organizing central recruitment, assessment, and data handling.
2. Organizing training and inter-rater reliability of diagnosticians.
3. Biomaterial collection
4. Coordinating allocation of funds to the individual projects together with the administration of the CIMH as well as Heidelberg University.
5. Coordinating assignments of the two rotational positions (GEROK-Stellen).
6. Maintaining the internet presence for the CRU.
7. Communicating the goals and results of the CRU to the academic and general public
(through the internet and other media)
8. Organizing and coordinating regular meetings of the project leaders and co-workers, scientific retreats, annual international symposia.
9. Allocate start-up funding for young researchers
Flor H, Bekrater-Bodmann R. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 04 Sensory-affective Interaction and Body Perception in BPD. 08/2015-07/2018.
BPD is characterized by dissociative symptoms that include intermittent somatosensory integration deficits and alterations in body perception. Frontoparietal dysfunctions, especially involving the temporoparietal junction (TPJ), may represent key mechanisms related to the processing of and interaction between the self and the environment. Our proposed project aims at the elucidation of psychobiological mechanisms of dissociative states and the evaluation of their importance for the psychopathology of BPD. In study 1, after the induction of dissociation or a neutral control condition, we will perform experiments that use of the processing of pain and pleasant touch as a tool to understand the perceptual mechanisms related to dissociative states. In study 2, we will facilitate or inhibit the activity of the TPJ or a control site using a neuronavigated transcranial magnetic stimulation (TMS) protocol. We will examine its effects on sensory integration associated with body perception and the processing of somatosensory stimuli with positive or negative valence, and their association with dissociation. By revealing the psychobiological basis and consequences of dissociative states, the results might enhance our understanding of the complex perceptual alterations in BPD.
Schmahl C. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP Z 1 Central Project 1 - Coordination, Administration, and Public Relations. 08/2015-07/2018.
1 Work program
The Central Project is responsible for the coordination and administration of the entire CRU. This
comprises the following functions:
1. Organizing central recruitment, assessment, and data handling.
2. Organizing training and inter-rater reliability of diagnosticians.
3. Biomaterial collection
4. Coordinating allocation of funds to the individual projects together with the administration of the CIMH as well as Heidelberg University.
5. Coordinating assignments of the two rotational positions (GEROK-Stellen).
6. Maintaining the internet presence for the CRU.
7. Communicating the goals and results of the CRU to the academic and general public
(through the internet and other media)
8. Organizing and coordinating regular meetings of the project leaders and co-workers, scientific retreats, annual international symposia.
9. Allocate start-up funding for young researchers
Schmahl C, Ende G. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 06 Tissue Damage and Pain - Modelling Cutting Behavior in BPD. 08/2015-07/2018.
1 Results of the first funding period
To investigate the influence of tissue damage in the context of non-suicidal self-injury (NSSI), we first characterized nociceptive non-invasive stimuli and a mechanical stimulus associated with tissue injury (incision). Twenty healthy men and women each were investigated regarding pain intensity and affective/sensory characteristics of the stimuli. Affective scores were significantly lower than sensory scores for all modalities, including the incision. In women, affective scores were not different for blade, laser and incision stimuli. In a second step, a non-invasive mechanical “blade” stimulus was matched by means of pain intensity with the
incision stimulus. Comparing time courses of blade and incision pain, the time course including the pain maximum was very similar (point-by-point comparison between p=0.8 and 1.0). In the ongoing second study, we were successful to induce stress in all groups (current BPD, remitted BPD, healthy controls), verified by significant increase of inner tension and heart rate. An interim analysis of the effects of incision, blade and sham treatment on stress levels in current BPD patients revealed a trend for stronger tension reduction following incision as compared to sham. A similar time course of tension reduction was observed following blade application which appears to be comparably successful to incision in reducing tension. Perception of mechanical pain was lower on both arms in current BPD patients compared to controls,
as a sign of generalized hypoalgesia in these patients. Additionally conducted pilot studies investigated the influence of seeing artificial blood together with a pain stimulus on tension reduction and established MR spectroscopy to quantify glutamate and GABA levels in pain-processing brain regions.
2 New questions and work schedule Since the blade stimulus appears to have similar affective pain properties as well as similar influence on tension reduction, it will be used in the studies of the next funding period. The new project has two major objectives. First, we aim to further elucidate mechanisms related to reduced pain sensitivity in BPD using recently established neuroimaging methods. In the second part of the project, we will further disentangle mechanisms related to NSSI with a particular focus on the role of seeing blood and the perspective of the injury (self- vs. other-inflicted) regarding stress reduction. In the first part, we will acquire structural MRIs at 3T and assess morphological group differences in amygdala,
anterior cingulate, anterior and posterior insula, and DLPFC as well as volumetric connectivity between these regions in 25 patients with current BPD and 25 healthy controls. Quantitative MRS measures of GABA and glutamate levels will be obtained from the insula and ACC, the glutamate/GABA ratio will be compared between groups, and the association of morphological differences with neurochemical alterations will be
investigated. Pseudo-continuous arterial spin labelling (pCASL), which allows absolute quantification of blood flow in pain-processing regions following single stimuli, will be conducted before and after blade stimulation. In the second part, patients with current NSSI will be randomized into four groups of 25 patients each (a)
blood, self-inflicted; b)blood, other-inflicted; c) no blood, self-inflicted; d) no blood, other-inflicted). For each patient, an individual stressful script will be prepared and presented while stress levels, and heart rate is 16 monitored. Immediately after the end of the script, the blade stimulus will be applied, either in conjunction with artificial blood or without and either self-inflicted or inflicted by the investigator.
The third part is an ambulatory assessment study in which BPD patients carry mobile devices in combination with sensors for physiological signals such as heart rate. Here, we aim to monitor the natural time course of NSSI events in the daily life of BPD patients. Patients will regularly enter their level of subjective stress. In
case of NSSI events, stress levels will be prompted more frequently; in addition, painfulness of the NSSI event as well as during the following time period will be closely monitored.
Spanagel R, Schneider M. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 07 Neurobiological Consequences and Mechanisms of Early Social Rejection Experiences. 08/2015-07/2018.
1 Results of the first funding period
The major aim of the present proposal is to further elucidate the molecular consequences and mechanisms of social rejection or ostracism in a rodent model with relevance to borderline personality disorder (BPD). The experience of social rejection by others is a major source of distress in humans and has been implicated in the development of various psychiatric disorders including BPD. BPD patients often report experiences of neglect and rejection during childhood and adolescence, and display a heightened sensitivity toward social rejection in adulthood. During the first funding period of our associated project (AP1) we accomplished the establishment of an innovative animal model for the long-term consequences of early adverse social experiences in laboratory rats. By manipulation of social requirements during childhood and/or adolescence we were able to evoke persistent behavioral changes in adult female rats that resemble core aspects BPD, such as disturbed social interaction and recognition memory and decreased pain sensitivity. In addition to these behavioral changes, our initial findings show alterations in the endocannabinoid system (ECS) as a long-term consequence to rejection experiences. In particular, adolescent social rejection was found to enhance levels of the endocannabinod anandamide (AEA) on the long-term. Related to our findings, a recent study reported
alterations of peripheral endocannabinoid levels in BPD patients, which is in support of a relevant role of the ECS not only in our animal model but also in BPD patients that may led to an improved understanding and new therapeutic approach to BPD.
2 New questions and work schedule
Although it is well established that social rejection plays a major role in BPD, the neurobiological consequences and mechanisms linked to social rejection are largely unknown. We here aim to further examine these neurobiological processes by investigating the consequences of alterations in social requirements in
adolescent rats - alone, and in combination with early modulations of mother-infant interaction. Our investigations will be focused on neurochemical systems involved in the modulation of social behavior and pain processing. Aside from our initial findings on alterations in the ECS we here aim to extend our analysis to the central oxytocin and the endogenous opioid system. These three neurochemical systems have been identified by our CRU as the most promising candidate systems for medication development and are also studied in the context context of the other IPs. Here we plan to utilize inter alia imaging techniques such as positron emission tomography (PET) and molecular (Western blot, autoradiography) and neurochemical analysis (e.g.
liquid chromatography/ tandem mass spectrometry (LC/MS-MS)). Alterations in thermal pain reactivity will be used as behavioral readout. Based on our previous findings we now also intend to monitor the time course of neurobiological consequences of social rejection experiences throughout adolescence and early adulthood at different time points more closely, in order to shed light on the timing of the mechanistic processes mediating the persistent behavioral and neurobiological changes in adulthood. Furthermore, in order to gain a causal link of a given molecular change and a specific BPD-like behavioral feature we will use a regional
viral-mediated gene transfer approach in an additional rescue experiment. A first target will be the normalization of enhanced amygdalar AEA levels and the hereby expected normalization of pain perception. Other identified persistent molecular changes will be also selectively targeted by viral-mediated gene transfer. This
approach will not only provide a mechanistical inside for BPD but will also deliver new intervention strategies for our CRU.
MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg AZ.31-7717.2-23/1/1: Anschubfinanzierung DFG Graduiertenkolleg “Der Einfluss von Gewalterfahrungen im Kindes- und Jugendalter auf psychische und somatische Erkrankungen über die Lebensspanne“. 10/2016-12/2017.
Die Erfahrung von Gewalt im Kindes- und Jugendalter, z.B. in Form von körperlichem oder sexuellem Missbrauch, stellt einen massiven Stressor dar und hat häufig lang anhaltende negative Konsequenzen für die seelische und körperliche Gesundheit. Die so auftretenden Erkrankungen stellen einen wesentlichen Faktor im Gesundheitswesen dar, der bislang bzgl. der Aufklärung der Mechanismen sowie der Entwicklung gezielter Behandlungen nur unzureichend berücksichtigt wurde. Die Erkrankungen zeigen sich in unterschiedlichen Altersgruppen in verschiedenen Ausprägungen, von Verhaltensauffälligkeiten im Kindes- und Jugendalter über Posttraumatische Belastungsstörungen und metabolische Syndrome im Erwachsenenalter bis hin zu Verbitterungsstörungen im höheren Lebensalter. Häufig wird die Stress-bezogene Pathologie auch an die folgenden Generationen weitergegeben, wobei epigenetische und psychosoziale Faktoren eine Rolle spielen. Die Erforschung und Behandlung von Stress-bezogener Psychopathologie über die gesamte Lebensspanne gehört zu den zentralen Bausteinen des Zentralinstituts für Seelische Gesundheit (ZI) und prädestiniert dieses für die Etablierung eines Graduiertenkollegs zur Förderung des wissenschaftlichen Nachwuchses auf diesem Gebiet. Außerdem besteht hier eine langjährige Erfahrung mit der postgradualen Ausbildung, so im Rahmen des Sonderforschungsbereichs 636 „Lernen und Gedächtnis: Implikationen für die Psychopathologie“ (2004-2015, Sprecherin: H. Flor)), der seit 2012 bestehenden Klinischen Forschergruppe 256 „Mechanismen der gestörten Emotionsverarbeitung bei der Borderline-Persönlichkeitsstörung“ (Sprecher: C. Schmahl) sowie des Internationalen Graduiertenkollegs „Diabetische Mikrovaskuläre Komplikationen“ (Sprecher: H.-P. Hammes). Die enge Kooperation mit der Medizinischen Fakultät Mannheim in mehreren Forschungsverbünden ermöglicht für das geplante Graduiertenkolleg insbesondere eine Stärkung des medizinischen Nachwuchses und die Erweiterung des wissenschaftlichen Fokus auf dem Gebiet der Stress-bezogenen Erkrankungen.
Das geplante Graduiertenkolleg wird ca. 20-30 DoktorandInnen, hpts. in den Fächern Medizin und Psychologie umfassen. Dabei basiert das Programm auf den drei Säulen „Wissensvermittlung“, „Karriereplanung“ und „Persönlichkeitsentwicklung“, die in unterschiedlichen didaktischen Konzepten vermittelt werden. Neben der Qualität der Forschung steht das Qualifizierungs- und Betreuungskonzept der Promovierenden im Vordergrund des Graduiertenkollegs. Der Bereich „Wissensvermittlung“ wird insbesondere durch die Teilnahme an wissenschaftlichen Vortragsveranstaltungen sowie einen Journal Club und Kompetenzvermittlung in relevanten Bereichen wie Statistik oder Verfassen und Veröffentlichen wissenschaftlicher Beiträge abgedeckt. Ziel in diesem Bereich ist der spezifische Erwerb grundlegenden Wissens und Fertigkeiten für das Gelingen einer Promotion. Für den Bereich „Karriereplanung“ ist eine jährlich stattfindende „Master Class“ mit internationalen Experten vorgesehen. Dieser Bereich soll insbesondere auf die Integration der TeilnehmerInnen des Graduiertenkollegs in nationale und internationale Forschungsnetzwerke zur Verbesserung des Wissensaustauschs sowie der individuellen Karrierechancen hinwirken. Als besonders innovatives Element ist der Bereich „Persönlichkeitsentwicklung“ anzusehen, bei dem ein bedarfsorientiertes Coaching in Einzel- und Gruppenarbeit vorgesehen ist. Hier sollen individuelle Ressourcen gestärkt, sowie Entwicklungspotentiale erkannt und Veränderungsmöglichkeiten erarbeitet werden. Ein Fokus soll auf die Erarbeitung von nachhaltigen, interessen- und bedürfnisbasierten Lösungen für die beruflichen Herausforderungen der DoktorandInnen liegen.
Dreßing H. : Sexueller Missbrauch an Minderjährigen durch katholische Priester, Diakone und männliche Ordensangehörige im Bereich der Deutschen Bischofskonferenz. 07/2014-12/2017.
Interdisziplinäre Zusammenarbeit
Das Projekt erfordert einen interdisziplinären wissenschaftlichen Ansatz, der kriminologische, psychologische, soziologische, psychiatrische und forensisch-psychiatrische Kompetenz einbezieht. Das Forschungskonsortium und der vorgesehene Beirat gewährleisten diese Voraussetzungen auf hohem wissenschaftlichem Niveau. Aufgrund der räumlichen Nähe der beteiligten Institutionen können die notwendigen regelmäßigen Treffen der beteiligten Wissenschaftler unkompliziert in Heidelberg oder Mannheim stattfinden. Die Studie wird auf großes Interesse der Öffentlichkeit und der Medien stoßen. Neben einer guten wissenschaftlichen Reputation bedeutet dies, dass die verantwortlichen Wissenschaftler über umfangreiche Erfahrungen im Umgang mit Medien und der Kommunikation wissenschaftlicher Daten in Gremien und der Öffentlichkeit verfügen müssen. Auch diese Qualifikation wird von dem Konsortium gewährleistet.
Epidemiologische Studien zur Prävalenz bestimmter Vorkommnisse in definierten Stichproben erfordern grundsätzlich die Erhebung der Primärdaten durch die verantwortlichen Wissenschaftler. Eine diesen wissenschaftlichen Standards genügende repräsentative Studie zum sexuellen Missbrauch durch Priester, Diakone und Ordensangehörige hätte also zur Voraussetzung, dass die Daten in den Archiven der jeweiligen Diözesen durch die Wissenschaftler selbst erhoben werden. Aufgrund besonderer kirchenrechtlicher Datenschutzregelungen ist dieser Forschungsansatz nicht umzusetzen. Hinzu kommt, dass aufgrund wahrscheinlich sehr heterogener Aufbewahrungs- und Aktenführungspraktiken die zu untersuchende Grundgesamtheit nicht exakt zu definieren bzw. klar abzugrenzen ist. Es erscheint deshalb notwendig, diese methodische Problematik von Anfang an sehr transparent allen Beteiligten und auch der Öffentlichkeit zu erklären. Ein Studiendesign, das sich ausschließlich auf die Datengewinnung über Dritte stützt, wie es im Vorgängerprojekt vorgeschlagen und wie es in ähnlicher Form auch in der vom John Jay College durchgeführten Studie angewandt wurde, stößt daher nicht nur auf grundlegende wissenschaftliche Vorbehalte, sondern würde auch zu Recht bei Betroffenen auf Einwände stoßen. Aus oben genannten Gründen ist die Mengenabschätzung oder -bestimmung der Prävalenz von Missbrauchsfällen im Bereich der Deutschen Bischofskonferenz weder quer- noch längsschnittlich mit herkömmlichen epidemiologischen Methoden möglich.
Das Konsortium schlägt deshalb eine modulare, aus mehreren sich aufeinander bezie-henden Hauptteilen bestehende interdisziplinäre Vorgehensweise vor, die unter Nutzung unterschiedlicher kircheninterner und externer Daten- und Informationsquellen auf mittelbare Art und Weise eine Mengenabschätzung des Problemumfangs sowie eine Gesamtanalyse des Problemfeldes ermöglichen soll. Zusätzlich kann eine längsschnittliche Deskription der von Mitarbeitern der Kirchenarchive dem Konsortium mitgeteilten Fälle des sexuellen Missbrauchs erfolgen, sofern dies vom Auftraggeber gewünscht wird. Wie in der Ausschreibung des Projektes formuliert, kann dies für 9 Bistümer von 1945 an und für 18 Bistümer von 2000 bis heute erfolgen.
Die Teilprojekte sind:
1. Qualitative Erfassung der Datenlage und Datenhaltungspraktiken hinsichtlich der Fälle sexuellen Missbrauchs an Minderjährigen durch katholische Priester, Diakone und männliche Ordensangehörige im Bereich der Deutschen Bischofskonferenz;
2. Qualitative biografische Analyse in Form von Interviews mit Tätern und Opfern;
3. Institutionenvergleich;
4. Analyse von Präventionsaspekten:
5. Sekundäranalyse von nationalen und internationalen empirischen Befunden und Studienergebnissen - methodenkritische Metaanalyse und
6. Quantitative Analyse von Personalakten.
Meyer-Lindenberg A. EU - Europäische Union HEALTH-F2-2013-602450: IMAGEMEND. 10/2013-09/2017.
Mental disorders are leading causes of disability, absence from work and premature retirement in Europe. While magnetic resonance imaging (MRI) facilities are broadly available and a vast research literature exists, few neuroimaging applications have reached clinical practice in psychiatry. A major problem is that mental illnesses are currently diagnosed as discrete entities defined clinically. Instead, recent results show that mental disorders are best understood as quantitative alterations in neural systems relevant across traditional diagnostic boundaries that reflect individual, genetic and environmental risk factors.
In the IMAGEMEND consortium, we aim to discover these systems to identify the patient characteristics most relevant for treatment, derive biomarkers and decision rules from this systems-level dimensional account, and systematically validate biomarker panels in patient, high-risk and epidemiological samples to produce automated imaging-based diagnostic and predictive tests tailored for wide distribution throughout Europe in standard clinical settings.
Focusing on schizophrenia, bipolar disorder and attention deficit-hyperactivity disorder, we have assembled one of Europe’s largest datasets combining neuroimaging, genetic, environmental, cognitive and clinical information on approximately 13.000 participants, and have recruited international replication datasets of more than 30.000 people. This unique resource will be processed using a new generation of multivariate statistical analysis tools to optimize existing imaging technology for the benefit of patients. We will also develop new imaging technology to enable the direct imaging-based therapeutic modification of neural circuits through rapid real-time MRI.
Our deliverables will promote personalized treatment through more accurate patient stratification, allow diagnoses at the pre-symptomatic stage for early intervention and prevention, and improve prediction of treatment response and disease progression.
Lis S, Bohus M. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 01 Neurobiological and Psychological Reaction Patterns in Response to Social Rejection in BPD. 08/2015-07/2017.
1 Results of the first funding period
The aim of this project was to add to the understanding of the mechanism underlying the pervasive experience of social exclusion in BPD which is assumed to contribute to severe interpersonal problems. In sum, our findings of the first funding period suggest that interpersonal problems in BPD may be primarily linked to an imbalance in the experiences of negative and positive events in every-day life. This is less caused by alterations in the processing of social rejection, but in the processing of positive social cues. In particular, we found that BPD patients experience happy faces as less intense and are less confident during their evaluation. They evaluate particularly positive information referenced to themselves as less positive and this has been related to an internal, negative and global attributional style. They feel less included during positive and neutral social encounters, expect less positive feedback of social co-players, fail to adjust their expectancies particularly in case of positive feedback and react with a drop of cooperative behavior in case of a provocation when previously included by social partners. Brain imaging data suggest that these
behavioral data may be linked to a lack in the modulation of the engagement of brain structures depending on the nature of a social encounter. Rejection sensitivity, i.e. a cognitive-affective disposition, which is increased in both acute as well as remitted BPD patients, influenced the intensity of many of these alterations. These distinct maladaptive mechanisms may result in a pervasive disruption of the sense of belonging, feeling different and separated from others, as well as feelings of loneliness and a reduced level of social functioning.
2 New questions and work schedule
The findings in funding period 1 emphasize the importance of alterations in the processing of positive social information in BPD. The planned project of funding period serves 2 aims:
1) Transferring these experimental findings into a modular, adaptive computer-assisted therapeutic intervention. This should provide an intensive, cost-efficient training, targeting the improvement of processing positive social information. This program will be evaluated within a randomized controlled trial.
2) Investigating further patho-mechanism in the development of feeling of belonging in BPD. During funding period 1 we had primarily studied features from the receiver perspective (i.e. the perception and evaluation of social rejection and inclusion). In period 2 we will focus on bidirectional processes incl. the sender perspective (i.e. behavioral expression of social signals; the adjustment of social behavior to social context and its consequences for the sense of belonging). We hypothesize, that basal affiliative processes such as behavioral matching, i.e. mimicry and synchronized action, and their interplay with the sensitivity to social reward, the storage of positive social information in memory, and the guidance of action based on positive social experiences are impaired in BPD patients. Effects will be measured by means of overt behavior, psychophysiological parameters (HR, EMG) and its neural correlates (fMRI).
Work schedule:
For this project, we will collect data from 60 female patients with BPD (age 18-45). For participating in study 2, we will recruit additionally a sample of 40 age, sex and educationally matched female healthy control subjects (age 18-45) and a clinical control group of 40 female patients with social phobia.
Meyer-Lindenberg A, Kirsch P. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 03 "Neural Mechanisms of Trust and Dyadic Interaction in BPD. 08/2015-07/2017.
1 Results of the first funding period
Aim of IP3 is the identification of abnormal activity and connectivity in brain systems associated with trust in BPD by means of a rather new brain imaging method, hyperscanning. Hyperscanning permits the measurements of brain activity simultaneously in two people interacting socially. During the first funding period, we
mainly focused on the development of a generalizable, robust and hypothesis-free analysis routine for hyperscanning data while collecting data from both healthy controls and patients. Method development was based on two independently recruited samples of healthy subjects, a sample of 26 subjects (13 pairs) including
both sexes, and a sample of 50 female subjects (25 pairs), which also serves as control sample for our BPD patients. A Joint Attention (JA) task was chosen for first investigation, representing a fundamental developmentally early form of specifically human social interaction. Data from both investigated samples showed that during JA, coupling between brain systems does emerge, uniquely to truly interacting subjects, and temporally and spatially highly specific, i.e. based upon function of the right temporo-parietal junction (rTPJ). Remarkably, in our patient study we found that neural coupling parameters during JA were already affected by illness status, suggesting a disruption in fundamental processing of social information in BPD at
early developmental and cognitive processing stages. Specifically, in 22 pairs, formed from one subject with BPD interacting with one healthy control participant, we found significantly lower coupling in dyads with a BPD subject during JA. Initial analysis of a multi-round trust game using the same methodology showed a comparable reduction in rTPJ coupling when BPD patients were involved in the interaction.
2 New questions and work schedule
The surprising discovery of disrupted basic social information processing in BPD during JA raises several questions. First, since JA arises very early in development (during the first year of life) and is required for the emergence of higher-order social skills, it may predict social dysfunction in adult social interaction requiring those skills. In the coming funding period, we will therefore examine whether JA impairment is predictive of neural coupling during trust and deception in a hyperscanning framework. Secondly, impairment of JA could index a state or trait phenomenon, with differing implications for therapy. To test trait aspects, JA disruption will be related to early environmental exposure data as well as to genotype information available through the
KFO, requiring a further buildup of sample size. To examine state properties of JA prediction, we will study the effects of a social interaction training battery, conducted in IP1, on neural synchrony before and after treatment, providing insights into the nature and biological importance of neural coupling parameters. This
work should provide an assessment to which degree cross-brain rTPJ-coupling can serve as a predictive biomarker to standard therapy and contribute to the investigation of innovative treatments for baseline social cognition. Further toward this end, induced changes in oxytocin will be related to neural changes in
hyperscanning and treatment effects. To achieve these gains in the coming funding period, our data set will be extended from currently female subjects and simple, cooperative interaction within JA to the inclusion of male patient- as well as control
samples, an oversampling of early childhood adversity participants to examine the effects of early environmental risk. Our analysis methods will be further developed to characterize cross-brain connections and cross-task predictive interactions in a variety of social settings and according fMRI tasks.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01EW1404: NEURON-Verbund COCADDICT: Cocaine addiction: A translational study of identify and characterize dysfunctional neuronal networks. 05/2014-04/2017.
Substance misuse is associated with economic costs equal to cancer, cardiovascular diseases or all other psychiatric disorders combined. The illicit substance with the highest societal costs is cocaine. Although the chronic relapsing nature of addictive behaviours suggests a reorganization of neural circuits processing drugs and drug-related stimuli, an integrated understanding is lacking.
Now, the present translational research team offers a rare opportunity to characterize, in a coordinated fashion, the relevant features in both humans and a high face validity animal model. In brief, identical functional and anatomical connectivity neuroimaging strategies will be used in human an rats; studies in the latter will be augumented by in vivo multisite electrophysiological recordings and optogenetic manipulations in behaving animals.
Together, we will:
1. Establish a valid translation between rodent and human for addiction-related brain network reorganization,
2. Map transmitter specific neuronal circuits, and
3. Test the contribution of these circuits to the development, expression and inhibition of addiction-like behaviours.
Together, this innovative approach increases our ability to identify neurobiological trajectories and novel treatment targets. We are starting with addictions because the societal needs are high, the animal models are best established, and the translational strategies requierd are most clear; once in place, though the same strategies could be applied to research on other disorders.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: e:Med - Maßnahmen zur Etablierung der Systemmedizin. 01/2014-12/2016.
Mit dem Förderkonzept soll zur Etablierung der Sytemmedizin in Deutschland beigetragen werden. Es bedarf hierzu einer disziplinübergreifenden Vernetzung von klinischen Arbeitsgruppen, von hochdurchsatz-orientierten Arbeitsgruppen der biomedizinischen Grundlagen-forschung sowie von Expertise für Informationstechnologien und Datenmanagement bzw. für mathematische Modellierung. Um weitere Synergieeffekte auszulösen und hierdurch die Forschungsförderung zu optimieren, ist beabsichtigt, die zur Förderung kommenden "Forschungskonsortien zur Systemmedizin" verbundübergreifend zu vernetzen.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: Alkohlabhängigkeit: Eine system-orientierte Herangehensweise. 01/2014-12/2016.
Bohus M. BMBF - Bundesministerium für Bildung und Forschung 01KR1303A: RELEASE: Behandlung psychosozialer und neuronaler Folgen von interpersoneller Gewalt in der Kindheit bei Erwachsenen. 08/2013-07/2016.
Patienten mit einer Posttraumatischen Belastungsstörung (PTBS) nach interpersonellen Gewalterfahrungen in der Kindheit und Jugend leiden meist unter schweren zusätzlichen psychischen Störungen. Insbesondere die Borderline-Persönlichkeitsstörung (BPS) ist eine häufige Folgestörung und führt zu komplexen Symptombildern. Am Zentralinstitut für Seelische Gesundheit in Mannheim (ZI) wurde mit der Dialektisch Behavioralen Therapie für PTBS (DBT-PTSD) erstmals ein stationäres Behandlungskonzept für dieses häufige Störungsbild entwickelt und evaluiert. Das Hauptziel des Verbundprojektes stellt nun die Überprüfung der Wirksamkeit dieses Behandlungsprogrammes im Vergleich zur Cognitive Processing Therapy (CPT) unter ambulanten Bedingungen dar (Projekt A). Darüber hinaus wird untersucht, welche Faktoren den Erfolg der Therapie maßgeblich beeinflussen (Teilprojekt B). In dem Teilprojekt C werden neuronale Mechanismen der Therapie und deren Auswirkung auf das emotionale Wiedererleben von traumatischen Erinnerungen beforscht.
Die Ergebnisse werden im Rahmen von Kongressbeiträgen, Zeitschriftenpublikationen und Medienberichten sowohl der Fachwelt als auch der breiten Öffentlichkeit zugänglich gemacht. Sollte die DBT-PTSD sich als wirksam erweisen werden ärztliche und psychologische Psychotherapeuten in der Behandlung ausgebildet. Die Erfahrungen und das Behandlungskonzept werden auf diese Weise in das Gesundheitssystem disseminiert und kommen so einer großen Gruppe von betroffenen Patienten zugute.
DFG - Deutsche Forschungsgemeinschaft SFB636: SFB 636: Learning, memory, and brain plasticity: Implications for psychopathology (Collaborative Research Center). 01/2004-12/2015.
Collaborative Research Centers (SFB) are long-term research institutions granted to universities for interdisciplinary programs.
SFB 636 focusses on learning and memory mechanisms and resulting plastic brain changes that are involved in psychopathology with an emphasis on disorders of emotion and motivation such as anxiety disorders, addiction, affective disorders and disorders of affect regulation.
SFB 636 has 22 subprojects grouped in the four areas: A: Molecular and cellular mechanisms of learning and plasticity, B: Behavioral and physiological mechanisms of learning and plasticity, C: Experimental psychopathology, D: Intervention-related brain plasticity. For these projects the Deutsche Forschungsgemeinschaft (DFG) provides funds up to 11.3 million euro for a period for up to twelve years. They are located at the Central Institute of Mental Health, the Medical Faculties Heidelberg and Mannheim of Heidelberg University, the German Cancer Research Center, the Interdisciplinary Center for Neuroscience as well as the Max-Planck-Institute for Medical Research.
The overall aim is a mechanism- rather than disease-oriented analysis of pathophysiological states and the translation of these findings into the development of new behavioral and pharmacological treatments of mental disorders.
SFB 636 includes researchers from molecular and cell biology, psychopharmacology, neuroimaging, neurophysiology, neurology, experimental psychology, biological psychiatry, psychotherapy and genetics. The first two funding periods (2004-2011) concentrated on the acquisition and extinction of maladaptive associative memories, the role of appetitive learning, the involvement of the hypothalamus-pituitary-adrenal axis as well as glutamatergic mechanisms.
In the third funding period (2012-2015) SFB 636 extends its research to comparative studies across disorders to delineate commonalities and differences with respect to appetitive and aversive associative learning processes. In addition, SFB 636 emphasizes structural remodeling of the involved neural networks and employs optogenetic tools and computational modeling to examine brain mechanisms of associative learning. We investigate mechanisms of extinction and reconsolidation processes across animals and humans with a focus on glutamatergic, dopaminergic and glucocorticoid mechanisms. Finally, SFB 636 works on the development of new interventions that combine behavioral and pharmacological tools and elucidates mechanisms underlying effective behavioral and pharmacological interventions.
Furthermore, in April 2008 SFB 636 started its international Graduate Program “Translational Neuroscience” to promote young scientists.
Durstewitz D. BMBF - Bundesministerium für Bildung und Forschung 01GQ1003B: BCCN: Bernstein Center for Computational Neuroscience: Implications of genetic variations for neural information processing in psychiatric conditions. 05/2010-04/2015.
The Bernstein Center Heidelberg-Mannheim investigates implications of genetic variations for neural information processing in psychiatric conditions.
Recent years have seen a tremendous progress in identifying risk genes for a number of psychiatric conditions, but we mostly lack a mechanistic understanding of the causal and dynamical links between genetically determined neuronal properties, their implications for cortical network dynamics, and their impact in turn on behavior and cognition. However, such knowledge would be of tremendous clinical relevance.
Computational models of neuronal systems are an excellent tool to study such causal links. The ultimate goal of the Bernstein Center Heidelberg-Mannheim is to derive an explanatory and theoretical framework for linking genetic conditions to higher cognitive function and its aberrations in schizophrenia, depression, and age-related mental decline.
To these ends, biologically detailed models of relevant brain structures as well as their connection to intracellular processes on the one hand and to macroscopic brain dynamics (fMRI, EEG) on the other hand, will be developed. In close exchange with experimental studies on different levels (genes, intracellular processes, network physiology, fMRI/EEG-measurements, behavior) these models will be parameterized, validated, and their predictions tested. Translation into clinical application is sought through novel diagnostic predictors and a computational platform for an "in-silico psychopharmacology". In Heidelberg the more cellular and network-physiological aspects of the proposal will be pursued, while work at the Central Institute of Mental Health in Mannheim will focus more on the psychiatric, human, and applicational aspects.
The BCCN Heidelberg-Mannheim integrates projects at the following research institutions:
Heidelberg University
Central Institute of Mental Health Mannheim
Bohus M. DFG - Deutsche Forschungsgemeinschaft KFO 256: Mechanisms of Disturbed Emotion Processing in Borderline Personality Disorder. 01/2012-12/2014.
Borderline personality disorder (BPD) is a highly prevalent and complex mental disorder that often takes a chronic and severely debilitating course if left untreated. Current theories view dysfunctions in emotion processing, social interaction, and mpulsivity as core mechanism of BPD. This often leads to prototypical behavioral patterns such as
suicide attempts, non-suicidal self-injury, high-risk behavior, and impulsive aggression. Most of these patterns can typically be traced back to mid-adolescence.
Recent research on psychological and neural mechanisms of BPD points towards an interplay between dysfunctional information processing, structural and functional impairments of fronto-limbic circuits, and learned maladaptive behavior. However, compared to other mental disorders of this importance, scientific knowledge on BPD is relatively sparse. Reasons include study samples that are small, heterogeneous, and often medicated; and a paucity of studies that include clinical controls. Also lacking are experimental data on remitted BPD patients, which might allow for the identification
of state-independent psychobiological characteristics that could be accounted for by endophenotypes. These limitations impede both the identification of genetic markers and the development of more specific pharmacologic and psychotherapeutic treatment strategies.
The Clinical Research Unit (CRU) at Heidelberg University will join the competences of their members which include clinical and psychopathological competence in both adult and adolescent BPD, expertise in neuropsychology, neuroimaging, genetics, and translational neuroscience. The aim is to further characterize subcomponents of dysfunctional emotion processing and social interaction in BPD and to elucidate their neural underpinnings. This should facilitate the development of specifically tailored psychotherapeutic interventions on one level, and provide the basis for further research on a molecular level on another. To this end, the CRU´s central project will carefully characterize and define the phenotypes of a total of 270 unmedicated patients with BPD, including current, remitted, and adolescent populations. The central project will recruit the patients needed in 6 closely related individual projects (IP1-IP6) that will focus on the following psychological and neural mechanisms:
i) rejection hypersensitivity and its consequences for social cooperation,
ii) dysfunctional responses to pro-social and aversive social stimuli,
iii) deficient capability in trust and coaxing,
iv) insufficient sensory integration and its impact on dissociation,
v) dysfunctional processing of emotional stimuli and neurofeedback training,
vi) self-injurious behavior as a form of dysfunctional emotion regulation, and
vii) functional and structural connectivity related to disturbed emotion processing.
These 6 projects, will be complemented by 3 associated projects. These associated projects (AP1-AP3) will focus on impulsivity, development of a new treatment, and development of an animal model.
Sartorius A. BMBF - Bundesministerium für Bildung und Forschung 01EW1110: ERA-Net NEURON SuppHab: Improvement of treatment resistant depression by suppression of lateral. 03/2011-02/2014.
About 15% of patients suffering from major depression do not respond to any antidepressant treatment. Recently, deep brain stimulation (DBS) was tested as a new therapeutic approach for these severely ill patients. Here we propose a well controlled study, in an animal model of depression, to test the therapeutic benefits of DBS of the lateral habenula (LHb). We believe that hyperactivity of this structure plays a central role in depression by inhibiting dopaminergic and serotonergic transmission. This hypothesis will be tested by means of magnetic resonance imaging and microdialysis in a well-known animal model of depression and additionally, in depressed patients.
Breeding and testing of all animals from the congenital Learned Helpless model will take place in Mannheim and animals will be distributed to partners from here. A subgroup of animals will be investigated by means of cerebral blood volume measurements, functional connectivity analysis and MR-spectroscopy at our 9.4 T scanner. In a final experimental step we will test if helpless behavior can be reversed by DBS and if alterations that have been detected by MR investigation can also be normalised.
There is no plan for any business or economic outlook or connectivity. Scientific outlook are excellent publications and improvement and refinement of existing theories of depression. The scientific outlook will be the initiation of a clinical DBS study that takes advantage of the LHb as a new stimulation target to treat therapy refractory depression.
Deuschle M. BMBF - Bundesministerium für Bildung und Forschung 01EW1109: ERA-Net NEURON POSEIDON: Pre-, peri- and postnatal Stress in human and non-human off-spring: a translational approach to study Epigenetic Impact on DepressiON. 03/2011-02/2014.
Exposure to early life adversities is associated with a prospectively increased risk for psychiatric disease, especially depression, in adulthood. Animal models implicate epigenetic regulation of gene expression to mediate this effect. So far, vulnerable time windows, candidate stressors, specific methylation profiles, time course and persistence of the effects of early life adversity on the methylome are not clear. Also, it is unclear whether blood or saliva are adequate “peripheral markers” of central nervous methylation patterns. The functional significance of gene methylation needs to be clarified by gene expression studies and, from a system biology point of view, methylation patterns could be analyzed using biological pathways in order to gain novel hypothesis how early adversities translate in later disease.
The POSEIDON study will focus on these questions in an integrated cross-species (rodent, non-human primate, humans) approach that covers different tissues (neuron, T-cells, buccal cells, saliva), stressors as well as time points of adversities (pre-, peri-, postnatal) and follow-up (infancy, adulthood). From a methodological point of view, we will study the methylation of candidate genes as well as do methylome analysis. The functional relevance of methylation profiles will be analyzed in expression studies as well as using discovery-based systems biology approaches. The relevance of animal findings can immediately be tested for significance in humans. From a work-flow perspective, the rodent studies (project 3a/3b) will give informations on type and time point of stressors (prenatal stress, perinatal asphyxia, good vs. bad maternal care) leading to effects on adult behavioural and neuroendocrine phenotype, glucocorticoid receptor (GR) and BDNF expression as well as methylome analyses in Moshe Szyf’s laboratory. The non-human primate study (project 2) will study maternal vs. nursery reared rhesus monkey phenotpyed at the lab of Dr. Suomi (NICHD). Using a whole genome methylation strategy, expression studies and system biology approaches, candidate genes and functional gene pathways will be identified in T-cells and neurons, which will allow to test whether T-cells could serve as “peripheral markers” in future studies. The human study (project 1) will prospectively analyze early life stressors and their relation to methylation patterns at birth and 6 month follow-up using a candidate approach (GR / BDNF) as well as, together with Moshe Szyf, a methylome approach. Using co-funding, candidate genes and stressors identified in the animal studies will be analyzed in humans.
Therefore, POSEIDON might identify DNA methylation signatures that could serve as predictive and diagnostic markers as well as guidance for prevention and intervention of psychiatric disorders in adulthood.
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.
Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01GS08152: NGFN Plus GENALC: Genetics of Alcohol Addiction. 06/2008-05/2011.
The overall theme of the present application focuses on the genetics of alcohol addiction, with the aim of identifying and validating candidate genes and molecular networks involved in the aetiology of this pathology. Importantly, this genetic and molecular information will guide us in the development of new medication strategies for alcohol-dependent patients.
Two research strategies are implemented into our IG: First, we are using genetic information derived from our previous NGFN studies along with genetic information from a previous EU-funded project (TARGALC) and several genome wide association (GWA) studies to extend our research projects into a systematic approach to identify more genes and molecular networks involved in excessive alcohol consumption and addiction (project areas 1 & 2). Second, we are taking a hypothesis-driven strategy, in which the involvement of the glutamatergic system in addictive behaviour is studied in great detail (project areas 3 and 4).
