Research Associations

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.

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.

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.

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.

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

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.

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

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.

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).

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.

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.

Kirsch P. 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.

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. 01/2015-12/2019.

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.

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

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).

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.

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.

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.

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.

Spanagel R. BMBF - Bundesministerium für Bildung und Forschung 01ZX1311A: Alkohlabhängigkeit: Eine system-orientierte Herangehensweise. 01/2014-12/2016.

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 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.

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.

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.

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.