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Projekte: Systemische Neurowissenschaften in der Psychiatrie

Andoh JA, Flor H. DFG - Deutsche Forschungsgemeinschaft SFB 1158: B 07 - Neural circuits involved in Phantom Limb Pain . 07/2019-06/2023.

Although there has been much progress in the understanding of phantom limb pain (PLP), we still do not know which factors are antecedents and which are consequences of the pain and how central, peripheral and psychological factors interact. This project seeks to determine the development of phantom limb pain in a longitudinal fashion and will examine how central and peripheral changes as well as psychological factors develop over time. In addition, the role of central nervous system excitability and plasticity and the influence of use-dependent plasticity and body perception will be examined. Further, we will examine how evoked phantom pain is represented in the brain. Finally, we will employ high field imaging, neurofeedback using real time functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to identify causal circuits for phantom pain.

DFG - Deutsche Forschungsgemeinschaft : SFB 1158, B04 Translational studies in pain chronicity: role of corticothalamostriatal pathway in stress-sensitisation and comorbidity development. 07/2019-06/2023.

Psychiatric comorbidities, such as depression, anxiety and alcohol abuse are a major medical challenge in chronic pain, especially in female pain patients with adverse childhood experiences. However, it is unknown whether these comorbidities are caused by specific brain circuit alterations. A brain area that is strongly activated by pain and mediates motivational and affective behaviors is the paraventricular thalamic nucleus (PVT). PVT neurons project to nucleus accumbens (NAc) and anterior cingulate cortex (ACC) – both key nodes of motivational and affective processing. Current knowledge highlights that plasticity alterations in NAc and ACC may cause comorbidities related to chronic pain. Our translational project in humans and mice aims to understand whether plasticity in PVT-to-NAc/-ACC projections causally mediates pain comorbidities and whether adverse childhood experiences and gender have significant influence on these circuit alterations. In adult mice, we will mechanistically disentangle the role of plasticity in PVT-to-NAc/ACC projections for development of comorbidities during chronic stages of neuropathic pain using patch-clamp electrophysiology and fiber photometry in combination with neurobehavioral testing and opto-/chemogenetics. In patients suffering from chronic musculoskeletal pain, we will cross-sectionally investigate structural and functional alterations of PVT-to-NAc/ACC projections using high-resolution neuroimaging, diffusion tensor imaging, fMRI and fiber tracking analysis and determine their correlations to motivational/ affective alterations in daily life and to biomarkers for allosteric load. Both in humans and in rodents, we will investigate whether early childhood adversity especially in female subjects significantly sensitizes these circuit alterations. For the future, we aim to modulate PVT activity by targeted neurofeedback- or TMS/tDCS and hence test, whether PVT circuitry can be a novel target region for therapy of chronic pain-related motivational deficits and anxiety. Our translational study will unravel novels mechanistic insights in higher-order processing of chronic pain and may open up the door for specific therapy of one of the major challenges in chronic pain.

Ebner-Priemer U. DFG - Deutsche Forschungsgemeinschaft : SFB TRR 265: Projekt S02: Infrastruktur für mobiles Assessment im Alltag. 07/2019-06/2023.

Entwickelt und implementiert wird eine mobile Infrastruktur für longitudinales Assessment (A01) mit Phasen hochfrequentem Samplings (A04). MovisensXS, als zentrale Plattform, ermöglicht die Erfassung elektronischer Tagebuchitems, das Tracking der Smartphone-Nutzung sowie die Kopplung weiterer Sensoren für körperliche Bewegung und Herzfrequenzvariabilität. Die verschlüsselte Übertragung auf gesicherte Server erfolgt nach DSGVO. Compliance und Phasenwechsel werden in Echtzeit berechnet. Hard- und Software Schnittstellen sichern die Integration weiterer Apps (A02) und Sensoren (A03). Trainingsmaßnahmen und kontinuierlicher Support ergänzen das Arbeitsprogramm.

Meyer-Lindenberg A. DFG - Deutsche Forschungsgemeinschaft : SFB 1158, B09 Plasticity in brain circuits underlying interactions between pain and depression . 07/2019-06/2023.

There is extensive comorbidity of chronic pain and major depression (MDD). Most MDD patients experience pain, and 30-60% of pain patients exhibit significant depressive symptoms. When it occurs, this comorbidity strongly predicts unfavourable outcomes and increased cost of treatment. Monoamine reuptake inhibitors (SSRIs and SNRIs) are standard treatment for both syndromes. The neural circuitry involved in pain and MDD syndromes has major overlaps (e.g. anterior cingulate, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, insula). Despite extensive clinical evidence, the neural mechanisms specific for the extensive comorbidity of pain and depression have not been characterized, plasticity in these circuits has not been examined, and the causal status of any neural systems abnormality is unclear because no longitudinal data are available. In subproject B09, we will use a comprehensive assessment of pain perception, pain plasticity and central pain control (including their mutual relationship) in conjunction with imaging techniques to (a) identify neural systems specifically linked to altered pain behaviour in MDD patients and (b) characterize plasticity in these circuits. We will examine a sample of MDD patients both during the acute and remitted state, intermediate phenotype (MDD relatives who are healthy but at increased risk) and healthy subjects to study the specific impact of major depression state and trait on the profile of somatic and visceral pain sensitivity, the processing of somatic and visceral pain (sensory vs. affective components), the expression and balance of experimentally-induced bidirectional pain plasticity (pain-LTP/LTD) and the control of pain sensitivity and pain plasticity. Psychophysical data obtained by comprehensive quantitative sensory testing will be paralled by imaging of structure and function of brain circuits involved in pain processing as well as executive functioning. Structural and functional imaging data will be joined for graph theoretical analysis to characterize network changes in MDD and/or MDD intermediate phenotype. We will also follow the sample longitudinally to examine the predictive relationship between systems-level plasticity and clinical response of pain symptoms and treatment-related changes.

Tost H, Ebner-Priemer U. DFG - Deutsche Forschungsgemeinschaft : SFB TRR 265: Projekt A04: Intensive Untersuchung von Auslösern, Moderatoren und neurobiologischen Mechanismen an Verlaufsübergängen bei Abhängigkeitserkrankungen. 07/2019-06/2023.

Diese kombinierte ambulante Assessment- und Bildgebungsstudie identifiziert intraindividuelle Unterschiede in den Auslösern, Moderatoren und vermittelnden neurobiologischen Mechanismen von Abhängigkeitserkrankungen an Verlaufsübergängen mit substantiell gesteigertem bzw. reduziertem Alkoholkonsum. Mit hochfrequentem ambulanten Assessment im Alltag werden phasenabhängige Unterschiede in den Effekten von Auslösern und Moderatoren auf Alkoholverlangen, Stimmung, Impulsivität und Trinkverhalten untersucht und mittels funktioneller Bildgebung die neurobiologischen Korrelate dieser Prozesse identifiziert. Der prospektive Vorhersagewert der Mechanismen für erhaltenes und verlorenes Kontrollverhalten über den Alkoholkonsum wird getestet um neue und personenzentrierte Präventions- und Interventionsstrategien kritisch zu informieren.

Meyer-Lindenberg A. EU - Europäische Union : AIMS 2 - AUTISM INNOVATIVE MEDICINE STUDIES-2-TRIALS. 06/2018-05/2023.

Linking the biomarkers of autism and data analysis projects, CIMH will be critically involved in biomarker discovery and validation. As core data acquisition site for the Longitudinal European Autism Project (LEAP), CIMH will reassess the local participants for the LEAP wave 3. CIMH will be responsible for the core analysis of the LEAP task-fMRI data and will be involved in the optimization of domain-specific (i.e. task-fMRI) analysis pipelines, along with the harmonization of the data to a common standard. Building upon these analyses, CIMH will contribute to the generation of normative models by analysing and providing phenotypes of brain function derived from task-fMRI. CIMH will also participate in the identification of stratification markers based on existing EU-AIMS and new LEAP data sets as well as by integrating data with other existing cohorts.

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.

Meyer-Lindenberg A, Tost H. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg : Psychoepidemiologisches Zentrum: Digitalisierte Methoden zur personalisierten Gesundheitsförderung und Krisenprävention in der Pandemie (Digi-PEZ). 04/2021-12/2022.

Die Covid-19-Pandemie ist eine noch nie dagewesene Herausforderung für die öffentliche Gesundheit mit schwerwiegenden Auswirkungen auf die Bewegungs- und Entfaltungsfreiheit, das Wohlergehen und die psychische Gesundheit der Bevölkerung. Das Ziel dieses Antrags ist es, durch die gezielte strategische Erweiterung des Psychoepidemiologischen Zentrums (PEZ) am Zentralinstitut für Seelische Gesundheit in Mannheim die Bekämpfung der Pandemie und ihrer Wirkungen mittels alltagstauglicher digitaler Erfassungs- und Interventionsmethoden nachhaltig zu unterstützen. Hierfür planen wir die Bereitstellung einer neuartigen digitalen Methodenplattform, die es ermöglicht, (i) soziale und individuelle Einflussfaktoren auf das Pandemie-bezogene Verhalten und Erleben in der gesunden Allgemeinbevölkerung und psychiatrischen Patienten mittels elektronischer Tagebücher (e-Tagebücher) und Sensoren im Alltag zu erfassen, (ii) psychosoziale und umweltbedingte Risikofaktoren für Pandemie-bezogene psychische Krisen mittels Echtzeit-Erhebungen zu identifizieren, und (iii) personalisierte und digitalisierte Hilfestrategien zur situationsgerechten Bewältigung der Pandemiefolgen zu entwickeln. Die geplante inhaltliche Anpassung des PEZ im Rahmen der Pandemie schafft einen neuen Zugang zur digitalisierten Diagnostik und Frühintervention psychischer Erkrankungen, ist unmittelbar auf die Standorte unserer Kollaborationspartner im Land übertragbar und verstärkt somit maßgeblich den Gesundheitsstandort Baden-Württemberg und seine Vorbildfunktion in der Personalisierten Medizin in Deutschland.

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

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.

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.

DFG - Deutsche Forschungsgemeinschaft : Interfaces and Interventions in Complex Chronic Conditions. 07/2019-06/2020.

Mößnang C. Universität Heidelberg Olympia Morata-Programm: Typical and atypical development of the social brain – neuroimaging evidence and implications for psychiatric research. 03/2018-02/2020.

Social neuroscience is a quickly evolving research discipline that aims at uncovering the cognitive and neural underpinnings of human social behavior. Difficulties in the social domain are a major risk for mental health and can be observed in a wide range of psychiatric conditions, in particular in developmental disorders such as autism. In order to understand the underlying pathophysiological mechanisms, one question is of particular importance: What are the changes in the brain that are responsible for the development of social abilities from childhood to adulthood? This question requires a developmental approach which allows to relate changes in neurobiology to changes in social abilities. Due to methodological challenges, such as the need for large sample sizes in a longitudinal design, this question remains unanswered. The current Habilitation project aims at filling this gap by characterizing the typical and atypical development of the so-called “social brain” in healthy individuals and individuals with autism from childhood to adulthood. Data were collected locally (project 1) and as part of the largest European multicenter study on autism (projects 2 and 3). By combining cross-sectional and longitudinal analyses of neuroimaging, behavioral and clinical data, detailed developmental trajectories of the social brain can be determined, along with their association with structural brain maturation, genetic influences and the acquisition of behavioral skills. With this Habilitation project, I will not only substantiate my expertise in the fields of social neuroscience and developmental psychiatry, but will also strengthen my methodological profile in the field of multimodal pediatric imaging.

DFG - Deutsche Forschungsgemeinschaft TO 539/3-1: Characterization of Neurodevelopmental Disease Trajectories using Richly Annotated Sequences of Graphs (RICHGRAPH) . 01/2017-12/2019.

Mental disorders are the main cause of suicide, disability, and early retirement in Europe. While recent developments in magnetic resonance imaging have opened unprecedented windows into the developing brain, the full potential of computational methods to analyse the longitudinal and multi-modal imaging information at hand has not yet been exploited. After psychiatric neuroimaging research has long been focusing on dedicated regions in the brain (local analysis), the emerging field of connectomics has enabled a characterization of topological properties (global analysis) by establishing graphs as a representation of the brain. Current techniques, however, require the available multi-modal information to be reduced to a simple set of edges that capture the relationship between different brain regions in a single weight and thus fail to exploit the manifold MRI-derived quantitative parameters as potentially complementary sources of information. They are also unable to model network dynamics. Inspired by major progress in the field of social network analysis, this project will develop the next generation of connectomics techniques based on rich graphs that enable holistic processing of heterogeneous data from multiple sources over time. Advanced machine learning techniques applied to sequences of rich graphs will allow analyses and prediction of neurodevelopmental trajectories based on both local tissue characteristics and global network features. Comprehensive validation studies with large cohorts of patients and controls that include longitudinal imaging, genetic, environmental, and behavioral data will be performed with the long-term goal of (1) establishing novel multi-modal and longitudinal imaging biomarkers that represent pathological changes before the appearance of clinical symptoms, (2) linking brain imaging traits to gene variants and (3) advancing our understanding of the underlying biological processes to pave the way for development of new treatments.

Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung : MEHIRA (MEntal Health in Refugees and Asylum Seekers). 01/2017-12/2019.

Projektziel ist eine die Überprüfung eines Modells zur effektiveren Gesundheitsversorgung von jugendlichen und erwachsenen Flüchtlingen mit affektiven Störungen. Die zentrale Forschungsfrage lautet, ob sich mithilfe einer zielgruppenadaptierten, kultursensiblen Diagnostik, Indikationsstellung und Therapie innerhalb gestuften und partizipativen Versorgungsmodells (Stepped and Collaborative Care Modell, SCCM) die Versorgung dieser Patientengruppe effektiver gestalten lässt. Gleichermaßen soll überprüft werden, ob dieses Versorgungsmodell geeignet ist Menschen außerhalb von psychiatrischen Ambulanzen kosteneffektiver zu versorgen. Dabei ist die primäre Arbeitshypothese, dass das vorgeschlagene Versorgungsmodell im Vergleich zur Routineversorgung eine erhöhte Effektivität aufweist. Als Sekundärhypothese wird angenommen, dass das Versorgungsmodell in weiteren Effektivitätsparametern (Response, Remission, Lebensqualität) sowie hinsichtlich der Effizienz (direkte und indirekte Kosten, Kosten-Nutzwert-Relation, Kosten-Effektivitäts-Relation) überlegen ist. Explorativ sollen die aktiv gewonnenen Patientendaten dazu verwendet werden an fünf bundesdeutschen Standorten mit unterschiedlichen Versorgungssituationen Inzidenz und Prävalenz von psychischen Erkrankungen bei geflüchteten Jugendlichen und Erwachsenen zu erfassen

DFG - Deutsche Forschungsgemeinschaft SFB 1158: B 07 - Neural circuits involved in Phantom Limb Pain . 07/2015-06/2019.

Meyer-Lindenberg A. EU - Europäische Union HEALTH-F2-2013-602805: Aggressotype - WP1 Neural correlates of aggression – human studies . 11/2013-09/2018.

WP1 Neural correlates of aggression – human studies WP1 evaluates the neural substrates of impulsive and instrumental aggression by identifying neural, neurocognitive and biomarker mechanisms underlying aggressive/antisocial behaviour in high-risk children and adolescents (subjects with ADHD). Furthermore, a new sample of children with Conduct Disorder (CD), as well as of adolescents with CD is collected. In addition, this WP measures cognitive, physiological and motor components of empathy in children and adolescents with CD and examines whether different empathy components are differentially affected across the various aggression subtypes. Finally, WP1 integrates the findings of the different tasks and examines the common (cross-disorder) and the disorder-specific correlates of the aggressive/antisocial behaviour.

DFG - Deutsche Forschungsgemeinschaft ME 1591/7-1: Neural stress processing and risk of coronary heart disease. 07/2014-06/2018.

This proposed project aims at testing the hypothesis that subjects with an increased risk of coronary heart disease (CHD) exhibit dysfunctional neural processing of mental stress. – Ample evidence from epidemiologic and laboratory studies indicates that mental stress is associated with CHD, acting both as pathophysiological risk factor and a trigger of acute events. Furthermore, dysfunctional stress system reactivity was repeatedly found to be associated with coronary risk factors including type 2 diabetes, visceral obesity, and smoking. However, the brain mechanisms that are involved in these stress systems changes are unknown. – To test our hypothesis, we use a mental stress task that can be performed during functional magnetic resonance imaging. Main outcome measures include increases in subjective stress level, cortisol secretion, cardiovascular measures, and changes in brain activity associated with acute mental stress exposure. Coronary risk is defined by an established algorithm based on classical risk factors. Measures indicating mental stress exposure are compared between subjects with low and high coronary risk. Our project proposal takes advantage of an innovative strategy to dissect epidemiologic findings by combining tools from neuroscience and stress research, exploring a brain mechanism that drives a cardiac disease of highest impact.

Gan G. : Olympia Morata-Programm: Neurogenetische Mechanismen und Umweltinteraktionen bei Störungen der Selbstkontrolle. 03/2017-02/2018.

Selbstkontrolle ist eine basale menschliche Fähigkeit, die unter Alkoholeinfluss oder bei aggressivem Verhalten stark beeinträchtigt sein kann. Leichtsinniges Verhalten unter Alkoholeinfluss und aggressive Impulstaten können persönliches Leid und hohe gesellschaftliche Kosten nach sich ziehen. Kontrollverlust über das eigene Verhalten wird mit einem Ungleichgewicht zwischen präfrontal-limbischen Kontroll- und Emotionsnetzwerken sowie einer veränderten Belohnungsverarbeitung in Zusammenhang gebracht. Neben veränderten neuronalen Prozessen spielen bei erhöhtem Alkoholkonsum und aggressivem Verhalten auch genetische Prädispositionen sowie ungünstige Umweltfaktoren (z.B., sozialer Druck) eine Rolle. In dem vorliegenden Projekt zu „neurogenetischen Mechanismen und Umweltinteraktionen bei Störungen der Selbstkontrolle“ werden innovative experimentelle Methoden eingesetzt, um die Neuro-Gen-Umwelt Ebenen zu verknüpfen. Der Fokus liegt auf funktionellen neuronalen Markern emotionaler Reaktivität und inhibitorischer Kontrolle, die bei Störungen der Selbstkontrolle beeinträchtigt sind, sowie auf funktioneller „resting-state“ Konnektivität. Diese neuronalen Prozesse werden mittels funktioneller Magnetresonanztomographie (fMRT) in Menschen mit klinisch ausgeprägter reaktiver Aggressivität am Beispiel der „intermittierenden explosiblen Störung“ und in Gesunden mit und ohne genetische Risikovarianten gemessen. Der Einfluss von Gen-Umweltfaktoren auf neuronale Prozesse wird mittels Geno-typisierung von Risikopolymorphismen aggressiven Verhaltens und der Messung von Umweltfaktoren im tatsächlichen Lebensumfeld von Menschen mit Smartphone-basiertem „ecological momentary assessment“ (EMA) untersucht. Die Erforschung von Wechselwirkungen zwischen neuronalen Prozessen, genetischen Prädispositionen und ungünstigen Umweltfaktoren hat zum Ziel, funktionelle Bereiche für neue effiziente Präventions- und Therapieansätze zur Reduktion klinisch aggressiven Verhaltens und exzessiven Alkoholkonsums zu identifizieren.

Meyer-Lindenberg A. Klaus Tschira Stiftung gGmbH 03.303.2016: Radiopharmazie mit Zyklotron. 10/2016-12/2017.

Neuropsychiatrische Erkrankungen sind in den letzten Jahren immer mehr in den Fokus der gesamtgesellschaftlichen Wahrnehmung getreten. Sie sind eine Hauptursache für verlorene gesunde Lebenszeit der alternden (Demenzen), aber gerade auch der in Ausbildung und Arbeit befindlichen Bevölkerung (z.B. Depressionen, inzwischen eine Hauptursache für Krankschreibungen und Frühberentungen). Im Gegensatz zu onkologischen Fragestellungen (Krebs oder kein Krebs) sind die Übergänge zwischen pathologischer und nicht pathologischer Situation bei den genannten neuropsychiatrischen Fragestellungen oft fließend. Häufig ist es auch schwierig, Ursache und Wirkung neuropsychiatrischer Erkrankungen zu differenzieren: Als Alois Alzheimer beispielsweise die nach ihm benannte Demenz näher untersuchte, fand er nach dem Tod seiner ersten Patientin, Auguste Deter, in ihrem Hirn Ablagerungen, sogenannte Plaques, die er für die Ursache der Erkrankung hielt. Heute wissen wir durch modernste diagnostische Verfahren, dass das Auftreten dieser Alzheimer-Plaques keineswegs ein sicheres Zeichen dafür ist, dass ein Mensch an einer Alzheimer-Demenz leiden muss. Umgekehrt konnte durch Auflösen dieser Plaques durch spezielle therapeutische Verfahren die Erkrankung auch nicht geheilt werden. Dies sind nur zwei Beispiele dafür, dass Ursachen neuropsychiatrischer Erkrankungen oder die Prävalenz dafür sehr häufig nur schwer zu ergründen sind. Das Zentralinstitut für seelische Gesundheit widmet sich genau diesen Fragestellungen. In den letzten beiden Dekaden haben zunehmend Verfahren der funktionellen und biochemischen Bildgebung entscheidend zur Aufklärung der Entstehung psychiatrischer Erkrankungen beigetragen. Durch funktionelle Bildgebung kann die psychiatrische und 2 psychologische Therapieforschung wesentliche Aspekte von Erkrankungen auf neuronaler Ebene isolieren. Funktionelle Marker können Störungen der Informationsverarbeitung auf der neuronalen Ebene oft schon dann unterscheiden, wenn sich diese Prozesse auf der Verhaltensebene noch nicht oder nicht mehr differenzieren lassen. Diese Marker können dabei mit modernen algorithmischen Verfahren (insbesondere machine learning und deep learning-Methoden) auf ihre Nützlichkeit für die Therapieforschung hin überprüft und anschließend angewendet werden. Gerade bei neuen Behandlungen können so spezifische Wirkungen in den betroffenen Gehirnsystemen auch auf molekularer Ebene quantifiziert und damit charakterisiert werden. Dies ermöglicht Aussagen für die personalisierte Medizin, die in diesem Bereich besonders dringlich ist. Keine andere Technologie ermöglicht außerdem die direkte Übertragung von relevanten und erfolgversprechenden Ergebnissen vom Tier auf den Menschen in diesem hohen Maße. Zur Umsetzung dieses Forschungsansatzes hat der Wissenschaftsrat am ZI das Zentrum für Innovative Psychiatrie- und Psychotherapieforschung (ZIPP) zur Förderung bewilligt, das gegenwärtig auf dem Gelände des ZI errichtet wird. Die übergreifende Aufgabe des ZIPP ist die Umsetzung eines neurobiologisch fundierten Therapieforschungskonzepts durch Identifizierung, Etablierung und Personalisierung psychotherapeutischer und pharmakologischer Wirkmechanismen für psychische Störungen. Dazu werden experimentell-medizinische und mechanistisch-neurowissenschaftliche Forschung verknüpft. Eine interdisziplinäre Kombination von Biomarker- und Bildgebungsforschung mit experimenteller Psychopharmaka- und Psychotherapieforschung und modernster algorithmischer Auswerteverfahren zielt ferner auf Erforschung und Charakterisierung von Erkrankungen für eine maßgeschneiderte Behandlung psychiatrischer Patienten. Entscheidend für den Erfolg ist es, die sensitivsten Bildgebungsmodalitäten zur Verfügung zu haben, die funktionelle pathologische Veränderungen möglichst frühzeitig darstellen können, und sie mit modernsten Methoden der Informationsverarbeitung auszuwerten und schließlich therapieren zu können.

Deuschle M. Dietmar Hopp Stiftung gGmbH 23011216: PreSchooler: Young Children's Health and Enviroment. 10/2014-09/2017.

Fragestellungen / Ziele - Persistieren die epigenetischen Merkmale von Geburt (Nabelschnurblut) oder 6 Monaten nach Geburt bis zum Alter von 4 Jahren? Sind psychosoziale Risiken der ersten 4 Lebensjahre mit spezifischen Veränderungen epigenetischer Marker assoziiert? - Lassen sich Auffälligkeiten in Verhaltenstests im Alter von 4 Jahren durch epigenetische Merkmale bei Geburt oder der Mutter-Kind-Interaktion im 6. Monat vorhersagen? - Können Stressoren in Schwangerschaft und früher Kindheit bzw. epigenetische Merkmale die Hirnentwicklung bis zum 4. Lebensjahr prognostizieren? - Stehen Auffälligkeiten in Verhaltenstests im Alter von 4 Jahren in Verbindung mit „Infektions-Historie“ (Antikörper im Speichel) oder der Darmflora?

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.

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.

Meyer-Lindenberg A. EU - Europäische Union 115300: EU-AIMS - European Autism Interventions – A Multicentre Study for Developing New Medications. 04/2012-03/2017.

There are no effective pharmacological treatments for the core symptoms of autism spectrum disorder (ASD), and our understanding of the pathophysiology of the disease is poor. Research is hampered by a lack of valid and reliable cellular assays and animal models; an absence of tests that demonstrate efficacy in healthy volunteers from childhood to adulthood; and the reliance of clinical trials on biologically heterogeneous groups of patients as operationally-defined by DSM/ICD10 categories. Further, even if novel treatments were developed, there is no EU platform to test them clinically. Despite these limitations, the recent identification of genetic risk factors for ASD provides unique opportunities to substantially improve this situation. We therefore propose an integrated, translational, effort to achieve key objectives for ASD research, which will deliver new research tools and standards for clinical development, and pave the way for drug discovery and clinical trials. To implement this integrated effort, 13 leading ‘hubs’ in European institutions (with linked ‘satellites’ across the EU) have partnered with Autism Speaks (the world’s leading Autism Research Charity), three SMEs and EFPIA to: a) develop cellular assays and animal models based on confirmed genetic risks, and utilize these models to focus on translational endophenotypes for facilitating new drug discovery; b) validate biomarkers and patient group stratification to optimize conditions for clinical trials; and c) develop a sustainable EU-wide clinical infrastructure to promote research and development of new drugs. We will couple this integrated research effort with the development of new training opportunities and the implementation of new analytical approaches. One of Europe’s leading scientific management SMEs (GABO:mi) will facilitate the management of EU-AIMS and a distinguished international Scientific Advisory Board will provide input and guidance to ensure that we integrate effectively with other ongoing international initiatives, and collaborate constructively with patient groups and international consortia and experts. For example, we will actively collaborate with the patient group, Autism Europe, and the Autism Genetic Resource Exchange (AGRE). Thus, we propose an innovative program that will have genuine impact on academic, pharmaceutical, and regulatory stakeholders in the field of ASD. By the end of the 5 year project we expect to provide novel validated cellular assays, animal models, new fMRI methods with dedicated analysis techniques, new PET radioligands, as well as new genetic and proteomic biomarkers for patient-segmentation or individual response prediction. We will provide a research network that can rapidly test new treatments in man. These tools should provide our EFPIA partners with an added competitive advantage in developing new drugs for ASD.

Rietschel M. BMBF - Bundesministerium für Bildung und Forschung 01ZX1314G: e:Med Integrament, Integrierte Untersuchungen von Ursachen und Mechanismen psychiatrischer Störungen. 01/2014-12/2016.

1. Vorhabenziel Teilprojekt 2 (ZP2) verfolgt die Ziele der Identifikation von Phenotyp-Phänotyp-Assoziationen, der Bereitstellung von großen Patientenstichproben sowie der Ausweitung der Patientenressource des Konsortiums auf eine deutschlandweite multizentrische Kohorte. In TP4 und TP5 stehen die Identifizierung und Validierung neuer Marker (Bildgebung/Imaging, Genetik, Klinik, Umwelteinflüsse) für Schizophrenie (SCZ) sowie Unipolare und Bipolare Störung (MD) im Vordergrund. Es sollen computationale Netzwerk-Modelle zur Darstellung der dynamischen Abläufe im Gehirn, vor allem des präfrontalen Cortex, von Patienten mit SCZ und MD erarbeitet werden (TP10). Es ist folgende Gliederung einzuhalten: 1. Vorhabenziel, 2. Arbeitsplanung 2. Arbeitsplanung TP2: Identifizierung robuster Genotyp-Phänotypmuster mittels Genomsequenzierung und ggf. Patienten-Wiederbegutachtung. TP4 und 5: Etablierung der Bioinformatik-Infrastruktur, Marker-Identifizierung und –Validierung, Festlegen prädiktiver Marker. TP 10: Statistische Beschreibung zellulärer und synaptischer Transferfunktionen bei Kandidatengenen (CACNA1C, NCAN) und anschließende Netzwerk-Darstellung. 3. Ergebnisverwertung Ein vertieftes Verständnis der Pathophysiologie psychiatrischer Erkrankungen wir mittel- und langfristig zur Entwicklung von neuen und besser wirkenden Behandlungsstrategien und Medikamenten führen.

EFIC-Grünenthal-Grant (EGG): Circuits of pain memory in chronic pain patients. 01/2015-12/2016.

Tost H. BMBF - Bundesministerium für Bildung und Forschung 01GQ1102: Multimodale Bildgebung fronto-striataler Plastizität im menschlichen Gehirn: Biomarker, genetische Mechanismen, . 04/2011-03/2016.

Dieses neurowissenschaftliche Forschungsvorhaben widmet sich bisher unvollständig erforschten Aspekten von neuronaler Plastizität, der essentiellen Fähigkeit synaptischer Schaltkreise zur erfahrungsabhängigen Adaptation, die bei psychiatrischen Erkrankungen wie der Schizophrenie häufig gestört ist. Das Vorhaben erweitert das bestehende Grundlagenwissen über die Mechanismen fronto-striataler Plastizität und soll multimodal bildgebenden Plastizitätsmarker mit hohem klinischen Potential erarbeiten.

Flor H. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP C01: Lernen und Plastizität des Gehirns bei PTSD: Risikofaktoren und die Rolle der Konditionierung von Hinweisreizen und Kontexten. 01/2012-12/2015.

The goal of this study is the analysis of learning processes and plastic brain changes in the development and maintenance of posttraumatic stress disorder (PTSD). We hypothesize that enhanced cue and deficient context conditioning along with high stress sensitivity lead to an enhanced risk to develop PTSD after traumatic experience and suggest that these alterations in associative and non-associative learning are accompanied by enhanced amygdalar and reduced hippocampal activation during acquisition and deficient midfrontal-amygdalar and midfrontal-hippocampal connectivity during extinction. In addition, we believe that traumatic stress, which alters the brain structure in these regions and leads to altered stress reactivity of the ypothalamus-pituitary-adrenal axis (HPA), contributes to the occurrence of PTSD along with peritraumatic factors. In the last funding period we continued the longitudinal study and added another 125 students in schools for rescue workers to the original 120 subjects (we plan to have 300 complete cases by the end of 2011) and characterized them with psychometric, psychophysiological, neuroimaging, endocrine and genetic methods. Since we do not yet have enough subjects who converted to PTSD we focused on predictors of cue and context conditioning in this sample. We found that hippocampal volume predicts context conditioning and that larger amygdala volume is associated with better cue conditioning, whereas cue conditioning is reduced with larger hippocampal volume. We also found that polymorphisms related to the minor alleles of HPA axis-related genes predict enhanced amygdala activation during cue conditioning and reduced prefrontal activation and prefrontal-amygdala connectivity during extinction. A polymorphism on the neurogranin gene, which has been associated with high risk for schizophrenia and memory disturbance, was found to predict hippocampal activation during context conditioning. In addition, traumatized persons with and without PTSD and healthy controls participated in cross-sectional neuroimaging studies. We found enhanced stress sensitivity as indexed by higher stress analgesia in the patients with PTSD and this was linked to enhanced activation in the rostral anterior cingulate. We also observed better second order conditioning with trauma cues as unconditioned stimuli in the PTSD patients accompanied by amygdala deactivation, which was associated with delayed extinction and abnormal dorsolateral prefrontal activation. In the PTSD group renewal was enhanced and associated with reduced hippocampal activation. A study on reinstatement is still ongoing as is the assessment of the effects of exposure treatment on renewal and einstatement. We also observed enhanced hippocampal activation during simple contextual conditioning in the PTSD group. These data are in line with our hypothesis of deficient context conditioning as a core pathological factor in PTSD. In the new funding period we will complete the longitudinal study by adding another 150 subjects to arrive at a total of 450, will retest persons who developed PTSD symptoms and compare them to persons who were traumatized without developing the disorder and matched controls from the rescue worker samples. In addition to retesting these predefined subjects we will use regression analyses to predict symptoms from the baseline tests in the entire sample. In the cross-sectional study we will expand the analysis of the role of deficient contextual processing in PTSD. Study 1 will test the hypothesis that PTSD patients focus their attention more on emotional cues at the expense of contexts compared to traumatized persons without PTSD and controls and that this is an early attentional process related to the perception rather than the evaluation of the stimuli that also determines that cues are better remembered than contexts. The study combines electroencephalographic recordings and eye tracking. A second study will examine the relationship of cued and contextual fear by combining differential fear conditioning to cues and contexts in one study. The contexts will be more complex than previous contexts in order to be able to model configural versus single item processing. Extinction to cues, contexts and their combination will be tested on a separate day and in a third session the response to the cues and contexts will be reversed (the previous danger cue/context will signal safety and vice versa) and tested with and without a retrieval cue. This will permit to test the role of inhibitory mechanisms and safety signals and will provide the possibility to determine how easily aversive memories can be updated. Functional magnetic resonance imaging will be employed to study the role of medial prefrontal and orbitofrontal circuits in this task. In these studies the effects of exposure treatment will also be examined to test if the deficient processing of cue-context interactions is an enduring deficit or can be reversed by effective treatment. Finally, we will address the specificity of the altered onditioning mechanisms and the brain correlates by using comorbidity, medication effects and trauma load as covariates and by comparing our patient group to others in and outside the collaborative research center with respect to the specificity of alterations in context conditioning.

Meyer-Lindenberg A, Rietschel M. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP B07: Plastizität präfrontaler Netzwerke beim Menschen: Genetische Variation, zelluläre Mechanismen und Modulation durch Neurofeedback. 01/2012-12/2015.

Das Arbeitsprogramm beinhaltet drei Experimente an gesunden Kontrollprobanden, die mit der in der gegenwärtigen Förderperiode entwickelten Methode durch repetitive transkranielle Magnetstimulation und multimodale Bildgebung in Hinblick auf ihre präfrontale Plastizität und Konnektivität charakterisiert werden. Im ersten Experiment werden die Auswirkungen genomweit signifikanter Risikogenvarianten auf die präfrontale Plastizität und Konnektivität untersucht, indem mit Methoden der „Imaging genetics“ die Assoziation dieser Genotypen mit den multimodalen Bildgebungsdaten in der Gesamtgruppe untersucht werden. Im zweiten Experiment werden neuronal-synaptische Marker der Plastizität bestimmt und mit den Bildgebungsdaten in Beziehung gesetzt. Dazu werden aus Hautbiopsien induzierte pluripotente Stammzellen gewonnen, neuronal differenziert und charakterisiert, und mit Bildgebungsparametern der Plastizität korreliert. Im dritten Experiment wird die Frage untersucht, ob die in der gegenwärtigen Förderperiode identifizierten neuronalen Interaktionen durch Neurofeedback veränderbar sind. Dazu wird ein zusätzliches Konnektivitäts-Echtzeit-funktionell-magnetresonanztomographisches Experiment durchgeführt, in denen die Probanden lernen, präfrontal-hippokampale und zingulär-amygdaläre Konnektivität zu modulieren.

Meyer-Lindenberg A. : Research Prix "ROGER DE SPOELBERCH". 05/2015-05/2015.

Advancing treatment discovery in schizophrenia through functionally relevant neuronal intermediate phenotypes: a combined neuroimaging, genetics and human induced pluripotent stem cells approach The problem: Therapy development in schizophrenia is at an impasse: no fundamentally new drugs have been discovered in decades, treatment, especially for cognitive and negative symptoms, is unsatisfactory, and a massive disinvestment of industry in the last years highlights the urgent need to rethink the translational process1. As a consequence, schizophrenia remains one of the largest sources of disability, cost2 and burden3 in all of medicine. A major obstacle to psychiatric translation has been the inaccessibility of neuronal target tissue. This has now changed in principle through the availability of human induced pluripotent stem cells (hiPSC) that can be differentiated into neural lineages (hiPSCN), and studies have shown that hiPSCN exhibit morphological signatures found in schizophrenia brains4. These morphological features could be used for cellular imaging based high-throughput screening in drug discovery. However, to turn this assay into a pathway to translation it must be specified which morphological changes are functionally relevant, linked to the pathophysiology of the illness and ideally also to clinical course. Previous work: We have been active for a number of years defining neural systems-level intermediate phenotypes for schizophrenia using a combined genetic-neuroimaging approach 5-8. In work funded by the German Research Council, we have established a robust pipeline to differentiate neurons from hiPSC derived from genotyped healthy subjects into glutamatergic, GABAergic (figure 1, left) and dopaminergic lineages. We characterize their morphology and plasticity (neuronal growth, axon segment movement, calcium imaging, marker proteins, synapse density, monosynaptic connectivity), and obtain in-vitro electrophysiological recordings using patch-pipettes9 (figure 1, right). We have also created the world’s largest dataset of imaging data in whole-genome sequenced subjects carrying high-risk copy number variants for schizophrenia and autism in collaboration with Aventis/deCode Genetics, funded by the European Union Innovative Medicine Initiative (projects NEWMEDS and EU-AIMS). In the IMAGEMEND project, recently funded by the EU (FP7), we bring together neuroimaging and genetics information on over 13.000 subjects with clinical course and treatment information, enabling us to identify systems-level phenotypes relevant for illness progression. We are therefore in a good position to identify neuronal phenotypes that are linked to genetic/ expression profiles and heritable systems-level mechanisms of schizophrenia. Research proposal: In the research proposed here, we aim to systematically identify robust cellular and assembly-level phenotypes linked to genetic risk, systems-level dysfunction and course of schizophrenia (see figure 2). The focus on genetic risk is motivated by (a) the high heritability of the illness and (b) the fact that hiPSC generation entails large-scale epigenetic reprogramming. hiPSCN will be morphologically quantified as described above. In addition, assemblies of glutamatergic cells will be characterized using electrophysiology with established protocols that probe passive properties and instantaneous and steady-state f/I curves. Using a recently established efficient, fast, and predictive model-fitting framework 9, we will translate these recordings into physiologically valid neuron descriptors which can be embedded in anatomically and physiologically realistic models. To identify the subset of these features that is heritable, we will compare hiPSCN from healthy controls and patients with schizophrenia with subjects at increased formal genetic risk (first-degree relatives of patients from high-density families). All of these subjects are available from funded work. Following the intermediate phenotype (or “endophenotype”) concept, we will select measures that are abnormal in patients and show intermediate expression in genetic risk subjects. From heritable neuronal features that associate with assembly level function, we will then select features that are linked to systems-level intermediate phenotypes for schizophrenia, in particular dorsolateral prefrontal cortex (PFC) activation and PFC-HF connectivity, that have demonstrated heritability and are linked to course through IMAGEMEND data. We will verify that these features can be measured reliably in control experiments from hiPSCN derived from the same participants and exclude somatic de-novo mutations in the hiPSCN through sequencing. Deliverables: This project will for the first time identify morphological features in hiPSCN linked to assembly and systems level function relevant to heritable risk and course for schizophrenia. This will enable a new generation of high throughput drug discovery for schizophrenia. The link achieved in this project between the cellular, assembly and systems level also closes a critical gap in our understanding of how neuronal abnormalities, through changing systems-level function, lead to the complex symptomatology of schizophrenia. Finally, this unique joint genetic-neuronal-imaging dataset should be useful to provide parameters for innovative computational approaches to comprehensively model brain function, such as the Human Brain Project.

Meyer-Lindenberg A, Leweke FM. EU - Europäische Union 241909: EU-GEI: European Network of National Schizophrenia Networks Studying Gene-Environment Interactions. 05/2010-04/2015.

The aim of EU-GEI is to identify, over a 5-year period, the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia. In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-the-art assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in (i) the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and (ii) the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in helpseeking individuals with an at-risk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of aim of EU-GEI is to identify, over a 5-year period, the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia. In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-theart assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in (i) the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and (ii) the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in help-seeking individuals with an atrisk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of skills required to deliver a program of research that meets all the call’s requirements and who have access to / will collect a number of unique European samples. The The aim of EU-GEI is to identify, over a 5-year period, the interactive genetic, clinical and environmental determinants involved in the development, severity and outcome of schizophrenia. In order to identify these interactive determinants, EU-GEI will employ family-based, multidisciplinary research paradigms, which allow for the efficient assessment of gene-environment interactions. In order to go beyond old findings from historical convenience cohorts with crude measures of environmental factors and clinical outcomes, the focus in EU-GEI will be on recruitment of new, family-based clinical samples with state-of-the-art assessments of environmental, clinical and genetic determinants as well as their underlying neural and behavioural mechanisms. New statistical tools will be developed to combine the latest multilevel epidemiological with the latest genome-wide genetic approaches to analysis. Translation of results to clinical practice will be facilitated by additional experimental research and risk assessment bioinformatics approaches. This will result in (i) the identification of modifiable biological and cognitive mechanisms underlying gene-environment interactions and (ii) the construction of Risk Assessment Charts and Momentary Assessment Technology tools which can be used for (i) early prediction of transition to psychotic disorder in help-seeking individuals with an at-risk mental state and (ii) early prediction of course and outcome after illness onset. In order to reach these goals, EU-GEI has assembled a multidisciplinary team of top schizophrenia researchers who have the range of skills required to deliver a program of research that meets all the call’s requirements and who have access to / will collect a number of unique European samples. The partners in EU-GEI represent the nationally funded schizophrenia / mental health networks of the UK, Netherlands, France, Spain, Turkey and Germany as well as other partners.

Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01GQ1003B: BCCN TP C7: PFC-HC coupling in schizophrenia. 05/2010-04/2015.

Zink M, Meyer-Lindenberg A, Kirsch P. DFG - Deutsche Forschungsgemeinschaft DFG ZI 1253/3-2, KI 576/14-2, ME 1591/6-2: Metakognitive Defizite bei Patienten mit erhöhtem Risiko für schizophrene Psychosen und deren Interaktion mit Psychopathologie, Neuropsychologie und funktioneller Bildgebung. 09/2012-02/2015.

Schizophrenia patients suffer from a broad variety of cognitive deficits that are very often resistant to antipsychotic treatment and interfere with the social and vocational rehabilitation. An international consensus initiative elaborated a comprehensive set of neuropsychological tests, the MATRICS battery (Measurement And Treatment Research to Improve Cognition in Schizophrenia) in order to improve treatment research (1). Besides the domains represented in the MATRICS battery, it has been shown that metacognitive capacities are impaired in schizophrenia, leading to a reduced ability to select appropriate responses, to appraise and weigh information effectively and to cope with cognitive limitations. Metacognitive impairments, (2) such as a self-serving attributional bias, hasty decision making (jumping to conclusion: JTC), a bias against disconfirmatory evidence (BADE) (3), overconfidence in errors, metamemory alterations (4;5), and finally deficits in mentalizing and social cognition („theory of mind“: ToM) (6;7), are thought to contribute to development and maintenance of delusions (8-10). Specific therapeutic interventions to improve metacognitive functions have been developed and tested in several controlled trials (11). In the present application, we mainly focus on ToM-deficits and the JTC-bias.

Flor H. EU - Europäische Union 230249: ERC PHANTOMMIND: Phantom Phänomene: Ein Fenster zu Geist und Gehirn. 01/2009-12/2014.

Obwohl nach der Amputation einer Gliedmaße fast immer Phantom Empfindungen, d.h. Empfindungen im nicht mehr vorhandenen Körperteil, auftreten ist dieses Phänomen noch nicht gut verstanden. Veränderungen der Repräsentation des Körpers im Gehirn wurden mit dem Ausmaß des Phantomschmerzes in Beziehung gesetzt. Außerdem gibt es große Ähnlichkeiten zwischen nicht schmerzhaften Phantomphänomenen und Körperillusionen wie z.B. der Gummihand-Illusion. Die Forschung konnte zeigen, dass das Gehirn nicht die tatsächliche, physischen sondern die empfunden Realität verarbeitet. Dies gibt sowohl in der Grundlagenforschung als auch bei der Behandlung von Phantomschmerz die Möglichkeit die erlebte Realität zu manipulieren. Verhaltenstherapeutische Interventionen wie ein Prothesentraining, ein sensorisches Diskriminationstraining oder ein Spiegeltraining beeinflussen den Phantomschmerz und verändern die Gehirnfunktionen. Das Ziel dieses Projektes ist (1) eine exakte Erhebung und Analyse der Beziehung verschiedener Phantomphänomene wie Phantomschmerz, Phantomempfindungen, Telescoping (die Wahrnehmung, dass sich das Phantomglied in seiner Länge verändert), Prothesennutzung, und Empfänglichkeit für Körperillusionen in einer großen Stichprobe durch zu führen, (2) die Analyse der neuronalen Korrelate dieser Phänomene in kleinen Subgruppen mittels der funktionellen Magnetresonanztomographie und der transkraniellen Magnetstimulation, (3) die Analyse der Determinanten und neuronalen Korrelate von Körperillusionen bei gesunden Personen um gemeinsame neuronale Mechanismen zu identifizieren und (4) ein virtuelles Training zur Nutzung der Prothese kurz nach der Amputation zu untersuchen um zu verstehen wie eine Manipulation des Körperschemas und sensorisches Feedback die Entstehung und die Korrelate der Phantome im Gehirn verändern.

Meyer-Lindenberg A, Kirsch P. DFG - Deutsche Forschungsgemeinschaft ME 1591/4-1: KFO 256 TP 3: Neural Mechanisms of Trust and Dyadic Interaction in BPD . 01/2012-12/2014.

Meyer-Lindenberg A. EU - Europäische Union 282586: ROAMER: A Roadmap for Mental Health Research in Europe. 10/2011-09/2014.

On the regional level, Europe has one of the highest levels of resources for mental health care. Despite this, the high burden and impact of mental disorders in Europe is expected to rise. “ROAdmap for Mental health Research” (ROAMER) is designed to develop a comprehensive, consensus-based roadmap to promote and integrate mental health and well-being research in Europe. Research advances and innovations are to be devoted to decreasing the burden of mental disorders and increasing the mental health and well-being of Europeans. ROAMER will combine a neutral, fact-based methodology with extensive stakeholder involvement in consultation and dissemination. During the kick-off phase, the methodology (including comprehensive EU-wide indicators to assess the current state of the art, gaps and advances) and the desired situation (scoping and objectives) will be finalised. Secondly, the current state of the art will be examined, using these tools. In the third phase, the desired situation will be compared with the current situation to identify gaps and advances. Phase four prioritises these gaps and advances, as well as solutions. In the fifth phase, this information is translated into roadmaps covering infrastructures, capacity building and funding strategies for scientific areas relevant to mental health and well-being: biomedical, psychological, social, economic and public health. Geographical, interdisciplinary, developmental, gender and age perspectives will be taken into account. To achieve consensus among a broad group of scientists, service users, carers, government and funding institutions and other stakeholders, ROAMER uses web-based survey’s, scientific workshops, scientific advisory board meetings, stakeholder meetings, consensus meetings, and policy meetings. The consortium consists of leading experts in the field, and is well balanced in terms of geographical distribution and complementary expertises across all relevant aspects of mental health research.

Meyer-Lindenberg A. EU - Europäische Union 115008: IMI JU NEWMEDS: Novel Methods Leading to New Medications in Depression and Schizophrenia. 09/2009-08/2014.

Despite remarkable advances in molecular and imaging technologies and nearly 15,000 articles on schizophrenia and depression (S&D) every year, there have been few truly innovative new chemical entities (NCEs) which have made it to the clinic. While there has been a tremendous explosion of new knowledge: dozens of single-nucleotide polymorphisms linked to disease, hundreds of new molecules and pathways identified, numerous imaging findings differentiating patients from controls, yet, it has been hard to take these findings from the bench to the clinic. We think there are three major bottlenecks that are holding the field back: i) a lack of pathophysiologically-accurate animal models guiding the drug discovery of NCEs; ii) a lack of tools and tests in healthy volunteers that can provide early indication of efficacy; and iii) the reliance of clinical trials on symptom-based DSM-categories which inevitably lead to biologically heterogeneous groups of patients. To overcome these limitations, we have brought together a consortium of six leading European and an Israeli academic institution (which bring expertise in animal models, genetics, functional MRI and PET imaging, clinical settings and analysis methods) and two SMEs (which bring expertise in high-throughput genetics, transcriptomics and proteomics) who will partner with the dozen EFPIA partners in the NEWMEDS consortium. To specifically target the challenges identified in Call 10, the NEWMEDS consortium will: a) develop animal models that focus on reliable cross-species endophenotypes (e.g., cognitive function, electrophysiology) and use crossspecies methods (small-animal MRI, EEG and micro-PET) to bring animal models closer to clinical endpoints; b) validate the use of fMRI-based paradigms as early and surrogate markers for efficacy; and to combine this with PET approaches for measuring changes in endogenous transmitters – thus providing new methods that can be implemented in small Phase 1B studies in healthy volunteers to provide guidance for drug development; and c) identify pharmacogenetic biomarkers that can be used to stratify patients within an umbrella DSM-diagnosis, thus allowing for targeted clinical trials, individualized treatment and back-translation of subgroup-specific biomarkers into preclinical drug discovery. To increase the chance of a breakthrough we will implement new analytical approaches – the use of support vector machine learning algorithms for image analyses; the use of Bayesian and growth mixture models for more meaningful analyses of clinical trial data. The project will be delivered through a series of integrated workpackages organized in three clusters – preclinical models, imaging methods, and biomarker development as exemplified in Figure 1. Our consortium has achieved its 1:1 in-kind match, indicative of the involvement and commitment of all EFPIA partners. One of Europe’s leading scientific management SMEs (GABO:mi) will facilitate the management of NEWMEDS and a distinguished international Scientific Advisory Board will provide input and guidance. To ensure that we maximally integrate with other ongoing international initiatives, we have commitments of collaborations from several international consortia and experts (e.g. MATRICS, NIH Biomarkers Consortium). By the end of the 5 year project we expect to provide ready to use new cross-validated animal models, new fMRI methods with dedicated analysis techniques, new PET radioligands, as well as new genetic and proteomic biomarkers for patient-segmentation or individual response prediction. These tools should provide our EFPIA partners with an added competitive advantage in developing new drugs for S&D.

Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01GS08147: NGFN Plus MooDS TP 6: Molekulare Ursachen von Affektiven Störungen und Schizophrenie: Imaging Genetics. 06/2011-05/2013.

Zentralinstitut für Seelische Gesundheit (ZI) -