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Prof. Dr. Dr. Heike Tost

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.

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.

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

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. 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.

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.

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. 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.


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