Competencies of C-I-R-C
Our Core Competencies Include
(1) Multi-scale & multi-species research into brain circuitries underlying maladaptive processes in normal and abnormal social interactions
(2) Inflammatory processes and their influence on neuroplasticity mechanisms
(3) Track record of multi-scale bio-imaging methods development
To contribute to the German Center for Mental Health this unique and integrative portfolio towards the elucidation of neural access points (NAPs)
Longitudinal profiles of these processes and markers in different time scales throughout development
In collaboration with the specific expertise of other future members this will ultimately result in novel diagnostic markers and therapeutic interventions
Translational Circuit Imaging (Neuroimaging)
Experience: We will build on our longstanding and internationally recognized expertise in advanced neuroimaging techniques combined with strategic multi-disciplinary strengths in biomedical and mental health research.
Complementary expertise: Partner institutions in Jena and Magdeburg have strong, complementary backgrounds in the development of novel multimodal imaging techniques for fundamental bioscience and their application in psychiatric research and therapeutic interventions.
Pioneering: We are one of the leading institutions in using field strengths of 7 Tesla (T) and among the pioneers in psychiatric ultra-highfield (UHF) MRI research. Pushing the boundaries of macroscopic resolution, we have produced the highest resolution T1-weighted in vivo anatomical scans in the world, with an isotropic resolution of 250 μm.
Resolution & scalability: Based on similar methodologies, the resolution of in vivo angiography has been pushed to an impressive 150 μm isotropic resolution. In addition to demonstrating our world-class abilities in methods development, these methods have been applied in several neuroscientific and clinical research studies. This allows for leading macro-, meso-, and micro-circuit analyses in both Magdeburg and Jena. We can now directly compare non-invasive clinical MRI methods at 7T with gold standard invasive methods in monkeys.
Examples & Perspectives:
- Engineering excellence in the Institute for Biomedical magnetic resonance (Head O. Speck) spearheaded pioneering research on signal processing and artifact removal on 7T MRI data. This allowed high resolution fMRI at 7T that led to seminal layer-specific activation detection in the brain. To overcome the biological resolution limit for high-field MR, innovative methods for prospective motion correction were developed and applied.
- Our methodological and biomedical imaging expertise in ultra-highfield imaging is also applied in sequence development for longitudinal clinical neuroimaging at 3T MRI.
- C-I-R-C partner sites have access to eight 3T research-dedicated Siemens Prisma MRI scanners. We have longstanding expertise in multicenter 3T MR imaging studies, providing harmonisation of measurements and quality control for thousands of scans and up to 9 imaging centers all across Germany. Our longitudinal multicenter studies link evolving structural brain changes to therapy outcome predictions and highlight the pressing need for early and recovery-oriented therapies.
- Our multimodal imaging expertise and the translation of neural access points in postmortem or animal research to human neuroimaging is supported by the interdisciplinary Center of Brain and Behavioral Sciences (CBBS).
- We organize regular interdisciplinary meetings to help translating our neuroimaging expertise into clinical practice (e.g. Brain-in-Depth-meeting, Locus Coeruleus Imaging meeting).
- We identify markers of disease vulnerability in subcortical and cortical brain structures using anatomical magnetic resonance imaging (MRI) and postmortem whole brain immunohistochemistry. This has allowed imaging of small nuclei and circuits with high psychiatric relevance such as the habenula and the locus coeruleus.
- Our multimodal imaging expertise is complemented by a strong focus on molecular imaging using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS).
Betts et al., 2017 (Neuroimage)
- The C-I-R-C partner sites have access to a concurrent MR-PET scanner, an animal PET and a research cyclotron.Together with our expertise in the development and optimization of MRS sequences at multiple field strengths, this will allow for identifying and monitoring synaptic and neuromodulatory neural access points in vivo.
- Application of cutting-edge imaging technologies in patients is rooted in our excellence in hardware and analysis methods in MRI, electroencephalography (EEG), and magnetoencephalography (MEG).
- Our excellence of hardware and acquisition methods in Magdeburg is complemented by leading expertise in advanced computation toolsin Jena which facilitate clinical application of novel imaging methods.
- As one of Germany’s main developers of anatomical analysis software, C. Gaser pioneered the voxel-based morphometry method (VBM) and developed the Computational Anatomy toolboxes (CAT) to conduct computational morphometry, which are heavily used by the scientific community (>40,000 downloads). We have further strong expertise in data modeling (G. Ziegler).
Neural Access Points
In C-I-R-C, we can rely on a unique circuit concept and proven research paradigms at multiple scales.
Circuits are confined networks with defined system functions, measurable input and output function, and dynamic experimentally inducible changes. We will enrich our psychiatric research by identification of neural access points within multiple scales.
At the macro scale we will investigate interregional connections, which underlie neural resource allocation, e.g. the prefrontal-limbic connectivity using MRI or MEG/EEG.
At the meso scale determinants of neural resources are followed up at the level of layer-specific intracortical and short interregional circuits using ultra high-field (UHF) MRI in humans and animals, including primates.
For these circuits, the molecular processes governing glutamatergic, GABAergic and dopaminergic signaling will be investigated at the micro scale in genetic, induced-stress, inflammation, and traumatic/sepsis models as well as 2-hit models of depression, schizophrenia and PTSD.
Future progress in this research will crucially depend on the availability of better animal models. Such models pave the way for target-specific translation of fundamental findings from preclinical research to the clinic.
The fact that neuropsychiatric disorders are generally polygenic makes it difficult to develop adequate genetic models. The combined approaches using genetic, pharmacogenetic, optogenetic, and behavioral challenges are the most promising to identify and test neural access points.
We have long-standing experience in developing and refining behavioral test paradigms in animals from flies to rodents (e.g. see the Sauvage lab, Albrecht lab, and Stork lab) and non-human primates (see the Krug lab). These are combined with electrophysiological recordings, optogenetics and neuroimaging to detect circuit mechanisms of disease processes (see the Remy lab, Mikulovic lab, and Pakan lab).
Our fundamental molecular research in neuron and synapse biology has revealed several candidates linked to essential elements of glutamatergic synapses, their neuromodulation, communication between synapse and nucleus (see Kreutz lab), and with the perisynaptic extracellular matrix (ECM) (see Dityatev lab).
Our expertise is documented in group grants like the collaborative research centers “Neurobiology of motivated behavior” and the recently established “Neural Resources of Cognition“, the graduate programs SynAge and ABINEP. To advance identification of neural access points at the synapse level, we contribute to the international SynGO consortium, providing an evidence-based resource for synaptic protein studies.
We believe that the elucidation of such neural access points at the nano-, meso- and macroscale will be instrumental for novel diagnostic and treatment solutions.
Social and Cognitive Processes
Social interaction and cognitive control play decisive roles in the underpinnings of psychiatric disorders and in all aspects of human life. Understanding and intervening neural circuits maladaptation in mental health therefore requires expertise in social cognition.
Within C-I-R-C, the Departments of Psychology are actively translating fundamental research in cognitive and social neuroscience to clinical populations and have well-established collaborations with Departments of Psychiatry and Psychosomatics.
Our research excellence concerns not only verbal and non-verbal communication but also social interaction, social neuroscience, and intrapsychic processes such as person perception, affectivity, olfactory processes and cognitive control. This extends to psychotherapy research, which has the central goal of modifying social interaction in health and disease.
Examples & Perspectives:
- Our research strength of olfaction and affective touch, represents a fundamental aspect of social interaction with crucial relevance for dyadic communication and its disturbance (I. Croy, Era-Net “Pretouch”).
- We provide complementary and comprehensive expertise in functional brain imaging of the social-emotional (face) interaction, reward, social anhedonia and social separation anxiety (R. Redlich, MLU).
- We hold a strong position in research in basic perceptual, social, and neuronal processes underlying how humans perceive each other, predominantly by facial and non-verbal vocal information (S. Schweinberger, DFG-RU “Person Perception”).
- Excellence in research on the neurobiology of psychosocial stress, neural dyadic stress covariance and the peripheral-physiological underpinnings of stress contagion (V. Engert, IPMPP).
- Long-standing tradition in multi-site clinical studies of psychotherapy process and outcomes, and experience in research on the neural patterns of attachment styles (B. Strauß, IPMPP).
- Advancing the understanding of motivational and cognitive control mechanismsand decision making (M. Ullsperger, OvGU).
- Recognized expertise in studying the neural background of predictive coding in social context, which we transfer to patients with schizophrenia (G. Kovascz, BPCN).
C-I-R-C provides an ideal platform to study function and development of NAPs and inflammatory processes as well as their interactions in a translational developmental context across all age groups.
Immune mechanisms can influence neuronal circuits and signaling leading to dysfunction of the brain ultimately causing complex psychiatric and neurological symptoms. Aberrant immune activity contributes to the development and progression of several psychiatry disorders such as major depression and schizophrenia and can induce characteristic autoimmune disorders, e.g. autoimmune encephalitis.
C-I-R-C researchers have a long-standing history in neuropsychoimmunology and are on the way to elucidate pathogenic disease mechanisms in the crosstalk of the immune system with the brain.
Examples & Perspectives:
- We provide special expertise in neurobiochemistry and experience in research on immunological and inflammatory molecular mechanisms that are linked to neuronal dysfunction (I. Dunay: CRC854; C. Geis: Neuroimmunology, J. Steiner: SASLAB)
- In-vivo non-invasive based topology of glial activation triggering abnormal neural function in brain systems modulating social and stress behavior can be analyzed by PET and MRI.
- Our translational line of researchexplains phenotypical consequences of inflammatory subtypes in psychiatric disorders for example by the large brain autopsy and blood biobank derived from patients with depression and psychotic disorders (J. Steiner: SASLAB).
- The translational research group of C. Geis, supported by the Schilling foundation, DFG-RU FOR 3004 SYNABS, and ERA-NET NEURON project “Autoscale”, has outstanding experience in researchon autoantibody-mediated disorders, e.g. NMDA receptor encephalitis and further subtypes of autoimmune encephalitis on the subcellular level, in animal models, and in clinical studies (C. Geis: Neuroimmunologie).
- We have an excellent clinical and translational research network and infrastructure to elucidate the effects of systemic inflammation on mental health in a multidisciplinary manner (CSCC).
- The interaction of the innate immune system with neurons is investigated in the context of neuropsychiatric diseases, e.g. by interfering with microglia activation using pharmacological and genetic models.
- We can rely on established patient cohorts with neuropsychiatric disorders and symptoms, e.g. following severe systemic inflammation (Mid German Sepsis Cohort) and with autoimmune brain disease (GENERATE).
The Microbiome as a Modifier of Mental Health
Alterations in the gut microbiome may be considered as one pathway linking chronic stress responses, the gut, increased cytokines levels, and mental health.
C-I-R-C has unique and outstanding, multidisciplinary expertise in microbiology and infection biology that will greatly contribute to the study of stress- and immune-related crosstalk in mental diseases.
C-I-R-C excellence in infection, microbiological, and particularly microbiome and phagosome research is shown in numerous collaborative research projects including clinical expertise, such as the Cluster of Excellence „Balance of Microverse“, the CRC/TR 124 “FungiNet”, the CSCC, and the BMBF consortium “InfectControl”.
Examples & Perspectives:
- The Cluster of Excellence EXC2051 “Balance of the Microverse” (A.A. Brakhage), funded in Germany’s Excellence Strategy since 2019, is investigating composition and interactive networks of microbial consortia in different habitats and interactions of microorganisms with the immune system.
- The Cluster builds on the successful Excellence Graduate School “Jena School for Microbial Communication” that has been funded in the Excellence Initiative since 2007 and is now funded by the Carl Zeiss Foundation.
- On a European level, this excellence is paralleled by an EU funded ITN “SmartAge” (O.W. Witte) where specific therapeutic targets are currently investigated.
- Within this network we are, amongst others, investigating the innovative aspect of crosstalk between epigenome and microbiome and their effects on cognition (C. Frahm).
- C-I-R-C further investigates how the modulation of gut microbiota composition affects adult hippocampal neurogenesis and neuronal impairment (I.R. Dunay), and has long-standing experience in microbiome associations with chronic inflammatory disorders in the CNS (A. Haghikia).
C-I-R-C provides an ideal platform to study function and development of neural access points and inflammatory processes as well as their interactions in a translational developmental context across all age groups.
Lifelong ageing is a thematic focus at all C-I-R-C partner institutions. C-I-R-C links the DZP with the German Center for Neurodegenerative diseases (DZNE) and a future center on childrens health (DZKG) subserving natural longitudinal interfaces.
Neuroimaging excellence in Magdeburg has successfully been transfered into the local DZNE site, which now coordinates all national DZNE macroimaging (MRI) activities, studies of more than 10 centers.
Examples & Perspectives:
- Understanding development as continuous change across the entire lifespan from childhood over adolescence to adulthood and old age allows us to study function and development of neural access points and inflammatory processes as well as their interactions.
- Identification of corridors of normal development of neural brain folding, cortical thickness, and myelination from birth to old age (C. Gaser). Using machine-learning, we synthesize such information into a brain aging index that relates to prenatal influences, gestational age and mental illness.
- Neurochemical pathways and linked neuroinflammatory aspects of mental health disorders in children, adolescents and adults are studied (F. Zepf).
- Transfer of neural access points and inflammatory processes to behavioral change and every day function:
- Development of standardized paradigms for measuring crucial developmental achievements, such as self-regulation, socio-emotional development, empathy development, memory and attention (CELISE, M. Riediger, and IKND, E. Düzel) is an important part of research in C-I-R-C.
- Identification of diagnostic and therapeutic strategies based on adaptive/maldaptive maturation trajectories (CRC Funding, K. Krauel). Examples are knowledge translation to train Kindergarten teachers and optimally equipment of classrooms (Leibnitz-Institute for Neurobiology; Prof. N. Wetzel).
We examine factors influencing development and effects of normal and abnormal functionality on development in other domains:
- Research on noadrenergic function in the elderly to understand cognitive control and value-based decision making, which led to an industry partnership on vagus nerve stimulation techniques (EFRE funding, D. Hämmerer).
- Research on the impact of C-tactile fiber development on parasympathetic control in preterm infants targets the impact on parent-infant interaction and the time to discharge from a neonatal unit (ERA-NET Funding, I. Croy).
Linkage & opportunities:
- Our experience with large patient & population surveys as well as cohort studies opens unique linkage opportunities (German National Cohort NAKO, M. Richter).
- Coherent standardized assessment of contextual behavioral and social determinants across neural and inflammatory studies enables to investigate the role of sociological factors on biological and psychological development as well as neural plasticity.
- The unique longitudinal inflammatory cohort Löwenkids at the German center for infection (DZIF) was established within C-I-R-C (R. Mikulajzik). Together with a future German Center for Mental Health this will allow to study causality models between infections, stressor and mental health development.
- Effects of abnormal biological and psychological development at a given stage on current and future (mal)adaptive behaviors, socioeconomic status and other clinical variables can be explored.
- Such assessments allow for determining the effects of heterogeneity and sampling selectivity and their implications.