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Projekte: Translationales Imaging

DFG - Deutsche Forschungsgemeinschaft SA 1869/15-1: Delineating neural circuitry of STress REsilience and Stress Susceptibility using DREADD combined with fMRI technique (STRESS-DREADD). 02/2019-01/2020.

Depression has become the second leading cause of illness-induced disability with 300 million people affected. Suicide due to depression is the second leading cause of death in 15-29-year-olds. Chronic stress exposure greatly raises depression risk. However, there is a degree of inter-individual variation in the way people respond to severe stress, with a spectrum ranging from vulnerability to resilience. Since no current antidepressant is effective for more than 50% of patients, a new frontier in psychiatry could be an induction of natural mechanisms of resilience to treat depression. Our aim is to understand the phenomenon of stress resilience in currently non-explored longitudinal perspective, i.e. to study brain before and after stress in order to separate trait and state-dependent markers of resilience and susceptibility, and also to separate maladaptive from pro-adaptive stress response. The understanding of what makes individuals more resistant to the deleterious effects of stress could suggest new path for the development of treatments. Once we know the key regions and projections discerning resilience and susceptibility, we aim to chemogenetically excite/inhibit these brain projections to find out whether it induces stress resilience in stress-susceptible rats, and vice versa. We will perform a longitudinal study using chronic mild stress model, one of the most realistic and extensively validated animal models of depression, and will use high-field functional magnetic resonance imaging (fMRI) to identify: (1) brain imaging endophenotypes of predisposition to resilience and susceptibility, i.e. trait markers (stress-free environment), (2) state-dependent endophenotypes of resilience and susceptibility (post-stress). Next, we will use a cutting-edge combination of high-field fMRI and a recently developed Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technique, to experimentally probe the effects of focal modulation of key regions and projections discerning resilience and susceptibility, in order to find out whether this manipulation would result in imaging endophenotype and behavior characteristic for stress resilience in stress-susceptible rats, and vice versa. Depression ist die zweithäufigste Ursache für krankheitsbedingte Behinderungen mit ca. 300 Millionen betroffenen Menschen weltweit. Die zweithäufigste Todesursache bei 15-29-Jährigen ist Suizid aufgrund von Depressionen. Eine chronische Belastung durch erhöht das Depressionsrisiko erheblich. Es gibt jedoch ein gewisses Maß an interindividuellen Schwankungen in der Art und Weise, wie Menschen auf schweren Stress reagieren, wobei das Spektrum von Anfälligkeit (Suszeptibilität) bis Belastbarkeit (Resilienz) reicht. Da mehr als 50% der Patienten nicht auf medikamentöse Therapien ansprechen, könnte die Induktion natürlicher Resilienzmechanismen zur Behandlung von Depressionen ein echter therapeutischer Fortschritt in der Psychiatrie sein. Unser Ziel ist es, das Phänomen der Stressresilienz auch longitudinal zu verstehen, d.h. das Gehirn vor und nach Stress zu untersuchen, um merkmals- und zustandsabhängige Marker von Resilienz und Suszeptibilität zu trennen und maladaptive, sowie adaptive Stress-Reaktionen zu erkennen. Das Verständnis dessen, was Individuen gegenüber den schädlichen Auswirkungen von Stress resistenter macht, könnte einen neuen Weg für die Entwicklung von Behandlungen vorschlagen. Sobald wir die Schlüsselregionen und -projektionen kennen, die in Resilienz- und Suszeptibilitätsprozesse involviert sind, wollen wir diese Gehirnprojektionen chemogenetisch anregen / hemmen, um herauszufinden, ob sie Stressresilienz bei Stress-empfindlichen Ratten induzieren und umgekehrt. Geplant ist eine longitudinale Studie mit einem chronisch-milden Stressmodell, welches als Tiermodelle der Depression umfassend validiert ist. Mittels funktioneller Magnetresonanztomographie (fMRT) an einem Hochfeldtomographen wollen wir Folgendes identifizieren: (1) bildgebende Endophänotypen des Gehirns zur Prädisposition Resilienz und Suszeptibilität, d.h. Merkmalsmarker (stressfreie Umgebung), (2) zustandsabhängige Endophänotypen von Resilienz und Suszeptibilität (post-Stress). Als nächstes werden wir eine hochmoderne Kombination aus Hochfeld-fMRT und einer kürzlich entwickelten Designerrezeptoren (DREADD) Technik verwenden, um die Effekte einer fokalen und spezifischen Modulation von Schlüsselregionen und Projektionen, die Stress-Resilienz bzw. -Anfälligkeit abbilden, experimentell zu untersuchen und um herauszufinden, ob diese gezielten Manipulationen zu einem bildgebenden Endophänotyp und Verhaltensänderungen führen, die für Stressresistenz bei Stress - empfindlichen Ratten charakteristisch ist.

Sartorius A. DFG - Deutsche Forschungsgemeinschaft SA 1869/14-1: Designer receptors exclusively activated by designer drugs (DREADDs) used for endophenoptyping neuronal networks of depression by functional connectivity magnetic resonance imaging (fc-fMRI). 07/2017-06/2019.

Depression is a common psychiatric illness affecting up to 17% of the Western population and estimated to be the most prominent cause of disability world-wide by 2020 [1]. About 15% of patients suffering from major depression do not respond to any antidepressant medications or to any other approved procedure. Thus, new treatment options for therapy resistant depression (TRD) are urgently needed. A better understanding of the underlying brain circuits of depression has led to the use of deep brain stimulation (DBS) to treat TRD, but optimal target(s) remain unclear [2]. The monoamine-deficiency hypothesis postulates a deficiency in serotonin or norepinephrine neurotransmission in the brain as a major pathomechanism underlying the disorder. There is, however, a growing body of evidence implicating a role for the glutamatergic system as well [3; 4]. Recently the lateral habenula (LHb) – as a central glutamatergic structure - was reported to mediate depressive-like behavior in rodents, to encode negative motivational value associated with primary punishment in humans and to reveal a new successful target for DBS for patients with therapy-refractory depression [5-9]. Abnormal function of the lateral habenula has been directly linked with major depression [10; 11]. We now aim to express genetically engineered receptors in neuronal cells of the lateral habenula. These receptors can exclusively be activated by a specific designer drug that does not activate endogenous receptors, but will up or downregulate habenula function when the designer drug is applied. Therefore, we will pharmacogenetically upregulate habenula activity to observe both, consecutive changes of depression related neurocircuitries by resting-state functional Magnetic Resonance Imaging (fMRI) [12-14] and concomitant behavioral changes regarding depressive-like behavior [15-17]. This proposed project aims to establish Designer Receptor Exclusively Activated by Designer Drugs (DREADD) of the lateral habenula in rodents as a new experimental treatment strategy. DREADD is a new genetic tool (also called “chemogenetics” or “pharmacogenetics”) to diminish the activity (or to cause burst firing) of genetically defined neurons. For example, the hM4Di-DREADD (a modified Gi-coupled human M4 muscarinic receptor) is activated by the otherwise inert drug-like small molecule clozapine-N-oxide (CNO), resulting in activation of G protein inwardly rectifying potassium channels, hyperpolarizing the cell and attenuating neuronal activity. In contrast, Gq-DREADD = hM3Dq activates another G-Protein cascade and triggers burst firing. In particular, this project would provide to the best of our knowledge the first combination of DREADD with functional connectivity fMRI to identify specifically induced changes of the affected habenular neurocircuitry. Further, for the identification of changes of depression associated neurocircuitry DREADD might be superior to optogenetics-assisted fMRI since it acts more physiological (by receptor activation) and omits imaging artifacts introduced through insertion of fiber optics in the brain for optogenetics [18]. In analogy to the successful implementation of electrical deep brain stimulation in Parkinson's disease (PD) [19], DREADDing may potentially serve as an alternative future treatment option other than cell replacement therapy for restoring neuronal populations and even deep brain stimulation (DBS) in PD. As a clear and fundamentally new future perspective, DREADD might enable novel treatment strategies of drug resistant depression beyond electric deep brain stimulation, since specific designer drugs have regional and functional specificity and may thus be highly effective with a desirable side effect profile. In other words, we propose a key experiment to show that DREADD could be the future alternative to deep brain stimulation (DBS). Resting state functional connectivity fMRI has been extensively established at our high field animal scanner [20]. After setting up resting state fMRI per se at our 9.4T small animal scanner [21; 22], we did first pharmacological functional connectivity fMRI projects with haloperidol [12] and ketamine challenges [14]. We performed translational functional connectivity fMRI studies to compare effects with clinical trials [23] and used graph theory analyses for translational studies as well [24].

Sartorius A. DFG - Deutsche Forschungsgemeinschaft SA 1869/11-2: "Einfluss von Schilddrüsenhormonen,Schilddrüsenhormonrezeptoren und Schilddrüsenhormontransportern auf Hirnstruktur und -funktion". 09/2015-08/2018.

Thyroid hormones influence brain structure and function not only during development but also have profound effects on cognitive and neural processes in the adult organism in the conditions of hypo- and hyperthyroidism. In the first funding period we used a multimodal imaging battery (voxel-based morphometry, diffusion-tensor-imaging, arterial spin labeling, resting state fMRI, fMRI) and cognitive battery to delinate the effects of hyper- and hypothyroidism. In addition, we have shown that polymorphisms in the thyroid hormone receptor alpha1 gene as well as in the thyroid hormone transporter MCT8 are associated with behavioral effects in the attention and executive function domains. In the second funding period we will apply the established test-battery in two additional cohorts: First, we will examine patients with a mutation in the thyroid hormone beta gene and thyroid hormone resistance to delineate their cognitive and neuronal phenotype. Second, in a new group of normal participants with the polymorphism in the THRA1-gene we will replicate and extend our findings on the cognitive and neuronal phenotype. In addition, we will extend our approach by adding multimodal imaging in transgenic mice (Pax8-/-, Mct8/Oatp1c1 dko) that will be obtained from cooperating projects. Our imaging battery will include resting state fMRI, voxel-based morphometry, and magnetic resonance spectroscopy. The examination of euthyroid, hypothyroid and hyperthyroid Pax8-/- mice will allow the characterization of thyroid hormone effects on brain structure and function in the adult animal similar to our approach in humans. In these animals we will be able to manipulate thyroid hormone levels to a greater extent than in the human, however. Mct8/Oatp1c1 double knock-out mice serve as a model for the human Allan-Herndon-Dudley-Syndrome, and the treatment of these animals with triiodothyroacetic acid or diiodothyropropionic acid will allow us to judge to what extent the effects of the knock-out on brain structure and function are reversible by treatment. Both approaches are complementary and serve our long-term goal to understand the interaction of the thyroid hormone system and the central nervous system.

Mann KF, Ende G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D07: Neuroplastische Veränderungen von Glutamat/ Glutamine im Gehirn und Zusammenhang mit der Therapieresponse bei Alkoholismus. 01/2012-12/2015.

D07 erforscht neurochemische und funktionelle Veränderungen der zerebralen Erregbarkeit in Alkoholentzug und Abstinenz. In einem translationalen und multimodalen Ansatz wird das präfrontale Glutamat/Glutamin Verhältnis in Patienten und „alkoholabhängigen“ Ratten mittels Magnetresonanzspektroskopie (MRS) gemessen. Die Werte könnten relevant für Rückfälle sein und sich als Biomarker eignen. Die humanen MRS Untersuchungen werden mit Blutoxygenierungsiveau abhängigen funktionell-magnetresonanztomographisch gemessener Reagibilität auf alkoholrelevante Reize als Prädiktor für Alkoholverlangen und Rückfall kombiniert. Damit könnten wir einen Ansatz zur „personalisierten Behandlung“ liefern. Parallel werden die Tiere während Alkoholexposition, Entzug und Abstinenz mit MRS untersucht. Die Wirkung antiglutamaterger Substanzen wird in beiden Spezies geprüft.

Sartorius A. BMBF - Bundesministerium für Bildung und Forschung 01GQ1003B: BCCN TP C3: Oscillations and functional connectivity. 05/2010-04/2015.

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.

Sartorius A. BMBF - Bundesministerium für Bildung und Forschung 01EW1110: ERA-Net NEURON SuppHab: Behandlung therapie-resistenter Depression durch Aktivitätsminderung der lateralen Habenula. 03/2011-02/2014.

Ca. 15% aller an Depression erkrankter Patienten sprechen nicht auf herkömmliche antidepressive Behandlungsverfahren an. Seit kurzem wird die Tiefehirnstimulation (THS), die bei M. Parkinson ein Standardverfahren darstellt, als innovatives Verfahren zur Behandlung schwerster Depressionen eingesetzt. Wir möchten in unserer Studie in einem Tiermodell der therapie-resistenten Depression die Verhaltensbesserungen unter THS der lateralen Habenula (LHb) untersuchen. Die Überaktivierung dieser Struktur scheint eine zentrale Rolle bei der Entstehung der Depression durch die Inhibierung dopaminerger und serotonerger Regelkreise zu spielen. Diese Hypothese soll durch Magnetresonanzbildgebung im Tiermodell der Depression und in weitestgehend identischer Weise bei depressiven Patienten überprüft werden.

Zentralinstitut für Seelische Gesundheit (ZI) -