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Projects: Translational 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: Neuroplasticity of brain glutamate and glutamine and treatment. 01/2012-12/2015.

The glutamate hypothesis of alcoholism posits that chronic alcohol intake leads to an enhanced activity of the glutamate system. As soon as alcohol is discontinued, withdrawal develops with marked brain hyperexcitability. Under abstinent conditions this hyperglutamatergic state could be reinstated by stress or alcohol cues and precipitate relapse. Anti-glutamatergic compounds are effective in preventing relapse and potentially also in alleviation of withdrawal. Effect sizes of this pharmacotherapy are moderate, a fact which may be accounted for by individual differences in the extent of neuroplastic changes of the glutamate system. Thus, we predict that antiglutamatergic medications work primarily in individuals who develop a pronounced hyperglutamatergic state, a condition that can be identified and monitored by magnetic resonance spectroscopy (MRS). We previously found that alcohol withdrawal is reflected by increased central glutamate levels. A new measure to be studied in the coming funding period is the glutamate/glutamine ratio which we now can also measure reliably in humans. This ratio will be tested as a potential biomarker for monitoring alcoholism, which may lay the grounds for a personalized treatment approach of this condition. We believe that a translational approach involving human patients and “alcohol dependent rats” serves the purpose of our research best. In both species prefrontal cortex changes in metabolite concentrations during acute withdrawal and into several weeks of abstinence are measured with and without pharmacological interference targeting the glutamatergic system. In the last funding period we developed methods for absolute quantification of metabolites in the human and rat brain. Under control conditions glutamate concentrations in the human anterior cingulate cortex (ACC) and the rat medial prefrontal cortex (mPFC) were highly similar. Thus, for the first time direct evidence for increased central glutamate levels during acute alcohol withdrawal in both species was provided. In the animal experiments, we will induce alcohol dependence through chronic, intermittent, ethanol-vapor exposure. Rats will be assessed repeatedly, over the course of acute alcohol withdrawal into abstinence, for neurometabolic changes in the medial-prefrontal cortex, using MRS at 9.4T. In the new funding period we shall concentrate on the effects of experimental pharmacotherapies for alcohol detoxification (glutamate modulators, such as acamprosate, memantine and lamotrigine) on neurometabolic profiles and on alcohol-related behaviors, comparing these therapies to standard treatments (GABAergic: diazepam). We will also compare neurometabolic profiles to in vivo, microdialysis measurements of extracellular glutamate release from parallel groups of rats. In the human study, we will continue to assess the effects of alcohol withdrawal. As a new element, alcohol cues and pharmacological intervention on levels of glutamate, glutamine and GABA in the prefrontal cortices of treatment-seeking alcoholics will be studied. Alcohol dependent inpatients (n=60) will undergo three combined measurements of MRS and fMRI cue reactivity. The first MR session will take place during acute withdrawal (without medication). The second group of measurements will be taken after five days of abstinence, in order to monitor the glutamate/glutamine ratio over time, and to what extent this ratio is affected by the diazepam that will at this point have been administered for withdrawal-symptom relief. The third MR session will take place on day 14 to monitor the effects of abstinence, both for patients under treatment with acamprosate (which will have been initiated as an open-label treatment following the second MR session) and for patients not being treated with medication. Relapse behavior will be monitored in follow-up assessments, and correlated to MRS metabolites. A control group of n=20 healthy subjects will undergo combined MRS and fMRI twice, two weeks apart.

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: Improvement of treatment resistant depression by suppression of lateral. 03/2011-02/2014.

About 15% of patients suffering from major depression do not respond to any antidepressant treatment. Recently, deep brain stimulation (DBS) was tested as a new therapeutic approach for these severely ill patients. Here we propose a well controlled study, in an animal model of depression, to test the therapeutic benefits of DBS of the lateral habenula (LHb). We believe that hyperactivity of this structure plays a central role in depression by inhibiting dopaminergic and serotonergic transmission. This hypothesis will be tested by means of magnetic resonance imaging and microdialysis in a well-known animal model of depression and additionally, in depressed patients. Breeding and testing of all animals from the congenital Learned Helpless model will take place in Mannheim and animals will be distributed to partners from here. A subgroup of animals will be investigated by means of cerebral blood volume measurements, functional connectivity analysis and MR-spectroscopy at our 9.4 T scanner. In a final experimental step we will test if helpless behavior can be reversed by DBS and if alterations that have been detected by MR investigation can also be normalised. There is no plan for any business or economic outlook or connectivity. Scientific outlook are excellent publications and improvement and refinement of existing theories of depression. The scientific outlook will be the initiation of a clinical DBS study that takes advantage of the LHb as a new stimulation target to treat therapy refractory depression.


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