RP1 Experimental Neurobiology – Ongoing Grants and Projects

NATIONAL PROJECTS EXCEPT OPERATIONAL PROGRAMMES

The Czech Science Foundation

Electromagnetic Models of Animal Brains (18-16218S)
Investigator: MUDr. Tomáš Páleníček, Ph.D.
Principle investigator: Brno University of Technology (prof. Dr. Ing. Zbyněk Raida)
Co-investigator/Partner: NIMH
Duration: 1.1.2018–30.6.2021
Total budget: 7 240 000 CZK
Total budget NIMH: 3 811 000 CZK
Abstract: The project is focused on the fundamental research of robust methods for the identification of source currents in brains of animals. Methods are unique in combination of quasi-static and full-wave approaches to numerical modeling, exploitation of 3D printing and agar gelatins for the creation of physical models. Created models allow a reliable calibration of inverse solvers which determine magnitude and orientation of source currents from potentials measured on the surface of a brain. Knowledge of source currents is important for neurological research.

 

Czech Health Research Council 

 

Psilocybin Versus Ketamine – Fast Acting Antidepressant Strategies in Treatment-Resistant Depression (NU21-04-00307)
Investigator: MUDr. Tomáš Páleníček, Ph.D.
Principle investigator: NIMH
Co-investigator/Partner: University of Chemistry and Technology, Faculty of Food and Biochemical Technology
Duration: 1.5.2021–31.12.2024
Total budget: 12 699 000 CZK
Total budget NIMH: 10 223 000 CZK
Abstract: Depression is the 4 most common cause of disability worldwide, with 20-30% of patients fulfilling the criteria for treatment-resistant depression (TRD). The unique rapid onset of antidepressant effect with subanesthetic/psychedelic doses of the dissociative anesthetic ketamine in TRD has been confirmed based on several meta-analyzes, however, it usually does not last longer than 7-10 days. Recent studies with serotonergic psychedelics psilocybin and ayahuasca describe the significant antidepressant potential of these agents in TRD. However, unlike ketamine, these effects last much longer, in the order of weeks to months. Although two large multicenter trials with psilocybin in depression are currently underway and one comparing the effect versus citalopram, there is no direct comparison between the two treatment strategies with a rapid onset of action. Our main goal is to compare the antidepressant effects of psilocybin and ketamine in patients with TRD versus the antidepressant inactive substance midazolam. The primary endpoint will be the antidepressant effect on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment, the key secondary endpoints being the duration of antidepressant effect, the number of responses and remissions, and the time to standard antidepressant treatment during 3 months of observation. The exploratory part of the study aims to monitor changes in the functional brain states using simultaneous EEG/fMRI, before treatment versus 1 day and 1 week after. Based on literature data and recent data from healthy volunteers who participated in our study with psilocybin, we will correlate antidepressant effects of drugs (using psychometric scales and reactions to emotionally salient stimuli (eye tracker)) with entropy and functional connectivity measures. Finally we will explore the role of plasmatic neurobiological biomarkers in depression (BDNF, prolactin, ACTH and oxytocin).

The Interplay Between the Gut Microbiota and Brain Functions: Implication for Metabolome and Metabolic Syndrome in Schizophrenia (17-31852A)
Investigator: MUDr. Tomáš Páleníček, Ph.D.
Principle investigator: NIMH
Co-investigators/Partners: Institute of Animal Physiology and Genetics of the CAS (RNDr. Kateřina Fliegerová, CSc.); Institute of Microbiology of the CAS
Duration: 1.4.2017–31.12.2021
Total budget: 13 553 000 CZK
Total budget NIMH: 10 163 000 CZK
Abstract: Schizophrenia is a serious mental disease with high morbidity. The modern antipsychotics are effective in its therapy, but they may induce obesity and metabolic syndrome. Alteration in metabolism, changes in gut microbiota, gut barrier failure and low-grade chronic inflammation are all involved in pathogenesis of both schizophrenia and metabolic syndrome. Therefore, by analysis of microbiome, metabolome, gut barrier function and inflammatory response, new biomarkers for prediction of this serious therapy side-effect may be found. Moreover, by analyzing the key mechanisms in the pathogenesis of both conditions, this approach may even uncover suitable target for future therapy of schizophrenia or metabolic syndrome. We will use samples of blood, stool or urine, collected from patients with schizophrenia at the beginning of the antipsychotic treatment and after several months, when the presence or absence of the metabolic syndrome will be clearly apparent. Few animal experiments will be performed to identify the best possible targets before these will be used in full-scale investigation on humans.

 

The Technology Agency of The Czech Republic

BrainTech: Innovative Technologies for Psychiatry and Clinical Neuroscience (BrainTech) (TP01010062)
Investigator: RNDr. Karel Valeš, Ph.D.
Principle investigator: NIMH
Dutarion: 1.1.2020–31.12.2022CZ CZK
Abstract: The BrainTech project aims to a comprehensive system to support individual projects proof-of-concepts in the field of psychiatry, aging and clinical neuroscience. Through the selection of partial projects in the fields of digital health, telemedicine and drug research and development, projects with commercial potential will be developed and the transfer of results of research and development to the application sphere, both in the Czech Republic and abroad, will accelerate.
Subproject:
Validation of the Method for the CBD and THC Quantification in CBD-rich Supplements 
Investigator: Ing. Martin Kuchař, Ph.D.
Duration: 1.9.2020–30.4.2022 
Total budget NIMH: 1 900 000 CZK 

 

OPERATIONAL PROGRAMMES

OP Enterprise and Innovation for Competitiveness

Application of Industrial Biotechnology Methods for Differential Diagnostics of Neurological Diseases (CZ.01.1.02/0.0/0.0/17_176/0015497)
Investigator: RNDr. Jan Říčný, CSc.
Principle investigator: VIDIA spol. s r.o.
Co-investigator/Partner: NIMH
Duration: 1.7.2019–30.6.2022
Total budget: 7 889 609,00 CZK
Total budget NIMH: 1 510 942,225 CZK
Abstract: The aim of the project is the development of a multiparametric diagnostic kit and prototypes of autoantibody kits against selected antigens to be used in differential diagnostics, disease evaluation and response to treatment of selected neurological diseases - Alzheimer's disease, Parkinson's disease, Frontotemporal neurodegeneration, Lewy's dementia and Vascular dementia . Although the problems with aging of population is becoming increasingly urgent, there are currently no commercial kits to diagnose these neurodegenerations. The developed highly specific tests will create a new segment of diagnostic kits for use in the global market.

 

INTERNATIONAL PROJECTS

The Ministry of Education, Youth and Sports of The Czech Republic

Targeted Depletion of the TRP-VR1 in Murine Nociception Models for Treatment of Analgesics Resistant Pain (LTAB19024)
Investigator: Prof. Saak Victor Ovsepian, MD, PhD
Principle investigator: NIMH
Project Partner: Technical University Munich and Helmholtz Zentrum Munich (Prof. Vasilis Ntziachristos)
Duration: 1.7.2019–31.12.2021
Total budget: 90 000 EUR
Total budget NIMH: 1 200 000 CZK
Abstract of the Czech part: There is major unmet need in developing effective and long-acting therapeutics for management of chronic, analgesic-resistant pain, including cancer pain. This project will apply a new genetic methodology developed by the Czech principal investigator for depletion of TRP-VR1 receptors in trigeminal nociceptors, to improve management of drug-resistant neuropathic and cancer pain in mouse models. IgG192 targeted lentivirus encoding VR1 shRNA will be used for retro-axonal depletion of TRP-VR1 pain sensing channels in trigeminal sensory neurons of mice in primary neuronal cultures and in vivo. Immunohistochemistry, biochemistry and confocal imaging will be used for verifying the effectiveness and specificity of VR1 depletion in trigeminal nociceptors. Reduced pain response will be confirmed using capsaicin-induced pain model in behaving animals, as well as specific molecular readouts such as expression of nuclear mGluR5 and phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. The new anti-nociceptive targeted vectors will be supplied to the German partner for its validation in cancer pain model, through the use of advanced methodologies for imaging dermal pain response as well as mapping brain response to pain in intact animals in vivo.
Abstract of the Bavarian part: The recently developed imaging methodologies such as raster-scanning optoacoustic mesoscopy (RSOM) will be utilized for detection of dermal nociceptive response to capsaicin-induced pain at the periphery. Multispectral optoacoustic tomography (MOST) on the other hand will be applied for mapping hemodynamic response in the brain in response to nociceptive inputs in intact animals in vivo. The effects of targeted anti-nociceptive vector depleting TRP-VR1 supplied by the Czech PI will be tested in capsaicin-induced pain models, as well as cancer pain model in mice produced by grafted subcutaneously with UM-SCC-104 (the human papillomavirus-16-positive head and neck Squamous Cell Carcinoma cells) into the sub-cutis of the external rostrum area of severe combined immunodeficiency (SCID). The anti-nociceptive effects of targeted VR1 in trigeminal ganglion neurons will be verified with RSOM and MSOT methods in vivo. The results of these studies will be rigorously tested versus controls, and correlated with data obtained by Czech principal investigator’s group using conventional immunohistochemistry and microscopic methods.

 

Restoring Motor Functions in Parkinson’s Disease with Noninvasive Hybrid Transcranial Neuromodulation (JPND-568-060)
Investigator: Mgr. Grygoriy Tsenov, MSc., Ph.D.
Principle investigator: NIMH
Project Partners: Robert Chen, University of Toronto, Canada; Marc Fournelle, Fraunhofer Gesellschaft, Germany
Nevzat G. Gençer, Middle East Technical University, Turkey; Walter Paulus, Ludwig Maximillians Universität München, Germany; Toygan Sönmez, Alvimedica Medical Technologies, Turkey
Duration: 1.1.2021–31.12.2023
Total budget: 1 464 661 EUR
Total budget NIMH: 359 262 EUR
Scientific abstract:
Deep Brain Stimulation (DBS) with electrode implants has been a success story in the treatment of Parkinson’s Disease (PD). This project will develop and apply noninvasive standalone and hybrid neuromodulation technology targeting basal ganglia to restore motor functions in PD with interference electrical fields and ultrasound (US). Two groups (Partners 2-3) will focus on patients, while the rest will pursue basic research and technology development. Non-invasive electrical stimulation: Partner 2 will apply electric temporal interference fields (TIF) induced by two high-frequency transcranial Alternating Current Stimulators (tACS) with shifted frequencies to activate the internal globus pallidus (GPi) by the resultant TIFs of lower (130 Hz) frequencies. The stimulation intensity will be optimized with modeling (Partner 5) and validated based on invasive recordings in patients during presurgical epilepsy evaluation, and in experimental rats (Coordinator-Partner 1 and 2). Clinical efficacy of TIF stimulation will be verified using Unified PD Rating Scale (UPDRS) scores and by recording well-defined excitability parameters of the motor cortex, via transcranial magnetic stimulation (TMS) (Motor Evoked Potentials, i.e. MEP, silent period, Short- Interval Intracortical Inhibition (SICI)) and others in PD patients and controls (Partner 2). Non-invasive highprecision US stimulation of basal ganglia using low-intensity focused US (LIFUS) will be investigated with a new, multichannel stimulator developed by Partner 4. The effects of LIFUS will be verified using UPDRS scores and by recording local field potentials from PD patients, targeting the subthalamic nucleus (STN) or GPi. Stimulation parameters will be optimized based on the clinical response, pathological β oscillations, and connectivity studies using fMRI (Partner3). The focus of Partner 2 will be primarily on pathophysiology in PD, while Partner 3 will conduct clinical efficacy studies. In exploratory, high-risk high-gain experiments, hybrid tACS and LIFUS will be applied by Partner 2, for testing synergistic effects. For this, the US frequencies will be reduced to ~150 kHz while the frequency of electrical stimulation will be increased to ~ 150 kHz to achieve an electroacoustic effect. Partner 5 will explore additive effects using a combination of various stimulation modalities (electric, magnetic, and LIFUS) along with realistic numerical models and tests in head phantoms, while the focus of Partner 6 is hardware development and adaptation of new hybrid systems for experimental use. The possible utility of an alternative neuro-stimulation based on Lorentz fields caused by interactions of LIFUS and magnetic fields will be also explored by Partner 5. The main focus of Partner 1 will be the mechanistic analysis of non-invasive neuro-modulation in rat brain and neurons in vitro, to define underlying electrochemical processes and circuit mechanisms. Safety margins and optimal operational range will be also defined by Partner 1, using functional and histochemical tests. By targeted activation of selected neurons with LIFUS, thermo and mechanosensitive effects will be dissected and assigned to specific channels expressed in neurons. Through an ingenious blend of innovative technologies and synergy of expertise, thus, for the first time, the most promising standalone and hybrid neuro-stimulation methods will be put to a rigorous trial, from cultured neurons in vitro, through animal experiments and clinical tests in PD patients. The non-invasive technologies described are expected to facilitate not only better management and restoration of motor functions in PD but to improve the understanding of underlying mechanisms and safety, for optimization and expatiated translation into routine medical practice.

 

 

 

 


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