«Smart Sleep» Laboratory

Scientific results:

• We have obtained new scientific data on the activation of the drainage function of the brain in sleep that we obtained using optical coherence tomography, gold nanorods as contrast agents, the technology of optical clearing of the cranial bone and EEG monitoring.
• New scientific information has been obtained concerning efficient nonlinear methods of frequency and amplitude analysis of electroencephalography, electromyography, electrooculography and electrocardiography data, as well as methods of image recognition by artificial neural networks for the highly-selective detection of slow sleep waves synchronized with the activation of the drainage function of the brain.
• We have developed a mathematical model that describes the adaptation of the motion of extracellular and perivascular fluids into the meningeal lymphatic system during sleep.
• New scientific information has been obtained concerning the role of the lymphatic system in the cleaning function of the brain during sleep and age-related changes of these processes.
• New scientific information has been obtained concerning the functional relation between the increase in the permeability of the hematoencephalic barrier (HEB) and the activation of the cleaning function of the brain in sleep.
• A breakthrough technology has been developed for the diagnostics of the state of the HEB from data of nonlinear analysis of nocturnal EEG patterns.
• New scientific information has been obtained concerning the lymphatic cleansing of tissues of a sleeping brain from beta-amyloid and blood products using animal models of the Alzheimer’s disease and neonatal intracranial hemorrhage respectively.
• The Laboratory has developed a telemetry system for monitoring intracranial pressure and simultaneous recording of EEG in rodents.
• We have obtained pioneering data on the anatomic relation between meningeal and peripheral lymphatic vessels of the head and the neck of humans and rodents of various ages.
• The Laboratory has developed a mathematical model of the glial regulation of flow of interstitial fluid during sleep.
• We have created new methods of functional cartography and three-dimensional functional imaging of the network of lymphatic vessels of the brain and its linings in mice/rats and humans.
• New scientific information has been obtained concerning the efficiency of the use of the technologies of nonlinear frequency and amplitude analysis of EEG, EMG, EOG and ECG data developed at the first stage under conditions of pathology, including methods of image recognition by neural networks to determine slow sleep waves (on examples of the Alzheimer’s disease and neonatal hemorrhages).
• We have developed software and an automated stations based on machine learning methods to determine slow sleep waves in the norm and pathology in the moment when   «therapeutic windows of sleep» open.
• New scientific information has been obtained concerning the possibility of increasing the drainage and cleaning function of the brain by noninvasive stimulation of the «therapeutic windows of sleep» found at the second stage of the project, which manifest themselves in slow wave activity of the brain.
• We have developed technologies for detecting deep sleep stages in the first days after birth and photostimulation of the lymphatic drainage of blood from brain tissues of newborn infants with intraventricular hemorrhage. We created software that can automatically provide photo interventions during deep sleep.
• In clinical tests involving healthy volunteers and patients with cognitive disorders it has been established that noninvasive treatment by exposure to binaural sound is accompanied by changes in the electrophysiological pattern associated with the glymphatic system. We analyzed the impact of sleep deficiency and binaural sound on beta-amyloid content in the blood of healthy volunteers. It was established that sleep deprivation is accompanied by a decrease in the level of beta-amyloid in the blood of test subjects, which indirectly indicates its accumulation in brain tissues and this is in agreement with other results with the use of positron emission tomography.
• We have studied the mechanisms of photostimulating effects on the drainage and cleaning functions of meningeal lymphatic vessels in mice.
• The Laboratory has developed a portable device in the form of a cap for the nocturnal therapy of excretion of blood products and toxins from the brains of newborn infants.
• Our researchers have developed a software and hardware complex for monitoring sleep electroencephalograms (EEG) in rodents, which allows to automatically detect slow sleep stages in real time to start laser therapy of the linings of the brain in this period.
• We have developed a technology for the photostimulation of lymphatic excretion of blood products from brain tissues in adult and newborn mice.
• A technology has been created for the nocturnal photostimulation of lymphatic excretion of beta-amyloid from brain tissues of mice.
• A technology has been developed for the sound stimulation of lymphatic excretion of beta-amyloid from brain tissues in mice.
• A new approach has been developed to analyzing biomedical systems in EEG records to search for and quantitatively evaluate the oscillation patterns on the basis of continuous wavelet transform.
• We have researched the coherence of the processes of breathing and the parasympathetic regulation of heart rate for individuals of various age groups in the state of wakefulness, during REM sleep and in deep sleep.
• A method has been proposed for computing the index of the aggregate percentage of phase synchronization of the components of signals of RR intervals and arterial pressure in the low-frequency range from 0.05 to 0.15 Hz.
• New theoretical concepts have been developed concerning sleep as a systemic marker of the state of the HEB. Models were developed that describe the activation of the nocturnal processes of brain tissue drainage and their possible mechanisms.
• An interactive database has been developed that contains information on the network of lymphatic vessels of the brain and its linings in the form of a 3D atlas with the use of digital technologies of creation of multimedia objects, virtual reality, three-dimensional computer graphics and machine learning.

Implementation of research results:

1. Russian Federation Patent No. 2766527. Method for stimulating the cleansing function of the lymphatic system of the brain / Oksana V. Semyachkina-Glushkovskaya, Jürgen G. Kurtz, Aleksandr A. Shirokov, Aleksandr P. Khorovodov, Andrey V. Terskov, Aleksandr I. Dubrovskiy, Valeriy V. Tuchin. Ivan V. Fedosov, Aleksey N. Bashkatov. Elina A. Genina, Aysel G. Mamedova, Mariya M. Klimova, Inna A. Blokhina, Nikita D. Lezhnev. Published on 15 March 2022. Bulletin No. 8. 
2. Russian Federation Patent No. 210873. A device for high-precision measurement of intracranial pressure. Ivan V. Fedosov, Vasily B. Ageyev, Oksana V. Semyachkina-Glushkovskaya. Published on 12 May 2022. Bulletin No. 15.
3. Russian Federation Patent No. 2781740. A method of detection of the state of deep sleep. Vasily B. Ageyev, Ivan V. Fedosov, Oksana V. Semyachkina-Glushkovskaya. Published on 17 October 2022. Bulletin No. 29.
4. Russian Federation Patent No. 2740123. Method of laser biomodulation and increase of blood-brain barrier permeability / Valeriy V. Tuchin, Oksana V. Semyachkina-Glushkovskaya, Elina A. Genina, Aleksey N. Bashkatov; Published on 11 January 2021. Bulletin No. 2

Education and retraining of personnel:

• We have developed and implemented the master’s degree program «Modern technologies of imaging and analysis of living systems».
• Three advanced training programs have been developed.
• Two monographs and one textbook have been published.
• We have conducted an academic internships of two postgraduate students from 22 November to 21 December 2021 at the Interdisciplinary Center of Sleep Medicine of Charité clinic (Berlin).
• The Laboratory conducted the 1^st Winter On-line School on «Brain Clearance Meets Complex Systems».
• Two Doctor of Sciences dissertations, one PhD thesis and two Candidate of Sciences dissertations have been prepared and defended.
• 7 bachelor’s degree students, one specialist degree student, 2 master’s degree students have been trained.

Collaborations:

• Interdisciplinary Center of Sleep Medicine of the Charité clinic (Germany): Internships are provided to young researchers with a focus on the research of the use of methods of machine learning and recurrent analysis, which are applied to biomedical data for the classification of states the organism (sleep, wakefulness, assessment of the permeability of the hematoencephalic barrier etc.), as well as predicting the onset of critical states of the organism (onset of pathologies).
• Cardiovascular Physics Laboratory of the Humboldt University of Berlin (Germany): internships are provided for the Laboratory’s researchers to study the use of nonlinear analysis methods to forecast the development of brain vessel catastrophes, including technologies for the assessment of the state of the hematoencephalic barrier during wakefulness and sleep.
• Somnology Department of the Charité clinic in Berlin (Germany):internships are organized to train employees of the Laboratory in conducting research of the nature of sleep and detecting early markers of the risk of the development of neurodegenerative diseases on the basis of the use of methods of machine learning and nonlinear dynamics.
• Biomedical Laboratory of the Huazhong University of Science and Technology in Wuhan (China PR): The Laboratory is conducting joint research to develop technologies for the photocontrol of the lymphatic processes of excretion of unwanted metabolites from brain tissues.
• University of New Mexico School of Medicine in Albuquerque (USA): conducting joint research of the nocturnal activity of the lymphatic system of the lining of the brain during sleep in healthy volunteers using functional magnetic resonance imaging.
• V. I. Razumovsky Saratov State Medical University (Russia).
• Research Center «Symbiosis» of the Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences (Russia).
• International Science and Education Center «Biophotonics» (Russia).
• Research Institute of Neurosciences and Medicine (Russia).