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Abstract With the increase in the aging population, the global number of people with Alzheimer’s disease (AD) progressively increased worldwide. The situation is aggravated by the fact that there is no the effective pharmacological therapy of AD. Photobiomodulation (PBM) is non-pharmacological approach that has shown very promising results in the therapy of AD in pilot clinical and animal studies. However, the mechanisms of therapeutic effects of PBM for AD are poorly understood. In this study on mice, we demonstrate that photodynamic effects of 5-aminolevulenic acid and laser 635 nm cause reduction of network of the meningeal lymphatic vessels (MLVs) leading to suppression of lymphatic removal of beta-amyloid (Aβ) from the right lateral ventricle and the hippocampus. Using the original protocol of PBM under electroencephalographic monitoring of wakefulness and sleep stages in non-anesthetized mice, we discover that the 7-day course of PBM during deep sleep vs. wakefulness provides better restoration of clearance of Aβ from the ventricular system of the brain and the hippocampus. Our results shed light on the mechanism of PBM and show the stimulating effects of PBM on the brain lymphatic drainage that promotes transport of Aβ via the lymphatic pathway. The effects of PBM on the brain lymphatics in sleeping brain open a new niche in the study of restorative functions of sleep as well as it is an important informative platform for the development of innovative smart sleep technologies for the therapy of AD. Graphical Abstract

The blood-brain barrier (BBB) has a significant contribution to the protection of the central nervous system (CNS). However, it also limits the brain drug delivery and thereby complicates the treatment of CNS diseases. The development of safe methods for an effective delivery of medications and nanocarriers to the brain can be a revolutionary step in the overcoming this limitation. Here, we report the unique properties of the lymphatic system to deliver tracers and liposomes to the brain meninges, brain tissues, and glioma in rats. Using a quantum-dot-based 1267 nm laser (for photosensitizer-free generation of singlet oxygen), we clearly demonstrate photostimulation of lymphatic delivery of liposomes to glioma as well as lymphatic clearance of liposomes from the brain. These pilot findings open promising perspectives for photomodulation of lymphatic delivery of drugs and nanocarriers to the brain pathology bypassing the BBB. The lymphatic “smart” delivery of liposomes with antitumor drugs in the new brain tumor branches might be a breakthrough strategy for the therapy of gliomas.

Amyloid beta (Aβ) is a neuronal metabolic product that plays an important role in maintaining brain homeostasis. Normally, intensive brain Aβ formation is accompanied by its effective lymphatic removal. However, the excessive accumulation of brain Aβ is observed with age and during the development of Alzheimer's disease (AD) leading to cognitive impairment and memory deficits. There is emerging evidence that plasmalogens (Pls), as one of the key brain lipids, may be beneficial for AD and cognitive aging. Here, we studied the effects of Pls on cognitive functions and the lymphatic clearance of Aβ from the brain of AD mice and mice of different ages. The results showed that Pls effectively reduce brain Aβ levels and facilitate learning in aged but not old mice. In AD mice, Pls improve the lymphatic clearance of Aβ that is accompanied by an increase in general motor activity and an improvement of the emotional status and learning ability. Thus, these findings suggest that Pls could be a promising candidate for the alternative or concomitant therapy of AD and age-related brain diseases to enhance the lymphatic clearance of Aβ from the brain and cognitive functions.

Here, we present the new vascular effects of photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA). PDT with 5-ALA induces a leakage of both the meningeal and cerebral blood vessels. The extravasation of photo-excited 5-ALA from the leaky blood vessels into the meninges causes photo-damage of the meningeal lymphatics (MLVs) leading to a dramatic reducing the MLV network and brain's drainage. The PDT-induced impairment of lymphatic regulation of brain's drainage can lead to excessive accumulation of fluids in brain tissues, which is important to consider in the PDT therapy for brain diseases as s possible side effect of PDT with 5-ALA., Competing Interests: The authors declare no conflict of interest., (© 2024 Optica Publishing Group.)

The meningeal lymphatic vessels (MLVs) play an important role in the removal of toxins from the brain. The development of innovative technologies for the stimulation of MLV functions is a promising direction in the progress of the treatment of various brain diseases associated with MLV abnormalities, including Alzheimer's and Parkinson's diseases, brain tumors, traumatic brain injuries, and intracranial hemorrhages. Sleep is a natural state when the brain's drainage processes are most active. Therefore, stimulation of the brain's drainage and MLVs during sleep may have the most pronounced therapeutic effects. However, such commercial technologies do not currently exist. This study presents a new portable technology of transcranial photobiomodulation (tPBM) under electroencephalographic (EEG) control of sleep designed to photo-stimulate removal of toxins (e.g., soluble amyloid beta (Aβ)) from the brain of aged BALB/c mice with the ability to compare the therapeutic effectiveness of different optical resources. The technology can be used in the natural condition of a home cage without anesthesia, maintaining the motor activity of mice. These data open up new prospects for developing non-invasive and clinically promising photo-technologies for the correction of age-related changes in the MLV functions and brain's drainage processes and for effectively cleansing brain tissues from metabolites and toxins. This technology is intended both for preclinical studies of the functions of the sleeping brain and for developing clinically relevant treatments for sleep-related brain diseases.

There is an association between sleep quality and glioma-specific outcomes, including survival. The critical role of sleep in survival among subjects with glioma may be due to sleep-induced activation of brain drainage (BD), that is dramatically suppressed in subjects with glioma. Emerging evidence demonstrates that photobiomodulation (PBM) is an effective technology for both the stimulation of BD and as an add-on therapy for glioma. Emerging evidence suggests that PBM during sleep stimulates BD more strongly than when awake. In this study on male Wistar rats, we clearly demonstrate that the PBM course during sleep vs. when awake more effectively suppresses glioma growth and increases survival compared with the control. The study of the mechanisms of this phenomenon revealed stronger effects of the PBM course in sleeping vs. awake rats on the stimulation of BD and an immune response against glioma, including an increase in the number of CD8+ in glioma cells, activation of apoptosis, and blockage of the proliferation of glioma cells. Our new technology for sleep-phototherapy opens a new strategy to improve the quality of medical care for patients with brain cancer, using promising smart-sleep and non-invasive approaches of glioma treatment.

In this study on healthy male mice using confocal imaging of dye spreading in the brain and its further accumulation in the peripheral lymphatics, we demonstrate stronger effects of photobiomodulation (PBM) on the brain's drainage system in sleeping vs. awake animals. Using the Pavlovian instrumental transfer probe and the 2-objects-location test, we found that the 10-day course of PBM during sleep vs. wakefulness promotes improved learning and spatial memory in mice. For the first time, we present the technology for PBM under electroencephalographic (EEG) control that incorporates modern state of the art facilities of optoelectronics and biopotential detection and that can be built of relatively cheap and commercially available components. These findings open a new niche in the development of smart technologies for phototherapy of brain diseases during sleep., Competing Interests: The authors declare no conflict of interest. Author Contributions. O.S.-G. initiated and supervised this work. I.F., V.A., E.I., D.M. D.T. carried out technological work to create method for PBM under EEG control; A.S., A.T., I.B. and A.D. performed the confocal analysis; M.Z. made the statistical analysis; D.Z., V.A., A.E., M.M., A.D., V.K., V.T. performed most of the experiments. O.S-G., A.Z., J.K. reviewed all results and wrote the manuscript. All authors have read and agreed to the published version of the manuscript., (Published by Optica Publishing Group under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

Anesthesia enables the painless performance of complex surgical procedures. However, the effects of anesthesia on the brain may not be limited only by its duration. Also, anesthetic agents may cause long-lasting changes in the brain. There is growing evidence that anesthesia can disrupt the integrity of the blood-brain barrier (BBB), leading to neuroinflammation and neurotoxicity. However, there are no widely used methods for real-time BBB monitoring during surgery. The development of technologies for an express diagnosis of the opening of the BBB (OBBB) is a challenge for reducing post-surgical/anesthesia consequences. In this study on male rats, we demonstrate a successful application of machine learning technology, such as artificial neural networks (ANNs), to recognize the OBBB induced by isoflurane, which is widely used in surgery. The ANNs were trained on our previously presented data obtained on the sound-induced OBBB with an 85% testing accuracy. Using an optical and nonlinear analysis of the OBBB, we found that 1% isoflurane does not induce any changes in the BBB, while 4% isoflurane caused significant BBB leakage in all tested rats. Both 1% and 4% isoflurane stimulate the brain's drainage system (BDS) in a dose-related manner. We show that ANNs can recognize the OBBB induced by 4% isoflurane in 57% of rats and BDS activation induced by 1% isoflurane in 81% of rats. These results open new perspectives for the development of clinically significant bedside technologies for EEG-monitoring of OBBB and BDS.

Intraventricular hemorrhage is one of the most fatal forms of brain injury that is a common complication of premature infants. However, the therapy of this type of hemorrhage is limited, and new strategies are needed to reduce hematoma expansion. Here we show that the meningeal lymphatics is a pathway to remove red blood cells from the brain's ventricular system of male human, adult and newborn rodents and is a target for non-invasive transcranial near infrared photobiomodulation. Our results uncover the clinical significance of phototherapy of intraventricular hemorrhage in 4-day old male rat pups that have the brain similar to a preterm human brain. The course of phototherapy in newborn rats provides fast recovery after intraventricular hemorrhage due to photo-improvements of lymphatic drainage and clearing functions. These findings shed light on the mechanisms of phototherapy of intraventricular hemorrhage that can be a clinically relevant technology for treatment of neonatal intracerebral bleedings., (© 2023. Springer Nature Limited.)

Over sixty years, laser technologies have undergone a technological revolution and become one of the main tools in biomedicine, particularly in neuroscience, neurodegenerative diseases and brain tumors. Glioblastoma is the most lethal form of brain cancer, with very limited treatment options and a poor prognosis. In this study on rats, we demonstrate that glioblastoma (GBM) growth can be suppressed by photosensitizer-free laser treatment (PS-free-LT) using a quantum-dot-based 1267 nm laser diode. This wavelength, highly absorbed by oxygen, is capable of turning triplet oxygen to singlet form. Applying 1267 nm laser irradiation for a 4 week course with a total dose of 12.7 kJ/cm 2 firmly suppresses GBM growth and increases survival rate from 34% to 64%, presumably via LT-activated apoptosis, inhibition of the proliferation of tumor cells, a reduction in intracranial pressure and stimulation of the lymphatic drainage and clearing functions. PS-free-LT is a promising breakthrough technology in non- or minimally invasive therapy for superficial GBMs in infants as well as in adult patients with high photosensitivity or an allergic reaction to PSs.

The global number of people with Alzheimer's disease (AD) doubles every 5 years. It has been established that unless an effective treatment for AD is found, the incidence of AD will triple by 2060. However, pharmacological therapies for AD have failed to show effectiveness and safety. Therefore, the search for alternative methods for treating AD is an urgent problem in medicine. The lymphatic drainage and removal system of the brain (LDRSB) plays an important role in resistance to the progression of AD. The development of methods for augmentation of the LDRSB functions may contribute to progress in AD therapy. Photobiomodulation (PBM) is considered to be a non-pharmacological and safe approach for AD therapy. Here, we highlight the most recent and relevant studies of PBM for AD. We focus on emerging evidence that indicates the potential benefits of PBM during sleep for modulation of natural activation of the LDRSB at nighttime, providing effective removal of metabolites, including amyloid-β, from the brain, leading to reduced progression of AD. Our review creates a new niche in the therapy of brain diseases during sleep and sheds light on the development of smart sleep technologies for neurodegenerative diseases.

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level laser treatment (LLLT, 1268 nm) in the mouse cortex. LLLT-BBBO is accompanied by activation of the brain drainage system contributing effective delivery of liposomes into glioblastoma (GBM). The LLLT induces the generation of singlet oxygen without photosensitizers (PSs) in the blood endothelial cells and astrocytes, which can be a trigger mechanism of BBBO. LLLT-BBBO causes activation of the ABC-transport system with a temporal decrease in the expression of tight junction proteins. The BBB recovery is accompanied by activation of neuronal metabolic activity and stabilization of the BBB permeability. LLLT-BBBO can be used as a new opportunity of interstitial PS-free photodynamic therapy (PDT) for modulation of brain tumor immunity and improvement of immuno-therapy for GBM in infants in whom PDT with PSs, radio- and chemotherapy are strongly limited, as well as in adults with a high allergic reaction to PSs.

Emerging evidence suggests that an important function of the sleeping brain is the removal of wastes and toxins from the central nervous system (CNS) due to the activation of the brain waste removal system (BWRS). The meningeal lymphatic vessels (MLVs) are an important part of the BWRS. A decrease in MLV function is associated with Alzheimer's and Parkinson's diseases, intracranial hemorrhages, brain tumors and trauma. Since the BWRS is activated during sleep, a new idea is now being actively discussed in the scientific community: night stimulation of the BWRS might be an innovative and promising strategy for neurorehabilitation medicine. This review highlights new trends in photobiomodulation of the BWRS/MLVs during deep sleep as a breakthrough technology for the effective removal of wastes and unnecessary compounds from the brain in order to increase the neuroprotection of the CNS as well as to prevent or delay various brain diseases.

There is strong evidence that augmentation of the brain's waste disposal system via stimulation of the meningeal lymphatics might be a promising therapeutic target for preventing neurological diseases. In our previous studies, we demonstrated activation of the brain's waste disposal system using transcranial photostimulation (PS) with a laser 1267 nm, which stimulates the direct generation of singlet oxygen in the brain tissues. Here we investigate the mechanisms underlying this phenomenon. Our results clearly demonstrate that PS-mediated stimulation of the brain's waste disposal system is accompanied by activation of lymphatic contractility associated with subsequent intracellular production of the reactive oxygen species and the nitric oxide underlying lymphatic relaxation. Thus, PS stimulates the brain's waste disposal system by influencing the mechanisms of regulation of lymphatic pumping., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The blood-brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice.

The lymphatic drainage system of the brain (LDSB) is the removal of metabolites and wastes from its tissues. A dysfunction of LDSB is an important sign of aging, brain oncology, the Alzheimer's and Parkinson's diseases. The development of new strategies for diagnosis of LDSB injuries can improve prevention of age-related cerebral amyloid angiopathy, neurodegenerative and cerebrovascular diseases. There are two conditions, such as deep sleep and opening of the blood-brain-barrier (OBBB) associated with the LDSB activation. A promising candidate for measurement of LDSB could be electroencephalography (EEG). In this pilot study on rats, we tested the hypothesis, whether deep sleep and OBBB can be an informative platform for an effective extracting of information about the LDSB functions. Using the nonlinear analysis of EEG dynamics and machine learning technology, we discovered that the LDSB activation during OBBB and sleep is associated with similar changes in the EEG θ-activity. The OBBB causes the higher LDSB activation vs. sleep that is accompanied by specific changes in the low frequency EEG activity extracted by the power spectra analysis of the EEG dynamics combined with the coherence function. Thus, our findings demonstrate a link between neural activity associated with the LDSB activation during sleep and OBBB that is an important informative platform for extraction of the EEG-biomarkers of the LDSB activity. These results open new perspectives for the development of technology for the LDSB diagnostics that would open a novel era in the prognosis of brain diseases caused by the LDSB disorders, including OBBB., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Author(s).)

Background: The development of new methods for modulation of drug distribution across to the brain is a crucial step in the effective therapies for glioblastoma (GBM). In our previous work, we discovered the phenomenon of music-induced opening of the blood-brain barrier (OBBB) in healthy rodents. In this pilot study on rats, we clearly demonstrate that music-induced BBB opening improves the therapeutic effects of bevacizumab (BZM) in rats with GBM via increasing BZM distribution to the brain along the cerebral vessels., Methods: The experiments were performed on Wistar male rats (200-250 g, n=161) using transfected C6-TagRFP cell line and the loud rock music for OBBB. The OBBB was assessed by spectrofluorometric assay of Evans Blue (EB) extravasation and confocal imaging of fluorescent BZM (fBZM) delivery into the brain. Additionally, distribution of fBZM and Omniscan in the brain was studied using fluorescent and magnetic resonance imaging (MRI), respectively. To analyze the therapeutic effects of BZM on the GBM growth in rats without and with OBBB, the GBM volume (MRI scans), as well as immunohistochemistry assay of proliferation (Ki67 marker) and apoptosis (Bax marker) in the GBM cells were studied. The Mann-Whitney-Wilcoxon test was used for all analysis, the significance level was p < 0.05, n=7 in each group., Results: Our finding clearly demonstrates that music-induced OBBB increases the delivery of EB into the brain tissues and the extravasation of BZM into the brain around the cerebral vessels of rats with GBM. Music significantly increases distribution of tracers (fBZM and Omniscan) in the rat brain through the pathways of brain drainage system (perivascular and lymphatic), which are an important route of drug delivery into the brain. The music-induced OBBB improves the suppressive effects of BZM on the GBM volume and the cellular mechanisms of tumor progression that was accompanied by higher survival among rats in the GBM+BZM+Music group vs . other groups., Conclusion: We hypothesized that music improves the therapeutic effects of BZM via OBBB in the normal cerebral vessels and lymphatic drainage of the brain tissues. This contributes better distribution of BZM in the brain fluids and among the normal cerebral vessels, which are used by GBM for invasion and co-opt existing vessels as a satellite tumor form. These results open the new perspectives for an improvement of therapeutic effects of BZM via the music-induced OBBB for BZM in the normal cerebral vessels, which are used by GBM for migration and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Semyachkina-Glushkovskaya, Diduk, Anna, Elina, Artem, Khorovodov, Shirokov, Fedosov, Dubrovsky, Blokhina, Terskov, Navolokin, Evsukova, Elovenko, Adushkina and Kurths.)

Background: The development of new methods of drug brain delivery is a crucial step for the effective therapy of the brain diseases. Pharma- and acupuncture are the forms of alternative therapy of the brain pathology, including an increase in the permeability of blood-brain barrier. However, the mechanisms of pharma- and acupuncture-mediated effects on the brain physiology remain not fully understood., Results: This pilot study on healthy mice clearly demonstrates the Evans Blue spreading in the mouse head and in the brain via the perivascular spaces (PVSs) of the trigeminal structure and the cribriform plate after the dye injection into the Feng Chi point (Galbladder 20, GB20)., Conclusion: These results suggest that pharmacopuncture at GB20 can be a perspective method for brain drug delivery via PVSs.