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Photobiomodulation Under Electroencephalographic Controls of Sleep for Stimulation of Lymphatic Removal of Toxins from Mouse Brain

The meningeal lymphatic vessels (MLVs) play an important role in the removal of toxins from the brain. The development of innovative technologies for the ...

reproducible-setup-for-vivo-two-photon-imaging-contractility-cervical

Reproducible Setup for <em>In vivo</em> Two-photon Imaging of the Contractility of Cervical Lymphatic Vessels and Lymph Flow in Mice

The contractility of cLVs is the driving force for lymph flow and a key mechanism underlying brain toxin cleansing. Here, we present an innovative method ...

Saratov State University

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.

Machine Learning Technology for EEG-Forecast of the Blood-Brain Barrier Leakage and the Activation of the Brain's Drainage System during Isoflurane Anesthesia.

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.

Technology of the photobiostimulation of the brain's drainage system during sleep for improvement of learning and memory in male mice.

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  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.

Different Effects of Phototherapy for Rat Glioma during Sleep and Wakefulness.

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.

Photodynamic opening of the blood-brain barrier affects meningeal lymphatics and the brain's drainage in healthy male mice.

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.

Plasmalogens Improve Lymphatic Clearance of Amyloid Beta from Mouse Brain and Cognitive Functions.

Age is a limiting factor in the efficacy of photobiomodulation (PBM) for brain drainage and cognitive functions. Meningeal lymphatic vessels (MLVs) are "tunnels" for removal of toxins from the brain and the target of PBM. Age-related decline in the MLV functions is one of the mechanisms by which the effects of PBM on brain drainage and cognitive process are limited. Sleep is a time of natural activation of brain drainage. Recent findings have shown that PBM during sleep has greater effects on lymphatic clearance of beta-amyloid and cognitive function in young and middle-age mice. Based on these data, this study tested the hypothesis that sleep enhances the effects of PBM on MLVs and cognitive function in the aging brain. Indeed, the results revealed that PBM during sleep, but not during wakefulness, has stimulatory effects on lymphatic clearance of beta-amyloid from the brain of old mice that improves memory. In sleep deficit experiments, it was found that chronic sleep deprivation is accompanied by suppression of brain drainage and removal of metabolites from the brain, such as beta-amyloid, tau, glutamate, lactate and glucose in young, middle-aged and most significantly in old mice. The course of PBM during sleep contributed better than in wakefulness to the restoration of the brain level of tested metabolites in young and middle-aged mice, while in old mice only PBM during sleep was effective. These results open a new strategy for the use of PBM during sleep to improve the efficacy of PBM on clearance of toxic metabolites from the brain, especially in aged subjects in whom the efficacy of PBM during wakefulness is limited.

Sleep is a therapeutic window for photostimulation of drainage of aging brain.

Photobiomodulation (PBM) is recognized as a promising, noninvasive, and safe therapy for brain diseases. However, age is a limiting factor for effective phototherapy of brain pathology. The mechanisms of decreasing efficiency of therapeutic effects of PBM in the aging brain remain poorly understood. Recently, it has been shown that PBM of brain lymphatic drainage by stimulation of the nitric oxide (NO) production in the lymphatic endothelium plays a key role in the PBM-therapy of brain diseases. In this study, we clearly show that PBM increases the NO production in the lymphatic endothelial cells and the contractility of the afferent (drainage function) and efferent (filtration function) cervical lymphatic vessels (cLVs), which is significantly suppressed after the NO blockade in 3- and 12-month-old mice. However, 24-month-old mice are insensitive to both factors, PBM and its suppression by the NO blockade. In old mice, a decrease in sensitivity to PBM is associated with age-related lymphatic endothelium dysfunction, including changes in the cLV morphology (hyperplasia), a decrease in the NO production, and the contractility of cLVs, leading to reduced lymphatic removal of beta amyloid from the brain. These results suggest that the combined therapy, including PBM with an increase in NO production in the lymphatic endothelium, can substantially improve the effectiveness of the stimulating effects of PBM on brain drainage and the removal of toxic metabolites from its tissues, which might generally contribute to improving phototherapy of brain diseases in the elderly.

ArticleTotal : 2	Year
Publication title Cited by 5	2024
Publication title	2026

Article	Year
Machine Learning Technology for EEG-Forecast of the Blood-Brain Barrier Leakage and the Activation of the Brain's Drainage System during Isoflurane Anesthesia. Biomolecules\| PubMed ID: 38002287	2023
Technology of the photobiostimulation of the brain's drainage system during sleep for improvement of learning and memory in male mice. Biomedical optics express\| PubMed ID: 38223185	2024
Different Effects of Phototherapy for Rat Glioma during Sleep and Wakefulness. Biomedicines\| PubMed ID: 38397864	2024
Photodynamic opening of the blood-brain barrier affects meningeal lymphatics and the brain's drainage in healthy male mice. Biomedical optics express\| PubMed ID: 39421760	2024
Plasmalogens Improve Lymphatic Clearance of Amyloid Beta from Mouse Brain and Cognitive Functions. International journal of molecular sciences\| PubMed ID: 39684263	2024
Sleep is a therapeutic window for photostimulation of drainage of aging brain. Frontiers of optoelectronics\| PubMed ID: 41258554	2025
NO-ergic mechanisms of age differences in photostimulation of lymphatic drainage, filtration, and clearance. Biomedical optics express\| PubMed ID: 41394499	2025

Dmitry Myagkov

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