We read the article by Pusic Sesar and colleagues [...].

The glymphatic system is a brain-wide clearance pathway that facilitates the removal of interstitial solutes, including amyloid-β, and plays a critical role in maintaining brain homeostasis. Impairments in glymphatic transport have been implicated in aging and neurodegenerative diseases, including Alzheimer’s disease. While glymphatic activity is most pronounced during sleep, emerging evidence suggests that specific patterns of neural activity, including gamma-frequency oscillations entrained by sensory stimulation, can modulate glymphatic transport even during wakefulness. Preclinical studies further indicate that 40 Hz sensory stimulation, delivered via light, sound, or multisensory paradigms, can induce gamma oscillations, reduce pathological protein accumulation, and enhance cognitive performance in animal models of Alzheimer’s disease. Early clinical investigations similarly suggest that gamma-frequency sensory stimulation may improve blood-based biomarkers, neuroimaging measures, and cognitive outcomes in patients with Alzheimer’s disease. To translate gamma-frequency stimulation into broadly applicable preventive or therapeutic strategies, approaches must be both effective and tolerable for long-term use. Conventional auditory gamma stimulation can be perceived as acoustically rough or monotonous, reducing listener comfort and limiting acceptability for prolonged use in broader populations. User-friendly auditory formats, such as “gamma music” and the more recently introduced “immersive gamma music”, have been proposed as potentially useful approaches for delivering gamma-frequency stimulation while improving listening comfort and facilitating sustained use. Collectively, gamma-frequency sensory stimulation represents a promising approach to support healthy brain aging and mitigate neurodegenerative processes, particularly when implemented via user-friendly auditory formats that facilitate repeated and long-term use. While these findings are encouraging, further research is needed to validate these approaches and determine their clinical relevance.

Spaceflight associated neuro-ocular syndrome (SANS) is a significant ophthalmic complication observed in astronauts during and after long-duration missions, characterized by optic disc edema, globe flattening, choroidal folds, and hyperopic shifts. Unlike papilledema in terrestrial idiopathic intracranial hypertension, optic disc edema in SANS is often asymmetric. The mechanisms underlying this asymmetry remain poorly understood. In this narrative review, we synthesize and critically interpret existing clinical observations, anatomical studies, neuroimaging findings, and experimental evidence, and propose that uneven ocular venous congestion, arising from microgravity-induced cephalad fluid shifts, pre-existing transverse sinus asymmetry, and orbital venous overload, leads to asymmetric optic disc edema by differentially disrupting anterograde ocular glymphatic transport between the eyes. This mechanistic framework highlights the interplay between venous hemodynamics and ocular glymphatic flow as a key factor in SANS pathophysiology. Targeted in-flight monitoring and ground-based analog studies will be essential to rigorously test this hypothesis. To this end, we outline a feasible experimental approach that prospectively integrates preflight cerebral magnetic resonance venography, providing data on transverse sinus dominance, with serial in-flight ophthalmic imaging on the International Space Station. This combined strategy could directly determine whether dural venous sinus anatomy predisposes to uneven ocular venous congestion and asymmetric optic disc edema in microgravity. Insights gained from this work may guide the development of effective countermeasures against SANS and broaden our understanding of ocular fluid dynamics under conditions of altered venous physiology on Earth.

To characterize how optic nerve tissue sheath (ONSp) responds to changes in intracerebral fluid infusion rate and consider if low rate intracerebral ventricular (ICV) infusion changes diurnal intracranial pressure (ICP) in rats. Anesthetized adult male rats underwent cannula placement into the lateral ventricles, for infusion and ICP monitoring. ICV infusion rate controlled ICP. A second syringe pump delivered sodium fluorescein for quantification of cerebrospinal fluid (CSF) flow to the optic nerve with fluorescence imaging (n = 14). Cannula were placed in lateral ventricle and under the optic nerve sheath (n = 6) for simultaneous pressure measurement at different ICV infusion rates, and at normal (n = 6, 95.6 ± 5.9mmHg) or high blood pressure (n = 4, 158.0 ± 9.5mmHg, intravenous Angiotensin II). Four rats were implanted with sub-dural sensors for awake ICP monitoring. Animals had ICV infusion of sterile saline at a low rate (2.5 ml/hr) for the first 4 weeks followed by a high rate (10 ml/hr) for week 5. Higher ICV flow rates produce predictable increases in ICP, which result in an increased ONSp. CSF pressure was 73 ± 3

Astronauts can develop a distinct collection of neuro-ophthalmic findings during long duration spaceflight, collectively known as Spaceflight Associated Neuro-ocular Syndrome (SANS). These clinical characteristics include optic disc edema, hyperopic refractive shifts, globe flattening, and chorioretinal folds, which may pose a health risk for future space exploration. Obtaining knowledge of SANS and countermeasures for its prevention is crucial for upcoming crewed space missions and warrants a multidisciplinary approach. This review examines the potential causes and countermeasures of SANS, including space anticipation glasses, lower body negative pressure, venoconstrictive thigh cuffs, impedance threshold devices, translaminar pressure gradient modulation, centrifugation, artificial gravity, pharmaceuticals, and precision nutritional supplementation. This paper highlights future research directions for understanding the genetic, anthropometric, behavioral, and environmental susceptibilities to SANS as well as how to use terrestrial analogs for testing future mitigation strategies.

Spaceflight occurs under extreme environmental conditions that pose significant risks to the physical and mental health and well-being of astronauts. Certain factors, such as prolonged isolation, monotony, disrupted circadian rhythms, heavy workload, and weightlessness in space, can trigger psychological distress and may contribute to a variety of mental health problems, including mood and anxiety disturbances. Recent findings regarding spaceflight-associated alterations in cerebrospinal fluid spaces, demonstrating enlargement of the brain's perivascular spaces from preflight to postflight, at least suggest reduced glymphatic clearance in microgravity, and have raised concerns about long-term cognitive health in astronauts. Therefore, it is critical for future long-duration human exploration missions to identify, develop and validate all potentially effective long-term countermeasures capable of reducing the risk of perivascular space enlargement and impaired glymphatic transport in space mission crews. Furthermore, it is crucial to implement effective strategies that would allow crew members to maintain optimal psychological well-being during future long-duration space exploration. In the present paper, we propose “immersive gamma music” as an add-on countermeasure that in combination with existing countermeasures can optimize glymphatic clearance in astronauts while improving their mental well-being. If confirmed, this approach could enrich the practice of space medicine, and might become increasingly important, given the plans for future human missions, including a return to the Moon and manned missions to Mars.

INTRODUCTION:Novel ocular findings have been identified in spaceflight. We discuss their potential association with Spaceflight Associated Neuro-ocular Syndrome (SANS) and integrate them in a framework that may help explain the pathophysiology. METHODS:We reviewed literature using the Medline/PubMed database starting in October 2020. Search terms included ocular circulation, hyperopia, serous chorioretinopathy, pigment epithelial detachment, choroidal folds, choroidal thickening, pachychoroid disease, optic disc edema, venous overload choroidopathy. No date exclusions were placed on the search. Articles were reviewed for relevance. Articles relevant to the pathophysiology of choroidal thickening and choroidal venous overload as it applies to SANS were included. RESULTS:Terrestrial venous overload choroidopathy is thought to be due to impediment to choroidal venous outflow, resulting in dilation of choroidal veins, increased choroidal thickness, pigment epithelial detachments, and serous detachment of the retina. Serous detachment of the retina, pigment epithelial detachments, choroidal folds, and thickening of the choroid were identified on in-flight optical coherence tomography testing. Postflight findings include these, as well as globe flattening. During spaceflight, there is a cephalad displacement of both blood and cerebrospinal fluid. This may lead to pathological consequences in the eye. Remodeling of the choroidal venous vortex system may result in continuance of pathophysiological findings after return to Earth, suggesting the best strategy is prevention. DISCUSSION:Microgravity induced venous overload of the choroid may play a role in SANS pathophysiology, and a venous overload choroidopathy may help explain several SANS features that remain unexplained by an etiology of elevated intracranial pressure. Mampre D, Spaide R, Mason S, Van Baalen M, Gibson CR, Mader TH, Wostyn P, Briggs J, Brown D, Lee AG, Patel N, Tarver W, Brunstetter T. Spaceflight-Associated Neuro-ocular Syndrome as a potential variant of venous overload choriodopathy. Aerosp Med Hum Perform. 2025; 96(6):496-508.

A spectrum of neuro-ocular changes has been observed in astronauts during and after prolonged exposure to microgravity on long-duration spaceflights. These changes, collectively referred to as “spaceflight associated neuro-ocular syndrome” (SANS), pose a significant challenge for space agencies as they prepare for future human missions, including a return to the Moon and manned missions to Mars. Optic disc edema, a hallmark feature of SANS, occurs in approximately 70% of astronauts on extended missions. Recent evidence suggests a potential link between poor sleep and the development of optic disc edema in individuals exposed to a spaceflight analog environment, providing critical insights into its underlying pathophysiology. Here, we propose a novel hypothesis: sleep deprivation may increase the risk of microgravity-induced optic disc edema by altering translaminar pressure dynamics and disrupting ocular glymphatic outflow. This perspective offers a new framework for understanding SANS and highlights potential targets to mitigate its risks in the context of human space exploration.

The high metabolic demand of retinal neurons requires tightly regulated mechanisms to maintain homeostasis and ensure the efficient clearance of metabolic waste and excess water. Recent studies have identified a glymphatic-like system in the rodent eye, and growing evidence supports the existence of a similar pathway in the human eye, facilitating fluid exchange and waste removal. The ocular glymphatic system supports bidirectional flow along the optic nerve - anterograde from the retina and retrograde from the brain.In this review, we integrate findings from preclinical models and clinically grounded hypotheses to identify key contributors to glymphatic dysfunction in ocular diseases. These include impaired laminar barrier integrity, pathological perivascular space expansion, aquaporin-4 abnormalities, immature vasculature, and pathological immune activation. Glymphatic impairment has been implicated in murine models of glaucoma, diabetic retinopathy, and ocular manifestations of Alzheimer’s disease. Additionally, disrupted glymphatic flow is suspected in papilledema, spaceflight associated neuro-ocular syndrome, and Terson syndrome.We further explore novel associations between glymphatic dysfunction and other blinding disorders such as myopic optic neuropathy, age-related macular degeneration, neuromyelitis optica spectrum disorders, and retinal vasculitis. In delineating these mechanistic links, this review provides a conceptual framework to guide future research in glymphatic contributions to ocular diseases.

Due to Translaminar Pressure Imbalance, Glymphatic Failure, or

Free AccessLetters to the EditorCould immersive sound improve glymphatic function in the awake brain? Peter Wostyn, MD, Piet Goddaer Peter Wostyn, MD Address correspondence to: Peter Wostyn, MD, Department of Psychiatry, PC Sint-Amandus, Reigerlostraat 10, 8730 Beernem, Belgium; Tel: 32-472713719; Fax: 32-50-819720; Email: E-mail Address: [email protected] Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium Search for more papers by this author , Piet Goddaer Studio Ozark Henry, Wulpen, Belgium Search for more papers by this author Published Online:January 1, 2024https://doi.org/10.5664/jcsm.10846SectionsEpubPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONWe read with great interest and enthusiasm the article by Van den Bulcke et al1 published recently in the Journal of Clinical Sleep Medicine. We are grateful to the authors for sharing their valuable research findings with the scientific community, and we would appreciate the opportunity to make a comment.The authors examined the effect of acoustic stimulation on slow-wave sleep in patients with Alzheimer’s disease (AD). Participants wore a self-applied headband device at home for multiple nights to record sleep data and to stimulate slow-wave activity by closed-loop acoustic stimulation. The authors demonstrated that acoustic stimulation could be a feasible and promising technique to significantly increase slow-wave sleep in AD. They further stated that enhancement of slow waves in AD could become a disease-modifying therapy in the future, given that high slow-wave activity supports the activity of the glymphatic system, a brain-wide perivascular pathway that enables the removal of waste metabolites, including amyloid-β, from the brain during sleep. We fully agree with this notion because we recently hypothesized that immersive sound therapy may be an innovative approach to reduce the individual risk of developing neurodegenerative diseases, such as AD, by inducing slow-wave delta oscillations, thereby promoting glymphatic clearance.2,3 Immersive sound refers to a 3-dimensional sound format where sounds can be perceived as coming from all directions simultaneously. It mimics the way we hear sounds in our daily lives, giving the listener a natural, lifelike sound experience and creating a sense of presence, ie, a feeling of “being there” through sound. Given that auditory stimuli and especially music can influence the bioelectrical brainwave activity,4 immersive sound could be specially designed to induce slow waves, potentially improving glymphatic clearance in the awake brain. If confirmed, this approach might complement the use of a device for acoustic stimulation of slow-wave activity as described by Van den Bulcke et al.1 Besides a positive impact on well-being, the application of immersive sound and the installation of immersive sound environments, eg, in aged care homes, could then help promote healthy brain aging and also help prevent neurodegenerative disorders such as AD. We therefore wish to encourage further research in this area.DISCLOSURE STATEMENTBoth authors have seen and approved the manuscript. Work for this study was performed at PC Sint-Amandus. Piet Goddaer has an ownership interest in the copyrights to his compositions. Dr. Wostyn reports no conflicts of interest.REFERENCES1. Van den Bulcke L, Peeters AM, Heremans E, et al.. Acoustic stimulation as a promising technique to enhance slow-wave sleep in Alzheimer’s disease: results of a pilot study. J Clin Sleep Med. 2023;19(12):2107–2112. LinkGoogle Scholar2. Wostyn P, Goddaer P. Can meditation-based approaches improve the cleansing power of the glymphatic system? Explor Neuroprot Ther. 2022;2:110–117. CrossrefGoogle Scholar3. Wostyn P, Goddaer P. Can immersive sound therapy counteract neurodegeneration by enhancing glymphatic clearance? Comment on Sachdeva et al. Effects of sound interventions on the permeability of the blood-brain barrier and meningeal lymphatic clearance. Brain Sci. 2022;12:742. Brain Sci. 2023;13(1):98. CrossrefGoogle Scholar4. Kučikienė D, Praninskienė R. The impact of music on the bioelectrical oscillations of the brain. Acta Med Litu. 2018;25(2):101–106. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 20 • Issue 1 • January 1, 2024 ISSN (print): 1550-9389ISSN (online): 1550-9397 Frequency: Monthly Metrics History Submitted for publicationSeptember 5, 2023Submitted in final revised formSeptember 23, 2023Accepted for publicationSeptember 25, 2023Published onlineJanuary 1, 2024 Information© 2024 American Academy of Sleep MedicinePDF download

We read with great interest the article by Tidwell and colleagues[1][1] entitled "Longitudinal Changes in Cerebral Perfusion, Perivascular Space Volume, and Ventricular Volume in a Healthy Cohort Undergoing a Spaceflight Analog" published recently in the American Journal of Neuroradiology . We

Glaucoma is one of the main causes of irreversible blindness in the world. The most common form, primary open-angle glaucoma, is an optic neuropathy that is characterized by a progressive loss of retinal ganglion cells and their axons, leading to structural changes in the optic nerve head and associated visual field defects. Elevated intraocular pressure remains the most important modifiable risk factor for primary open-angle glaucoma. However, a significant proportion of patients develop glaucomatous damage in the absence of increased intraocular pressure, a condition known as normal-tension glaucoma (NTG). The pathophysiology underlying NTG remains unclear. Several studies have revealed that vascular and cerebrospinal fluid (CSF) factors may play significant roles in the development of NTG. Vascular failure caused by functional or structural abnormalities, and compartmentation of the optic nerve subarachnoid space with disturbed CSF dynamics have been shown to be associated with NTG. In the present article, based on the concept of the glymphatic system and observations in patients with NTG, we hypothesize that failure of fluid transport via the glymphatic pathway in the optic nerve may be involved in the pathogenesis of some if not many cases of NTG. According to this hypothesis, vascular and CSF factors may share reduced glymphatic transport and perivascular waste clearance in the optic nerve as a final common pathway leading to the development of NTG. In addition, we speculate that some cases of NTG may reflect glymphatic dysfunction in natural brain aging and central nervous system diseases, such as Alzheimer's disease. Clearly, further studies are needed to gain additional insight into the relative contribution of these factors and conditions to reduced glymphatic transport in the optic nerve.

We would like to congratulate Sachdeva and colleagues for establishing an informative review regarding the effects of music/sound exposure on blood–brain barrier permeability and meningeal lymphatic/glymphatic clearance, and would appreciate the opportunity to make a comment. The review by Sachdeva and colleagues documents the beneficial effects of sound interventions on blood–brain barrier permeability and the activity of the meningeal lymphatic/glymphatic system. The authors further note that sound interventions may have the potential to reduce the accumulation of amyloid-β within the brain in Alzheimer’s disease through improved meningeal lymphatic/glymphatic clearance. The authors also nicely discuss evidence that music influences sleep quality, which may facilitate glymphatic solute clearance as a result of an increase in the interstitial space, which results in reduced resistance to fluid transport. We fully agree with this notion, since we recently hypothesized that immersive sound therapy may be an innovative approach to reduce the individual risk of developing neurodegenerative diseases, such as Alzheimer’s disease, by inducing EEG slow-wave delta oscillations (which characterize deep sleep), thereby promoting glymphatic clearance.