Drainage Of Brain Research Articles

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

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.

Impact Of Brain Drain and Factors Contributing to Migration of Staff Abroad in The University of Ibadan

This study examines the impact of brain drainage and factors contributing to migration of universities staff abroad. A Well-structured questionnaire was developed to gather information needed from the universities staff in the University of Ibadan. The result shows that migration of university staff abroad is not owned to perceived gender discrimination but is owned to insecurity, naira fall, political and economic instability, unfriendly working condition and insufficient wages. Furthermore, there is evidence of increased willingness to relocate among those that are yet to relocate with no evidence of any educational career development opportunities which has the potential of reducing brain drainage if it is sufficiently available. Thus, the study recommends the provision of educational career development opportunities in government fight against brain drainage

Rapidly Increasing Brain Drainage in Türkiye: Causes, Effects, and Solutions

Rapidly Increasing Brain Drainage in Türkiye: Causes, Effects, and Solutions

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 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.

Inside Front Cover: Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system (EXP2 2/2024)

Inside Front Cover: Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system (EXP2 2/2024)

Edaravone Maintains AQP4 Polarity Via OS/MMP9/β-DG Pathway in an Experimental Intracerebral Hemorrhage Mouse Model.

Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood-brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.

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

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.

Transcranial photobiomodulation improves insulin therapy in diabetic microglial reactivity and the brain drainage system

The dysfunction of microglia in the development of diabetes is associated with various diabetic complications, while traditional insulin therapy is insufficient to rapidly restore the function of microglia. Therefore, the search for new alternative methods of treating diabetes-related dysfunction of microglia is urgently needed. Here, we evaluate the effects of transcranial photobiomodulation (tPBM) on microglial function in diabetic mice and investigate its mechanism. We find tPBM treatment effectively improves insulin therapy on microglial morphology and reactivity. We also show that tPBM stimulates brain drainage system through activation of meningeal lymphatics, which contributes to the removal of inflammatory factor, and increase of microglial purinergic receptor P2RY12. Besides, the energy expenditure and locomotor activity of diabetic mice are also improved by tPBM. Our results demonstrate that tPBM can be an efficient, non-invasive method for the treatment of microglial dysfunction caused by diabetes, and also has the potential to prevent diabetic physiological disorders.

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

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.

Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system

AbstractThe glymphatic system plays a key role in the clearance of waste from the parenchyma, and its dysfunction has been associated with the pathogenesis of Alzheimer's disease (AD). However, questions remain regarding its complete mechanisms. Here, we report that efflux of cerebrospinal fluid (CSF)/interstitial fluid (ISF) solutes occurs through a triphasic process that cannot be explained by the current model, but rather hints at the possibility of other, previously undiscovered routes from paravenous spaces to the blood. Using real‐time, in vivo observation of efflux, a novel drainage pathway was discovered, in which CSF molecules enter the bloodstream directly through dynamically assembled, trumpet‐shaped pores (basolateral ϕ<8 μm; apical ϕ < 2 μm) on the walls of brain venules. As Zn2+ could facilitate the brain clearance of macromolecular ISF solutes, Zn2+‐induced reconstruction of the tight junctions (TJs) in vascular endothelial cells may participate in pore formation. Thus, an updated model for glymphatic clearance of brain metabolites and potential regulation is postulated. In addition, deficient clearance of Aβ through these asymmetric venule pores was observed in AD model mice, supporting the notion that impaired brain drainage function contributes to Aβ accumulation and pathogenic dilation of the perivascular space in AD.

Monitoring the cerebral venous drainage in space missions: the Drain Brain experiments of the Italian Space Agency

It is well known that the space environment induces major alterations to various human physiological systems, determining a general deconditioning of the body. Medical research programs aim to keep the astronaut’s health status during the mission, enable their ready operation once they arrive at their destination, and allow their safe recovery when returned to Earth. Among the programs coordinated and supported by the Italian Space Agency (ASI), the experiments called Drain Brain, performed by the University of Ferrara, are particularly relevant in this respect. The project, which began with the collaboration of Samantha Cristoforetti in 2014, has demonstrated the capability of a plethysmograph system to study the cerebral circulation and the venous return from the brain to the heart, onboard the International Space Station (ISS). Demonstrating the progressive reduction of the cross-sectional area of the internal jugular vein, particularly significant between pre-flight data collection and the last assessment after 6 months of flight on the ISS (p<0.001). Over the next two years, thanks to the Drain Brain 2.0 project, crews of the International Space Station will be studied with a new version of the plethysmograph, synchronized with the electrocardiogram, to assess cardiac efficiency and brain drainage in relation to symptoms such as blurred vision, numbness, or the feared onset of jugular thrombosis, that is linked to blood flow slowdown due to the absence of the gravitational gradient. Drain Brain 2.0 will also generate important returns to Earth, closing the virtuous circle of terrestrial application of space research.

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma.

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.

LYMPHATIC DRAINAGE SYSTEM OF THE BRAIN: A NEW PLAYER IN NEUROSCIENCE

The lymphatic system not only plays an important role as a drainage eliminating metabolic wastes and toxins from tissues, but also represents an arena for the unfolding of immune response scenarios aimed at protecting the organism from bacteria and viruses. In the central nervous system (CNS), drainage processes proceed with the same intensity as in peripheral tissues. The brain actively exchanges nutrients with the blood and excretes metabolic waste products through the drainage paths closely related to the peripheral lymphatic system. The same routes allow the traffic of immune cells and antibodies to the CNS, thus providing a communication between the peripheral and central immune systems. Over the two-century history of brain drainage studies, a lot of facts have been accumulated to suggest indirectly the presence of lymphatic vessels in the CNS. However, even with the advent of high-tech imaging of brain structures and a rediscovery of the meningeal lymphatic vessels (MLVs), which was a watershed in neuroscience, scientists have not advanced beyond4 confirming the already existing dogma that the lymphatic network is present exclusively in the brain meninges, but not in brain tissues. In fact, however, the rediscovery of MLVs by American scientists was not a “true revelation”, as they were first described by the Italian anatomist Mascagni two centuries earlier, and his results were confirmed later on in many other studies performed on the meninges in humans, macaques, rodents, dogs, rabbits and zebrafish. As a result, the scientific community did not recognize the “forgotten” MLVs as a new discovery. This review highlights the turning points that occurred in neuroscience, when a new player has entered the game and set in order bicentennial efforts of scientists to explain how unnecessary molecules and toxins are removed from the brain, as well as how drainage and immunity are implemented in the CNS. This is an important informational and creative platform both for new fundamental knowledge about the lymphatic system in the brain, as well as for the development of innovative neurorehabilitation technologies based on the management of lymphatic drainage processes.

The impairment of intramural periarterial drainage in brain after subarachnoid hemorrhage

Interstitial fluid (ISF) from brain drains along the basement membranes of capillaries and arteries as Intramural Periarterial Drainage (IPAD); failure of IPAD results in cerebral amyloid angiopathy (CAA). In this study, we test the hypothesis that IPAD fails after subarachnoid haemorrhage (SAH). The rat SAH model was established using endovascular perforation method. Fluorescence dyes with various molecular weights were injected into cisterna magna of rats, and the pattern of IPAD after SAH was detected using immunofluorescence staining, two-photon fluorescent microscope, transmission electron microscope and magnetic resonance imaging tracking techniques. Our results showed that fluorescence dyes entered the brain along a periarterial compartment and were cleared from brain along the basement membranes of the capillaries, with different patterns based on individual molecular weights. After SAH, there was significant impairment in the IPAD system: marked expansion of perivascular spaces, and ISF clearance rate was significantly decreased, associated with the apoptosis of endothelial cells, activation of astrocytes, over-expression of matrix metalloproteinase 9 and loss of collagen type IV. In conclusion, experimental SAH leads to a failure of IPAD, clinically significant for long term complications such as CAA, following SAH.

Lymphatic drainage at the meningeal‐brain interface in aging and Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent form of dementia. We have recently shown that proper meningeal lymphatic drainage is important for brain fluid flow, learning and memory in aging and for brain amyloid beta (Aβ) clearance in mouse models of AD. Interestingly, genetic factors that increased the risk for AD are also linked to altered meningeal lymphatic function.MethodMeningeal lymphatic function was evaluated in mouse models of AD at different ages by RNA sequencing of sorted meningeal lymphatic endothelial cells (LECs) and by assessing of lymphatic vessel morphology and drainage capacity. Meningeal lymphatic dysfunction was induced by photoablation, whereas enhancement of meningeal lymphatic drainage was achieved by increasing the levels of VEGF‐C. The transcriptional signatures of brain blood endothelial cells and microglia were determined by single‐cell RNA sequencing upon manipulation of meningeal lymphatic drainage. Changes in Aβ plaque clearance by monoclonal antibodies were assessed upon prolonged manipulation of meningeal lymphatic drainage. Integrated analysis was performed using murine and human cell RNA‐seq data, as well as AD summary statistics.ResultWe show that a progressive deposition of meningeal Aβ with aging leads to gene expression changes in meningeal lymphatic endothelial cells and an accelerated reduction in meningeal lymphatic vessel coverage in the 5xFAD mouse model. Interestingly, modulating meningeal lymphatic function in AD transgenic mice affects the clearance of Aβ by monoclonal antibodies, a feature that is closely associated with the activation signatures in brain blood endothelial cells and microglia. Furthermore, genes that are highly expressed in lymphatic vasculature are associated with increased risk for AD and altered levels of Aβ in the CSF of AD patients. Integrated analysis of murine and human microglia transcriptomes revealed an association between the signatures of activated microglia from mice with defective meningeal lymphatic function and activated microglia isolated from the AD brain. We are now turning our attention to the interaction between the main genetic risk factor for AD, expression of the apolipoprotein E4, and changes in brain drainage by the meningeal lymphatic vascular system.ConclusionCollectively, our data underline the notion that a dysfunctional meningeal lymphatic vasculature may impact on AD pathophysiology and therapeutic outcome.

Deciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain

Perivascular macrophages (pvMs) are associated with cerebral vasculature and mediate brain drainage and immune regulation. Here, using reporter mouse models, whole brain and section immunofluorescence, flow cytometry, and single cell RNA sequencing, besides the Lyve1+F4/80+CD206+CX3CR1+ pvMs, we identify a CX3CR1– pvM population that shares phagocytic functions and location. Furthermore, the brain parenchyma vasculature mostly hosts Lyve1+MHCII– pvMs with low to intermediate CD45 expression. Using the double Cx3cr1GFP x Cx3cr1-Cre;RosatdT reporter mice for finer mapping of the lineages, we establish that CD45lowCX3CR1– pvMs are derived from CX3CR1+ precursors and require PU.1 during their ontogeny. In parallel, results from the Cxcr4-CreErt2;Rosa26tdT lineage tracing model support a bone marrow-independent replenishment of all Lyve1+ pvMs in the adult mouse brain. Lastly, flow cytometry and 3D immunofluorescence analysis uncover increased percentage of pvMs following photothrombotic induced stroke. Our results thus show that the parenchymal pvM population is more heterogenous than previously described, and includes a CD45low and CX3CR1– pvM population.

Music improves the therapeutic effects of bevacizumab in rats with glioblastoma: Modulation of drug distribution to the brain.

BackgroundThe 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.MethodsThe 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.ResultsOur 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.ConclusionWe 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.

Brain Fluid Channels for Metabolite Removal.

The adult human brain represents only 2% of the body's total weight, however it is one of the most metabolically active organs in the mammalian body. Its high metabolic activity necessitates an efficacious waste clearance system. Besides the blood, there are two fluids closely linked to the brain and spinal cord drainage system: interstitial fluid (ISF) and cerebrospinal fluid (CSF). The aim of this review is to summarize the latest research clarifying the channels of metabolite removal by fluids from brain tissue, subarachnoid space (SAS) and brain dura (BD). Special attention is focused on lymphatic vascular structures in the brain dura, their localizations within the meninges, morphological properties and topographic anatomy. The review ends with an account of the consequences of brain lymphatic drainage failure. Knowledge of the physiological state of the clearance system is crucial in order to understand the changes related to impaired brain drainage.

A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion.

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-As: MOG92-106 specific transgenic T cell receptor (TCR1640) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.

Cerebral venous drainage in patients with dural arteriovenous fistulas: correlation with clinical presentation.

Dural arteriovenous fistulas (DAVFs) are abnormal, acquired arteriovenous connections within the dural leaflets. Their associated symptoms may be mild or severe and are related to the patient's venous anatomy. With the hypothesis that the patient's venous anatomy determines the development of symptoms, the authors aimed to identify which venous anatomy elements are important in the development of major symptoms in patients with a DAVF. A multicenter study was performed based on the retrospective analysis of cerebral angiographies with systematic assessment of brain drainage pathways (including fistula drainage) in patients over 18 years of age with a single DAVF. The patients were divided into two groups: those with minor (group 1, n = 112) and those with major (group 2, n = 89) symptoms. Group 2 was subdivided into two groups: patients with hemorrhage (group 2a, n = 47) and patients with severe nonhemorrhagic symptoms (group 2b, n = 42). The prevalence of stenosis in DAVF venous drainage and the identification of tiny anastomoses between venous territories were significantly higher in group 2 (32.6% and 19.1%, respectively) compared with group 1 (2.68% and 5.36%, respectively). Stenosis of DAVF venous drainage was significantly more frequent in group 2a than in group 2b (51.1% vs 11.9%, p < 0.001). Group 2b patients had increased prevalence of shared use of the cerebral main drainage pathway (85.0% vs 53.2%, p = 0.002), the absence of an alternative route (45.0% vs 17.0%, p = 0.004), and the presence of contrast stagnation (62.5% vs 29.8%, p = 0.002) compared with group 2a patients. In patients with high-grade fistulas, the group with major symptoms had increased prevalence of a single draining direction (31.3% vs 8.33%, p = 0.003), stenosis in the draining vein (35.0% vs 6.25%, p = 0.000), the absence of an alternative pathway for brain drainage (31.3% vs 12.5%, p = 0.017), and the presence of contrast stagnation (48.8% vs 22.9%, p = 0.004). Major symptoms were observed when normal brain tissue venous drainage was impaired by competition with DAVF (predominance in group 2b) or when DAVF venous drainage had anatomical characteristics that hindered drainage, with consequent venous hypertension on the venous side of the DAVF (predominance in group 2a). The same findings were observed when comparing two groups of patients with high-grade lesions: those with major versus those with minor symptoms.