# Numerical Modeling of Venous Outflow from the Cranial Cavity in the Supine Body Position
## 4 Discussion  
In this in silico study, we demonstrated that both upper and lower strictures in the IJV can be hemodynamically significant and potentially clinically relevant. Besides, some types of these strictures, e.g., asymmetrically positioned nozzle-like stenoses located at the level of the jugular foramen or a membrane-shaped jugular valve particularly compromising the flow through the IJV, shift the outflow towards the vertebral pathway. Our results can, at least partially, resolve some clinical dilemmas, which will be further discussed. Of note, in the past, some papers describing the numerical simulations of flow in the IJV were published. Yet, these models did not investigate vein morphologies with the nozzle-like strictures in the proximal part of this vein [25,26]. In our previous paper, based on the results of computational flow simulations using the same CFD package, we suggested that strictures located at the level of the jugular foramen are more clinically relevant than pathological jugular valves [19]. Yet, in this study, we evaluated the flow only in models without alternative outflows through the vertebral pathway. Also, flow disturbances evoked by the stenoses were evaluated qualitatively by an assessment of flow characteristics. In the current study, we evaluated the flow quantitatively and with an alternative outflow route, and thus they are more similar to real patients. In contrast to the former study, the present study found that both types of the strictures--located upstream and downstream--can significantly compromise the outflow. Importantly, since severe flow impairments were caused by the short nozzle-like stenoses, especially those located eccentrically, it is probable that flow separation and flow reversal were the main causes of an increased flow resistance and a shift in the outflow towards the vertebral pathway (Figures 8 and 9). But stenotic jugular valves (Figures 10 and 11), especially membrane-shaped, could equally evoke significant flow impairments. Usually, albeit in living humans, the IJVs exhibit slightly irregular shapes and there is an asymmetry regarding their size (typically the right IJV is wider than the left one), there are no strictures in these veins that significantly alter the cerebral venous outflow. Of note, the IJVs represent the major outflow route from the brain in the horizontal body position, including during sleep. Recently, it has been hypothesized that an impaired cerebral venous outflow can affect function of the glyphmatic system, which is responsible for cleansing the brain from noxious metabolites, including pathological proteins [27,28]. Importantly, the glyphmatic system is mainly active during sleep; therefore, an unrestricted venous outflow from the brain during sleep is potentially indispensable. Although, for the time being, direct observations proving that there is indeed a causative association between venous abnormalities and neurological pathologies are lacking, it is known that malformed IJVs are more often seen in neurological patients in comparison with healthy controls [13,15]. Interestingly, a decade ago, many multiple sclerosis patients were managed using endovascular angioplasty of their narrowed IJVs. Unfortunately, although early results of such a treatment were encouraging, positive outcomes in a long run were seen only in some subgroups of these patients [29, 30, 31]. Therefore, this treatment modality is no longer the standard one. However, a majority of the aforementioned endovascular procedures comprised balloon angioplasties of pathological jugular valves. External compression at the level of the jugular foramen were not addressed, while it is known that such strictures are quite common in these patients [13,20]. This may account for the unfavorable results of the clinical trials in multiple sclerosis patients. In addition, stenotic lesions of the IJVs are found in other neurological pathologies, including [PERSON]'s and Parkinson's diseases, [PERSON] disease, and lateral amyotrophic sclerosis.