Furthermore, when we noninvasively assessed for MMP activity, which can be related to BBB breakdown, we again found no significant difference between sham and JVL mice in the amount of the activated fluorescent probe detected, which was minimal and could not be visualized. Both sham and JVL mice sections demonstrated similar colocalization of these molecules with the endothelium, consistent with an intact BBB. On the other hand, EAE mice showed endothelial cells that were not associated with these barrier molecules, revealing that breakdown in the BBB had occurred. In this study, we developed a murine model of chronic cerebral venous insufficiency in order to evaluate the relationship between CCSVI and demyelination. Our model consisted of bilateral JV ligation to mirror the cerebral venous abnormalities previously reported, including multiple stenoses, formation of the cervical collateral venous drainage pathways similar to those described in CCSVI, and cerebral hemodynamic disturbances. Despite both structural and hemodynamic abnormalities in the JVL group consistent with successful induction of chronic cerebral venous insufficiency, we did not find any evidence of BBB breakdown, neuroinflammation, or demyelination in the brain. For each parameter of disease progression that we assessed, we consistently found no difference between the sham and JVL groups. Our findings suggest that even significant disturbances in JV hemodynamics, such as those seen in this model, do not result in neuroinflammation and/or demyelinating plaques. While animal models are invaluable research tools in helping us understand human disease, they are imperfect models. The human circulation system differs from that of the mouse in both structure and position. Since humans are bipeds and stand erect, the human brain axis is aligned approximately 90 degrees more ventral than the mouse brain with respect to the axis of the body. The exact effect that this postural difference has, if any, on mouse cerebral hemodynamics versus human cerebral hemodynamics is unclear. Furthermore, it is possible that additional stress or stimuli might be needed to increase cardiovascular demand in our animal model since mice are more sedentary compared to humans. Both posture and activity may therefore potentially play a role in exacerbating the effects of venous congestion resulting from venous stenosis. To address these possible confounding variables, we aimed to maximize the resting state of venous pressure by surgically ligating both JVs in order to create an extreme scenario of increased venous cerebral venous insufficiency. Some studies have reported that 91% of MS patients having either unilateral or bilateral JV stenosis, with 14% exhibiting bilateral stenosis in the jugular veins. In this way, we believe we have accounted for possible differences in cerebral venous hemodynamics between mice and humans by creating a murine model with relatively greater cerebral venous insufficiency than previous positive studies have reported in humans. The mice were followed for up to 6 months after JVL, a considerable part of the lifespan of SJL mice which, particularly given the maximization of venous pressure by bilateral JVL, should be more than sufficient for disease manifestation if there was a relationship between venous congestion and demyelination. Currently, the hypothesis that CCSVI causes MS is unproven but remains highly attractive to many patients and physicians.