Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood–brain barrier: mechanisms of brain clearing

Abstract

The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood-brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels. We first demonstrate successful application of optical coherence tomography (OCT) for imaging of the lymphatic vessels in the meninges after opening of the BBB, which might be a new useful strategy for noninvasive analysis of lymphatic drainage in daily clinical practice. Also, we give information about the depth and size of the meningeal lymphatic vessels in mice. These new fundamental data with the applied focus on the OCT shed light on the mechanisms of brain clearance and the role of lymphatic drainage in these processes that could serve as an informative platform for a development of therapy and diagnostics of diseases associated with injuries of the BBB such as stroke, brain trauma, glioma, depression, or Alzheimer disease.

Age differences in photodynamic therapy‐mediated opening of the blood‐brain barrier through the optical clearing skull window in mice

“…The activation of lymphatic drainage contributes to the elimination of water from the extracellular space and recovery of fluid balance in the brain. In our serial works, we clearly show the recruitment of the meningeal lymphatics by BBB opening, including PDT‐mediated opening of the BBB .…”

Photodynamic therapy of brain tumors and novel optical coherence tomography strategies for in vivo monitoring of cerebral fluid dynamics

“…Our results clearly show that PDT caused the strong the BBB leakage that was associated with vasogenic edema and with a signi¯cant increase in the CSF volume in the cisterna magna vs. the control group. The mild BBB disruption by sound was not associated with visible (histological data) 106 changes in the PVS and the changes in the CBF volume in the cisterna magna were within a normal range. 109 We hypothesize that mild changes in the BBB might be completely compensated by an activation of the brain drainage and clearing system as in the case with soundrelated opening of the BBB.…”

“…We used two methods for the BBB openingthe sound that induces the mild BBB opening and PDT causing the strong BBB leakage with the accumulation of extensive°uids in the PVS. 106,107 Indeed, using confocal imaging of dextran extravasation and spectro°uorimetric assay of Evans Blue albumin complex level in the brain tissues, we showed opening of the BBB for these tracers that was more pronounced in the PDT group vs. the sound group. These changes stimulated the brain drainage with an increase in the volume of cerebral spinal°uid (CSF) in the cisterna magna that was also more pronounced in the PDT group vs. the sound group.…”

Loud music and the specific sound stress open the blood-brain barrier: new fundamental, biomedical, and social aspects

“…In our recent work, we discovered an important role of the meningeal lymphatic systems in the brain clearing from substances, which permeate from blood into the brain parenchyma through opened BBB induced by sound or photodynamic effects. 43,44 iii. Does sound open BBB directly or via stress?…”

“…31 Assessment of apoptosis, brain histology and neurobehavioral pattern did not reveal excessive apoptosis, morphological alterations in the brain tissues and vessels, or hearing loss and cognitive impairment in mice in 1h after sound exposure when BBB was opened and in 4h/24h after sound exposure when BBB integrity was fully restored. The reversibility of sound-induced BBB breakdown might be linked to the activation of the brain drainage and clearing systems via the meningeal lymphatic pathway after BBB opening 43,44 . In our recent work, we discovered an important role of the meningeal lymphatic systems in the brain clearing from substances, which permeate from blood into the brain parenchyma through opened BBB induced by sound or photodynamic effects.…”