Chronic intraocular pressure elevation alters cerebrovascular reactivity in the visual cortex and basal forebrain

Abstract

Purpose : Glaucoma is an eye disease with widespread involvement of the brain. Since visual cortex (VC) may possess lower choline levels in glaucoma, and basal forebrain (BF) has cholinergic projections to VC for modulating cerebral blood flow and visual processing, we postulate that the vascular functions of the VC and BF are involved in glaucoma (PMID: 31242454). Recently, we used a novel whole-brain relative cerebrovascular reactivity (rCVR) mapping technique via resting-state functional MRI (rsfMRI) without gas challenge, and observed rCVR decrease in VC and rCVR increase in BF in patients with increasing glaucoma severity (PMID: 34892116). However, the underlying mechanisms remain to be elucidated. Here, we applied a hydrogel-induced glaucoma mouse model to elevate intraocular pressure (IOP) (PMID: 31176841), mapped whole-brain rCVR using rsfMRI, and measured optomotor responses (OMR). We hypothesize that chronic IOP elevation can lead to rCVR changes in the glaucomatous brain along with visual impairments.

Methods : For the glaucoma model, C57BL/6J mice (male, 15-weeks, n=15) received intracameral injection of cross-linking hydrogel to the right eye to obstruct aqueous outflow and induce chronic IOP elevation. Controls (male, 15-weeks, n=13) were untreated. IOP was measured in both eyes 2-3 times per week for 3 weeks, followed by OMR and rsfMRI experiments at 7 Tesla (Fig. 1A).

Results : Sustained IOP elevation was confirmed in the right eyes of the glaucoma model (Fig. 1B). Over 90% of mouse optic nerve fibers are known to project to the contralateral visual brain; rCVR decreased in the left but not right VC, whereas rCVR increased in the right BF in the glaucoma model but not the controls (Fig. 2A). These rCVR changes were inversely coupled (Fig. 2B). In addition, IOP of the injected eye was inversely correlated with rCVR in the left VC, while positively correlated with rCVR in the right BF (Fig. 2C). OMR revealed a decrease in visual acuity and an increase in visual contrast threshold for the injected eye (Fig. 2D) indicating visual impairment. The decrease in visual acuity was inversely correlated with rCVR in the BF (Fig. 2E).

Conclusions : Mouse rCVR mapping using rsfMRI detects widespread brain changes induced by chronic IOP elevation, and demonstrates vascular involvement in glaucoma both within and beyond the primary visual pathways.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.