Major reviewAutoregulation and neurovascular coupling in the optic nerve head
Introduction
Glaucoma is an optic neuropathy characterized by progressive death of retinal ganglion cells (RGCs) and irreversible visual loss. Glaucoma is the second leading cause of blindness worldwide,177 and yet its etiology and treatment remain unclear. The main modifiable risk factor in glaucoma patients is elevated intraocular pressure (IOP)1, 45, 110, 118, 121; however, a high percentage of individuals with elevated IOP (a condition called ocular hypertension) never develop glaucoma,103 and many glaucoma patients continue to experience disease progression despite lowering IOP to target levels or have no history of elevated IOP–a condition called normal tension glaucoma (NTG).203
Several studies suggest correlations between impaired ocular blood flow and glaucoma.56, 60, 67, 84, 85, 90, 241 In healthy conditions, vascular beds exhibit an intrinsic ability to maintain relatively constant blood flow over a large range of arterial pressures. This autoregulatory behavior is recognized in most vascular beds—including the eye,3, 169 brain,162 heart,21 kidney,178 skeletal muscle,61 and gut129—but the effectiveness of autoregulation differs among these vascular beds according to importance of function. For example, the brain and kidney receive stable flow over a range of arterial pressure,32, 162 whereas autoregulation in other beds such as the gut is less effective. In the eye, the retinal and optic nerve head (ONH) vascular beds are known to exhibit autoregulation, though to differing extents. Details and experimental measures of autoregulation are better established in the retina than in the ONH. In experiments assessing hemodynamic responses to light stimulation,68, 69, 184, 186 blood flow in the retina and ONH seems to be highly correlated to increased neural activity. This phenomenon is called neurovascular coupling.130
In glaucoma the location of damage to nerve cells is hypothesized to be predominantly in the ONH,176 and thus a clearer understanding of the factors affecting the blood supply to the ONH is necessary to determine how this may be compromised and potentially contribute to the pathophysiology of glaucoma.
The aim of this review is to 1) summarize the mechanisms of autoregulation and neurovascular coupling that function in the ONH; 2) describe the current ability to assess autoregulation in the ONH using methodologies capable of determining ONH blood flow (or volume and velocity); 3) compare data on blood flow for varying pressure or metabolic needs in the ONH to assess autoregulation in healthy and pathologic conditions; and 4) describe the current status of ophthalmic research and support the potential of mathematical modeling to further the understanding of the relationship between ocular blood flow mechanisms and ocular diseases such as glaucoma. In order to help the reader, a list of the acronyms used in this paper is provided in Table 1.
Section snippets
Anatomy
The ONH is where RGC axons leave the eye through the scleral portion of the neural canal, forming bundles separated by astrocytes, a particular type of glial cell.28 For the purpose of description, the anatomy and vascular supply of the ONH is best divided into 4 regions, from anterior to posterior segments (see Fig. 1).
The most anterior part of the ONH is the superficial nerve fiber layer (SNFL). Some vascular details of this layer can be resolved on ophthalmoscopy examination or angiography.
Techniques for in vivo studies of ONH hemodynamics
As described in section 2, the complex vasculature of the ONH is comprised of small diameter vessels arranged in an intricate 3-dimensional geometry. At present, no technology allows a noninvasive measurement of volumetric blood flow in absolute units; however, some hemodynamic measurement techniques provide surrogates for ONH blood flow in arbitrary units. Four of these measurement techniques for in vivo studies of ONH hemodynamics are discussed and compared in the following sections. Table 2
Evidence of blood flow autoregulation in the ONH
Autoregulation is the intrinsic ability of vascular beds to maintain relatively constant blood flow over a large range of pressure, while meeting the metabolic demand of the tissue. Autoregulation is evaluated most often on a flow versus pressure graph, where pressure may be expressed as mean arterial pressure (MAP), IOP, or ocular perfusion pressure (OPP) (see Fig. 6).
OPP refers to the arterovenous pressure difference driving blood flow through the intraocular vasculature. The intraocular
Mechanisms of blood flow regulation
Several important response mechanisms combine to cause changes in vascular tone that lead to blood flow regulation to a particular tissue. A complete overview of the biochemistry of all the mediators and modulators involved is beyond the scope of this review. We will focus on studies relevant for the control of blood flow in the ONH.
Pathologic effects of impaired blood flow regulation in the ONH
Impaired blood flow regulation has been suggested to render the ONH more susceptible to damage by compromising blood supply (leading to ischemia) and, consequently, oxygen delivery (leading to hypoxia) in potentially dangerous situations of reduced BP, increased IOP, and/or increased local metabolic demands.12, 117, 141 However, the mechanisms through which the damage occurs are still not completely understood.175, 231 Evidence suggests that ischemia and related hypoxia might influence the
Mathematical modeling of ONH blood flow regulation
In the previous sections, we have reviewed experimental and clinical evidence of blood flow autoregulation in the ONH, the mechanisms contributing to autoregulation and the pathologic consequences of vascular dysregulation. Despite significant recent advances in the understanding of ONH blood flow autoregulation, important questions remain unanswered. What are the relative contributions of various mechanisms, including responses to mechanical, metabolic, and neurovascular stimuli, in achieving
Method of literature search
A literature search using the PubMed and Web of Science search engines and available library databases was used with reference cross-matching to obtain relevant peer reviewed articles published on blood flow autoregulation and ocular biomechanics and hemodynamics. The article search included available published studies from 1900 to April 2015. Separate searches were performed by the primary author (D.P.), and 3 independent researchers (G.G., A.M.H., and J.A.) until relevant articles were
Acknowledgments
The authors acknowledge the valuable contribution of Alessandra Cantagallo, who realized the anatomic drawings (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5) published in this article.
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