survey of ophthalmology 61 (2016) 164e186 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/survophthal Major review Autoregulation and neurovascular coupling in the optic nerve head Daniele Prada, PhDa,*, Alon Harris, MS, PhD, FARVOb, Giovanna Guidoboni, PhDa,b,c, Brent Siesky, PhDb, Amelia M. Huang, BSb, Julia Arciero, PhDa a Department of Mathematical Sciences, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis, Indiana, USA b Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USA c LabEx IRMIA, University of Strasbourg, Strasbourg, Alsace, France article info abstract Article history: Impairments of autoregulation and neurovascular coupling in the optic nerve head play a Received 8 May 2015 critical role in ocular pathologies, especially glaucomatous optic neuropathy. We critically Received in revised form review the literature in the field, integrating results obtained in clinical, experimental, and 2 October 2015 theoretical studies. We address the mechanisms of autoregulation and neurovascular Accepted 2 October 2015 coupling in the optic nerve head, the current methods used to assess autor- Available online 20 October 2015 egulationdincluding measurements of optic nerve head blood flow (or volume and velocity)dblood flow data collected in the optic nerve head as pressure or metabolic Keywords: demand is varied in healthy and pathologic conditions, and the current status and autoregulation in the optic nerve potential of mathematical modeling work to further the understanding of the relationship head between ocular blood flow mechanisms and diseases such as glaucoma. neurovascular coupling ª 2016 Elsevier Inc. All rights reserved. ocular biomechanics and hemodynamics mechanical influences on autoregulation metabolic autoregulation effects of impaired blood flow regulation optic neuropathies glaucoma blood flow regulation modeling * Corresponding author: Mr. Daniele Prada, PhD, Department of Mathematical Sciences, Indiana University-Purdue University Indi- anapolis (IUPUI), 402 North Blackford Street, LD 270, Indianapolis, IN 46202, USA. Tel.: þ1 317 274 3460. E-mail address: [email protected] (D. Prada). 0039-6257/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2015.10.004 survey of ophthalmology 61 (2016) 164e186 165 1. Introduction Table 1 e Table with abbreviations Abbreviation Full name Glaucoma is an optic neuropathy characterized by progressive 20-HETE 20-hydroxy-eicosatetraenoic acid death of retinal ganglion cells (RGCs) and irreversible visual loss. BP Blood pressure Glaucoma is the second leading cause of blindness world- CCD Charge coupled device 177 wide, and yet its etiology and treatment remain unclear. The CDI Color Doppler imaging main modifiable risk factor in glaucoma patients is elevated CO2 Carbon dioxide intraocular pressure (IOP)1,45,110,118,121; however, a high percent- CRA Central retinal artery age of individuals with elevated IOP (a condition called ocular CRV Central retinal vein CSFp Cerebrospinal fluid pressure hypertension) never develop glaucoma,103 and many glaucoma dAR Dynamic autoregulation patients continue to experience disease progression despite EC Endothelial cell lowering IOP to target levels or have no history of elevated IOPea EDV End diastolic velocity condition called normal tension glaucoma (NTG).203 EET Epoxyeicosatrienoic acid Several studies suggest correlations between impaired ET Endothelin ocular blood flow and glaucoma.56,60,67,84,85,90,241 In healthy IOP Intraocular pressure LDF Laser Doppler flowmetry conditions, vascular beds exhibit an intrinsic ability to main- LSFG Laser speckle flowgraphy tain relatively constant blood flow over a large range of arterial MAP Mean arterial pressure pressures. This autoregulatory behavior is recognized in most NB Normalized blur 3,169 162 21 vascular bedsdincluding the eye, brain, heart, kid- NO Nitric oxide ney,178 skeletal muscle,61 and gut129dbut the effectiveness of NOS Nitric oxide synthase autoregulation differs among these vascular beds according to NTG Normal tension glaucoma importance of function. For example, the brain and kidney OCT Optical coherence tomography ONH Optic nerve head receive stable flow over a range of arterial pressure,32,162 OPP Ocular perfusion pressure whereas autoregulation in other beds such as the gut is less PCA Posterior ciliary artery effective. In the eye, the retinal and optic nerve head (ONH) PGE2 Prostaglandin E2 vascular beds are known to exhibit autoregulation, though to PI Pulsatility index differing extents. Details and experimental measures of PO2 Oxygen partial pressure autoregulation are better established in the retina than in the POAG Primary open-angle glaucoma ONH. In experiments assessing hemodynamic responses to PSV Peak systolic velocity RGC Retinal ganglion cell light stimulation,68,69,184,186 blood flow in the retina and ONH RI Resistive index seems to be highly correlated to increased neural activity. This RLTp Retro laminar tissue pressure 130 phenomenon is called neurovascular coupling. ROS Reactive oxygen species In glaucoma the location of damage to nerve cells is sAR Static autoregulation hypothesized to be predominantly in the ONH,176 and thus a SBR Square blur ratio clearer understanding of the factors affecting the blood supply SNFL Superficial nerve fiber layer SSADA Split spectrum amplitude to the ONH is necessary to determine how this may be decorrelation angiography compromised and potentially contribute to the pathophysi- ology of glaucoma. The aim of this review is to 1) summarize the mechanisms of autoregulation and neurovascular coupling that function in astrocytes, a particular type of glial cell.28 For the purpose of the ONH; 2) describe the current ability to assess autor- description, the anatomy and vascular supply of the ONH is egulation in the ONH using methodologies capable of deter- best divided into 4 regions, from anterior to posterior seg- mining ONH blood flow (or volume and velocity); 3) compare ments (see Fig. 1). data on blood flow for varying pressure or metabolic needs in The most anterior part of the ONH is the superficial nerve the ONH to assess autoregulation in healthy and pathologic fiber layer (SNFL). Some vascular details of this layer can be conditions; and 4) describe the current status of ophthalmic resolved on ophthalmoscopy examination or angiography. A research and support the potential of mathematical modeling part of the appearance of the SNFL comes from light back- to further the understanding of the relationship between scattered from deeper tissue.51 Immediately behind the SNFL ocular blood flow mechanisms and ocular diseases such as is the “prelaminar region,” which lies adjacent to the peri- glaucoma. In order to help the reader, a list of the acronyms papillary choroid. Posterior to the prelaminar region, the used in this paper is provided in Table 1. “laminar region” is composed of the lamina cribrosa, a structure consisting of fenestrated connective tissue beams through which the RGC axons pass on their path from the 2. Anatomy and vascular supply of the ONH retina to the optic nerve. Finally, the “retrolaminar region” lies posterior to the lamina cribrosa. It is marked by the 2.1. Anatomy beginning of axonal myelination and is surrounded by meninges. The ONH is where RGC axons leave the eye through the scleral The lamina cribrosa bears the translaminar pressure portion of the neural canal, forming bundles separated by difference: the difference between the IOP, which is the 166 survey of ophthalmology 61 (2016) 164e186 Fig. 1 e Anatomy and vascular supply of the optic nerve head (ONH). The ONH includes the superficial nerve fiber layer, the prelaminar region, the laminar region, and the retrolaminar region. pressure in the intraocular space, and the retrolaminar astrocytes. From there, they may go into the astrocytes or tissue pressure, which is the pressure in the retrolaminar percolate in the extracellular space between them, ultimately region. The retrolaminar tissue pressure is usually lower reaching the adjacent axons. than the IOP and is strongly correlated to the cerebrospinal fluid pressure and the pressure in the subarachnoid space 2.2. Vascular supply of the optic nerve when cerebrospinal fluid pressure > 2mmHg(1mmHgz 133.3224 Pa).134,142 A hoop stress is The vascular system nourishing the ONH is quite complex89,92 also transferred to the lamina by the sclera.28 There is and shows high interindividual and intraindividual vari- evidence that an annulus of collagen fibrils exists around ability.94,95,211 An important anatomic distinction between the the scleral canal in the peripapillary sclera. These fibrils different portions of the ONH is that blood flow to the ONH is appear to be oriented mostly radially in the periphery of primarily supplied by the posterior ciliary arteries (PCAs), the lamina.79,188,240 The peripapillary annulus significantly whereas the SNFL receives oxygenated blood primarily from reduces the IOP-related expansion of the scleral canal and retinal arterioles.155 These small vessels, called “epipapillary shields the lamina from high-tensile stress. The radially vessels,” originate in the peripapillary SNFL and run toward oriented fibrils in the lamina periphery reinforce the lam- the center of the ONH (see Fig. 2). ina against transversal shear stresses and reduce laminar In approximately 30% of all people, a cilioretinal artery bending deformations.79