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Major review

Autoregulation and neurovascular couplingin 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

aDepartment of Mathematical Sciences, Indiana University-Purdue University Indianapolis (IUPUI), Indianapolis,

Indiana, USAbDepartment of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USAc LabEx IRMIA, University of Strasbourg, Strasbourg, Alsace, France

a r t i c l e i n f o

Article history:

Received 8 May 2015

Received in revised form

2 October 2015

Accepted 2 October 2015

Available online 20 October 2015

Keywords:

autoregulation in the optic nerve

head

neurovascular coupling

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 Pradaanapolis (IUPUI), 402 North Blackford Street,

E-mail address: [email protected] (D. Pra0039-6257/$ e see front matter ª 2016 Elsevhttp://dx.doi.org/10.1016/j.survophthal.2015.

a b s t r a c t

Impairments of autoregulation and neurovascular coupling in the optic nerve head play a

critical role in ocular pathologies, especially glaucomatous optic neuropathy. We critically

review the literature in the field, integrating results obtained in clinical, experimental, and

theoretical studies. We address the mechanisms of autoregulation and neurovascular

coupling in the optic nerve head, the current methods used to assess autor-

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

demand is varied in healthy and pathologic conditions, and the current status and

potential of mathematical modeling work to further the understanding of the relationship

between ocular blood flow mechanisms and diseases such as glaucoma.

ª 2016 Elsevier Inc. All rights reserved.

, PhD, Department of Mathematical Sciences, Indiana University-Purdue University Indi-LD 270, Indianapolis, IN 46202, USA. Tel.: þ1 317 274 3460.da).ier Inc. All rights reserved.10.004

mailto:[email protected]

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s u r v e y o f o p h t h a lm o l o g y 6 1 ( 2 0 1 6 ) 1 6 4e1 8 6 165

1. Introduction Table 1 e Table with abbreviations

Abbreviation Full name

20-HETE 20-hydroxy-eicosatetraenoic acid

BP Blood pressure

CCD Charge coupled device

CDI Color Doppler imaging

CO2 Carbon dioxide

CRA Central retinal artery

CRV Central retinal vein

CSFp Cerebrospinal fluid pressure

dAR Dynamic autoregulation

EC Endothelial cell

EDV End diastolic velocity

EET Epoxyeicosatrienoic acid

ET Endothelin

IOP Intraocular pressure

LDF Laser Doppler flowmetry

LSFG Laser speckle flowgraphy

MAP Mean arterial pressure

NB Normalized blur

NO Nitric oxide

NOS Nitric oxide synthase

NTG Normal tension glaucoma

OCT Optical coherence tomography

ONH Optic nerve head

OPP Ocular perfusion pressure

PCA Posterior ciliary artery

PGE2 Prostaglandin E2PI Pulsatility index

PO2 Oxygen partial pressure

POAG Primary open-angle glaucoma

PSV Peak systolic velocity

RGC Retinal ganglion cell

RI Resistive index

RLTp Retro laminar tissue pressure

ROS Reactive oxygen species

sAR Static autoregulation

SBR Square blur ratio

SNFL Superficial nerve fiber layer

SSADA Split spectrum amplitude

decorrelation angiography

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 world-

wide,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 percent-

age 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 nohistory of elevated IOPea

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 main-

tain relatively constant blood flowover a large range of arterial

pressures. This autoregulatory behavior is recognized in most

vascular bedsdincluding the eye,3,169 brain,162 heart,21 kid-

ney,178 skeletal muscle,61 and gut129dbut 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 pathophysi-

ology 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 autor-

egulation in the ONH using methodologies capable of deter-

mining 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.

2. Anatomy and vascular supply of the ONH

2.1. 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 seg-

ments (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. A

part of the appearance of the SNFL comes from light back-

scattered from deeper tissue.51 Immediately behind the SNFL

is the “prelaminar region,” which lies adjacent to the peri-

papillary choroid. Posterior to the prelaminar region, the

“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

retina to the optic nerve. Finally, the “retrolaminar region”

lies posterior to the lamina cribrosa. It is marked by the

beginning of axonal myelination and is surrounded by

meninges.

The lamina cribrosa bears the translaminar pressure

difference: the difference between the IOP, which is the



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

tissue pressure, which is the pressure in the retrolaminar

region. The retrolaminar tissue pressure is usually lower

than the IOP and is strongly correlated to the cerebrospinal

fluid pressure and the pressure in the subarachnoid space

of the optic nerve when cerebrospinal fluid pressure >

2 mm Hg (1 mm Hg z 133.3224 Pa).134,142 A hoop stress is

also transferred to the lamina by the sclera.28 There is

evidence that an annulus of collagen fibrils exists around

the scleral canal in the peripapillary sclera. These fibrils

appear to be oriented mostly radially in the periphery of

the lamina.79,188,240 The peripapillary annulus significantly

reduces the IOP-related expansion of the scleral canal and

shields the lamina from high-tensile stress. The radially

oriented fibrils in the lamina periphery reinforce the lam-

ina against transversal shear stresses and reduce laminar

bending deformations.79 The lamina cribrosa remodels

into a thicker, more posterior structure, which in-

corporates more connective tissue after chronic IOP

elevation.80,188

In the prelaminar, laminar, and retrolaminar regions, RGC

axons are surrounded by astrocytes, which are believed

to maintain the homeostasis of the extracellular environ-

ment. In particular, astrocytes remove potassium and gluta-

mate from the extracellular space, provide cellular support to

the axons, and synthesize extracellular matrix macromole-

cules.28,101 In the prelaminar and retrolaminar region, it is

presumed that nutrient delivery to the axons occurs both via

diffusion and advection.28 In the laminar region, the extra-

cellular matrix of laminar beams lies in between capillaries

and astrocytes. Consequently, nutrients likely diffuse from

laminar capillaries, across the endothelial and pericyte

basement membranes, through the extracellular matrix of

the laminar beams, across the basement membranes of

astrocytes. From there, they may go into the astrocytes or

percolate in the extracellular space between them, ultimately

reaching the adjacent axons.

2.2. Vascular supply

The vascular system nourishing the ONH is quite complex89,92

and shows high interindividual and intraindividual vari-

ability.94,95,211 An important anatomic distinction between the

different portions of the ONH is that blood flow to the ONH is

primarily supplied by the posterior ciliary arteries (PCAs),

whereas the SNFL receives oxygenated blood primarily from

retinal arterioles.155 These small vessels, called “epipapillary

vessels,” originate in the peripapillary SNFL and run toward

the center of the ONH (see Fig. 2).

In approximately 30% of all people, a cilioretinal artery

may be present and supply the temporal SNFL. This artery, if

present, may be a direct branch of the ciliary or choroidal

arteries, emerging from the temporal SNFL of the ONH and

extending laterally along the papillomacular bundle. The

retinal arteries and the cilioretinal arteries lack anastomotic

blood exchange in the case of an artery occlusion, leading to

an ischemic infarct in the area supplied by the artery or its

branches.161

The prelaminar region is mainly supplied by direct

branches of the short PCAs and by branches from the circle of

Zinn-Haller (see Fig. 3).

The circle of Zinn-Haller, if present, is a complete or

incomplete ring of arterioles within the perineural sclera

formed by the confluence of branches of the short PCAs. The

arterial circle branches into the prelaminar region, lamina

cribrosa, and retrolaminar pial system and supplies the peri-

papillary choroid. This vascular ring can be recognized in vivo

using indocynanine green videoangiography in highly myopic



Fig. 2 e Superficial nerve fiber layer (SNFL). The SNFL receives oxygenated blood primarily from retinal arterioles. These

small vessels, called epipapillary vessels, originate in the peripapillary SNFL and run toward the center of the optic nerve

head.


eyes.153 These vessels exhibit an anastomotic blood

exchange,17 but it is unclear whether this exchange can

counterbalance an insufficiency of a single PCA. There is also

evidence of direct arterial supply to the prelaminar layer

arising from the choroidal vasculature,92 even though the

extent to which it contributes to the perfusion of the region is

still a matter of debate.89 Blood flow to the laminar region is

provided by centripetal branches of the short PCAs (see Fig. 4).

Such a 3-D architecture differs from, without effectively

denying, what is proposed in some histology studies, where

Fig. 3 e Prelaminar region. The prelaminar region is mainly supp

(PCAs) and by branches of the circle of Zinn-Haller. The circle of

arterioles within the perineural sclera formed by the confluenc

the lamina is viewed as a set of stacked perforated sheets

containing vessels, with pores in each sheet aligned to create

tunnel for bundles of nerve fibers to exit from the eye.8,9

Unlike in vivo imaging, histology imaging suffers from

distortions because of the loss of pressure (IOP, intracranial

pressure, and blood pressure), distortions during tissue prep-

aration, and tissue degradation after death. Nevertheless, care

is needed when comparing optical coherence tomography

(OCT) results to histology because of differences in optical

resolution and sampling density. OCT has significantly worse

lied by direct branches of the short posterior ciliary arteries

Zinn-Haller, if present, is a complete or incomplete ring of

e of branches of the short PCAs.



Fig. 4 e Laminar region. Blood flow to the laminar region is provided by centripetal branches of the short PCAs. The

centripetal branches arise either directly from the short PCAs or from the circle of Zinn-Haller. The lamina cribrosa is shown

as a 3-D network, as suggested in recent in vivo imaging studies based on optical coherence tomography

(OCT)106,146,215,235,236 and in finite element modeling studies of the lamina cribrosa microarchitecture.29,55,188


lateral resolution when compared with electron microscopy

or other forms of microscopy used to study the lamina cri-

brosa, and it likely overemphasizes beams, compared to his-

tology.236 Hence, many questions still need to be answered to

characterize the 3-D geometry of the lamina cribrosa

accurately.209

The centripetal branches arise either directly from the

short PCAs or from the circle of Zinn-Haller. These precapil-

lary branches perforate the outer boundary of the lamina and

then branch into an intraseptal capillary network, which runs

inside the laminar beams. It is still unclear whether there are

anastomoses between the capillary or precapillary bed of the

laminar region, the prelaminar region, and the SNFL region. If

these anastomoses exist, it is unclear whether they play a role

when a sudden (or slowly progressive) vascular occlusion on

the precapillary or intracapillary level happens.161 The retro-

laminar region is supplied by the central retinal artery (CRA)

and the pial system (see Fig. 5). The pial system is an anas-

tomosing network of capillaries located immediately within

the pia mater. The pial system originates from the circle of

Zinn-Haller and may also be fed directly by the short PCAs.

The branches of the pial system extend centripetally to

nourish the axons of the optic nerve. The CRA may supply

several small intraneural branches in the retrolaminar region.

Some of these branches may also anastomose with the pial

system.

In the ONH the capillaries form a continuous network

throughout its entire length, being continuous posteriorly

with those in the rest of the optic nerve and anteriorly with

the adjacent retinal capillaries.7,122 It is unclear whether this

implies that blood flow regulation is similar122 or not92 in

both vascular regions, independent of the arterial source.

Critical questions remain unanswered. The CRA within the

intraorbital optic nerve is innervated, but innervation stops (at

least) anterior to the lamina cribrosa, and it does not follow

the branches of the CRA inside the eye.243 Neurotransmitter

receptors, however, are present on the surface of retinal ves-

sels.58,104 In addition, normal retinal vessels lack fenestra-

tions.161 Hence, vasoactive hormones cannot leak from

capillaries and reach the muscular coat of nearby arterioles

where they can influence blood flow. The branches of the PCA

that feed the intrascleral portion of the optic nerve may or

may not be innervated and/or fenestrated. Such knowledge is

crucial to understand how blood flow is regulated in the ONH.

Venous drainage of the ONH occurs primarily through the

central retinal vein (CRV). In the SNFL, blood is drained directly

into the retinal veins, which then join to form the CRV. In the

prelaminar, laminar, and retrolaminar regions, venous

drainage occurs via the CRV or axial tributaries to the CRV.

3. Techniques for in vivo studies of ONHhemodynamics

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 volu-

metric blood flow in absolute units; however, some he-

modynamic measurement techniques provide surrogates

for ONH blood flow in arbitrary units. Four of these

measurement techniques for in vivo studies of ONH he-

modynamics are discussed and compared in the following

sections. Table 2 summarizes their main features, ad-

vantages, and limitations.



Fig. 5 e Retrolaminar region. The retrolaminar region is supplied by the central retinal artery (CRA) and the pial system. The

pial system is an anastomosing network of capillaries located immediately within the pia mater.


3.1. Laser Doppler flowmetry

Laser Doppler flowmetry (LDF) is a noninvasive method of

assessing blood flow and perfusion in the ONH. LDF is based

on the Doppler effect. It measures the shift in frequency that

occurs when light is scattered by the red blood cells moving

through capillaries. LDF uses a fundus camera and a com-

puter system to detect these changes in frequency. This

information is used to calculate 3 hemodynamic parame-

ters: velocity, blood volume, and blood flowwithin the ONH.

Velocity is defined as the average speed of red blood cells

traveling through capillaries and is proportional to the

mean change in Doppler shift frequency. Blood volume is

defined as the number of red blood cells in the given sample.

Blood flow or flux is defined as the flux of red blood cells

Table 2 e Techniques for in vivo studies of ONH hemodynamic

Technique Measurements Location ofmeasurement

Laser Doppler

flowmetry

Velocity, volume, and flow

in arbitrary units

ONH

OCT angiography Flow in arbitrary units ONH

Color Doppler

imaging

Velocity Ophthalmic artery,

CRA, and short PCAs

Laser speckle

flowgraphy

Velocity, flow in arbitrary

units

ONH

CRA, central retinal artery; OCT, optical coherence tomography; ONH, op

through a specific part of a capillary at a given time. The

main advantage of LDF is its ability to measure 3 different

hemodynamic parameters; however, LDF only provides

measurements of blood perfusion in arbitrary (and not ab-

solute) units, which limits its usefulness in a clinical

setting.183 Moreover, LDF measurements depend signifi-

cantly on the depth of the sampled tissue. This depth de-

termines the relative contribution to the Doppler signal of

the superficial layers, the layers supplied by the CRA, and

the deeper layers supplied by the short PCAs. Blood flow

autoregulation may or may not differ within these vascular

beds. In a study on monkey eyes, LDF appeared to be more

heavily influenced by blood flow changes in the more su-

perficial layers of the ONH than in deeper ones, but to what

extent remains uncertain.187

s

Advantages Limitations

Multiple hemodynamic

parameters

No absolute measurements;

no interindividual comparisons

High quality images, fast No absolute measurements;

difficult to localize measurements

Vessel selective, no need for

pupil dilation, clear media, or

fixation

No absolute measurements;

velocity measurements only;

expert operator required

Time evolution of velocity at

the same site of the same eye

No absolute measurements; no

interindividual comparisons

tic nerve head; PCA, posterior ciliary artery.




3.2. OCT angiography

OCT angiography, a combination of high speed OCT and a new

3D angiography system called split-spectrum amplitude-

decorrelation angiography, is a noninvasive method used to

estimate blood flow in the ONH, especially within the micro-

circulation.108 It computes the flow index, which is a surrogate

for blood flow in arbitrary units.

OCT is a technique that takes cross-sectional images of a

biologic tissue using a low-coherence interferometer. These

cross-section images are captured using a low-coherence

beam directed at the target tissue. The light signals reflect

off of the tissue back to the interferometer, which stacks a

series of longitudinal tomographic b-scans to derive a

3-dimensional image. Doppler OCT, a commonly used subtype

of OCT, can detect the Doppler frequency shift of the reflected

light, providing additional information on blood flow. The

split-spectrum amplitude-decorrelation angiography algo-

rithm allows 3-dimensional angiography to be done 4 times

faster than previous algorithms and also improves blood flow

detection, creates better visualization of the microvascula-

ture, and removes motion errors automatically.105

OCT angiography has many advantages over Doppler

OCT. Doppler OCT can only quantify blood flow in large

superficial vessels of the ONH and cannot visualize the

microvasculature.105 OCT angiography minimizes the pul-

satory bulk motion noise along the axial direction and

optimizes flow detection along the transverse direction.108

As with all measuring techniques, OCT angiography has

limitations. One of the main disadvantages is that blood

flow from superficial layers can be projected to deeper

layers, thereby incorrectly indicating that the imaged blood

flow is a few layers deeper than its location in vivo.108 Also,

split-spectrum amplitude-decorrelation angiography cannot

distinguish between perfusion defects caused by damaged

tissue or ischemia,109 and ONH blood flow estimates are

provided in arbitrary units. Despite these limitations, OCT

angiography is a very useful tool to measure blood flow in

the ONH.

3.3. Color Doppler imaging

Color Doppler imaging (CDI), also known as color Doppler

ultrasound, is a noninvasive procedure that allows the user to

visualize a color-coded image of blood velocity against a gray-

scale image of the surrounding structures. This technique

uses the principle of Doppler frequency shift tomeasure blood

flow velocity in absolute units. Various transducers are used

to measure the Doppler frequency shift, which produces color

pixels.239 The color red represents blood flowing toward the

ultrasound probe, whereas blue represents blood flowing

away from the probe.214

CDI is most commonly used to measure the peak systolic

velocity (PSV) and end diastolic velocity (EDV), which are then

used to measure the resistive index [RI ¼ (PSV�EDV)/PSV] and

pulsatility index [PI ¼ (PSV�EDV)/Tmax, where Tmax is the

time averaged peak velocity]. These values estimate resis-

tance to blood flow caused by the microvasculature distal to

the site of measurement. The RI is particularly suitable for

investigating the low resistance retrobulbar vasculature.239

The major advantages of CDI are that it is noninvasive,

vessel selective, reproducible, and does not require pupil

dilation, clear media, or fixation. CDI is limited in its ability to

measure only velocity (not flow) and calculate vascular

resistance and requires for an experienced operator to obtain

accurate results.87 CDI has particular difficulty imaging and

interpreting small vessels, and the PCAs are close to the size

limit that can be studied.

3.4. Laser speckle flowgraphy

Laser speckle flowgraphy (LSFG) is a noninvasive method of

measuring blood flow and velocity in the ONH. LSFGmeasures

bloodflowbyusing the laser speckle phenomenon,which is an

interference event that occurswhen laser light scatters off of a

diffusing tissue. This creates a speckle pattern that varies in

proportion to thevelocity of redbloodcells and thus represents

capillary blood flow. The faster the velocity of the red blood

cells, the greater the rate of pattern variation. Although the

velocity cannot bemeasured directly, the normalized blur and

square blur ratio values can be calculated as quantitative in-

dicators of blood velocity. Normalized blur values are well

correlated with blood flow measurements simultaneously

taken with the hydrogen gas clearance method, colored mi-

crospheres technique, and other methods in the ONH, iris,

choroid, and retina.218,220e226Thedistributionof bloodflowcan

be displayed in a 2 dimensional color-coded map, which re-

flects the time variation of the speckles at each pixel point.217

This allows for visualization of blood flow in real time.

LSFG uses a diode laser, image sensor, infrared charge-

coupled device camera, and digital charge-coupled device

camera. The diode laser and image sensor are used for laser

speckle measurements. The laser is focused on the image

sensor and creates a speckle pattern, which is scanned at 512

scans/second.217 The digital charge-coupled device camera

measures vessel diameter and takes pictures of the fundus.

The advantages of LSFG are that its results are adequately

reproducible and that the change in velocity at the same site

of the same eye can be followed over time. A major disad-

vantage of LSFG is that themeaning of its measurement is not

clearly understood and does not allow for intereye or inter-

individual comparisons.87

4. Evidence of blood flow autoregulation inthe ONH

Autoregulation is the intrinsic ability of vascular beds to main-

tain relatively constant blood flow over a large range of pressure,

while meeting the metabolic demand of the tissue. Autor-

egulation is evaluated most often on a flow versus pressure

graph, where pressure may be expressed as mean arterial pres-

sure (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 intraoc-

ular venous pressure is very close to IOP,15,46,73,81 and thus,

OPP is usually estimated as the difference between the arterial

BP and IOP in the upright position. OPP may be defined as

mean, systolic, or diastolic OPP. Mean OPP is typically calcu-

lated as



OPP

Ste

ady-

stat

e bl

ood

flow

Autoregulationplateau

Fig. 6 e A schematic representation of a static

autoregulation curve describing the relationship between

steady-state blood flow responses in the ONH and OPP.

ONH, optic nerve head; OPP, ocular perfusion pressure.


mean OPP ¼ 23MAP� IOP

where

MAP ¼ diastolic BPþ 13ðsystolic BP� diastolic BPÞ:

The factor 2/3 accounts for the drop in BP between the

brachial and ophthalmic artery when the subject is seated182

and the fact that the orbital arteries are further downstream.

In clinical studies, the brachial arterial pressure has been

often considered as representative of systemic BP and is used

as the basis for calculating the ophthalmic arterial pressure

in the calculation of OPP. The pressure in the brachial artery,

however, is not a precise predictor of the pressure in the

ophthalmic artery. It is not clear how accurately the above

formula approximates the difference between the ocular

arterial BP and the brachial arterial pressure because of the

hydrostatic column effect when an individual is sitting.30 We

also cannot assume that the difference between the ocular

and brachial arterial pressures is the same in normal and

diseased vascular beds. Moreover, blood flow is determined

not only by OPP but also by vascular tone. Regulation of blood

flow may occur through changes in vascular resistance

(vasoconstriction or vasodilation, see section 5) indepen-

dently of changes in OPP. Physical exercise may or may not

cause a change both in cardiac output and in the net resis-

tance of the many microvascular pathways in parallel.

Equating venous pressure to IOP is also sometimes erro-

neous. For example, if the cerebrospinal fluid pressure is

higher than IOP, the venous pressure must exceed cerebro-

spinal fluid pressure in the subarachnoid space for the CRV to

remain patent, and thus venous pressure could not be

approximated by IOP. In this way, the estimate for OPP in-

volves systematic errors; however, even if more reliable for-

mulas for computing the OPP have been proposed,46 the

previously mentioned relations are consistently used in

clinical studies. A reliable, direct measure of OPP would of

course be desirable, but without this, care is needed when

interpreting blood flow regulation studies.

4.1. Evidence of ONH autoregulatory capacity duringOPP changes in healthy subjects

In several animal70,186,212 and human studies,166,181 the ONH

vascular bed was shown to maintain autoregulatory capacity

over a wide range of perfusion pressures. Autoregulatory ca-

pacity is conventionally assessed by a “two-point” blood flow

measurement: blood flow or other hemodynamic parameters

are measured before and after the OPP is artificially modified

by a step challenge in either the IOP or the systemic arterial BP.

If blood flow changes significantly from normal after the

pressure challenge, then autoregulation is said to be impaired;

if blood flow remains nearly constant over the pressure

change, autoregulation is said to be intact.

When the pressure step challenge is applied rapidly, it

induces 2 phases of hemodynamic response: 1) an initial

transient, or dynamic, phase lasting a few seconds during

which the vasculature tries to return blood flow to its original

level by adjusting vascular resistance and 2) a steady-state

phase when transient blood flow changes have equilibrated

to a steady state level. High temporal resolution blood flow

measures made during the initial phase following pressure

changes are referred to as dynamic autoregulation (dAR),

whereas those made during the steady-state phase are

referred to as static autoregulation (sAR).120 To date, most

studies assessing autoregulatory capacity in the ONH have

been limited to sAR.

In this section, some important clinical studies that

address dAR and sAR in the ONH in healthy conditions are

reviewed.

4.1.1. Dynamic autoregulation studiesThe dAR refers to the transient vascular changes preceding

the equilibrated steady state. Interestingly, dAR was pointed

out as a more sensitive indicator of cerebral blood flow

autoregulation than sAR since dAR is better correlated to

neuronal activities than sAR.160,191 Moreover, a dynamic blood

flow response contains both time and frequency information

that can effectively reveal potential autoregulation dysfunc-

tion. In fact, dAR measurements have become the standard

method for assessing cerebral blood flow autoregulation in

cerebral diseases.230

A blood flow time course similar to that described in the

brain was observed in the ONH of rabbits220 and nonhuman

primates119 after an acute increase in IOP. The time course of

relative ONH blood flow changes from baseline (IOP ¼ 10 mm

Hg) to elevated IOP (IOP ¼ 30 mm Hg), and then back to

baseline, was tracked for 3 different ranges of BP in mon-

keys.119 In the high-BP group, there was no significant change

in ONH blood flow during the IOP alterations; however, the

same IOP alterations caused a significant ONH blood flow

change in the 2 lower BP groups, suggesting that autor-

egulation of the ONH is deficient in the lower BP groups.

To characterize dAR in the ONH, time-domain parameters

were extracted from high temporal resolution blood flow

measurement obtained using an LSFG device in a group of

monkeys.120 A rapid OPP decrease induced by a sudden IOP

step increase evoked a transient and reproducible dAR in the

ONH. The duration of blood flow decrease was much shorter




than that of the pressure change. In otherwords,while the IOP

was still increasing, the blood flow had already started

recovering. This observation suggests that autoregulation is

activated immediately after IOP elevation.

Responses of OPP, ONH blood flow, and vascular resistance

to increases in BP were investigated by hand gripping.39 BP

and ONH blood flow parameters were simultaneously and

continuously measured by LDF. Healthy subjects could be

subdivided into 2 groups because of marked differences in the

efficiency and OPP range of autoregulation: in one group,

autoregulation was found to be highly efficient once OPP was

increased by approximately 15% above baseline; in another

group, autoregulation was found to be less efficient. These

findings are in accordance with other studies.24

The dAR studies mentioned above are summarized in

Table 3.

4.1.2. Static autoregulation studiesThe sAR refers to steady-state responses of ONH blood flow to

a wide range of OPP values. These responses constitute a

classic autoregulation curve or pressure-flow relationship (see

Fig. 6). This plateau of the autoregulation curve indicates the

range of OPP where autoregulation is functioning. When the

OPP values are outside the range defined by this plateau,

autoregulation fails and blood flow will gradually decrease or

increase passively as OPP changes.

Microspheres were used to measure blood flow in the

various compartments of the monkey optic nerve following

manometric IOP elevation.70 Small changes in IOP which

reduced OPP as low as 29 mm Hg had small effects on prel-

aminar blood flow. At OPP less than 29 mm Hg, prelaminar

flow was proportional to OPP. Laminar blood flow was nearly

unchanged even at high IOP (low OPP).

OPP was decreased by increasing IOP with a scleral suction

cup in normal human subjects.68,166,181 An LDF probing laser

beamwasdirectedat theONHtissueat temporal andnasaldisk

areas, at least 200 mm from the disk margin and outside the

physiologic cup. Autoregulation was active for OPP values as

low as 15e20 mm Hg (IOP ¼ 40e45 mm Hg),181 or until IOP

reached 45 mm Hg.166 Apparently, the ONH vasculature was

not fully dilatedat this point, becausediffuse luminanceflicker

increased ONH blood flow even more.68 Regional variability in

the degree of autoregulation has been reported.166 Some optic

Table 3 e Summary of dynamic autoregulation studies in heal

Study Methods

Liang et al119 Combined changes in IOP and MAP in monkeys

Liang et al120 Sudden IOP step increase in monkeys

Chiquet et al39 MAP elevation in healthy humans

BP, blood pressure; IOP, intraocular pressure; LDF, Laser Doppler flowmetr

optic nerve head; OPP, ocular perfusion pressure.

disk locations of some individuals appeared unable to regulate

blood flow under even a minimal IOP challenge.

Effects of elevated OPP on the ONH blood flow of healthy

volunteers were investigated by increasing MAP through iso-

metric exercise (squatting).144 An LDF probing laser beamwas

directed at temporal disk areas of the ONH, at least 200 mm

from the diskmargin and outside of the physiologic cup. In the

range of OPP between 56 � 4 and 80 � 5 mm Hg (30% � 8%),

there was no significant variation of mean velocity, volume,

and flux of red blood cells, but vascular resistance increased

by about 50%. These results suggest that the maintenance of

constant blood flow is achieved by an increase in vascular

resistance. Similar results were obtained in another study.171

Regulation of ONH blood flow was investigated during

combined changes in IOP and systemic BP. ONH blood flow

was measured in monkeys using LSFG during artificial

changes in IOP and BP.119 When IOP was increased to 30 mm

Hg and MAP was normal (102 mm Hg), no significant change

was observed in ONH blood flow, indicating that autor-

egulation was functioning. However, when IOP was increased

to 30 mm Hg and MAP was reduced to 56 mm Hg, significant

reductions in ONH blood flow were observed, suggesting that

autoregulation was unable to maintain blood flow at low OPP.

These blood flow results, as well as those obtained in other

studies,234,237 must be interpreted in the context of where and

how they were measured.

ONH blood flow was investigated in 40 healthy subjects

using continuous LDF during a separate increase in IOP and

MAP as well as during their combined elevation.24 The laser

beam was directed toward the neurovascular rim. MAP was

increased by isometric exercise consisting of squatting, and

IOP was raised via suction cup. During both experiments, the

change in ONH blood flow was less pronounced than the

change in OPP, indicating autoregulation.

The sAR studies mentioned in the previous paragraphs are

summarized in Table 4.

In Figure 7, OPP-ONH blood flow relationships reported in a

few studies24,70,144,166,181 have been gathered. Each data set

has been normalized to its corresponding baseline OPP and

ONH blood flow estimate. Care is needed to interpret this

figure correctly. First, different species and different tech-

niques for estimating ONH blood flowwere involved in these 6

studies. Second, in one study,70 monkeys were supine,

thy subjects

Technique Main findings

LSFG The duration of the changes in ONH blood flow

from baseline to a peak and to a steady state was

significantly delayed in subjects with medium or

low, but not high, BP

LSFG While the IOP was still increasing, the blood flow

had already started recovering

LDF Marked differences in the efficiency and OPP

range of autoregulation were found among

subjects, in accordance with another study24

y; LSFG, laser speckle flowgraphy; MAP, mean arterial pressure; ONH,



Table 4 e Summary of static autoregulation studies in healthy subjects

Study Methods Technique Main findings

Geijer et al70 IOP elevation in healthy monkeys Microspheres The laminar and retrolaminar portions of the

ONH showed higher autoregulation capabilities

than the prelaminar portion

Riva et al181 IOP elevation in healthy humans LDF ONH blood flowwas relatively constant to an OPP

as low as 15e20 mm Hg

Pillunat et al166 IOP elevation in healthy humans LDF ONH blood flow was regulated to an IOP up to

45 mm Hg

Movaffaghy et al144 MAP was elevated in healthy humans LDF In the range of OPP between 56� 4 and 80� 5mm

Hg, there was no significant variation of mean

velocity, volume, and flux of red blood cells, but

vascular resistance increased by about 50%

Liang et al119 Combined changes in IOP and MAP in monkeys LSFG When IOP was increased to 30 mm Hg and MAP

was normal (102 mmHg), ONH blood flow did not

change significantly. Instead, blood flow

decreased when IOP was increased to 30 mm Hg

and MAP was reduced to 56 mm Hg

Boltz et al24 Combined and separate IOP and MAP elevation in

healthy humans

LSFG ONH blood flow increased with OPP for OPP

values of 66% above baseline. ONH blood flow

decreased for OPP values of 40% below baseline

Wang et al237 IOP elevation in monkeys LSFG ONH blood flow is effectively regulated for OPPs

of approximately 41 mm Hg and above

IOP, intraocular pressure; LDF, Laser Doppler flowmetry; LSFG, laser speckle flowgraphy; MAP, mean arterial pressure; ONH, optic nerve head;

OPP, ocular perfusion pressure.


whereas, in the others, human volunteers were standing.

Third, some data were obtained by increasing IOP, whereas

other data were obtained others by increasing MAP. Last,

displaying all the data in a single graph presumes the use of a

common baseline. Despite these limitations, Figure 7 shows

that the static OPP-blood flow curve in the ONH is consistent

with the curve schematized in Figure 6.

On reviewing a number of clinical studies addressing

dynamic and static blood flow autoregulation in the ONH

in healthy conditions, note the different sensitivity of

OPP (mean % change from baseline)-100 -50 0 50 100

ON

H b

lood

flow

(mea

n %

cha

nge

from

bas

elin

e)

-100

-50

0

50

Geijer (1979), prelaminar regionGeijer (1979), laminar regionPillunat (1997), ONHRiva (1997), ONHMovaffaghy (1998), ONHBoltz (2013), ONH

Fig. 7 e Pressure-flow relationships for ONH blood flow in 6

experimental studies in healthy monkeys (Geijer et al.,70

circles and asterisks), and in healthy humans (Pillunat

et al.,166 squares), (Riva et al.,181 downward-pointing

triangles), (Movaffaghy et al.,144 upward-pointing

triangles), (Boltz et al.,24 crosses). ONH, optic nerve head;

OPP, ocular perfusion pressure.

autoregulation components. Dynamic and static aspects are

2 related, but different, components of the autoregulation

process. Importantly, measuring dAR could succeed in

revealing potential autoregulation dysfunction in situations

where the conventional “two-point” method measured dur-

ing the sAR phase would fail.

4.2. Clinical studies of static blood flow autoregulationin the ONH in pathologic conditions

Underpathologic conditions,ONHbloodflowregulationmaybe

disrupted.5 Impairedautoregulation in theONHassociatedwith

altered blood flow has been observed in experimental dia-

betes204 and hypercholesterolemia.205 In glaucoma, and espe-

cially in NTG, impaired autoregulation in the ONH has been

speculated to be an important risk factor for the progression of

the disease.43,60,75,91,156 Glaucomapatients havebeen suggested

to exhibit abnormal autoregulation especially in response to

acute changes in OPP, as reviewed in the following paragraphs.

The autoregulatory control of retrobulbar blood flow in

response to postural challenge was investigated in NTG

patients in comparison with primary open-angle glaucoma

patientsandhealthyvolunteers.66 PSV, EDV, andRI in the short

PCAs were recorded after a change from sitting upright to a

supine body position using CDI. Ten minutes after postural

change, blood flow velocities in the short PCAs remained un-

changed in controls, whereas a significant increase of PSV and

EDV occurred in both glaucoma groups. The RI in the short

PCAswas significantly lower in theNTGgroupwhencompared

to healthy and primary open-angle glaucoma individuals. The

authors suggested that the unaltered flow velocities in the

short PCAs of healthy controls might indicate tight autor-

egulatory control. In contrast, the accelerated flow in the short




PCAs exhibited by NTG and primary open-angle glaucoma

patientsmight indicatean insufficient compensatory response

topostural change.However, it isnot clear towhatextent these

interpretations are consistent with the experimental data. It is

unknown how the supine position affects intraocular venous

pressure and, in turn, OPP.46 It is accepted that, in the supine

position, there is adifferent interactionbetweenorbital venous

pressure and intraocular venous pressure than in the upright

position. This interaction is affected by the tissue pressure,

which experiences huge variations due to differences in body

mass and the hydrostatic water column effect on venous

pressure.30 Consequently, it ishard to establishhowthesupine

position impacts OPP and, hence, blood flow.

Chronic unilateral elevation of IOP was induced in mon-

keys by laser treatment to the trabecular meshwork, leading

to glaucomatous damage.234 The authors found compromised

blood flow in the anterior ONH (including SNFL, prelaminar

tissue, and lamina cribrosa) of glaucomatous eyes measured

by both LSFG and the microsphere method. ONH blood flow

was measured for IOP ¼ 40 mm Hg in both control and glau-

comatous eyes. In a parallel study, longitudinal changes in

basal blood flow of the ONH were investigated in the same

monkey model.47 There are a couple of possible explanations

for the reduced flow observed in these 2 studies during the

later stages of glaucoma. If there is a reduced amount of

neural tissue requiring nutrition, the flow would be regulated

to avoid supplying more blood than what is necessary for the

remaining tissue. ONH blood flow could also be reduced if

autoregulation is impaired.

There was no evidence of altered autoregulation in the

ONH in glaucoma in some studies. Regulation of ONH blood

flow in response to an increase of OPP was investigated

through a challenge in systemic BP induced by isometric

exercise in NTG patients and in age-matched healthy volun-

teers.171 ONH blood flow parameters, as determined by LDF,

did not indicate abnormal blood flow regulation in either

healthy subjects or NTG patients; however, NTG patients

showed a greater percent increase in vascular resistance

compared to the normal subjects for a similar percent

increase in OPP in both groups during squatting.

To our knowledge, neither dynamic nor static mechanisms

of ONH blood flow regulation have been quantified in patients

with arterial hypertension. Arterial hypertension can poten-

tially interfere with ONH blood flow in many ways.94 For

example, atherosclerosis resulting from prolonged arterial

hypertension can cause inadequate changes in vessel size in

response to fluctuations in OPP.88 Chronic arterial hyperten-

sion can also cause the range of autoregulation to shift to

higher levels to adapt to high BP.97 Such an adjustmentmakes

the patientmore tolerant to high BP but less tolerant to low BP.

In this situation, a sudden reduction of BP in hypertensive

subjects can cause anterior ischemic optic neuropathy.96,98

Systemic hypertension is associated with pathologic

changes in retinal vasculature.123 Endothelial function of the

retinal vasculature is impaired in early essential hyperten-

sion,50 and hypertensive retinopathy is associated with

endothelial dysfunction111,112 (see section 5 for a discussion

about the role of endothelial cells (ECs) in regulating blood

flow). Hence, since systemic hypertension is linked to a wide

range of major eye diseases, it is incredibly important to

quantify its effects on ONH blood flow regulation.

In a study of the ONH of control and glaucomatousmonkey

eyes,237 static blood flow autoregulation was characterized,

and impaired autoregulation was tested as a potential mech-

anism involved in the reduction of ONH blood flow observed

in previous studies.47,234 Autoregulation curves were created

based on a series of relative ONH blood flow changes, each

measured with an LSFG device in response to an acute OPP

decrease induced by instantaneous IOP elevation monitored

across stages of glaucoma. Within the ONH of the control

eyes, blood flow was effectively regulated within the OPP

range from 41 mm Hg to 115 mm Hg. When OPP was below

41 mm Hg, blood flow declined linearly with OPP. Autor-

egulation curves of control and glaucomatous eyes were not

significantly different from each other. Thus, the authors

argued that sAR is not a predominant factor accounting for the

reduced ONH blood flow observed in the monkey model.47,234

All of these clinical studies addressing autoregulation in

pathologic conditions are summarized in Table 5.

5. 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.

5.1. Mechanical influences

An important class of autoregulation is seemingly more

dependent on mechanical influences. In the myogenic

response, vascular smooth muscle cells constrict as intra-

vascular pressure, and consequently the circumferential wall

tension, is elevated. Indeed, circumferential wall tension

depends on both the vessel radius R and transmural pressure

DP, defined as the difference between the intravascular and

extravascular pressures. According to Laplace’s law, as DP

rises, the vessel wall stretches, leading to increased wall

tension T:

T ¼ DP� R:

In the myogenic response, arterioles respond to the

increased wall tension by constricting to reduce the vessel

radius R and restore the wall tension to a normal level. The

myogenic response has been observed in the ONH. More

effective blood flow autoregulation was observed in the ONH

of healthy humans during an increase inMAP than IOP.24 Such

behavior could be compatible with a myogenic mechanism of

autoregulation.

The contractility of smooth muscle cells involved in the

myogenic response is regulated by ECs. In addition to chemical

agents, ECs respond to mechanical stimuli, such as fluid shear

stress and stretch.38 Externally applied forces with a clear di-

rection, such as shear stress from pulsatile flow or uniaxial

stretch, induce the release of vasoactive substances which then



Table 5 e Autoregulation studies in pathologic conditions

Study Methods Technique Main findings

Pournaras et al171 MAP elevation in NTG patients LDF NTG patients did not show abnormal ONH

blood flow regulation but only a greater

percent increase in vascular resistance

compared to healthy subjects

Galambos et al66 Investigation of autoregulatory control of

retrobulbar blood flow in response to postural

changes in NTG and POAG patients

CDI NTG and POAG patients exhibited an

insufficient compensatory response to

postural change, leading to accelerated flow

in the short PCAs

Shibata et al205 IOP elevation in hypercholesterolemic rabbits LSFG Hypercholesterolemia induced impairment in

the autoregulation of ONH blood flow and

deterioration in visual function and histology

Shibata et al204 IOP elevation in rabbits with induced diabetes

and induced gap junction uncoupling

LSFG Autoregulation was disrupted both in the

animals who were induced diabetes and in

those who received gap junction uncouplers

Wang et al234 Chronic unilateral IOP elevation induced in

monkeys by laser treatment to the trabecular

meshwork

Microspheres and LSFG Blood flow was compromised in the SNFL,

prelaminar, and laminar tissues, possibly due

to impaired autoregulation

Cull et al47 Chronic unilateral IOP elevation induced in


meshwork

LSFG A 2-phase pattern of ONH blood flow

alteration was observed in treated animals.

ONH blood flow increased during the earliest

stage (while retinal nerve fiber layer thickness

was within 10% of baseline) followed by a

linear decline strongly correlated with loss of

RGCs

Wang et al237 Chronic unilateral IOP elevation induced in


meshwork

LSFG Chronic IOP elevation caused no remarkable

change to the static autoregulation of

glaucomatous eyes

CDI, Color Doppler imaging; IOP, intraocular pressure; LDF, Laser Doppler flowmetry; LSFG, laser speckle flowgraphy; MAP, mean arterial

pressure; NTG, normal tension glaucoma; ONH, optic nerve head; PCA, posterior ciliary artery; POAG, primary open-angle glaucoma; RGC,

retinal ganglion cell; SNFL, superficial nerve fiber layer.


determine ECs remodeling. This remodeling phenomenon in-

cludes changes in the orientation of ECs cytoskeletal fibers,38 the

morphology of cell surface49,152 and/or cell stiffness99,137,194,195 to

minimize the alterations in intracellular stress. Whereas ECs

remodeling results from molecular signaling due to mechano-

transduction, this adaptive behavior, in turn, modulates the

molecular signaling. Thus, a close coupling exists between

mechanics and vascular endothelium. In addition, experiments

have shown that myogenic tone of the PCAs is regulated by

prostaglandin formation and the release of endothelium-

derived relaxing factor by arteries.150 To our knowledge, regu-

lation of myogenic tone and sheer stress responses in the ONH

vasculature has not been studied. Further research is needed to

investigate the contribution of mechanical influences on ONH

blood flow regulation.

5.1.1. Nitric oxide and endothelin-1Two important vasoactive substances released by the ECs

after local stimulation by, for example, shear stress from

pulsatile flow or uniaxial stretch, are nitric oxide (NO) and

endothelin-1 (ET-1). A constant balance between the opposing

functions of NO and ET-1 is necessary for proper regulation of

the vascular system.156,157,232 NO is a potent vasodilator

secreted by smooth muscle cells that causes the dilation of

arterioles via activation of smooth muscle cells and the dila-

tion of capillaries via pericytes.93 Owing to the radical nature

of NO, it has a short half-life, which is made even shorter in

the presence of oxygen and superoxide and longer in the

absence or lower concentrations of oxygen.20,140 Because NO

cannot be stored in vivo, regulation of NO production is

controlled at the level of the biosynthesis.198 Hence, NO syn-

thesis largely depends on the amount of nitric oxide synthase

(NOS). Inhibiting NOS in cats resulted in a decrease in ONH

blood flow, both at baseline and with light flicker stimulation

of neuronal activity.27 Administration of a nonspecific NOS

inhibitor, NG-monomethyl-L-arginine, appeared to reduce

baseline ONH blood flow in humans.128,199 NO also exerts

antioxidative and neuroprotective effects by interacting with

reactive free radicals such as superoxide anions, hydroxyl,

and peroxyl lipid radicals.40

ET-1, a potent vasoconstrictor that is released from

ECs,8,156,179,180,200,232 acts on 3 types of ET receptors: ETA, ETB1,

and ETB2. More precisely, ETA receptors are present in vascular

smooth muscle and mediate vasoconstriction.156,179,200 The

stimulation of ETB1 receptors, which are located on ECs, results

in vasodilation via clearance of ET-1 and the release of NO and

prostacyclin.200 ETB2 receptors mediate vasoconstriction.167

Despite the opposing roles of the B1 and B2 receptors, a net

vasodilation is shown to result from the stimulation of the ETB

subtype receptors.238 Pharmacologically blocking ETA and ETB

receptors resulted in a significant increase in blood flow to the

retina, choroid, and ONH in patients with glaucoma as well as

healthy subjects, suggesting a potential role for endothelial

blockers to be used in the treatment of glaucoma.180




5.2. Metabolic response

Metabolic regulation results in the adjustment of blood flow

during inadequate or excessive nutrient supply, because of

either a change in the metabolic activity of the tissue or a

change in flow by virtue of cardiovascular factors such as

atherosclerosis or systemic vasospasm. No matter the cause,

when tissues are not receiving the appropriate amount of

blood flow, an adjustment is made by control mechanisms.

Overall, the vascular response to tissue demand is influenced

by the metabolic conditions in the tissue such as levels of

oxygen, carbon dioxide levels (mediated by pH), NO, ET-1, and

other chemical signals.157 For example, when the eye is

exposed to a flickering light, the number of action potentials

and the consequent need for (re)polarization of the RGC axon

membranes in the ONH is increased with each “on” and “off”

light switch. In response to this increased metabolic demand,

blood flow in the ONH appears to increase.184e186 Importantly,

metabolism in the various parts of RGC axons may be

controlled independently. In the prelaminar and lamina cri-

brosa regions, RGC axons are unmyelinated and acquire a

myelin sheath only after passing the posterior boundary of the

lamina cribrosa.11 The unmyelinated portions of the axons are

in need of energy to repolarize the axons along the entire

surface, whereas, in themyelinated portion, only the axons at

the nodes of Ranvier need to be repolarized. Thus, mito-

chondria are numerous andmetabolic activity is much higher

in the unmyelinated nerves, but less in the myelinated

portion.19 According to themetabolic hypothesis of blood flow

regulation, tissue perfusion and tissue metabolism are tightly

coupled in such a way that any reduction in arterial inflow

causes an increase of vasodilator metabolites in the tissue.157

5.2.1. OxygenAll living tissues require a steady supply of oxygen to meet,

but not exceed, their nutritional needs. Oxygen tension in a

tissue provides an important indication of its current meta-

bolic status. In hypoxic conditions, ONH blood flow is regu-

lated to establish a healthy partial pressure of oxygen in the

tissue. Under moderate hypoxic conditions, the intravascular

tissue’s partial pressure of oxygen at 200 mm depth within the

ONH was observed to be constant, reflecting, probably,

autoregulation of blood flow.25 Decreased partial pressure of

oxygen was found in the ONH when IOP was increased (OPP

was decreased) above 45mmHg.23 Both oxygenmetabolism in

the mitochondria of optic nerve cells and tissue oxygen ten-

sion were observed to decrease when hypoxia was induced.149

In contrast, under hyperoxic conditions, capillary blood flow

in the ONH decreases via vasoconstriction.115

5.2.2. Carbon dioxideCO2 is a vasodilator in all vascular beds at the posterior pole of

the eye.200 The mechanisms driving this vasodilation response

are not clearly understood. In human197 and animal studies,196

hypercapnia-induced vasodilation was shown to depend on

NO, whereas, in other animal studies, the vasodilation was

shown to be independent of NO.52,72 Hypercapnia triggers an

increase in flow to the short PCAs.189 Patients with untreated

primary open-angle glaucoma have shown a normal increase

in the blood velocity of the CRA with hypercapnia, but a

decrease in blood velocity in the OA.210 Although the prepon-

derance of data suggests that blood vessels dilate or constrict

in response to CO2 levels, it is possible that hypercapnia-

induced vasodilation is mainly because NO is brought into

play by lowered levels of oxygen, which would increase NO

half-life. Future research further defining the mechanisms of

this is needed.

5.2.3. Nitric oxideNOwas shown to mediate vasodilation in response to marked

hypoxia in the forearm resistance vessels in healthy

humans22 and in response to increased myocardial oxygen

demand.4 As mentioned in the previous sections, the role of

NO in hypercapnia-related vasodilation is not clearly

understood.

5.3. Neurovascular coupling

Experiments measuring vascular responses to light stimula-

tion have suggested that ONH blood flow and neuronal

activity of RGCs are coupled.68,185,186 Traditionally, in the ONH

and other regions like the retina and the brain, vascular

responses to changes in neural activity were assumed to be

controlled exclusively by a local metabolic feedback system in

which neural activity leads to energy demand and thus

vasodilation. This idea has been challenged, however,

following the discovery that feedforward mechanisms

mediate the vascular energy supply by neuronal activity.16

According to these mechanisms, active neurons either send

a signal directly to blood vessels or activate astrocytes to

release vasoactive agents onto the vessels to increase local

blood flow, a process known as “functional hyperemia.” Both

cases involve neurotransmitter signaling, particularly via

glutamate. In the brain, blocking glutamate receptors reduces

functional hyperemia but does not affect the energy use

associated with neuronal activity, providing evidence that

metabolic feedback and neurovascular feedforward mecha-

nisms can be distinguished and both contribute to blood flow

regulation in response to neuronal activity.151,216 The inter-

play between metabolic feedback and neuronal feedforward

mechanisms should then be taken into account whenever

considering clinical studies addressing ONH vascular

responses to light stimulation.

Astrocytes exhibit extremely complex and dynamic

behaviors. One of their functions is to control the extracellular

environment for neurons; for example, by clearing the space of

potassium after action potentials pass by and taking up excess

glutamate that leaks from synapses.100,101 Astrocytes also play

a fundamental role in regulating blood flow to the brain.16 As-

trocytes are the predominant glial cell type in the nonmyelin-

ated ONH inmostmammalian species.19 Structural similarities

suggest that retinal and ONH astrocytes may behave similarly

to cerebral astrocytes.10 Retinal and ONH astrocytes surround

blood vessels,8,233 and this close relationship further supports a

potential contribution of astrocytes to blood flow regulation in

the retina and ONH.

There is evidence of neurovascular coupling in the retina

and ONH occurring via glial signaling mediated by vasoactive




agents released onto the vessels (not through nerve fibers and

synapsis with glutamate receptors on contractile cells). The

retinal vascular branches are devoid of such innervation once

they emerge onto the retinal surface, although the CRAwithin

the intraorbital optic nerve is innervated.243 Yet, retinal ves-

sels do retain receptors for various neurotransmitters on their

surface.58,104 To our knowledge, the innervation of the arte-

riolar branches of the ONH has not been studied yet. Future

research further elucidating the mechanisms of neuro-

vascular coupling in the retina and the ONH is essential.

Axon-glial signaling pathways have been observed in the

optic nerve.41,64,107 Following IOP elevation, autoregulation of

ONH blood flowwas not maintained in rabbit eyes where glial

cells were selectively impaired by a gliotoxic compound, L-2-

aminoadipic acid, indicating a possible involvement of astro-

cytes in ONH blood flow autoregulation.206 The cell processes

of astrocytes are connected to each other via gap junctions190

forming a functional syncytium that allows astrocytes to

communicate andmaintain control of the ionic andmetabolic

homeostasis in the ONH. Decreased gap junction communi-

cation between ONH astrocytes was reported under condi-

tions of elevated IOP.133 Closure of gap junctions interrupts

the continuity of astrocyte intercellular communication,

causing loss of cell-cell contact and homeostatic regulation.

Uncoupling gap junctions resulted in impaired ONH blood

flow autoregulation in healthy rabbits.204 Such conditions

may lead to RGC axonal loss and optic disk remodeling char-

acteristic of glaucomatous optic neuropathy.100

In studies on brain slice and isolated retina, evidence is

found that astrocytes contribute to blood flow regulation by

producing and releasingmetabolites of arachidonic acid. After

glutamate is released at synapses following neuronal activity,

some of the released neurotransmitter escapes the synaptic

cleft and activates metabotropic glutamate receptors on

astrocytes, increasing Ca2þ in astrocytes.170 The increased

Ca2þ activates phospholipase A2 and results in arachidonic

acid production. The build-up of arachidonic acid leads, in

turn, to the production of its metabolites, including prosta-

glandin E2 and epoxyeicosatrienoic acids (EETs), which dilate

nearby arterioles.74,138,163,164,219,245 In brain slices and in the

isolated retina, increased Ca2þ can also cause vessels to

constrict.44,138,145 This is made possible by the conversion of

arachidonic acid to 20-hydroxy-eicosatetraenoic acid (20-

HETE).138 When the synthetic enzymes for EETs and prosta-

glandin E2 are inhibited, glial-evoked vasodilation is reduced

by 88%.138,139 Under physiologic conditions, the effect of the

vasodilators prostaglandin E2 and EETs surpasses the effect of

20-HETE, and vasodilation occurs. However, under non-

physiologic conditions such as hyperoxia or elevated NO

levels, 20-HETEemediated vasoconstriction dominates.148

5.3.1. PotassiumGlial cells might also cause vasodilation (and hence increased

blood flow) by releasing potassium ions. Modest increases in

extracellular Kþ concentration cause the hyperpolarization of

smoothmuscle cells, a reduced influx of Ca2þ through voltage-

gated channels, and vasodilation. When glutamate released

from neurons activates astrocyte metabotropic glutamate

receptors, the resultant rise in astrocyte Ca2þ causes large-

conductance Ca2þ-activated Kþ channels in astrocyte

endfeet to open, releasing Kþ onto vessels.59 This potential

role of Kþ in neurovascular coupling has not been tested either

in the retina or in the ONH yet.

5.3.2. Nitric oxideNO is believed to mediate neurovascular coupling in the cer-

ebellum.242 Changes in neuronal activity induce Ca2þ

increases within neurons and activate neuronal NOS, leading

to the production of NO. NO is then able to permeate mem-

branes and diffuse to blood vessels, where it opens Kþ chan-

nels and relaxes vascular smooth muscle cells, leading to

vasodilation and increased blood flow.34 NO has also been

suggested to mediate neurovascular coupling in the ONH.

Increased NO levels were found in the ONH of humans during

changes in neuronal activity due to light flicker stimuli.26 In

addition, in the retina of humans54 and the retina and the

ONH of cats,114 systemic administration of nonselective NOS

inhibitors reduces flicker-evoked increases in blood flow.

These results would appear to support NO as an important

mediator of neurovascular coupling in the retina and theONH.

However, evidence has been found that NO could be pre-

dominantly a modulator of neurovascular coupling, but not a

mediator. In the whole-mount rat retina,138 at NO levels less

than 100 nmol/L, flickering lighteinduced vasodilation, but

not vasoconstriction. At increased NO levels, smaller vasodi-

lation was observed, while vasoconstriction became more

common. At 10 mmol/L NO, a flickering light evoked large

vasoconstriction, mediated by 20-HETE. It is still not clear how

NO inhibits flicked-induced vasodilation. The modulatory

mechanism of NO has been suggested to be due to its

inhibitions of P450 epoxygenase, which synthesizes the

vasodilator EETs. With less EETs being produced, vasodilation

will be smaller and vasoconstrictionmediated by 20-HETEwill

prevail.148

5.3.3. AdenosineAdenosine, which is produced when adenosine triphosphate

is hydrolyzed, is a vasodilator that contributes to functional

hyperemia in the human brain. Blocking adenosine receptors

has been shown to reduce the increase in blood flow evoked

by neuronal activity.113 Given its function in the brain, aden-

osine is also thought to be involved in the control of ocular

blood flow. Intravenous administration of adenosine was

shown to cause increased choroidal and ONH blood flow in

humans168 andwas established as an important participant in

mediating retinal blood flow autoregulation during hypoxia

and hypotension in piglets.71

5.3.4. LactateLactate, which is produced by anaerobic glycolysis and

released by both glial cells and neurons, is thought to

contribute to neurovascular coupling as a metabolic negative-

feedbackmediator. Blood flow in the human retina is sensitive

to changes in blood lactate levels,69 but lactate responses in

the ONH have not been established yet.

5.3.5. OxygenOxygen modulates neurovascular coupling in brain tissue by

altering the synthesis of glial and neuronalmessengers and by

altering the levels of lactate and adenosine. O2 is needed for




the synthesis of NO and the vasoactive messengers derived

from arachidonic acid. At in vivo levels of O2, the synthesis of

NO and 20-HETE is expected to be limited by the amount of O2

available.16 More specifically, 20-HETE formation is sup-

pressed in the presence of low O2 concentrations, leading to a

reduced vasoconstriction when arachidonic acid is generated

in astrocytes. A lower O2 also results in a reduced amount of

NO being present to inhibit the formation of vasodilatory EETs

in tissues. In addition, when O2 concentrations decrease, the

lack of energy for adenosine triphosphate synthesis causes an

increase in the level of extracellular adenosine, which binds to

adenosine A2A receptors on vascular smooth muscle cells to

depress vessel constriction.16 Moreover, low oxygen concen-

trations induce a decrease in the rate of oxidative phosphor-

ylation relative to the rate of glycolysis, resulting in lactate

production. Monocarboxylate transporters release the lactate

into the extracellular space, where it reduces the reuptake of

prostaglandin E2 by the prostaglandin transporter, promoting

vasodilation.74 Importantly, it is possible that oxygen modu-

lates neurovascular coupling by affecting NO half-life. Future

research to further elucidate the mechanisms involved is

needed.

5.4. The anatomic agents of blood flow regulation in theONH

Understanding which vessels in the ONH exhibit blood flow

regulation is still an open problem. In general, the structures

that control blood flow to a particular tissue are the resistance

arterioles (arterial branches smaller than 40 mm), which

change diameter actively to achieve autoregulation.172 Capil-

laries have smaller diameters than arterioles. Because resis-

tance to flow is inversely proportional to the fourth power of

the vessel radius (Poiseuille’s law),65 capillaries exhibit high

resistance individually; However, they are numerous and in

parallel array outweigh the reduction in vessel size, having a

large cross-sectional area that does not contribute much to

the net resistance between arteries and veins.246 In addition to

the arterial role in autoregulation, flow to a local capillary

network is controlled by a precapillary sphincter (where it

exists), a band of smooth muscle located where capillaries

originate from small arterioles.6 Finally, blood flow could also

be controlled by changes in the resistance of the capillaries

themselves because of the contractile properties of pericytes.6

The retinal and optic nerve capillaries lack precapillary

sphincters but have abundant pericytes.62,63,161 It has been

shown that pericytes respond to carbon dioxide concentra-

tions (mediated by pH), oxygen levels (affected by changes in

NO concentrations), and adenosine levels.161 Vascular smooth

muscle cells respond in a very similar manner.36,82,136 Peri-

cytes on isolated retinal capillaries were found to constrict or

dilate in response to neurotransmitters, following Ca2þ alter-

ations.173 In situ in brain slices, pericytes constricted in

response to noradrenaline and dilated in response to gluta-

mate,165 and in the isolated retina, blocking ionotropic

receptors of the neurotransmitter g-aminobutyric acid was

shown to constrict capillaries, suggesting that endogenous

transmitter release could regulate capillary diameter.83,165

Thus, capillaries are equipped to participate in the control of

ONH blood flow through metabolic feedback and neuronal

feedforward coupling mechanisms, but this still needs to be

further investigated.

In contrast to retinal capillaries, choroidal capillaries are

fenestrated and have sparse pericytes.161 The retinal tissue,

part of the central nervous system, has a preserved blood-

brain barrier due to the tight junctions between the retinal

pigment epithelial cells.161,179 Circulating vasoconstrictive

hormones, such as angiotensin, epinephrine, and so forth,

raise intracellular Ca2þ when they occupy receptors.157,161,200

In vascular smooth muscle, as well as in pericytes, an

increase of intracellular Ca2þ induces contraction of the cell.

Consequently, ECs produce more NO, which relax vascular

smooth muscle and pericytes. In this way, the circulating

hormones leak through fenestrated vessels, reach the

muscular coat of vessels in the region, causing vasoconstric-

tion in the skin and many visceral organs. In contrast, central

nervous vessels, where hormones can only affect ECs and are

prevented from reaching the contractile coat of the vessels to

the blood-tissue barrier, exhibit vasodilation.157,161,200 It is

unclear whether the branches of the PCAs that feed the

intrascleral portion of the optic nerve are innervated and/or

fenestrated. Such knowledge is fundamental to understand

how the intrascleral papillary tissue reacts to various insults,

including abnormally high IOP.

6. Pathologic effects of impaired blood flowregulation 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 situa-

tions 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 astrocytes in the ONH101

and/or the mitochondria of RGC axons,158 and that the ulti-

mate death of RGCs can occur via apoptosis158,175 and/or

autophagy.124

Astrocytes in the ONH are considered to be quiescent in

normal conditions,18 but they appear to become reactive in

response to pathologic conditions and contribute to changes

in the ONH environment, which do not favor the survival or

growth of the RGC axons.125 During ischemia, hydrogen

peroxide was observed to be abundantly produced and to

promote pathologic excitatory amino acid release and

swelling of reactive astrocytes.102 In glaucoma, ONH astro-

cytes were observed to have lower basal levels of antioxidant

glutathione, which plays an important role in protecting the

mitochondrial electron transport chain from damage by

oxidative stress in both astrocytes and neurons.132 Evidence

suggests that reactive astrocytes also produce NO in supra-

normal quantities, and this excessive production seems to

have neurotoxic effects on the RGC axons.126,143,147,244

Ischemia, hypoxia, and perfusion instability can also dam-

age the astrocyte-astrocyte gap junctions, and, as a conse-

quence, compromise the homeostasis of the RGC axons101 and




reduce the autoregulation capabilities of the ONH vasculature,

thereby rendering the ONH even more susceptible to damage.

Impaired autoregulation might also cause perfusion

instability in the ONH,141 which, in turn, might compromise

the normal function of mitochondria in the RGCs and their

axons.158 Mitochondria play a critical role in the maintenance

of cellular homeostasis and they are abundantly present in

the RGCs, both inside and outside the eye globe.158 Mito-

chondria are involved in numerous metabolic functions,

including the metabolism of oxidative energy, the regulation

of intracellular calcium levels and pH, and the production of

reactive oxygen species, which promote and regulate

apoptosis.35,201

Apoptosis (“self-killing”) and autophagy (“self-eating”)

are 2 different mechanisms that regulate cell life. The rela-

tionship between apoptosis and autophagy is complex in the

sense that, under certain circumstances, autophagy consti-

tutes a stress adaptation that avoids cell death (and sup-

presses apoptosis), whereas in other cellular settings, it

constitutes an alternative cell-death pathway.131 Ischemia

and hypoxia increase the reactive oxygen species produc-

tion rate from mitochondria35,42,159 and favor the

mitochondria-mediated cellular apoptosis; however,

reactive oxygen species accumulation stimulates cellular

authophagy under conditions of nutrient deficiency,192

hypoxia, ischemia, and perfusion instability86 and other

pathologic conditions.57

7. Mathematical modeling of ONH blood flowregulation

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 patho-

logic consequences of vascular dysregulation. Despite sig-

nificant recent advances in the understanding of ONH blood

flow autoregulation, important questions remain unan-

swered. What are the relative contributions of various

mechanisms, including responses to mechanical, metabolic,

and neurovascular stimuli, in achieving ONH blood flow

autoregulation? Do these relative contributions change in

health and disease? Is the vascular energy supply by neural

activity in the ONH mediated by feedforward mechanisms, as

it happens in the brain? Are capillaries involved in ONH blood

flow autoregulation? To which extent do impairments in dAR

and sAR mechanisms contribute to glaucomatous damage?

Can dynamic and static mechanisms be independently

impaired?

The quest for answers to these questions is hindered by

limitations in both the technological and scientific tools

currently available to the community. Major limitations in

the current technologies for ONH measurements include the

fact that LDF, LSFG, and OCT angiography only provide ONH

blood flow estimates in arbitrary units and intereye

comparison is problematic. LDF appears to be mainly influ-

enced by blood flow changes in the more superficial layers of

the ONH than deeper ones, but to what extent remains un-

certain. OCT angiography provides measurements for the

ONH deeper layers which may contain spurious projections

from the superficial layers. In addition to the difficulties

related to structural and functional imaging of the ONH,

there are scientific challenges in designing experimental and

clinical studies capable of disentangling the complex inter-

play between chemical, mechanical, and hemodynamic

factors that contribute to the pathogenesis of optic neu-

ropathies. Given these challenges, mathematical modeling

provides a unique tool that can play a significant role in

advancing the understanding of ONH physiology in health

and disease. A mathematical model can serve as a virtual

laboratory where the influence of each factor acting on the

system can be singled out and investigated, from a theo-

retical viewpoint, in isolation or in relation with other fac-

tors. In the following, we review the main contributions to

the modeling of the biomechanics, perfusion, and autor-

egulation in the ONH and indicate some interesting future

directions of research.

7.1. Biomechanics of the ONH

Alterations in the ONH biomechanical response to changes in

IOP have been identified as a major factor in the pathogenesis

of glaucoma.28,174 Particular attention has been devoted to

the mathematical description of the mechanical stresses and

strains arising within the lamina cribrosa, which is thought

to be a primary site of axonal injury in glaucoma.176 A linear

model of elastic mechanics theory on the bending of thin

circular plate was developed for the lamina cribrosa.53 Such

an idealization allowed quantitative estimates to be obtained

of the extent to which the degree of fixity offered by the

connection with the sclera, the pretension caused by scleral

expansion, and the ratio between flexural and in-plane

stiffness influence the mechanical response of the lamina

cribrosa to IOP. An idealized, analytical microstructural

model of the ONH load bearing tissues based on an octagonal

cellular solid description of the porosity within the lamina

identified the material and geometrical properties of the

sclera as major determinants in the strain distributions

within the lamina.193 The analysis also showed that much

larger strains are developed perpendicular to the major axis

of an elliptical canal rather than in a circular canal. Eye-

specific finite element models based on experimentally

reconstructed geometries have been used recently.188,207,208

These models are used to study in depth influences of ge-

ometry and material properties of the ONH to changes in IOP

and to investigate growth and remodeling mechanisms in

glaucoma, including adaptation of tissue anisotropy, tissue

thickening/thinning, tissue elongation/shortening, and tissue

migration. Macro- and micro-scale strains are proposed as

potential control mechanisms governing mechanical home-

ostasis.76e80 Further development of these sophisticated

finite element models may benefit from the recent advances

in OCT imaging aimed at providing a more accurate charac-

terization of the architectural microstructure within the

lamina cribrosa.209

7.2. Perfusion of the ONH

Perfusion of the ONH results from the complex interplay

between BP, which provides the driving force for the blood




through the vasculature, “mechanical stress,” which acts as

external forces on the vessels, and “vascular regulation,”

which mediates vessel dilation/constriction to compensate

for changes in the system. To the best of our knowledge, only

one model combines biomechanics and hemodynamics in

the lamina cribrosa.33 In this model, the lamina cribrosa is

treated as a 2 dimensional poroelastic material, where blood

vessels are viewed as pores in a solid matrix. The presence of

blood vessels in the tissue defines a vascular porosity N

which changes with the local state of stress and strain. The

tissue permeability, which defines the ability of the porous

material to allow fluid passing through it, is assumed pro-

portional to the square of N; the solid matrix is assumed to

behave as nonlinear elastic material. Blood flow is driven by

the difference between the arterial pressure in the short PCAs

and the venous pressure in the CRV. The lamina cribrosa

deforms under the combined action of IOP, retrolaminar

tissue pressure and scleral tension. This exploratory 2-

dimensional analysis suggested that the degree of fixity at

the conjunction with the sclera has a strong influence on the

distributions of stresses and strains, as suggested in other

studies,53,193 but also on the blood flow within the lamina. In

particular, the inner surface of the lamina was found to be

more susceptible to experiencing reduced blood supply

following IOP elevation. Despite the many simplifying

assumptions adopted in the model, most importantly the

choice of a 2-dimensional geometry, the satisfactory quali-

tative agreement between experimental data and numerical

simulations encourages further investigation of poroelastic

models to describe the complex mechanisms governing ONH

perfusion.

7.3. Autoregulation of ONH blood flow

Mathematical models have been used to describe autor-

egulation of blood flow in various organs, including

brain,2,48,213,229 kidney,37,116,127,202 and skeletal muscle.13,31,227

To date, though, the theoretical modeling of autoregulation

in the ONH has not yet been addressed. Our group has

developed a vascular wall mechanics model to predict the

relative importance of regulatory mechanisms in achieving

blood flow regulation in the retina.14 Resistance vessels are

assumed to respond to changes in pressure, shear stress,

carbon dioxide (CO2), and the downstream metabolic state

communicated via conducted responses. The model quan-

tifies the relative contributions of different mechanisms to

retinal autoregulation and shows that the combined effects of

the metabolic and CO2 responses are critical for achieving

retinal autoregulation. It would be extremely interesting to

apply a similar modeling approach to the autoregulation in

the ONH, combine it with the poroelastic model mentioned

above,33 and explore the relative contributions of the various

mechanisms described in section 5. Most of the models for

blood flow autoregulation, including the one developed by our

group for the retinal circulation,14 are not time dependent.

Thus, they are suitable to study static, but not dynamic,

autoregulation. The dAR has been addressed by models for

brain154,228 and kidneys.135

7.4. Conclusions and future directions

The mathematical modeling of the interplay between

biomechanics, perfusion and autoregulation in the ONH is

still at its early stages, but is quickly attracting attention.

Elucidating the complex interactions of ONH perfusion and

tissue structure in health and disease using current imaging

methodologies is difficult, and mathematical modeling pro-

vides an approach to solving these limitations. One of the

main difficulties lies in the fact that the biophysical phe-

nomena governing the ONH physiology occur at different

scales in time and space. For example, BP, IOP and retro-

laminar tissue pressure oscillate within a cardiac cycle (1

second), but also during the course of a day (24 hours). The

characteristic time for the onset of autoregulation is

approximately 20 seconds,119 and the biomechanically

induced remodeling of the collagen network in the ONH takes

several months or years. The accurate modeling and simu-

lation of multiscale problems is still an open area of research,

and therefore the modeling of the ONH offers stimulating

opportunities for groundbreaking activities from both the

clinical and theoretical viewpoints. The application of dy-

namic modeling to reveal the mechanistic interplay of pre-

viously unseen physiologic relationships holds the potential

to advance medical care in ophthalmic disease and provide

patients and clinicians new hope for future diagnosis and

therapy.

8. 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 identified. A few selected articles

published before 1990 are included for their clinical relevance,

but the review ismainly based on articles published in the last

2 decades. The following were themajor search terminologies

used: “autoregulation in the optic nerve head,” “neurovascular

coupling,” “ocular biomechanics and hemodynamics,” “me-

chanical influences on autoregulation,” “metabolic autor-

egulation,” “effects of impaired blood flow regulation,” “optic

neuropathies,” “glaucoma,” “blood flow regulation modeling.”

Articles published in languages other than English were also

included during the literature search.

Acknowledgments

The authors acknowledge the valuable contribution of Ales-

sandra Cantagallo, who realized the anatomic drawings (Figs.

1e5) published in this article.




r e f e r e n c e s

1. The Advanced Glaucoma Intervention Study (AGIS): 7. Therelationship between control of intraocular pressure andvisual field deterioration. The AGIS Investigators. Am JOphthalmol. 2000;130(4):429e40

2. Alastruey J, Moore SM, Parker KH, et al. Reduced modellingof blood flow in the cerebral circulation: coupling 1-D, 0-Dand cerebral auto-regulation models. Int J Numer MethodsFluids. 2008;56(8):1061e7

3. Alm A, Bill A. Ocular and optic nerve blood flow at normaland increased intraocular pressures in monkeys (Macacairus): a study with radioactively labelled microspheresincluding flow determinations in brain and some othertissues. Exp Eye Res. 1973;15(1):15e29

4. Altman JD, Kinn J, Duncker DJ, Bache RJ. Effect of inhibitionof nitric oxide formation on coronary blood flow duringexercise in the dog. Cardiovasc Res. 1994;28(1):119e24

5. Anderson DR. Introductory comments on blood flowautoregulation in the optic nerve head and vascular riskfactors in glaucoma. Surv Ophthalmol. 1999;43(Suppl 1):S5e9

6. Anderson DR. Glaucoma, capillaries and pericytes. 1. Bloodflow regulation. Ophthalmologica. 1996;210(5):257e62

7. Anderson DR. Ultrastructure of the optic nerve head. ArchOphthalmol. 1970;83(1):63e73

8. Anderson DR. Vascular supply to the optic nerve of primates.Am J Ophthalmol. 1970;70(3):341e51

9. Anderson DR. Ultrastructure of human and monkey laminacribrosa and optic nerve head. Arch Ophthalmol.1969;82(6):800e14

10. Anderson D, Hoyt W, Hogan M. The fine structure of theastroglia in the human optic nerve and optic nerve head.Trans Am Ophthalmol Soc. 1967;65:275e305

11. Andrews RM, Griffiths PG, Johnson MA, Turnbull DM.Histochemical localisation of mitochondrial enzyme activityin human optic nerve and retina. Br J Ophthalmol.1999;83(2):231e5

12. Araie M, Crowston J, Iwase A, et al. Clinical relevance ofocular blood flow (OBF) measurements including effects ofgeneral medications or specific glaucoma treatment, inWeinreb RN, Harris A (eds) Ocular Blood Flow in Glaucoma.Amsterdam, Kugler Publications; 2009, pp 59e128

13. Arciero JC, Carlson BE, Secomb TW. Theoretical model ofmetabolic blood flow regulation: roles of ATP release by redblood cells and conducted responses. Am J Physiol Heart CircPhysiol. 2008;295(4):H1562e71

14. Arciero J, Harris A, Siesky B, et al. Theoretical analysis ofvascular regulatory mechanisms contributing to retinalblood flow autoregulation. Invest Ophthalmol Vis Sci.2013;54(8):5584e93

15. Attariwala R, Giebs CP, Glucksberg MR. The influence ofelevated intraocular pressure on vascular pressures inthe cat retina. Invest Ophthalmol Vis Sci.1994;35(3):1019e25

16. Attwell D, Buchan AM, Charpak S, et al. Glial and neuronalcontrol of brain blood flow. Nature. 2010;468(7321):232e43

17. Awai T. Angioarchitecture of intraorbital part of humanoptic nerve. Jpn J Ophthalmol. 1985;29(1):79e98

18. Bachoo RM, Kim RS, Ligon KL, et al. Molecular diversity ofastrocytes with implications for neurological disorders. ProcNatl Acad Sci U S A. 2004;101(22):8384e9

19. Balaratnasingam C, Kang M, Yu P, et al. Comparativequantitative study of astrocytes and capillary distribution inoptic nerve laminar region. Exp Eye Res. 2014;121:11e22

20. Beckman JS, Beckman TW, Chen J, et al. Apparent hydroxylradical production by peroxynitrite: implications for

endothelial injury from nitric oxide and superoxide. ProcNatl Acad Sci U S A. 1990;87(4):1620e4

21. Berne RM, Knabb RM, Ely SW, Rubio R. Adenosine in the localregulation of blood flow: a brief overview. Fed Proc.1983;42(15):3136e42

22. Blitzer ML, Lee SD, Creager MA. Endothelium-derived nitricoxide mediates hypoxic vasodilation of resistance vessels inhumans. Am J Physiol. 1996;271(3 Pt 2):H1182e5

23. Blumenroder S, Augustin AJ, Koch FH. The influence ofintraocular pressure and systemic oxygen tension on theintravascular pO2 of the pig retina as measured withphosphorescence imaging. Surv Ophthalmol.1997;42(Suppl 1):S118e26

24. Boltz A, Schmidl D, Werkmeister R, et al. Regulation of opticnerve head blood flow during combined changes inintraocular pressure and arterial blood pressure. J CerebBlood Flow Metab. 2013;33(12):1850e6

25. Bouzas EA, Donati G, Pournaras CJ. Distribution andregulation of the optic nerve head tissue PO2. SurvOphthalmol. 1997;42(Suppl 1):S27e34

26. Buerk D, Riva C. Adenosine enhances functional activationof blood flow in cat optic nerve head during photicstimulation independently from nitric oxide. Miscovasc Res.2002;64(2):254e64

27. Buerk DG, Riva CE, Cranstoun SD. Nitric oxide has avasodilatory role in cat optic nerve head during flickerstimuli. Microvasc Res. 1996;52(1):13e26

28. Burgoyne CF. A biomechanical paradigm for axonal insultwithin the optic nerve head in aging and glaucoma. Exp EyeRes. 2011;93(2):120e32

29. Burgoyne CF, Downs JC, Bellezza AJ, et al. The optic nervehead as a biomechanical structure: a new paradigm forunderstanding the role of IOP-related stress and strain in thepathophysiology of glaucomatous optic nerve head damage.Prog Retin Eye Res. 2005;24(1):39e73

30. Caprioli J, Coleman AL. Blood Flow in Glaucoma D. Bloodpressure, perfusion pressure, and glaucoma. Am JOphthalmol. 2010;149(5):704e12

31. Carlson BE, Arciero JC, Secomb TW. Theoretical model ofblood flow autoregulation: roles of myogenic, shear-dependent, and metabolic responses. Am J Physiol HeartCirc Physiol. 2008;295(4):H1572e9

32. Carlstrom M, Wilcox CS, Arendshorst WJ. Renalautoregulation in health and disease. Physiol Rev.2015;95(2):405e511

33. Causin P, Guidoboni G, Harris A, et al. A poroelastic modelfor the perfusion of the lamina cribrosa in the optic nervehead. Math Biosci. 2014;257:33e41

34. Cavet M, Vittitow J, Impagnatiello F, et al. Nitric oxide (NO):an emerging target for the treatment of glaucoma. InvestOphthalmol Vis Sci. 2014;55(8):5005e15

35. Chan DC. Mitochondria: dynamic organelles in disease,aging, and development. Cell. 2006;125(7):1241e52

36. Chen Q, Anderson DR. Effect of CO2 on intracellular pH andcontraction of retinal capillary pericytes. Invest OphthalmolVis Sci. 1997;38(3):643e51

37. Chen J, Sgouralis I, Moore LC, et al. A mathematical model ofthe myogenic response to systolic pressure in the afferentarteriole. Am J Physiol Renal Physiol. 2011;300(3):F669e81

38. Chien S. Mechanotransduction and endothelial cellhomeostasis: the wisdom of the cell. Am J Physiol Heart CircPhysiol. 2007;292(3):H1209e24

39. Chiquet C, Lacharme T, Riva C, et al. Continuous response ofoptic nerve head blood flow to increase of arterial blood pressurein humans. Invest Ophthalmol Vis Sci. 2014;55(1):485e91

40. Chiueh CC. Neuroprotective properties of nitric oxide. Ann NY Acad Sci. 1999;890:301e11

http://refhub.elsevier.com/S0039-6257(15)00182-4/sref1














































































































































































41. Choi I, Chiu S. Expression of high-affinity neuronal and glialglutamate transporter in the rat optic nerve. Glia.1997;20(3):184e92

42. Christophe M, Nicolas S. Mitochondria: a target forneuroprotective interventions in cerebral ischemia-reperfusion. Curr Pharm Des. 2006;12(6):739e57

43. Chung H, Harris A, Evans D, et al. Vascular aspect in thepathophysiology of glaucomatous optic neuropathy. SurvOphthalmol. 1999;43(Supplement I):S43e50

44. Chuquet J, Hollender L, Nimchinsky EA. High-resolutionin vivo imaging of the neurovascular unit during spreadingdepression. J Neurosci. 2007;27(15):4036e44

45. Coleman AL, Caprioli J. The logic behind target intraocularpressure. Am J Ophthalmol. 2009;147(3):379e80

46. Costa V, Harris A, Anderson D, et al. Ocular perfusionpressure in glaucoma. Acta Ophthalmol.2014;92(4):e252e66

47. Cull G, Burgoyne C, Fortune B, Wang L. Longitudinalhemodynamic changes within the optic nerve head inexperimental glaucoma. Invest Ophthalmol Vis Sci.2013;54(6):4271e7

48. David T, Alzaidi S, Chatelin R, Farr H. Coupledautoregulation models. 13th International Conference onBiomedical Engineering, Vols 1-3. 2009;23(1-3):1896e1899.

49. Davies PF. Overview: temporal and spatial relationships inshear stress-mediated endothelial signalling. J Vasc Res.1997;34(3):208e11

50. Delles C, Michelson G, Harazny J, et al. Impaired endothelialfunction of the retinal vasculature in hypertensive patients.Stroke. 2004;35(6):1289e93

51. Delori FC, Pflibsen KP. Spectral reflectance of the humanocular fundus. Appl Opt. 1989;28(6):1061e77

52. Donati G, Pournaras CJ, Munoz JL, Tsacopoulos M. [The roleof nitric oxide in retinal vasomotor regulation]. Klin MonblAugenheilkd. 1994;204(5):424e6

53. Dongqi H, Zeqin R. A biomathematical model for pressure-dependent lamina cribrosa behavior. J Biomech.1999;32(6):579e84

54. Dorner GT, Garhofer G, Kiss B, et al. Nitric oxide regulatesretinal vascular tone in humans. Am J Physiol Heart CircPhysiol. 2003;285(2):H631e6

55. Downs JC, Roberts MD, Burgoyne CF, Hart RT. Multiscalefinite element modeling of the lamina cribrosamicroarchitecture in the eye. Conf Proc IEEE Eng Med BiolSoc. 2009;2009:4277e80

56. Drance SM, Douglas GR, Wijsman K, et al. Response of bloodflow to warm and cold in normal and low-tension glaucomapatients. Am J Ophthalmol. 1988;105(1):35e9

57. Essick EE, Sam F. Oxidative stress and autophagy in cardiacdisease, neurological disorders, aging and cancer. Oxid MedCell Longev. 2010;3(3):168e77

58. Ferrari-Dileo G. Beta 1 and beta 2 adrenergic binding sites inbovine retina and retinal blood vessels. Invest OphthalmolVis Sci. 1988;29(5):695e9

59. Filosa J, Bonev A, Straub S, et al. Local potassium signalingcouples neuronal activity to vasodilation in the brain. NatNeurosci. 2006;9:1397e403

60. Flammer J, Orgul S, Costa V, et al. The impact of ocular bloodflow in glaucoma. Prog Retin Eye Res. 2002;21(4):359e93

61. Folkow B, Sonnenschein RR, Wright DL. Loci of neurogenicand metabolic effects on precapillary vessels of skeletalmuscle. Acta Physiol Scand. 1971;81(4):459e71

62. Frank RN, Dutta S, Mancini MA. Pericyte coverage is greaterin the retinal than in the cerebral capillaries of the rat. InvestOphthalmol Vis Sci. 1987;28(7):1086e91

63. Frank RN, Turczyn TJ, Das A. Pericyte coverage of retinal andcerebral capillaries. Invest Ophthalmol Vis Sci.1990;31(6):999e1007

64. Fu C, Sretavan D. Ectopic vesicular glutamate release at theoptic nerve head and axon loss in mouse experimentalglaucoma. J Neurosci. 2012;32(45):15859e76

65. FungYC. Biomechanics: circulation. NewYork, Springer; 199766. Galambos P, Vafiadis J, Vilchez S, et al. Compromised

autoregulatory control of ocular hemodynamics in glaucomapatients after postural change. Ophthalmology.2006;113(10):1832e6

67. Galassi F, Giambene B, Varriale R. Systemic vasculardysregulation and retrobulbar hemodynamics in normal-tension glaucoma. Invest Ophthalmol Vis Sci.2011;52(7):4467e71

68. Garhofer G, Resch H, Weigert G, et al. Short-term increase ofintraocular pressure does not alter the response of retinaland optic nerve head blood flow to flicker stimulation. InvestOphthalmol Vis Sci. 2005;46(5):1721e5

69. Garhofer G, Zawinka C, Huemer K, et al. Flicker light-induced vasodilation in the human retina: effect of lactateand changes in mean arterial pressure. Invest OphthalmolVis Sci. 2003;44(12):2216e27

70. Geijer C, Bill A. Effects of raised intraocular pressure onretinal, prelaminar, laminar, and retrolaminar optic nerveblood flow in monkeys. Invest Ophthalmol Vis Sci.1979;18(10):1030e42

71. Gidday J, Park T. Adenosine-mediated autoregulation ofretinal arteriolar tone in the piglet. Invest Ophthalmol VisSci. 1993;34(9):2713e9

72. Gidday JM, Zhu Y. Nitric oxide does not mediateautoregulation of retinal blood flow in newborn pig. Am JPhysiol. 1995;269(3 Pt 2):H1065e72

73. Glucksberg MR, Dunn R. Direct measurement of retinalmicrovascular pressures in the live, anesthetized cat.Microvasc Res. 1993;45(2):158e65

74. Gordon GR, Choi HB, Rungta RL, et al. Brain metabolismdictates the polarity of astrocyte control over arterioles.Nature. 2008;456(7223):745e9

75. Grieshaber M, Mozaffarieh M, Flammer J. What is the linkbetween vascular dysregulation and glaucoma? SurvOphthalmol. 2007;52(Suppl 2):S144e54

76. Grytz R, Girkin CA, Libertiaux V, Downs JC. Perspectives onbiomechanical growth and remodeling mechanisms inglaucoma. Mech Res Commun. 2012;42:92e106

77. Grytz R, Meschke G. A computational remodeling approachto predict the physiological architecture of the collagen fibrilnetwork in corneo-scleral shells. Biomech ModelMechanobiol. 2010;9(2):225e35

78. Grytz R, Meschke G. Constitutive modeling of crimpedcollagen fibrils in soft tissues. J Mech Behav Biomed Mater.2009;2(5):522e33

79. Grytz R, Meschke G, Jonas JB. The collagen fibril architecturein the lamina cribrosa and peripapillary sclera predicted by acomputational remodeling approach. Biomech ModelMechanobiol. 2011;10(3):371e82

80. Grytz R, Sigal IA, Ruberti JW, et al. Lamina cribrosathickening in early glaucoma predicted by a microstructuremotivated growth and remodeling approach. Mech Mater.2012;44:99e109

81. Guidoboni G, Harris A, Cassani S, et al. Intraocularpressure, blood pressure, and retinal blood flowautoregulation: a mathematical model to clarify theirrelationship and clinical relevance. Invest Ophthalmol VisSci. 2014;55(7):4105e18

82. Haefliger IO, Chen Q, Anderson DR. Effect of oxygen onrelaxation of retinal pericytes by sodium nitroprusside.Graefes Arch Clin Exp Ophthalmol. 1997;235(6):388e92

83. Hall CN, Reynell C, Gesslein B, et al. Capillary pericytesregulate cerebral blood flow in health and disease. Nature.2014;508(7494):55e60


















































































































































































84. Hamard P, Hamard H, Dufaux J. Blood flow rate in themicrovasculature of the optic nerve head in primary openangle glaucoma. A new approach. Surv Ophthalmol.1994;38(Suppl):S87e93, discussion S4.

85. Hamard P, Hamard H, Dufaux J, Quesnot S. Optic nerve headblood flow using a laser Doppler velocimeter andhaemorheology in primary open angle glaucoma and normalpressure glaucoma. Br J Ophthalmol. 1994;78(6):449e53

86. Hariharan N, Zhai P, Sadoshima J. Oxidative stressstimulates autophagic flux during ischemia/reperfusion.Antioxid Redox Signal. 2011;14(11):2179e90

87. Harris A, Januleviciene I, Siesky B, et al. Clinicalmeasurements of ocular blood flow, in Weinreb RN, Harris A(eds) Ocular Blood Flow in Glaucoma. Amsterdam, KuglerPublications; 2009, pp 19e56

88. Harris A, Jonescu-Cuypers C, Martin B, et al. Simultaneousmanagement of blood flow and IOP in glaucoma. ActaOphthalmol Scand. 2001;79(4):336e41

89. Harris A, Jonescu-Cuypers CP, Kagemann L, et al. Atlas ofocular blood flow. Oxford, UK, Butterworth-Heinemann; 2ed, 2010

90. Harris A, Rechtman E, Siesky B, et al. The role of optic nerveblood flow in the pathogenesis of glaucoma. OphthalmolClin North Am. 2005;18(3):345e53, v.

91. Harris A, Sergott R, Spaeth G, et al. Color Doppler analysis ofocular vessel blood velocity in normal-tension glaucoma.Am J Ophthalmol. 1994;118(5):642e9

92. Hayreh SS. The blood supply of the optic nerve head and theevaluation of itdmyth and reality. Prog Retin Eye Res.2001;20(5):563e93

93. Hayreh SS. Factors influencing blood flow in the optic nervehead. J Glaucoma. 1997;6(6):412e25

94. Hayreh SS. The 1994 Von Sallman Lecture. The optic nervehead circulation in health and disease. Exp Eye Res.1995;61(3):259e72

95. Hayreh SS. Inter-individual variation in blood supply of theoptic nerve head. Its importance in various ischemicdisorders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders. Doc Ophthalmol.1985;59(3):217e46

96. Hayreh SS, Joos KM, Podhajsky PA, Long CR. Systemicdiseases associated with nonarteritic anterior ischemic opticneuropathy. Am J Ophthalmol. 1994;118(6):766e80

97. Hayreh SS, Servais GE, Virdi PS. Fundus lesions in malignanthypertension. V. Hypertensive optic neuropathy.Ophthalmology. 1986;93(1):74e87

98. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL.Nocturnal arterial hypotension and its role in optic nervehead and ocular ischemic disorders. Am J Ophthalmol.1994;117(5):603e24

99. Helmke BP. Molecular control of cytoskeletal mechanics byhemodynamic forces. Physiology (Bethesda). 2005;20:43e53

100. Hernandez M. The optic nerve head in glaucoma: role ofastrocytes in tissue remodeling. Prog Retin Eye Res.2000;19(3):297e321

101. Hernandez MR, Miao H, Lukas T. Astrocytes in glaucomatousoptic neuropathy. Prog Brain Res. 2008;173:353e73

102. Hirrlinger J, Gutterer JM, Kussmaul L, et al. Microglial cells inculture express a prominent glutathione system for thedefense against reactive oxygen species. Dev Neurosci.2000;22(5-6):384e92

103. Hollows FC, Graham PA. Intra-ocular pressure, glaucoma,and glaucoma suspects in a defined population. Br JOphthalmol. 1966;50(10):570e86

104. Hoste AM, Boels PJ, Brutsaert DL, De Laey JJ. Effect of alpha-1 and beta agonists on contraction of bovine retinalresistance arteries in vitro. Invest Ophthalmol Vis Sci.1989;30(1):44e50

105. Huang D, Swanson EA, Lin CP, et al. Optical coherencetomography. Science. 1991;254(5035):1178e81

106. Inoue R, Hangai M, Kotera Y, et al. Three-dimensional high-speed optical coherence tomography imaging of laminacribrosa in glaucoma. Ophthalmology. 2009;116(2):214e22

107. Jeffery G, Sharp C, Malitschek B, et al. Cellular localisation ofmetabotropic glutamate receptors in the mammalian opticnerve: a mechanism for axon-glia communication. BrainRes. 1996;741(1-2):75e81

108. Jia Y, Morrison JC, Tokayer J, et al. Quantitative OCTangiography of optic nerve head blood flow. Biomed OptExpress. 2012;3(12):3127e37

109. Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherencetomography. Opt Express. 2012;20(4):4710e25

110. Kass MA, Heuer DK, Higginbotham EJ, et al. The OcularHypertension Treatment Study: a randomized trialdetermines that topical ocular hypotensive medicationdelays or prevents the onset of primary open-angleglaucoma. Arch Ophthalmol. 2002;120(6):701e13, discussion829e30.

111. Katsi V, Vlachopoulos C, Souretis G, et al. Associationbetween retinal microcirculation and aortic stiffness inhypertensive patients. Int J Cardiol. 2012;157(3):370e3

112. Klein R, Sharrett AR, Klein BE, et al. Are retinal arteriolarabnormalities related to atherosclerosis?: TheAtherosclerosis Risk in Communities Study. ArteriosclerThromb Vasc Biol. 2000;20(6):1644e50

113. Ko K, Ngai A, Winn H. Role of adenosine in regulation ofregional cerebral blood flow in sensory cortex. Am J Physiol.1990;259(6):H1703e8

114. Kondo M, Wang L, Bill A. The role of nitric oxide inhyperaemic response to flicker in the retina and optic nervein cats. Acta Ophthalmol Scand. 1997;75(3):232e5

115. Langhans M, Michelson G, Groh M. Effect of breathing 100%oxygen on retinal and optic nerve head capillary blood flowin smokers and non-smokers. Br J Ophthalmol.1997;81(5):365e9

116. Layton AT. Mathematical modeling of kidney transport.Wiley Interdiscip Reviews-Systems Biol Med.2013;5(5):557e73

117. Leske MC. Ocular perfusion pressure and glaucoma: clinicaltrial and epidemiologic findings. Curr Opin Ophthalmol.2009;20(2):73e8

118. Leske MC, Heijl A, Hussein M, et al. Factors for glaucomaprogression and the effect of treatment: the earlymanifest glaucoma trial. Arch Ophthalmol.2003;121(1):48e56

119. Liang Y, Downs J, Fortune B, et al. Impact of systemicblood pressure on the relationship between intraocularpressure and blood flow in the optic nerve head ofnonhuman primates. Invest Ophthalmol Vis Sci.2009;50(5):2154e60

120. Liang Y, Fortune B, Cull G, et al. Quantification of dynamicblood flow autoregulation in optic nerve head of rhesusmonkeys. Exp Eye Res. 2010;90(2):203e9

121. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinicaloutcomes in the Collaborative Initial Glaucoma TreatmentStudy comparing initial treatment randomized tomedications or surgery. Ophthalmology.2001;108(11):1943e53

122. Lieberman MF, Maumenee AE, Green WR. Histologic studiesof the vasculature of the anterior optic nerve. Am JOphthalmol. 1976;82(3):405e23

123. Liew G, Campbell S, Klein R, et al. Ten-year longitudinalchanges in retinal microvascular lesions: the atherosclerosisrisk in communities study. Ophthalmology.2011;118(8):1612e8





















































































































































































124. Lin WJ, Kuang HY. Oxidative stress induces autophagy inresponse to multiple noxious stimuli in retinal ganglioncells. Autophagy. 2014;10(10):1692e701

125. Liu B, Chen H, Johns TG, Neufeld AH. Epidermal growthfactor receptor activation: an upstream signal for transitionof quiescent astrocytes into reactive astrocytes after neuralinjury. J Neurosci. 2006;26(28):7532e40

126. Liu B, Neufeld AH. Expression of nitric oxide synthase-2(NOS-2) in reactive astrocytes of the human glaucomatousoptic nerve head. Glia. 2000;30(2):178e86

127. Loutzenhiser R, Bidani A, Chilton L. Renal myogenicresponsedKinetic attributes and physiological role. Circ Res.2002;90(12):1316e24

128. Luksch A, Polak K, Beier C, et al. Effects of systemic NOsynthase inhibition on choroidal and optic nerve head bloodflow in healthy subjects. Invest Ophthalmol Vis Sci.2000;41(10):3080e4

129. Lundgren O. Autoregulation of intestinal blood flow:physiology and pathophysiology. J Hypertens Suppl.1989;7(4):S79e84

130. Mackenzie PJ, Cioffi GA. Vascular anatomy of the optic nervehead. Can J Ophthalmol. 2008;43(3):308e12

131. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating andself-killing: crosstalk between autophagy and apoptosis. NatRev Mol Cell Biol. 2007;8(9):741e52

132. Malone PE, Hernandez MR. 4-Hydroxynonenal, a product ofoxidative stress, leads to an antioxidant response in opticnerve head astrocytes. Exp Eye Res. 2007;84(3):444e54

133. Malone P, Miao H, Parker A, et al. Pressure induces loss ofgap junction communication and redistribution ofconnexin-43 in astrocytes. Glia. 2007;55(10):1085e98

134. Marek B, Harris A, Kanakamedala P, et al. Cerebrospinal fluidpressure and glaucoma: regulation of trans-lamina cribrosapressure. Br J Ophthalmol. 2014;98(6):721e5

135. Marsh DJ, Sosnovtseva OV, Chon KH, Holstein-Rathlou NH.Nonlinear interactions in renal blood flow regulation. Am JPhysiol Regul Integr Comp Physiol. 2005;288(5):R1143e59

136. Matsugi T, Chen Q, Anderson DR. Adenosine-inducedrelaxation of cultured bovine retinal pericytes. InvestOphthalmol Vis Sci. 1997;38(13):2695e701

137. Matthews BD, Overby DR, Mannix R, Ingber DE. Cellularadaptation to mechanical stress: role of integrins, Rho,cytoskeletal tension and mechanosensitive ion channels.J Cell Sci. 2006;119(Pt 3):508e18

138. Metea M, Newman E. Glial cells dilate and constrict bloodvessels: a mechanism of neurovascular coupling. J Neurosci.2006;26(11):2862e70

139. Mishra A, Hamid A, Newman E. Oxygen modulation ofneurovascular coupling in the retina. Proc Natl Acad Sci U SA. 2011;108(43):17827e31

140. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology,pathophysiology, and pharmacology. Pharmacol Rev.1991;43(2):109e42

141. Moore D, Harris A, Wudunn D, et al. Dysfunctionalregulation of ocular blood flow: a risk factor for glaucoma?Clin Ophthalmol. 2008;2(4):849e61

142. Morgan WH, Yu DY, Alder VA, et al. The correlationbetween cerebrospinal fluid pressure and retrolaminartissue pressure. Invest Ophthalmol Vis Sci.1998;39(8):1419e28

143. Motallebipour M, Rada-Iglesias A, Jansson M, Wadelius C.The promoter of inducible nitric oxide synthase implicatedin glaucoma based on genetic analysis and nuclear factorbinding. Mol Vis. 2005;11:950e7

144. Movaffaghy A, Chamot S, Petrig B, Riva C. Blood flow in thehuman optic nerve head during isometric exercise. Exp EyeRes. 1998;67(5):561e8

145. Mulligan SJ, MacVicar BA. Calcium transients in astrocyteendfeet cause cerebrovascular constrictions. Nature.2004;431(7005):195e9

146. Nadler Z, Wang B, Wollstein G, et al. Repeatability of in vivo3D lamina cribrosa microarchitecture using adaptive opticsspectral domain optical coherence tomography. Biomed OptExpress. 2014;5(4):1114e23

147. Neufeld AH, Hernandez MR, Gonzalez M. Nitric oxidesynthase in the human glaucomatous optic nerve head.Arch Ophthalmol. 1997;115(4):497e503

148. Newman E. Functional hyperemia and mechanisms ofneurovascular coupling in the retinal vasculature. J CerebBlood Flow Metab. 2013;33(11):1685e95

149. Novack RL, Stefansson E, Hatchell DL. Intraocular pressureeffects on optic nerve-head oxidative metabolism measuredin vivo. Graefes Arch Clin Exp Ophthalmol.1990;228(2):128e33

150. Nyborg NC, Nielsen PJ. The level of spontaneous myogenictone in isolated human posterior ciliary arteries decreaseswith age. Exp Eye Res. 1990;51(6):711e5

151. Offenhauser N, Thomsen K, Caesar K, Lauritzen M. Activity-induced tissue oxygenation changes in rat cerebellar cortex:interplay of postsynaptic activation and blood flow.J Physiol. 2005;565(Pt 1):279e94

152. Ohashi T, Ishii Y, Ishikawa Y, et al. Experimental andnumerical analyses of local mechanical propertiesmeasured by atomic force microscopy for shearedendothelial cells. Biomed Mater Eng. 2002;12(3):319e27

153. Ohno-Matsui K, Futagami S, Yamashita S, Tokoro T. Zinn-Haller arterial ring observed by ICG angiography in highmyopia. Br J Ophthalmol. 1998;82(12):1357e62

154. Olufsen MS, Nadim A, Lipsitz LA. Dynamics of cerebralblood flow regulation explained using a lumped parametermodel. Am J Physiol Regul Integr Comp Physiol.2002;282(2):R611e22

155. Onda E, Cioffi GA, Bacon DR, Van Buskirk EM.Microvasculature of the human optic nerve. Am JOphthalmol. 1995;120(1):92e102

156. Orgul S, Gugleta K, Flammer J. Physiology of perfusion as itrelates to the optic nerve head. Surv Ophthalmol.1999;43:S17e26

157. Orgul S, Meyer P, Cioffi G. Physiology of blood flow regulationand mechanisms involved in optic nerve perfusion.J Glaucoma. 1995;4(6):427e43

158. Osborne NN. Mitochondria: their role in ganglion cell deathand survival in primary open angle glaucoma. Exp Eye Res.2010;90(6):750e7

159. Osborne NN, Wood JP, Chidlow G, et al. Ganglion cell deathin glaucoma: what do we really know? Br J Ophthalmol.1999;83(8):980e6

160. Panerai R. Assessment of cerebral pressure autoregulation inhumansda review of measurement methods. Physiol Meas.1998;19(3):305e38

161. Pasquale L, Jonas JB, Anderson DR. Anatomy and physiology,in Weinreb RN, Harris A (eds) Ocular Blood Flow inGlaucoma. Amsterdam, Kugler Publications; 2009, pp 3e13

162. Paulson OB, Strandgaard S, Edvinsson L. Cerebralautoregulation. Cerebrovasc Brain Metab Rev.1990;2(2):161e92

163. Peng X, Carhuapoma JR, Bhardwaj A, et al. Suppression ofcortical functional hyperemia to vibrissal stimulation in therat by epoxygenase inhibitors. Am J Physiol Heart CircPhysiol. 2002;283(5):H2029e37

164. Peng X, Zhang C, Alkayed NJ, et al. Dependency of corticalfunctional hyperemia to forepaw stimulation onepoxygenase and nitric oxide synthase activities in rats.J Cereb Blood Flow Metab. 2004;24(5):509e17





















































































































































































165. Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectionalcontrol of CNS capillary diameter by pericytes. Nature.2006;443(7112):700e4

166. Pillunat L, Anderson D, Knighton R, et al. Autoregulation ofhuman optic nerve head circulation in response to increasedintraocular pressure. Exp Eye Res. 1997;64(5):737e44

167. Pollock DM, Keith TL, Highsmith RF. Endothelin receptorsand calcium signaling. FASEB J. 1995;9(12):1196e204

168. Polska E, Ehrlich P, Luksch A, Fuchsjager-Mayrl G. Effects ofadenosine on intraocular pressure, optic nerve head blood,and choroidal blood flow in healthy humans. InvestOphthalmol Vis Sci. 2003;44(7):3110e4

169. Porsaa K. Experimental studies on the vasomotorinnervation of the retinal arteries. Acta Ophthalmol.1941;19(S18):9e201

170. Porter JT, McCarthy KD. Hippocampal astrocytes in siturespond to glutamate released from synaptic terminals.J Neurosci. 1996;16(16):5073e81

171. Pournaras C, Riva C, Bresson-Dumont H, et al. Regulation ofoptic nerve head blood flow in normal tension glaucomapatients. Eur J Ophthalmol. 2004;14(3):226e35

172. Pries AR, Secomb TW, Gaehtgens P. Biophysical aspects ofblood flow in the microvasculature. Cardiovasc Res.1996;32(4):654e67

173. Puro DG. Physiology and pathobiology of the pericyte-containing retinal microvasculature: new developments.Microcirculation. 2007;14(1):1e10

174. Quigley HA. Glaucoma. Lancet. 2011;377(9774):1367e77175. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res.

1999;18(1):39e57176. Quigley HA. Pathophysiology of the optic nerve head in

glaucoma, in McAllister JA, Wilson RP (eds) Glaucoma.London; Boston, Butterworths; 1986

177. Quigley HA, Broman AT. The number of people withglaucoma worldwide in 2010 and 2020. Br J Ophthalmol.2006;90(3):262e7

178. Rein H. Vasomotorische regulationen. Ergebnisse derPhysiologie. 1931;32(1):28e72

179. Resch H, Garhofer G, Fuchsjager-Mayrl G, et al. Endothelialdysfunction in glaucoma. Acta Ophthalmol.2009;87(1):4e12

180. Resch H, Karl K, Weigert G, et al. Effect of dual endothelinreceptor blockade on ocular blood flow in patients withglaucoma and healthy subjects. Invest Ophthalmol Vis Sci.2009;50(1):358e63

181. Riva CE, Cranstoun SD, Petrig BL. Effect of decreased ocularperfusion pressure on blood flow and the flicker-inducedflow response in the cat optic nerve head. Microvasc Res.1996;52(3):258e69

182. Riva C, Falsini B, Logean E. Flicker-evoked responses ofhuman optic nerve head blood flow: luminance versuschromatic modulation. Invest Ophthalmol Vis Sci.2001;42(3):756e62

183. Riva CE, Geiser M, Petrig BL, Beijing PRCOBFRA. Ocular bloodflow assessment using continuous laser Doppler flowmetry.Acta Ophthalmol. 2010;88(6):622e9

184. Riva CE, Grunwald JE, Petrig BL. Autoregulation of humanretinal blood flow. An investigation with laser Dopplervelocimetry. Invest Ophthalmol Vis Sci. 1986;27(12):1706e12

185. Riva CE, Harino S, Petrig BL, Shonat RD. Laser Dopplerflowmetry in the optic nerve. Exp Eye Res.1992;55(3):499e506

186. Riva C, Hero M, Titze P, Petrig B. Autoregulation of humanoptic nerve head blood flow in response to acute changes inocular perfusion pressure. Graefe’s Arch Clin ExpOphthalmol. 1997;235(10):618e26

187. Riva C, Logean E, Falsini B. Visually evoked hemodynamicalresponse and assessment of neurovascular coupling in the

optic nerve and retina. Prog Retin Eye Res.2005;24(2):183e215

188. Roberts MD, Grau V, Grimm J, et al. Remodeling of theconnective tissue microarchitecture of the lamina cribrosain early experimental glaucoma. Invest Ophthalmol Vis Sci.2009;50(2):681e90

189. Roff EJ, Harris A, Chung HS, et al. Comprehensiveassessment of retinal, choroidal and retrobulbarhaemodynamics during blood gas perturbation. GraefesArch Clin Exp Ophthalmol. 1999;237(12):984e90

190. Rose C, Ransom B. Gap junctions equalize intracellular Naþconcentration in astrocytes. Glia. 1997;20(4):299e307

191. Rosengarten B, Hecht M, Kaps M. Brain activity affectsdynamic but not static autoregulation. Exp Neurol.2007;205(1):201e6

192. Russell FD, Hamilton KD. Nutrient deprivation increasesvulnerability of endothelial cells to proinflammatory insults.Free Radic Biol Med. 2014;67:408e15

193. Sander EA, Downs JC, Hart RT, et al. A cellular solid model ofthe lamina cribrosa: mechanical dependence onmorphology. J Biomech Eng. 2006;128(6):879e89

194. Satcher R, Dewey CF Jr, Hartwig JH. Mechanical remodelingof the endothelial surface and actin cytoskeleton induced byfluid flow. Microcirculation. 1997;4(4):439e53

195. Sato M, Ohashi T. Biorheological views of endothelial cellresponses to mechanical stimuli. Biorheology.2005;42(6):421e41

196. Sato E, Sakamoto T, Nagaoka T, et al. Role of nitric oxide inregulation of retinal blood flow during hypercapnia in cats.Invest Ophthalmol Vis Sci. 2003;44(11):4947e53

197. Schmetterer L, Findl O, Strenn K, et al. Role of NO in the O2and CO2 responsiveness of cerebral and ocular circulation inhumans. Am J Physiol. 1997;273(6 Pt 2):R2005e12

198. Schmetterer L, Polak K. Role of nitric oxide in the control ofocular blood flow. Prog Retin Eye Res. 2001;20(6):823e47

199. Schmidl D, Boltz A, Kaya S, et al. Role of nitric oxide in opticnerve head blood flow regulation during an experimentalincrease in intraocular pressure in healthy humans. Exp EyeRes. 2013;116:247e53

200. SchmidlD,GarhoferG,SchmettererL.Thecomplex interactionbetween ocular perfusion pressure and ocular bloodflowdrelevance for glaucoma. Exp Eye Res. 2011;93(2):141e55

201. Schon EA, Manfredi G. Neuronal degeneration andmitochondrial dysfunction. J Clin Invest. 2003;111(3):303e12

202. Sgouralis I, Layton AT. Theoretical assessment of renalautoregulatory mechanisms. Am J Physiol Renal Physiol.2014;306(11):F1357e71

203. Shah R, Wormald RP. Glaucoma. BMJ Clin Evid. 2011;2011204. Shibata M, Oku H, Sugiyama T, et al. Disruption of gap

junctions may be involved in impairment of autoregulationin optic nerve head blood flow of diabetic rabbits. InvestOphthalmol Vis Sci. 2011;52(5):2153e9

205. Shibata M, Sugiyama T, Hoshiga M, et al. Changes in opticnerve head blood flow, visual function, and retinal histologyin hypercholesterolemic rabbits. Exp Eye Res.2011;93(6):818e24

206. Shibata M, Sugiyama T, Kurimoto T, et al. Involvement ofglial cells in the autoregulation of optic nerve head bloodflow in rabbits. Invest Ophthalmol Vis Sci.2012;53(7):3726e32

207. Sigal IA, Flanagan JG, Tertinegg I, Ethier CR. Modelingindividual-specific human optic nerve head biomechanics.Part I: IOP-induced deformations and influence of geometry.Biomech Model Mechanobiol. 2009;8(2):85e98

208. Sigal IA, Flanagan JG, Tertinegg I, Ethier CR. Modelingindividual-specific human optic nerve head biomechanics.Part II: influence of material properties. Biomech ModelMechanobiol. 2009;8(2):99e109























































































































































































209. Sigal IA, Wang B, Strouthidis NG, et al. Recent advances inOCT imaging of the lamina cribrosa. Br J Ophthalmol.2014;98(Suppl 2):ii34e9

210. Sines D, Harris A, Siesky B, et al. The response of retrobulbarvasculature to hypercapnia in primary open-angle glaucomaand ocular hypertension. Ophthalmic Res. 2007;39(2):76e80

211. Singh S, Dass R. The central artery of the retina. II. A study of itsdistribution and anastomoses. Br J Ophthalmol. 1960;44:280e99

212. Sossi N, Anderson D. Effect of elevated intraocular pressureon blood flow. Occurrence in cat optic nerve head studiedwith iodoantipyrine I 125. Arch Ophthalmol.1983;101(1):98e101

213. Spronck B, Martens EG, Gommer ED, van de Vosse FN.A lumped parameter model of cerebral blood flow controlcombining cerebral autoregulation and neurovascularcoupling. Am J Physiol Heart Circ Physiol.2012;303(9):H1143e53

214. Srikanth K, Kumar MA, Selvasundari S, Prakash ML. ColourDoppler imaging of ophthalmic artery and central retinalartery in glaucoma patients with and without diabetesmellitus. J Clin Diagn Res. 2014;8(4):VC01e2

215. Srinivasan VJ, Adler DC, Chen Y, et al. Ultrahigh-speedoptical coherence tomography for three-dimensional and enface imaging of the retina and optic nerve head. InvestOphthalmol Vis Sci. 2008;49(11):5103e10

216. St Lawrence KS, Ye FQ, Lewis BK, et al. Measuring the effectsof indomethacin on changes in cerebral oxidativemetabolism and cerebral blood flow during sensorimotoractivation. Magn Reson Med. 2003;50(1):99e106

217. Sugiyama T, Araie M, Riva CE, et al. Use of laser speckleflowgraphy in ocular blood flow research. Acta Ophthalmol.2010;88(7):723e9

218. Sugiyama T, Utsumi T, Azuma I, Fujii H. Measurement ofoptic nerve head circulation: comparison of laser speckleand hydrogen clearance methods. Jpn J Ophthalmol.1996;40(3):339e43

219. Takano T, Tian GF, PengW, et al. Astrocyte-mediated controlof cerebral blood flow. Nat Neurosci. 2006;9(2):260e7

220. Takayama J, Tomidokoro A, Ishii K, et al. Time course of thechange in optic nerve head circulation after an acuteincrease in intraocular pressure. Invest Ophthalmol Vis Sci.2003;44(9):3977e85

221. Tamaki Y, Araie M, Fukaya Y, et al. Effects of lomerizine, acalcium channel antagonist, on retinal and optic nerve headcirculation in rabbits and humans. Invest Ophthalmol VisSci. 2003;44(11):4864e71

222. Tamaki Y, Araie M, Kawamoto E, et al. Non-contact, two-dimensional measurement of tissue circulation in choroidand optic nerve head using laser speckle phenomenon. ExpEye Res. 1995;60(4):373e83

223. Tomita K, Araie M, Tamaki Y, et al. Effects of nilvadipine, acalcium antagonist, on rabbit ocular circulation and opticnerve head circulation in NTG subjects. Invest OphthalmolVis Sci. 1999;40(6):1144e51

224. Tamaki Y, Araie M, Tomita K, Tomidokoro A. Time-course ofchanges in nicardipine effects on microcirculation in retinaand optic nerve head in living rabbit eyes. Jpn J Ophthalmol.1996;40(2):202e11

225. Tamaki Y, AraieM, Tomita K, UrashimaH. Effects of pranidipine,a new calcium antagonist, on circulation in the choroid, retinaand optic nerve head. Curr Eye Res. 1999;19(3):241e7

226. Tomita K, Tomidokoro A, Tamaki Y, et al. Effects ofsemotiadil, a novel calcium antagonist, on the retina andoptic nerve head circulation. J Ocul Pharmacol Ther.2000;16(3):231e9

227. Ursino M, Colantuoni A, Bertuglia S. Vasomotion and bloodflow regulation in hamster skeletal muscle microcirculation:

a theoretical and experimental study. Microvasc Res.1998;56(3):233e52

228. Ursino M, Giannessi M. A model of cerebrovascularreactivity including the circle of willis and corticalanastomoses. Ann Biomed Eng. 2010;38(3):955e74

229. Ursino M, Lodi CA. A simple mathematical model of theinteraction between intracranial pressure and cerebralhemodynamics. J Appl Physiol (1985). 1997;82(4):1256e69

230. van Beek A, Claassen J, Rikkert M. Cerebral autoregulation:an overview of current concepts and methodology withspecial focus on the elderly. J Cereb Blood Flow Metab.2008;28(6):1071e85

231. Vasudevan SK, Gupta V, Crowston JG. Neuroprotectionin glaucoma. Indian J Ophthalmol. 2011;59(Suppl):S102e13

232. Venkataraman S, Flanagan J, Hudson C. Vascular reactivityof optic nerve head and retinal blood vessels in glaucomadareview. Microcirculation. 2010;17(7):568e81

233. Wang L, Burgoyne C, Cull G, et al. Static blood flowautoregulation in the optic nerve head in normal andexperimental glaucoma. Invest Ophthalmol Vis Sci.2014;55(2):873e80

234. Wang L, Cioffi GA, Cull G, et al. Immunohistologic evidencefor retinal glial cell changes in human glaucoma. InvestOphthalmol Vis Sci. 2002;43(4):1088e94

235. Wang L, Cull G, Piper C, et al. Anterior and posterior opticnerve head blood flow in nonhuman primate experimentalglaucoma model measured by laser speckle imagingtechnique and microsphere method. Invest Ophthalmol VisSci. 2012;53(13):8303e9

236. Wang B, Nevins JE, Nadler Z, et al. Reproducibility of in-vivoOCT measured three-dimensional human lamina cribrosamicroarchitecture. PLoS One. 2014;9(4):e95526

237. Wang B, Nevins JE, Nadler Z, et al. In vivo lamina cribrosamicro-architecture in healthy and glaucomatous eyes asassessed by optical coherence tomography. InvestOphthalmol Vis Sci. 2013;54(13):8270e4

238. White LR, Bakken IJ, Sjaavaag I, et al. Vasoactivitymediated by endothelin ETA and ETB receptors in isolatedporcine ophthalmic artery. Acta Physiol Scand.1996;157(2):245e52

239. Williamson TH, Harris A. Color Doppler ultrasoundimaging of the eye and orbit. Surv Ophthalmol.1996;40(4):255e67

240. Winkler M, Jester B, Nien-Shy C, et al. High resolutionthree-dimensional reconstruction of the collagenousmatrix of the human optic nerve head. Brain Res Bull.2010;81(2-3):339e48

241. Wong TY, Mitchell P. The eye in hypertension. Lancet.2007;369(9559):425e35

242. Yang G, Zhang Y, Ross M. Attenuation of activity-inducedincreases in cerebellar blood flow in mice lacking neuronalnitric oxide synthase. Am J Physiol Heart Circ Physiol.2003;285(1):H298e304

243. Ye XD, Laties AM, Stone RA. Peptidergic innervation of theretinal vasculature and optic nerve head. Invest OphthalmolVis Sci. 1990;31(9):1731e7

244. Yuan L, Neufeld AH. Activated microglia in the humanglaucomatous optic nerve head. J Neurosci Res.2001;64(5):523e32

245. Zonta M, Angulo MC, Gobbo S, et al. Neuron-to-astrocytesignaling is central to the dynamic control of brainmicrocirculation. Nat Neurosci. 2003;6(1):43e50

246. Zweifach B, Lipowski H. Pressure-flow relations in blood andlymph microcirculation, in Renkin EM, Michel CC, Geiger SR(eds) Microcirculation. 4. Bethesda, Md, AmericanPhysiological Society; 1984, pp 251e307















































































































































































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