Journal of Vision (2015) 15(15):9, 114 1

Functional effects of unilateral open-angle glaucoma on the

primary and extrastriate visual cortex
School of Optometry and Vision Science, University of
Victor M. Borges Auckland, Auckland, New Zealand $
Department of Ophthalmology, University of Auckland,
Helen V. Danesh-Meyer Auckland, New Zealand $
School of Optometry and Vision Science, University of
Joanna M. Black Auckland, Auckland, New Zealand $
School of Optometry and Vision Science, University of
Auckland, Auckland, New Zealand
School of Optometry and Vision Science, University of
Benjamin Thompson Waterloo, Waterloo, Canada $

The purpose of this study was to use functional magnetic
resonance imaging (fMRI) to investigate the response of
the visual cortex to unilateral primary open-angle
glaucoma (POAG). Specifically, we assessed whether
regions of V1 and V2 with lost input from the
glaucomatous eye had a greater response to input from
the nonaffected fellow eye. Nine participants with
unilateral POAG causing paracentral visual field defects
and four controls participated in the study. We found no
evidence for an increased response to the fellow eye in
glaucoma-affected regions of the visual cortex; however,
in agreement with previous studies, there was a
pronounced, retinotopically localized reduction of
activation in both the primary (V1) and extrastriate
visual cortex (V2), when participants viewed through
their glaucomatous eye. Our results suggest a
remarkable level of stability within the adult primary
and extrastriate visual cortex in response to unilateral
neurodegeneration of the optic nerve.
Introduction
Glaucoma is a leading cause of blindness that is
predicted to affect over 80 million people by the year
2020 (Quigley & Broman, 2006). Glaucoma causes a
loss of retinal ganglion cells (RGC), which results in
scotomas within the visual eld of the affected eye
(Medeiros et al., 2013; Weinreb & Khaw, 2004). There
is increasing evidence that the neurodegenerative effects
of glaucoma are not restricted to the retina and optic
nerve, but extend to the brain (Boucard et al., 2009;
Graham & Klistorner, 2013; Gupta & Yucel, 2007a;
Yucel & Gupta, 2008). For example, it has been
reported that glaucoma decreases cell density and
metabolic activity within the lateral geniculate nucleus
(LGN) of the thalamus and the primary visual cortex,
possibly due to trans-synaptic neural degeneration
(Crawford, Harwerth, Smith, Mills, & Ewing, 2001;
Vickers et al., 1997; Yucel & Gupta, 2008; Yucel,
Zhang, Weinreb, Kaufman, & Gupta, 2003). Consis-
tent with this idea, structural changes indicative of cell
loss have been found within the visual cortex of human
patients with glaucoma using both histological (Gupta,
2006) and neuroimaging techniques (Boucard et al.,
2009; Hernowo, Boucard, Jansonius, Hooymans, &
Cornelissen, 2011). However, it is currently unclear
whether the loss of afferent neural input caused by
glaucoma results in functional changes within the
human visual cortex. This is an important issue as it
relates to our understanding of the visual decits
experienced by glaucoma patients and to the broader
issue of neuroplasticity within the adult human visual
cortex.
Due to the orderly retinotopic mapping of the visual
eld across the surface of the primary and extrastriate
visual cortex (Dougherty et al., 2003; Engel, Glover, &
Wandell, 1997; Wandell, Dumoulin, & Brewer, 2007), it
is possible to precisely relate specic retinal locations to
their corresponding representations within the visual

Citation: Borges, V. M., Danesh-Meyer, H. V., Black, J. M., & Thompson, B. (2015). Functional effects of unilateral open-angle
glaucoma on the primary and extrastriate visual cortex. Journal of Vision, 15(15):9, 114, doi:10.1167/15.15.9.
doi: 10 .116 7 /1 5. 15 . 9 Received March 10, 2015; published November 17, 2015 ISSN 1534-7362 2015 ARVO

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson
cortex. Using this approach, it has been suggested that
monocular and binocular focal retinal lesions in adult
primates result in changes to the receptive elds of cells
at the borders of the lesion projection zone (LPZ; the
area of cortex corresponding to the lesioned retinal
location) in the primary visual cortex (Baseler, Gouws,
& Morland, 2009; Gilbert & Wiesel, 1992; Heinen &
Skavenski, 1991; Kaas et al., 1990; Schmid, Rosa,
Calford, & Ambler, 1996). It should be noted that this
effect is not universally accepted and may reect the
presence of existing long range connections rather than
changes in the size of receptive elds (Botelho, Ceriatte,
Soares, Gattass, & Fiorani, 2012; Calford et al., 2005;
Wandell and Smirnakis, 2009). A number of functional
magnetic resonance imaging (fMRI) studies of humans
with macular degeneration have also found evidence
for remapping of the visual cortex whereby regions of
the cortex within the LPZ became responsive to visual
stimuli falling upon undamaged regions of the retina
(Baker, Dilks, Peli, & Kanwisher, 2008; Baker, Peli,
Knouf, & Kanwisher, 2005; Schumacher et al., 2008).
The interpretation of these ndings has been disputed.
Specically it has been proposed that the functional
activation within the LPZ is due to an unmasking of
task-dependent feedback signals from higher cortical
areas and not due to low-level changes in cortical
function (Liu et al., 2010; Masuda, Dumoulin, Naka-
domari, & Wandell, 2008). In addition, a complete
absence of visual eld remapping has recently been
reported in groups of participants with age-related or
juvenile macular degeneration (Baseler et al., 2011).
Therefore it is still unclear whether functional plasticity
occurs within the adult human visual cortex following
peripheral damage to the visual system. Further, the
human studies conducted in this area to date have
focused primarily on macular degeneration, which
affects photoreceptors in the retina. The effects of
neurodegenerative diseases of the optic nerve such as
glaucoma on visual cortex plasticity have not yet been
investigated using fMRI. This is important as neuro-
degeneration is common to a large number of
neurological disorders and therefore understanding the
impact of neurodegeneration on the visual cortex could
provide information that is relevant to understanding
the impact of neurodegeneration on the brain in
general (Gupta and Yucel, 2007a).
With regard to glaucoma, a number of studies have
shown that regions of the primary visual cortex
corresponding to glaucoma-affected areas of the retina
show a reduced BOLD (blood-oxygen-level dependent)
response when patients view visual stimuli during fMRI
(Duncan, Sample, Weinreb, Bowd, & Zangwill, 2007b;
Qing, Zhang, Wang, & Wang, 2010). This indicates
that fMRI is sensitive to the loss of visual function
experienced by these patients. However, the question of
whether remapping of cortical function occurs in
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2
patients with glaucoma remains an area of debate. Our
aim was to build upon this previous work by using
fMRI to assess whether regions of cortex within the
LPZ responded differently to input from the fellow eye
(non-glaucomatous eye) than regions of visual cortex
outside of the LPZ. Differential responses would
indicate functional changes within the LPZ that are
sufciently pronounced to affect processing of infor-
mation from the fellow-eye. We have adopted the term
lesion projection zone to be consistent with previous
work.
Although the issue of functional changes in the
primary and extrastriate visual cortex has not previ-
ously been addressed in humans, data from primate
models of unilateral glaucoma support two different
predictions. Lam, Kaufman, Gabelt, To, and Matsu-
bara (2003) found a number of neurochemical changes
in the primary visual cortex of monkeys with unilateral
glaucoma, which would be highly conducive to
functional plasticity. These changes occurred in both
glaucomatous and fellow eye ocular dominance col-
umns and included evidence for a reduction in GABA
(gamma-aminobutyric acid) mediated inhibition. If the
reduction in inhibition is most pronounced in regions
most affected by glaucoma, a greater functional
response to fellow eye input would be expected within
the LPZ than for other areas of the cortex with
preserved binocular input and greater inhibition. An
increased functional response to fellow eye stimulation
within the LPZ would also be consistent with the effects
of long-term monocular deprivation that results in a
potentiation of neural responses to the nondeprived eye
(Crozier, Wang, Liu, & Bear, 2007; Sawtell et al., 2003;
Smith, Heynen, & Bear, 2009).
On the other hand, Yucel et al. (2003) found that
unilateral glaucoma caused loss and shrinkage of LGN
neurons connected to the fellow eye in a primate model.
This suggests that unilateral glaucoma is associated
with a loss of cortical inputs from both eyes, possibly
due to transsynaptic neurodegeneration, whereby
transport of specic growth factors and other key
metabolites is blocked or hindered (Almasieh, Wilson,
Morquette, Cueva Vargas, & Di Polo, 2012; Gupta &
Yucel, 2007b). If this is the case, it follows that the
functional response within the LPZ may be reduced for
both eyes relative to other regions of the cortex that
have not yet been measurably affected by glaucoma.
We also investigated whether any glaucoma-related
functional changes within the primary visual cortex
extend to extrastriate visual area V2. To the best of our
knowledge, the effect of glaucoma on the functional
responses of extrastriate visual areas in humans has not
previously been investigated.
We recruited participants with glaucoma resulting in
localized para-foveal monocular visual eld defects and
used established retinotopic mapping techniques to
 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson 3

HFA 24-2 HRT OCT

Most Mean rim Mean rim Mean Sup. Inf. Nasal Temp. GCL
affected area volume RNFL RNFL RNFL RNFL RNFL Thickness
Participant Age Sex Eye hemifield MD PSD (mm2) (mm3) (lm) (lm) (lm) (lm) (lm) (lm)
P1 71 M ODGl Superior 10.6 12.1 2.2 0.36 74 90 65 87 90 55
OSFl Normal 0.7 2.1 2.6 0.65 86 101 79 72 90 86
P2 76 M ODFl Normal 0.9 1.8 1.2 0.16 76 100 80 70 92 -
OSGl Superior 14.2 12.4 0.9 0.13 86 99 69 87 91 -
P3 74 M ODGl Superior 15.3 12.4 1.3 0.33 67 85 70 76 38 57
OSFl Normal 1.6 2.1 1.8 0.47 86 110 111 73 51 82
P4 72 M ODGl Superior 9.7 12.5 0.8 0.14 71 93 76 75 41 63
OSFl Normal 2.0 2.7 1.1 0.29 87 124 96 78 49 76
P5 80 M ODFl Normal 2.2 1.9 1.9 0.49 86 85 130 68 60 78
OSGl Inferior 9.7 10.0 1.6 0.42 65 65 86 59 49 64
P6 59 M ODFl Normal 0.6 1.2 0.7 0.11 98 120 124 92 55 71
OSGl Superior 2.3 8.3 1.0 0.26 87 126 100 70 50 44
P7 65 M ODGl Inferior 9.8 13.1 - - 62 61 82 64 42 38
OSFl Normal 2.4 3.23 - - 61 51 85 67 42 60
P8 72 F ODGl Superior 11.4 14.6 0.8 0.08 50 68 43 50 41 61
OSFl Normal 0.0 1.8 1.6 0.33 70 91 88 50 52 72
P9 54 M ODGl Superior 12.2 8.5 1.5 0.22 59 72 44 58 63 58
OSFl Normal 4.2 2.0 0.9 0.10 60 72 75 54 39 64
Table 1. Clinical details. Notes: Values outside of the normal range are indicated in bold. M: male; Gl: glaucomatous eye; Fl: fellow eye;
HFA: Humphrey Field Analyser; MD: mean deviation; PSD: pattern standard deviation; HRT: Heidelberg retinal tomography; OCT:
optical coherence tomography; RFNL: retinal nerve fiber layer; GCL: ganglion cell layer.

identify the LPZ of the glaucomatous eye in V1 and V2

(Dougherty et al., 2003; Engel et al., 1994; Sereno et al.,
1995; Wandell et al., 2007). We then presented the
participants with central eld (168) dynamic checker-
board stimuli under monocular viewing conditions and
recorded the functional response within the LPZ and a
closely matched control area corresponding to a
healthy region of retina. Stimulus contrast was
modulated to putatively target parvocellular (high
contrast) and magnocellular (low contrast) cortical
inputs (Albrecht & Hamilton, 1982; Hess, Li, Lu,
Thompson, & Hansen, 2010; Shapley & Hugh Perry,
1986). The group results showed no evidence for either
an increased or decreased response within the LPZ for
fellow eye viewing. In addition, we found that
stimulation of the glaucomatous eye evoked a weak but
measurable functional response within the LPZ. In a
preliminary analysis we found that the eccentricity
mapping of these LPZ responses did not differ
systematically between the fellow and glaucomatous
eyes, suggesting that they were not a result of
remapping. However, the use of visual stimuli opti-
mized for receptive eld mapping will be required to
fully address this question in future studies. As a whole,
our results indicate considerable stability of the adult
human primary and extrastriate visual cortex in
response to unilateral glaucoma.
Methods
Participants and clinical measures
Of 1,650 patients screened, nine (eight male and one
female, mean age 70 years, SD 8.7, Table 1) had
unilateral primary open angle glaucoma (dened as a
unilateral, reproducible visual eld defect and charac-
teristic glaucomatous optic nerve head changes) that met
the inclusion criteria. The inclusion criteria required a
unilateral visual eld loss that (a) was of at least 10 dB
mean deviation, (b) was within the central 208 of the
visual eld, (c) was at least 108 in diameter in at least one
quadrant, (d) had been present for a minimum of 3 years
over at least ve consecutive visits, and (e) did not
preclude stable xation with the affected eye. Patients
also had to be willing to undergo both structural and
functional MRI testing with no contraindications for
MRI, be older than 18 years, have best corrected visual
acuity of 20/40 or better, and refractive error within 6 5
diopters (D) sphere and 63 D cylinder.
Exclusion criteria were unreliable visual eld mea-
surements (xation loss, false negative, and false
positive errors .25%), unstable xation with the
glaucomatous eye and the presence of any other
disorders that may affect vision. In particular, patients
were excluded if there was a history of amblyopia,

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson
uveitis, or intraocular surgery (except uncomplicated
cataract surgery), diabetes, and ocular diseases possibly
affecting the peripapillary area (such as large peripap-
illary atrophy). Patients were also excluded if there was
evidence of any media opacities that prevented good
quality imaging and any retinal (including macular) or
neurologic disease other than glaucoma, which could
confound the evaluations. Finally, patients were
excluded if any visual eld defects were identied in the
fellow eye.
Visual eld testing was performed monocularly with
a Humphrey Visual Field Analyzer (HFA, Carl Zeiss
Meditec, Dublin, CA) using the 242 Swedish interac-
tive thresholding algorithm (SITA). Full refractive
correction was provided. Results were compared to the
HFA normative database. Glaucomatous optic nerve
head changes were dened as an asymmetric vertical
cup-to-disk ratio of 0.2, rim thinning, notching,
excavation, disc hemorrhages, or nerve ber layer
defects. All participants underwent complete ophthal-
mologic examination including slit-lamp biomicrosco-
py, gonioscopy, intraocular pressure, dilated
stereoscopic fundus examination, stereophotography of
the optic nerve heads, and ocular imaging with a
spectral domain optical coherence tomography (OCT,
Cirrus HD-OCT; Carl Zeiss Meditec) and scanning
laser ophthalmoscopy with Heidelberg retinal tomog-
raphy (HRT, HRT-3 Eye Explorer software version
1.5.1.0; Heidelberg Engineering, GmbH, Heidelberg,
Germany; Table 1). All participants were required to
have normal visual elds and optic nerve head
appearance in the fellow eye.
The retinal nerve ber layer (RNFL) parameters
provided by the OCT system were average RNFL
thickness within a 3.4 mm diameter circular region
centered on the optic nerve head (ONH) and temporal,
superior, nasal, and inferior quadrant RNFL thick-
nesses. Only good quality scans with signal strength  7
and the absence of motion and blinking artifacts and
segmentation failures were analyzed.
Fixation stability was measured using a ViewPoint
EyeTracker PC-60 HMD infrared eye tracking system
(Arrington Research, Scottsdale, AZ). Each eye was
assessed individually (the nonviewing eye was occluded
with an eye patch) while participants viewed the stimuli
used during scanning. All participants were able to
maintain xation within 28 of a central xation point
with either eye.
Four control participants (one female, mean age 59
years, SD 8.2) with no history of visual or
neurological defects were also scanned to conrm that
monocular retinotopic mapping results were compara-
ble between the two eyes in the absence of glaucoma.
This study adhered to the declaration of Helsinki
and was approved by institutional ethics review boards.
All participants provided informed written consent.
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4
Visual stimuli
Participants took part in two scanning sessions. The
rst involved retinotopic mapping and the second
involved central visual eld stimulation using counter-
phase checkerboard stimuli.
Standard wedge and ring stimuli were used for
retinotopic mapping (Sereno et al., 1995). Following Li,
Lu, Tjan, Dosher, and Chu (2008) the wedge and ring
stimuli were constructed from high contrast (100%)
checkerboards counterphasing at 8 Hz (Figure 1). The
wedge stimulus had a radius of 88, a width of one-
eighth of a circle and rotated in a clockwise direction
around a central xation point at a rate of 9.48/s. A full
sweep of the visual eld took 38.4 s (32 TRs) and each
scanning run contained 12 sweeps. The ring stimulus
was scaled for width in order to factor in cortical
magnication with the widest part of the stimulus (2.48)
occurring at the periphery (Harvey & Dumoulin, 2011).
The ring stimulus expanded from the center and
covered the viewable region of the visual eld in 24
seconds (20 TRs). Each scan consisted of 14 expansions
each separated by 4.8 s (4 TRs) of blank xation.
A broadband checkerboard stimulus counterphased
at 8 Hz was used for central visual eld stimulation
(Figure 2). This stimulus consisted of 0.25 cpd (cycles
per degree) checks and subtended 188 by 168 of visual
angle. Checkerboards of low (5%), medium (25%), and
high (80%) contrast were displayed for 20 s (10 TRs)
separated by 20 s of mean luminance blank xation
following a block design. Each contrast was repeated
three times within a scanning session and the sequence
of contrast presentation was randomized.
Throughout all scans, participants viewed a central
xation mark that changed from an X to an O,
and vice versa, at unpredictable intervals. The partic-
ipants had to signal each change with a button press.
Visual stimuli were generated using Psykinematix
version 1.3 (KyberVision, Montreal, Canada) and were
presented on a gamma-corrected MRI-compatible
TFTLCD monitor (Invivo, Gainesville, FL) posi-
tioned at the head-end of the scanner bore and viewed
via a front-surface mirror mounted on the head-coil.
MRI-compatible corrective lenses were provided, to
ensure best-corrected vision for the viewing distance.
Participants viewed monocularly with a tight-tting eye
patch covering the nonviewing eye. The viewing eye
was alternated between scans.
Data acquisition
Scanning was conducted on a 3.0 Tesla Philips
Achieva scanner (Eindhoven, The Netherlands)
equipped with an eight-channel head coil. Each session
began with the acquisition of a T1-weighted 3D turbo
 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson 5

Figure 1. (A) The visual stimuli used for retinotopic mapping. Standard wedge (polar-angle) and ring (eccentricity) retinotopic
mapping stimuli were used. (B) Example of a retinotopic map generated from the stimuli in panel A projected onto an inflated model
of the left and right hemispheres. The red dashed lines represent the horizontal meridian, which falls along the calcarine sulcus. The
black dashed lines represent the boundaries between distinct visual areas identified as phase reversals in the polar map.

eld-echo anatomical volume (1000 ms inverted pre- Data analysis

pulse, 1 3 1 3 1 mm voxel resolution, 180 sagittal slices,
2.7 ms TE, 5.9 ms TR, 808 ip angle). In the rst
session, four functional datasets were then acquired;
one polar angle (wedge stimulus, 366 volumes) and one
eccentricity (ring stimulus, 414 volumes) map for each
eye. Functional data were acquired using a T2*-
weighted gradient echo EPI sequence (TR 1.2 s, TE
30 ms, ip angle 658, voxel resolution 2.5 3 2.5 3 2.5
mm). Each volume consisted of 20 coronal slices
oriented perpendicular to the calcarine sulcus and
covering the whole occipital lobe.
In the second session an additional four functional
datasets (two datasets per eye) were collected while
participants viewed the checkerboard stimuli. A T2*-
weighted gradient echo, EPI sequence (TR 2.0 s, TE
30 ms, ip angle 908, voxel resolution 3.0 3 3.0 3 3.0
mm) was used to acquire 190 volumes, constructed
from 39 axial slices oriented parallel to the calcarine
sulcus.
Data were analyzed using Brain Voyager (Brain
Innovation B.V., Maastricht, The Netherlands). The
anatomical MRI images were transformed to Talairach
space and each hemisphere was inated and attened
using automated segmentation procedures. Each stage
of this process was subject to visual inspection and
manual correction where necessary. Functional data
were high-pass ltered, slice-time corrected, motion
corrected, and coregistered to the anatomical data
using subroutines within BrainVoyager.
Retinotopic mapping data were analyzed using
linear correlation analysis to identify the preferred
stimulus position within the visual eld for each voxel.
The data were then viewed on the attened represen-
tation of the occipital lobe to reveal polar angle and
eccentricity maps for each hemisphere. The boundaries
between visual areas V1, V2, V3, V3A, and V4 were

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson 6

Figure 2. (A) The stimuli used for central visual field stimulation. Broadband checkerboard stimuli counter-phased at 8Hz were used
for central visual field stimulation. (B) Each contrast was repeated three times within a scanning session and the sequence of contrast
presentation was randomized.

identied as reversals in the preferred position for the
wedge stimulus running approximately parallel to the
representation of the horizontal meridian within the
calcarine sulcus with V3A having a full-eld represen-
tation (Wandell et al., 2007). Lesion projection zones
(LPZ) were identied for one hemisphere of each
participant (the hemisphere with the greater visual eld
decit) by superimposing the polar angle maps for each
eye (thresholded at r  0.3) on the attened cortical
surface. Each LPZ was apparent as a hole in the
glaucomatous eye map relative to the fellow eye map
(Figure 3). LPZ regions of interest (ROIs) were readily
identiable in V1 and V2 for all participants. Control
ROIs were generated by mirroring the LPZ ROIs into a
visual quadrant with no visual eld decits in order to
match the corresponding LPZ ROI for eccentricity and
polar-angle.
The data from the checkerboard stimulus scans were
analyzed using a region-of-interest approach. Time
series data were extracted from each ROI and
normalized to the mean of the blank xation blocks.
The mean BOLD change was then calculated for each
block of checkerboard stimulation (six blocks for each
of the three contrasts) by averaging the BOLD change
values within a 7TR window, starting 3TRs (6 s) after
the onset of each block to account for the hemody-
namic delay and ending at the offset of the stimulus.
Finally, grand average values were calculated for each
contrast for each ROI for each participant. These data
were then subjected to statistical analyses, which were
corrected for multiple comparisons using the false

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson 7

Figure 3. (A) A 242 central automated Humphrey visual field test for the right eye of the participant P1. (B) The threshold activity
from the polar-angle retinotopic mapping sequence for the fellow eye (blue) and the glaucomatous eye (red) are overlaid on the
inflated surface of the right hemisphere. Note that this figure does not show the phase reversals present in the maps. Instead all
voxels with activity that was correlated with the retinotopic mapping stimulus with an R value  0.3 are shown. Areas that are blue
show a lack of activity from the glaucomatous eye and were defined as the LPZ (yellow dashed line). The control ROI (green dashed
line) is a mirrored representation of the LPZ corresponding to an area of retina with no measureable visual loss on the Humphrey
visual field test.

discovery rate algorithm (Benjamini & Hochberg,

1995).
In a separate preliminary ROI analysis, the data
from the expanding ring stimulus were used to compare
the representation of eccentricity within the V1 and V2
LPZ and control ROIs for glaucomatous versus fellow
eye viewing. Vectors were projected onto the attened
cortical surface of each participant. Each vector ran
parallel to the horizontal meridian and passed through
the center of either the LPZ or the control ROI (Figure
4). The preferred eccentricity for each voxel intersected
by each vector was calculated for glaucomatous eye
viewing and fellow eye viewing. For each participant, a
plot of fellow eye viewing eccentricities versus glau-
comatous eye viewing eccentricities was generated for
each ROI (LPZ vs. control) and for each visual area
(V1 vs. V2) to assess whether systematic differences
existed between the two eyes. In addition, group
eccentricity values were plotted as a cumulative
distribution for each ROI (LPZ vs. control) for each
eye (glaucomatous vs. control) and tted with a
cumulative Gaussian function using a boot-strapping
technique available within the Psignit software pack-
age (Wichmann & Hill, 2001).
Results
BOLD change within the primary visual cortex
(V1) and extrastriate visual cortex (V2)
LPZ and control ROIs could be identied for all nine
participants with glaucoma and the cortical location of
the LPZ ROIs were consistent with the participants
visual eld defects. Individual polar angle maps for
each patient are shown in Supplementary Figure 1. No
LPZ ROIs could be found in control participants
suggesting that the holes in the retinotopic maps of
participants were due to glaucoma (Supplementary
Figure 2). To further support this, no statistically
signicant difference in activation between the eyes of
controls was found for the centrally-presented check-
erboard stimuli.
The BOLD changes evoked by the central-eld
checkerboard stimuli within the LPZ and control ROIs
under fellow versus glaucomatous eye viewing condi-
tions (Figure 5) were compared using a three-way
within-subjects ANOVA with factors of ROI (LPZ vs.
control), Eye (fellow vs. glaucomatous eye), and
Contrast (low, medium, and high). Within V1, the

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson
Figure 4. Regions of interest for analyzing the representation of
eccentricity. Vectors (white dashed lines) running parallel to the
horizontal meridian and passing through the center of either
the LPZ (orange dashed line) or the control ROI (green dashed
line) were projected onto the flattened representation of the
visual cortex for each participant. The preferred eccentricities of
the voxels falling along each vector were used to compare the
representation of eccentricity within V1 and V2 for glaucoma-
tous versus fellow eye viewing. The dashed black lines show
visual area boundaries. The figure shows representative data
from participant P1.
BOLD change differed signicantly between the two
eyes, F(1, 8) 61.4, p , 0.001, and the two ROIs, F(1,
8) 6.9, p 0.031, and varied signicantly with
stimulus contrast, F(2, 16) 59.0, p , 0.001. There was
also a signicant three-way interaction between ROI,
Eye, and Contrast, F(2, 16) 14.9, p 0.002, indicating
that the difference between the two eyes varied with
both ROI and Contrast. In order to examine the nature
of this three-way interaction, a series of two-way
ANOVAs was conducted.
An ANOVA with factors of ROI and Contrast
conducted on the fellow eye data revealed a signicant
main effect of stimulus contrast, F(2, 16) 39.3, p ,
0.001; however, BOLD change did not differ reliably
between the two ROIs, F(1, 8) 0.8, p 0.4, and there
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was no interaction between ROI and contrast, F(2, 16)
0.009, p 0.49. This indicated that the cortical
response to the fellow eye was similar between the LPZ
and control regions. The same analysis conducted for
the glaucomatous eye data revealed a signicant effect
of contrast, F(2, 16) 38.1, p , 0.001, and a signicant
difference between the two ROIs, F(1, 8) 13.6, p
0.006, consistent with visual eld loss. This clearly
demonstrates that fMRI is sensitive to the scotoma
caused by glaucoma, as previously reported (Duncan,
Sample, Weinreb, Bowd, & Zangwill, 2007b; Furuta,
Nakadomari, Misaki, Miyauchi, & Iida, 2009; Gupta,
2006). In addition, this analysis demonstrated that the
difference in BOLD response between the LPZ and
control ROIs varied with stimulus contrast (signicant
ROI by Contrast interaction, F(2, 16) 14.9, p 0.004).
Post-hoc paired sample t tests revealed that the
functional loss was evident for the medium (t4 3.97,
p 0.004) and high contrast stimuli (t4 3.88, p
0.005), but was not signicant for the low contrast
stimulus (t4 2.65, p 0.03, FDR corrected critical p
value 0.02). The same pattern of results was present
in V2.
Eccentricity mapping in V1 and V2
Although there was a reduction in BOLD change in
the LPZ ROIs for glaucomatous eye viewing, consid-
erable residual activation was still evident for the high
and medium contrast stimuli (Figure 5). A mixed
ANOVA with factors of ROI (LPZ vs. control), Eye
(glaucomatous vs. fellow) and Participant (nine par-
ticipants) conducted on the raw preferred eccentricity
values for V1 revealed no signicant interaction
between ROI and Eye, F(1, 449) 1.84, p 0.18.
Therefore, the eccentricity mapping of responses in the
region of both ROIs did not differ signicantly between
the glaucomatous and fellow eyes for the voxels
sampled by our vector-based technique (Figure 4). The
relationship between eccentricity mapping for the
glaucomatous and fellow eye in the LPZ and control
ROIs is shown for three participants in Figure 6.
Although the relationship between eccentricity re-
sponses for the two eyes was noisier for the LPZ ROI
compared to the control ROI, there were no systematic
shifts in eccentricity mapping that could be identied
consistently across participants. This was consistent
with the lack of an interaction in the ANOVA model.
The noisier response in the LPZ ROI was likely due to
the weaker BOLD response in this region. Figure 7
shows group mean cumulative distributions of pre-
ferred eccentricity for each combination of eye and
ROI. Again no systematic differences between eyes or
ROIs were apparent. The extent of residual activation
in V1 or V2 was not correlated with the visual eld
 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson 9

Figure 5. BOLD change within the LPZ and control ROIs for V1 and V2. Light bars show BOLD changes for the fellow eye and dark bars
for the glaucomatous eye. Solid bars indicate the LPZ ROI and hatched bars the control ROI. Reduced responses were found within
the LPZ for the glaucomatous eye. The fellow eye responses did not differ between the two ROIs. Results were consistent for V1 and
V2. Error bars show 6 1 standard error of the mean. * p  0.05, ** p  0.01.

mean deviation scores corresponding to the LPZ region
( p . 0.05).
Discussion
The effect of unilateral glaucoma on the functional
organization of the human visual cortex is currently
unknown. However, evidence from primate models
suggests that the cortical response to the nonglaucom-
atous eye may be either (1) increased due to a reduction
in GABA-mediated inhibition (Lam et al., 2003) or (2)
reduced due to transsynaptic neurodegeneration (Al-
masieh et al., 2012; Gupta et al., 2007; Yucel et al.,
2003). Our aim was to address this question in humans
with unilateral POAG using fMRI. This was achieved
by comparing the response of retinotopic regions
within V1 and V2 that corresponded to the scotoma in
the glaucomatous eye (LPZ) and a matched region of
intact visual eld (control ROI) when participants
viewed with each eye.
In agreement with previous work, we found reduced
BOLD activation within the LPZ when participants
viewed with their glaucomatous eye, indicating that
fMRI is sensitive to the effect of glaucoma on visual
function (Duncan et al., 2007a; Qing et al., 2010). A
comparison between the LPZ and control ROI for
fellow eye viewing showed no reliable differences
between the ROIs. These effects were seen in both V1
and V2, making this one of the rst fMRI studies in

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson 10

Figure 6. Relationships between eccentricity responses for

fellow eye versus glaucomatous eye viewing. Data from three
participants (P1, P4, and P7) are shown for the LPZ and control
(Cntrl) ROIs in V1 and V2. The gray unity line represents
perfectly correlated preferred eccentricity responses between
the two eyes across the voxels sampled by the linear vector that
intersected each ROI (Figure 4). Data points above the unity line
indicate a more foveal preferred eccentricity response for a
particular voxel when driven by the glaucomatous eye relative
to the fellow eye. The solid black line represents the best linear
fit to the data. P1 showed relationships that were close to unity
for all ROIs. P2 exhibited a lack of correlation between the two
eyes for the V1 LPZ ROI only. P7 exhibited noisier relationships
between the two eyes for the LPZ ROIs in both V1 and V2.

humans to demonstrate the effects of glaucoma on a

higher visual area.
Our results were not consistent with reduced GABA-
mediated inhibition of cortical inputs from the fellow eye
within the LPZ or with transsynaptic degeneration.
Based on our current understanding of the BOLD
signal, regions of reduced GABA would be expected to
result in a larger BOLD response (Muthukumaraswamy,
Edden, Jones, Swettenham, & Singh, 2009), whereas a
loss of cells responsive to the fellow eye would result in a
decreased LPZ BOLD signal. Our results demonstrated
a striking level of stability within the primary and
extrastriate cortex, whereby responses to the fellow eye
were equivalent within the LPZ and the control ROIs.

Figure 7. Cumulative distributions of eccentricity responses

within the LPZ and control ROIs in V1 and V2. Data are shown as
the cumulative distribution of preferred eccentricities for
individual voxels collapsed across participants. The preferred
eccentricities of voxels within V1 and V2 were similar for
glaucomatous eye viewing and fellow eye viewing.

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 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson
The results from our group of patients, therefore, do not
support either the cortical degeneration or increased
cortical plasticity hypotheses, but rather suggest that
when the retina is intact, fellow eye responses within V1
and V2 are similar within the LPZ and control regions.
Experimental models of glaucoma have shown that
the magnocellular and parvocellular pathways undergo
atrophy within the LGN and V1 (Yucel, Zhang,
Weinreb, Kaufman, & Gupta, 2001; Yucel et al., 2003).
By using varying degrees of contrast in the central eld
checkerboard stimulation, we intended to provide
initial insights into whether either one of these
geniculo-cortical pathways was more susceptible to the
functional losses caused by glaucoma. Cells in the
parvocellular pathway have a low-contrast gain and
only saturate at high contrast, whereas cells in the
magnocellular pathway have a high-contrast gain and
reach saturation at medium contrast (Hess et al., 2010;
Kaplan & Shapley, 1986). We found that for the LPZ
ROI, the most signicant loss of BOLD signal occurred
at higher contrasts for glaucomatous eye viewing
(Figure 5). This is consistent with a greater functional
impairment of the parvocellular pathway. However,
manipulating stimulus contrast does not allow for a
direct measure of magnocellular versus parvocellular
function. Furthermore, the lowest contrast stimulus
induced low levels of BOLD response across all ROIs.
Together these considerations prevent us from drawing
strong conclusions on this point.
We found it interesting to observe that measurable
BOLD activity, albeit reduced, was present within the
LPZ when participants viewed with their glaucomatous
eye. Typically glaucoma progress from peripheral to
central areas of the visual eld and therefore we wanted
to explore whether preferred eccentricity of voxels within
the LPZ differed when participants viewed with their
fellow versus glaucomatous eye. Specically, a shift of
preferred eccentricities toward the fovea for the glau-
comatous eye relative to the fellow eye may be indicative
of cells within the LPZ remapping to process
information from intact ganglion cells within the
glaucomatous eye. Previous fMRI studies have reported
remapping of this type in participants with AMD
(Baker et al., 2005; Dilks, Baker, Peli, & Kanwisher,
2009). Another possibility for remapping of visual space
is that receptive elds along the edges of the LPZ may
increase in size. There is evidence for an increase in
cortical receptive eld size in regions corresponding to
the edge of induced retinal lesions in animals, possibly
due to an unmasking of long-range horizontal connec-
tions (Calford et al., 2000; Giannikopoulos & Eysel,
2006; Gilbert, Hirsch, & Wiesel, 1990; Gilbert & Wiesel,
1992; Heinen & Skavenski, 1991; Kaas et al., 1990).
However, the presence of remapping in V1 and V2 is
strongly debated (Chino, Kaas, Smith, Langston, &
Cheng, 1992; Chino, Smith, Kaas, Sasaki, & Cheng,
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11
1995; Masuda et al., 2008; Murakami, Komatsu, &
Kinoshita, 1997; Schmid et al., 1996; Wandell &
Smirnakis, 2009) and a recent fMRI study has reported
an absence of remapping in large samples of participants
with macular degeneration (Baseler et al., 2011). We did
not detect any signicant differences in the eccentricity
mapping of LPZ BOLD responses for glaucomatous eye
viewing versus fellow eye viewing for the group of
patients as a whole, which suggests a lack of remapping.
However, this analysis should be considered as prelim-
inary because our mapping stimuli were not optimized
for the estimation of receptive eld size and may not
have been sensitive enough to reliably distinguish
between responses emanating from within the LPZ and
those resulting from activation of cortical tissue
surrounding the LPZ. Therefore, precise mapping of
residual cortical responses in the vicinity of the LPZ will
be required to fully understand the origin of these
signals. This issue is important, because the possibility of
residual cortical activity within an LPZ is directly
relevant to the success of retinal prostheses as these
devices will rely on the presence of functioning cortical
cells even after long periods of visual deprivation
(Weiland, Cho, & Humayun, 2011).
Conclusion
Our data in a limited number of participants with
unilateral POAG do not support the hypothesis that
cortical inputs from the fellow eye are subject to
decreased inhibition that would be conducive to neural
plasticity. Furthermore, we did not nd evidence of
neurodegeneration affecting cells receiving information
from the fellow eye. Rather we found high levels of
stability within both the primary and extrastriate visual
cortex of patients with unilateral glaucoma.
Keywords: fMRI, retinotopic mapping, cortical reor-
ganization, plasticity, optic neuropathy
Acknowledgments
This study was funded by the Neurological Foun-
dation of New Zealand, the Auckland Medical
Research Foundation, and the Stevenson Trust. The
authors thank Ayton Hope, Maurice Moriarty, Jeremy
Morrison, and the Trinity MRI team for their support
and expertise.
Commercial relationships: none.
Corresponding author: Benjamin Thompson.
Email: ben.thompson@uwaterloo.ca.
 Journal of Vision (2015) 15(15):9, 114 Borges, Danesh-Meyer, Black, & Thompson
Address: School of Optometry and Vision Science,
University of Waterloo, Waterloo, Canada.
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