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Interocular suppression in strabismic amblyopia results

in an attenuated and delayed hemodynamic response


function in early visual cortex
Athinoula A. Martinos Center for Biomedical Imaging,
Charlestown, MA, USA, &
Harvard Medical School, Boston, MA, USA Reza Farivar
Department of Optometry and Vision Science, University of
Auckland, Auckland, New Zealand Benjamin Thompson
Division of Neurology, Department of Internal Medicine,
University of Manitoba, Winnipeg, Canada Behzad Mansouri
McGill Vision Research Center, McGill University,
Montreal, Canada Robert F. Hess
Factors such as strabismus or anisometropia during infancy can disrupt normal visual development and result in amblyopia,
characterized by reduced visual function in an otherwise healthy eye and often associated with persistent suppression of
inputs from the amblyopic eye by those from the dominant eye. It has become evident from fMRI studies that the cortical
response to stimulation of the amblyopic eye is also affected. We were interested to compare the hemodynamic response
function (HRF) of early visual cortex to amblyopic vs. dominant eye stimulation. In the rst experiment, we found that
stimulation of the amblyopic eye resulted in a signal that was both attenuated and delayed in its time to peak. We postulated
that this delay may be due to suppressive effects of the dominant eye and, in our second experiment, measured the cortical
response of amblyopic eye stimulation under two conditionsVwhere the dominant eye was open and seeing a static pattern
(high suppression) or where the dominant eye was patched and closed (low suppression). We found that the HRF in
response to amblyopic eye stimulation depended on whether the dominant eye was open. This effect was manifested as
both a delayed HRF under the suppressed condition and an amplitude reduction.
Keywords: functional imaging, visual cortex, visual development, hemodynamic modulation, hemodynamic response
Citation: Farivar, R., Thompson, B., Mansouri, B., & Hess, R. F. (2011). Interocular suppression in strabismic amblyopia
results in an attenuated and delayed hemodynamic response function in early visual cortex. Journal of Vision, 11(14):16,
112, http://www.journalofvision.org/content/11/14/16, doi:10.1167/11.14.16.
Introduction
Amblyopia is a visual disorder caused by a difference in
the images seen by each eye during early development
(Holmes & Clarke, 2006). The visual loss typically
occurs in one eye and is characterized by a reduction of
sensitivity to high spatial frequencies (Hess, 1979; Hess &
Howell, 1977), positional uncertainty (Levi, Klein, &
Yap, 1987), and a range of higher level decits including
impaired global motion processing (Simmers, Ledgeway,
Hess, & McGraw, 2003). Importantly, these visual decits
cannot be corrected optically or surgically, as the visual
loss is not due to a problem with the eye but rather due to
neural processing of information from the eye (Hess, 2001;
Wiesel & Hubel, 1965). In addition to this monocular loss
of function, amblyopia is also associated with impaired
or absent binocular vision (Sireteanu, 2000). The major
contributing factor to this binocular loss is suppression of
the amblyopic eye input to the visual cortex (Baker, Meese,
Mansouri, & Hess, 2007; Harrad, Sengpiel, & Blakemore,
1996; Mansouri, Thompson, & Hess, 2008; Sengpiel &
Blakemore, 1996; Sengpiel, Blakemore, Kind, & Harrad,
1994; Sengpiel, Jirmann, Vorobyov, & Eysel, 2006).
While interocular suppression can be generated in the
normal visual system using binocular rivalry paradigms
(Tong, Meng, & Blake, 2006), in amblyopia, the suppres-
sion is typically chronic (de Belsunce & Sireteanu, 1991).
This means that while during normal binocular viewing
the amblyopic eye is open and providing neural input to
the lateral geniculate and the visual cortex, this input does
not reach awareness. This is evidenced clinically by a
general lack of double vision in strabismic amblyopes
without anomalous retinal correspondence and the experi-
ence of a single focused image in anisometropic amblyopes.
Importantly, in the strabismic form of the disorder, chronic
Journal of Vision (2011) 11(14):16, 112 http://www.journalofvision.org/content/11/14/16 1
doi: 10. 1167/ 11. 14. 16 Received March 22, 2011; published December 19, 2011 ISSN 1534-7362 * ARVO
suppression is considered to cause the loss of perception in
the amblyopic eye (Holmes & Clarke, 2006) raising the
possibility that neural input from the amblyopic eye may
still be subject to residual suppression under monocular
viewing conditions.
Although much research has been carried out on the
monocular loss of function in amblyopia, very little is
known about the nature of interocular suppression. For
example, a considerable number of functional magnetic
resonance imaging (fMRI) studies have been conducted
on humans with amblyopia (for example, Algaze, Roberts,
Leguire, Schmalbrock, & Rogers, 2002; Anderson &
Swettenham, 2006; Barnes, Hess, Dumoulin, Achtman,
& Pike, 2001; Choi et al., 2001; Conner, Odom, Schwartz,
& Mendola, 2007a, 2007b; Goodyear, Nicolle, Humphrey,
& Menon, 2000; Goodyear, Nicolle, & Menon, 2002;
Hess, Li, Lu, Thompson, & Hansen, 2010; Hess, Li,
Mansouri, Thompson, & Hansen, 2009; Hess, Thompson,
Gole, & Mullen, 2009; Lerner et al., 2006; Li, Dumoulin,
Mansouri, & Hess, 2007; Lv et al., 2008). In general,
studies have revealed an attenuated neural response to
amblyopic eye stimulation within the visual cortex and,
more recently, the lateral geniculate (Hess, Li et al., 2009).
While these ndings are consistent with a cortical suppres-
sion of amblyopic eye inputs, the inference cannot be
made directly. This is because the vast majority of these
studies used monocular stimulus presentation paradigms
whereby the eye not being stimulated was occluded,
therefore minimizing suppression. At least one study,
however, did employ a dichoptic stimulus presentation
paradigm, which allowed for a direct comparison between
monocular viewing with the dominant eye occluded and
dichoptic stimulation with the dominant eye viewing a
uniform mean luminance eld (Conner et al., 2007b).
For one amblyopic participant, foveal suppression was
clearly evident as an absent phase-encoded response to
retinotopic mapping stimuli at the occipital pole during
dichoptic but not monocular stimulation, although it is
unclear whether the absence of a phase map is due to
BOLD attenuation or modication of the BOLD hemody-
namic response function so as to produce a poorer t. As
noted by Conner et al. (2007b), however, mean luminance
is unlikely to drive interocular suppression to the same
extent as viewing a pattern with the dominant eye.
Direct neurophysiological investigations of amblyopic
suppression have been conducted in strabismic cats with
stimuli presented to the amblyopic and dominant eyes
simultaneously (Harrad et al., 1996; Sengpiel & Blakemore,
1996; Sengpiel et al., 1994, 2006). These studies demon-
strate that strabismic suppression is cortical rather than
thalamic and is mediated by GABAergic inhibition of
amblyopic eye ocular dominance columns in the striate
cortex. Particularly strong support for this hypothesis
comes from the nding that the GABA
A
antagonist bicucul-
line greatly reduces the suppression of amblyopic eye
neurons in the primary visual cortex of strabismic cats
(Sengpiel et al., 2006).
Therefore, while there is strong evidence from human
fMRI studies to suggest that the cortical response to
amblyopic eye inputs is reduced under monocular view-
ing, the neural basis of amblyopic suppression in humans
is yet to be elucidated. This is an important issue as
impaired binocularity is a key feature of human amblyopia
(Holmes & Clarke, 2006) and the suppressive effects that
are thought to play a causal role in the development of
amblyopia are, by denition, most evident during binoc-
ular viewing. In this study, we used fMRI to investigate
both the nature of the hemodynamic response function
generated by amblyopic eye stimulation and the effects of
dominant eye stimulation on the response of the early
visual cortex to amblyopic eye stimulation. It has pre-
viously been found that excitatory and inhibitory neural
interactions are represented differently by the blood oxy-
genation level dependent (BOLD) signal that forms the basis
of fMRI measurements (Shmuel, Augath, Oeltermann, &
Logothetis, 2006; Shmuel et al., 2002). We therefore used
an event-related design and measured both the magnitude
and the temporal characteristics of the hemodynamic
response function (HRF) in the early visual cortex. In
Experiment 1, we compared the response of the visual
cortex to stimulation of the amblyopic vs. the dominant eye
when the non-viewing eye was occluded. In Experiment 2,
we then compared this response to stimulation of the
amblyopic eye when the dominant eye was either (1) occluded
or (2) viewing a static pattern under dichoptic viewing
conditions.
Methods
Participants
In total, 11 observers with strabismic amblyopia (6 with
a mixed strabismic/anisometropic etiology) participated in
the experiments. All participants granted informed con-
sent, in accordance with the McGill University Guide-
lines on Research Ethics. A standard clinical workup was
performed on all patients. Their visual acuity was measured
with a Sloan letter chart, their binocular status was assessed
with a synoptophore and cover test, and their fundus was
examined ophthalmoscopically. All subjects were refracted
and wore their best correction. Clinical details of our
participants are given in Table 1.
Stimuli
The visual stimulus used to drive the HRF response
consisted of a ashing spatial frequency fractal noise
pattern covering approximately 26- of visual angle
horizontally and 20- vertically. A Perlin noise algorithm
was used to construct the spatial frequency fractal noise
patterns. The algorithm begins by taking an array of
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 2
values randomly drawn from a uniform distribution and
rescaling the array to the nal image size, using cubic
spline interpolation. Subsequently, larger arrays, with
array sizes dened by powers of two (2
n
, up to image
size that was 1024, or 2
10
), are then constructed in the
same mannerVby drawing from a uniform random
distribution and rescaling to nal image size with cubic
interpolation. Finally, all images are summed and rescaled
to an 8-bit grayscale image and its contrast inverse image.
Such fractal noise patterns have statistics similar to natural
images (Fourier amplitude falls off as a function of 1/f)
and contain a large set of different orientations and spatial
frequencies. They are therefore likely to stimulate neurons
with different feature selectivities (see Supplementary
Figure 1).
The fractal noise pattern was presented at 70% contrast
and cycled at 10 Hz. On each cycle, a new pattern was
displayed, followed by its negative image, which was then
replaced by a new fractal noise pattern. Following each 1-s
stimulation, a rest period of variable duration followed,
with the duration sampled randomly from a normal dis-
tribution (mean = 15 s, SD = 2 s). In the dichoptic viewing
condition of Experiment 2, where only the amblyopic
eye saw the dynamic fractal noise pattern stimulus, the
dominant eye viewed a single static fractal noise pattern
of the same size that never changed. Experimental
presentation was realized using the psychophysics toolbox
(Brainard, 1997; Pelli, 1997) with the stimuli generated
using Matlab (The Mathworks) and the Image Processing
Toolbox.
Design
During all experiments, subjects were asked to xate on
a centrally presented cross and reported conforming to this
instruction. For Experiment 1, participants viewed the
dynamic fractal noise stimulus monocularly while wearing
a tight-tting eye patch over their non-viewing eye. Three
scanning runs, each consisting of twenty-four stimulus
presentation events, were conducted for each eye. When
the dynamic fractal noise pattern was not present, a mean
luminance gray screen with the central xation cross was
presented and the participant was required to maintain
xation.
For Experiment 2, a dichoptic stimulus presentation
system consisting of aligned polarized lters was
employed to achieve full-eld dichoptic presentation with
Obs Age/Sex Type Refraction Acuity Squint History, stereo
ML 20/F RE +1.00.75 90- 20/80 ET 6- Detected at age 5 years, patching for 2 years,
no stereopsis LE mixed j3.25 DS 20/20
GN 30/M RE mixed +5.002.00 120- 20/70 ET 8- Detected at age 5 years, patching for 3 m,
no glasses tolerated, 2 strabismus surgery RE,
no stereopsis, age 1012 years
LE +3.501.00 75- 20/20
PH 33/M RE j2.0 + 0.50 DS 20/25 XT 5- Detected at age 4 years, patching for 6 m, surgery
when he was 5 years, no stereopsis LE strab +0.50 DS 20/63
VD 23/F RE +0.25 20/20 ET 3- Detected at age 56 years, patching for 6 m,
no surgery, no stereopsis LE mixed +2.751.25 175- 20/40
XL 31/F RE j2.50 20/20 ET 15- Detected at age 13 years, no treatment, no stereopsis
LE strab j2.75 + 0.75 110- 20/400
WM 20/M RE K 20/20 XT 1- Detected at age 12 years, no patching, no surgery,
no stereopsis LE strab +1.750.5 180- 20/63
GH 45/M RE j1.75 + 0.5 90- 20/20 ET 6- Detected at 11 years, no surgery, no patching,
eye exercise 12 years, glasses since 12 years,
no stereopsis
LE mixed +1.25 DS 20/63
SS 32/M RE mixed +3.00 20/50 XT 5- No stereopsis
LE +3.00 20/25
AS 25/F RE strab K 20/160 ET 15- Detected at 4 years, strabismus corrected surgically
at 7 years, intermittent patching, no stereopsis LE j0.5 20/25
KS 43/M RE mixed +5.001.00 20/125 ET 4- Detected at 4 years, patching and training for 1 m,
glasses for 1 year. At 15 years, glasses again
for 2.5 years. No stereopsis
LE +0.5 20/25
SH 24/F RE j0.5 90- 20/25 XT 6- Detected at birth, glasses at 67 years, not patched,
no stereopsis LE strab +2.5 + 2 180- 20/63
Table 1. Clinical details of the amblyopic observers participating in the experiments. The following abbreviations have been used: strab for
strabismus, aniso for anisometrope, mixed for mixed strabismicanisometropic, Sq for squint, Obs for observers, RE for right eye, LE for
left eye, ET for esotropia, XT for exotropia, DS for diopter sphere.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 3
no detectable cross talk (Thompson, Farivar, Hansen, &
Hess, 2008). For this experiment, the dynamic event-
related fractal noise pattern was always presented to the
amblyopic eye while the dominant eye was either occluded
with a tight-tting eye patch (condition 1Vminimal
suppression) or viewed a constantly presented static fractal
noise pattern (condition 2Vfull suppression). The exper-
imental design is shown in Figure 1. Since the static
fractal noise pattern was presented constantly to the
dominant eye, we could identify the visual cortex activity
due to the stimulation of the amblyopic eyeVinduced by
the brief dynamic stimulus presented independently to the
amblyopic eyeVby using an event-related design. Three
scanning runs were conducted with the dominant eye
patched and three under dichoptic viewing conditions,
with twenty-four stimulation events presented to the
amblyopic eye per run.
Acquisition and analysis
All measurements were made using a Siemens Sonata
1.5 Tesla MRI scanner with a exible receive surface coil
positioned on the posterior of the head. Following an
anatomical scan (MPRAGE), 415 frames were captured
for each functional run using an EPI sequence (TE = 50 ms,
ip angle = 90-, voxel size = 3 3 4 mm, 64 64 matrix,
TR = 1.0 s, descending acquisition, 11 slices, no slice
gap). The slices were centered on the calcarine and the
FOV covered most of the occipital lobe. Because of the
random length of the interstimulus intervals (see above)
and assuming a linear and time-invariant response func-
tion, we were able to subsample the HRF at a temporal
resolution ner than the TR, thus allowing us to make
estimates of delays that are shorter than the TR itself.
All preprocessing and statistical analyses were per-
formed using SPM2 (http://www.l.ion.ucl.ac.uk). Fol-
lowing slice-time correction by sinc interpolation, all
frames in a session were aligned to the fourth frame in the
rst run. GLM of the canonical HRF convolved with the
stimulus onsets was used to select activated voxels
Figure 1. Schematic description of Experiment 2. Using dichoptic
presentation, we selectively stimulated the amblyopic eye while
the dominant eye was either patched or open and viewing a static
pattern. The top row depicts the binocular viewing condition (high
suppression), where the dominant eye was open but not
stimulated by the ashing stimulusVonly the amblyopic eye was
stimulated with the ashing stimulus. Instead, the dominant eye
simply viewed a static pattern for the entire run. The bottom row
depicts the monocular viewing condition (low suppression) where
the dominant eye was patched for the entire run.
Figure 2. Cortical response to ickering fractal noise pattern in a
typical subject. The gure depicts the cortical response to the
ickering fractal noise pattern in the occipital lobe of a typical subject,
thresholded at p G 0.05, corrected for multiple comparisons.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 4
proximal to the calcarine cortex for subsequent extraction
and analysis. Figure 2 represents an ROI for a sample
subject. Extracted time courses were high-pass ltered and
temporal autocorrelations were modeled with the SPM AR
(1) model. Average HRFs were estimated for each run
using nite impulse response lters with 0.5-s bins. This
deconvolved HRF was subsequently tted as the differ-
ence of two gamma functions using the Curve Fitting
Toolbox in Matlab (Mathworks). Each gamma function
has three parameters for amplitude, width, and time to
peak. While many fMRI analysis packages make use of
only one gamma function, two gamma functions have
been found to better t the HRF, particularly the HRF
undershoot (Friston et al., 1998). Here, we took the time-
to-peak estimate of the rst gamma function as the
measure of HRF delay for the inferential statistical tests.
Results
Experiment 1: Monocular viewing, amblyopic
eye vs. dominant eye
The HRFs for amblyopic eye and dominant eye stim-
ulation under monocular viewing conditions are shown in
Figure 3. While the magnitude of the effects varied across
participants, two main differences in the HRFs between
the two eyes were apparent. First, the response of the
amblyopic eye to our high-contrast, briey presented
dynamic stimulus was signicantly reduced compared to
the response of the dominant eye (t(5) = 2.62, p G 0.03).
This is consistent with previous fMRI studies of amblyo-
pia (see Introduction section for sample references). The
novel nding was that the HRF of the amblyopic eye was
delayed by an average of 500 ms compared to the
response of the dominant eye. This delay was reliable
across subjects (F(1,10) = 8.372, p G 0.034) and did not
differ across sessions (F(2,10) = 0.47, p 9 0.95) and there
was no session by eye interaction (F(2,10) = 0.055, p 9 0.9).
To measure correlation of HRF delays and amplitudes and
visual acuity, we converted acuity measures to logMAR
values. We excluded the results from one participant
because the individuals acuity was more than 2 standard
deviations from the group average. The HRF delay
measured here correlated strongly and negatively with
logMARacuity difference of the dominant vs. amblyopic eye
(r = 0.91) and the relationship was signicant (p G 0.03)V
the worse the acuity in the amblyopic eye, the greater the
delay in the response of that eye. In addition, the
correlation between the relative amplitude of the HRF
(amblyopic eye amplitude/dominant eye amplitude) and
relative acuity was also strong and signicant (r = 0.96,
Figure 3. Results from monocular stimulation of the amblyopic and dominant eyes. The red line depicts response of the amblyopic eye to
a 1-s ickering fractal pattern of 70% contrast, while the blue line represents the response of the dominant eye to the same stimulus. Each
panel depicts responses from one subject. In this experiment, the stimulation was always monocularVthe unstimulated eye was patched.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 5
p G 0.01; Figure 4). Without the exclusion of the one
outliers results, the correlation between HRF delay
and logMAR acuity difference remained signicant
(r = 0.81, p G 0.05), while the correlation between HRF
amplitude and logMAR acuity failed to reach signi-
cance (r = 0.01).
Experiment 2: Dichoptic viewing, dominant
eye patched vs. dominant viewing a static
stimulus
In Experiment 2, the amblyopic eye was presented
with the event-related ashing fractal noise stimulus
while the dominant eye was either occluded (minimal
suppression) or viewing a static, constant fractal noise
pattern (suppression; see Figure 1). Across the nine
subjects we tested, a comparison between the HRFs
generated by amblyopic eye stimulation under low or
high suppression conditions revealed that when the
dominant eye was open and seeing a static pattern, the
HRF response in the amblyopic eye was not only
signicantly lower in amplitude relative to when the
dominant eye was patched (21% lower, t(8) = 3.637, p G
0.003) but was also signicantly delayed (mean delay =
0.670 s, t(8) = 2.525, p G 0.017). The correlation between
the amplitude reduction and delay was weak (r = 0.05,
p 9 0.9). Figure 5 presents individual data from the nine
subjects who took part in the second experiment. Surpris-
ingly, the suppression-induced delay and amplitude
reduction observed here did not correlate with interocular
acuity difference (Figure 6), suggesting that the neural
suppression measured using fMRI and relative acuity
differences observed in amblyopia are separable factors.
Exclusion of outliers had no effect on the strength or
signicance of these correlations.
Discussion
We measured the event-related HRF in the early visual
cortex of observers with strabismic amblyopia under both
monocular and dichoptic viewing conditions in order to
assess the effect of interocular suppression on cortical
responses. When the amblyopic and dominant eyes were
compared under monocular presentation conditions (non-
tested eye occluded, Experiment 1), we found that the
response of the amblyopic eye was both reduced in
amplitude and delayed in time relative to the dominant
eye. The reduced amplitude is consistent with previous
studies of amblyopia using fMRI and is indicative of a
cortical loss of function (Algaze et al., 2002; Anderson &
Swettenham, 2006; Barnes et al., 2001; Choi et al., 2001;
Conner et al., 2007a, 2007b; Goodyear et al., 2000, 2002;
Hess et al., 2010; Hess, Li et al., 2009; Hess, Thompson
et al., 2009; Lerner et al., 2006; Li et al., 2007; Lv et al.,
2008). The temporal delay in the amblyopic eye response
is novel and may be indicative of chronic suppression of
the ocular dominance columns representing the amblyopic
eye even under monocular viewing conditions. To further
explore this temporal delay and its relationship to
suppression, we compared the cortical response to
amblyopic eye stimulation when the dominant eye was
occluded to a condition where the dominant eye was open
and viewed a static pattern. Presenting a static stimulus to
Figure 4. Scatter plots of the HRF delay and relative percent signal change compared to relative acuity. This gure shows the
relationship between delay of HRF in response to amblyopic eye stimulation and relative acuity (logMAR
dominant
j logMAR
amblyopic
,
negative values signify lower acuity in the amblyopic eye) and the relationship between the relative percent signal change (amblyopic eye
response/dominant eye response) and relative acuity. Data shown are with the outlier excluded. Without the exclusion of the outlier, the
relationship between relative amplitude and logMAR acuity difference fails to reach signicance, but the relationship between HRF delay
and acuity remains signicant.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 6
the dominant eye caused both a reduction in the
magnitude of the amblyopic eye response and a signicant
delay in the time to peak of the response, suggesting that
suppressive interactions underlie both of these effects.
It would appear therefore that the signature of
amblyopic suppression, as detected with fMRI, is an
attenuated and delayed BOLD response. What does this
tell us about the underlying neural mechanisms? Although
our data do not allow for a conclusive answer to this
question, in the following section, we propose a possible
explanation for these effects.
Local summation of positive and negative
BOLD
One possibility for the delay observed in our two
experiments is the summation of two opposing BOLD
responses: one negative BOLD response representing
local neural inhibition and one positive BOLD response
representing neural activation (Figure 7). While negative
and positive BOLD are likely extremes of a continuum of
possible BOLD responses, for the sake of discussion, it
may be helpful to consider them as separate. Specically,
Figure 5. Hemodynamic responses of visual stimulation of the amblyopic eye under conditions of low and high suppression. Both red and
blue lines depict stimulation of the amblyopic eye but under conditions of high suppression (red line) and low suppression (blue line).
Suppression by means of static visual stimulation of the dominant eye increased the delay and further reduced the amplitude of the HRF
resulting from amblyopic eye stimulation. Each panel depicts the responses of one subject.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 7
we speculate that under conditions of high suppression,
increases in inhibition within a given voxel bring about an
increase in the negative BOLD amplitude. Given the
shape and timing of the two BOLD functions as described
recently (Shmuel et al., 2006), this negative response
summed with the positive BOLD response from within
that same voxel would give rise to an appearance of a
delayed response (see Supplementary Figure 2).
In the second experiment, we only stimulated the
amblyopic eye. By way of a dichoptic stimulation setup,
we were able to selectively stimulate the amblyopic eye
while the dominant eye either viewed a static random
pattern or was patched (no stimulation). Given the
constant suppression of the amblyopic eye by the
dominant eye, if columns representing the amblyopic eye
were to respond to stimulation under this ongoing
suppression, they would need to countersuppress the
dominant eye columnsVin other words, they would have
to suppress their suppressor. This would bring about a
reduction in neural activity in the dominant eye columns
and, thus, a negative BOLD response. Future studies with
high-resolution functional imaging may allow us to test
such a model directly.
Another possibility is that negative BOLD is induced in
some voxels while positive BOLD is observed in others,
and the ratio of these changes is a result of suppression.
However, the number of voxels exhibiting negative beta
values (as estimated by the canonical HRF) in the high
suppression condition did not differ substantially with that
observed in the low suppression condition. Yet the
possibility remains that negative BOLD may be exhibited
in cortical patches larger than a column but smaller than
our voxels during high binocular suppression. This may
need to be assessed in future studies. Another alternative
explanation is that a neural delay underlies the HRF delay,
or neural modulation by the lateral geniculate nucleus of
the thalamus is the source of the HRF delay. We nd the
argument for a neural delay unlikely, given the fact that
the neurons in early visual areas have very short response
latencies. Thus, even in the presence of inhibitory inputs,
it is unlikely that neurons delayed their responses by the
amount observed in the HRF delay. While we believe that
the HRF delay is due primarily to suppressive activity in
the early visual cortex, it is possible and even likely that
such a suppression arises from recurrent modulation
between early visual areas and the LGN. Thus, while we
do not believe that the LGN is the source of the HRF
delay observed due to the argument against a neural delay,
we do not exclude the possibility that the LGN plays an
important role in the suppressive processes carried out in
the early visual cortex.
The results of Experiment 1 could also be explained in
the context of physiological changes brought on by
chronic suppression. It is conceivable that chronic
suppression of amblyopic eye representations by that of
the dominant eye over a lifetime resulted in degeneration
of neurons, reduced synapses, or reduced capillary
density. Such changes would then contribute to a differ-
ence in HRF of the amblyopic eye as opposed to the
dominant eye. However, these putative changes would not
explain the results of Experiment 2, where all stimulation
was in the amblyopic eye.
Finally, it is possible that the HRF delay is not related to
a neural difference but simply a difference in the vascular
response. Given that BOLD is an indirect measure of
neural function and foremost a measure of blood oxygen-
ation, ow, and volume, the possibility may exist that the
neural response to amblyopic eye stimulation is left intact,
but the vascular response is affected, hence the affected
HRF. While we have no direct electrophysiological
evidence to test this possibility, patients do report
suppression of vision in their amblyopic eye when their
Figure 6. Scatter plots of percent signal change difference and delay in Experiment 2 compared to relative acuity. Relative magnitude here
is dened as the ratio of response to the binocular condition over the monocular condition (i.e., high suppression/low suppression). The
magnitude and delay differences seen in Experiment 2 cannot be explained by relative acuity of the amblyopic eye compared to the
dominant eye. Thus, reduced acuity and suppression of vision in the amblyopic eye may have different sources.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 8
dominant eye is open, suggesting that our measure-
ments are at least correlated with the subjective effects of
suppression.
Variability in amblyopia and comparison
with normals
Our results point to a link between cortical suppression
and the hemodynamic delay as observed in BOLD fMRI.
The data from the second experiment demonstrate a
simple paradigm within which such suppressive mecha-
nisms may be measured. Amblyopic suppression has
been studied previously in animal models and appears to
be mediated by GABAergic mechanisms (Sengpiel &
Blakemore, 1994; Sengpiel et al., 1994, 2006). A short-
coming of our study is that we were unable to visualize
ocular dominance columns to directly assess our proposed
model, given the limitations of current MRI technology.
While we anticipate similar results in normal subjects
under conditions of binocular suppression (e.g., continuous
ash suppression, Tsuchiya &Koch, 2005), it is not known
whether such a putative effect in normal subjects could be
equally well ascribed to local suppressive mechanisms.
While a delay was not observed in every participant of
Experiment 2, none showed the reverse effectVi.e., the
results are not explicable as a random observation around
a mean of zero delay. The variability of suppression
Figure 7. Schematic model of negative and positive BOLD summation as an index of neural activity and inhibition. Column (a) represents
a voxel containing ocular dominance columns, with red columns responsive to the amblyopic eye and white columns responsive to the
dominant eye. According to this view, the columns representing vision in the amblyopic eye are persistently suppressed by the columns
representing the dominant eye. Thus, when the dominant eye is patched, the amblyopic eye columns (AECs) need less inhibition of the
dominant eye columns (NECs) to represent the visual stimulus. This results in corresponding positive BOLD signals for the AECs and
small negative BOLD signals for the NECs. However, when the dominant eye is open, the AECs must overcome a greater amount of
suppression by a correspondingly large inhibition of the NECs. This enhanced inhibition of the NECs manifests itself as a stronger
negative BOLD signal. These signals are represented in column (b). When the negative and positive signals from the two sets of columns
are linearly added, the result is an apparently delayed hemodynamic response function, as depicted by the red lines in the gures of
column (c). Thus, the delay in the measured response may serve as an index of neural inhibition.
Journal of Vision (2011) 11(14):16, 112 Farivar, Thompson, Mansouri, & Hess 9
within the amblyopic population is known (Jampolsky,
1955; Travers, 1938) and also seen in fMRI (e.g., Conner
et al., 2007b). For example, even in the patients with the
same type of strabismus, there is a degree of variability in
the density of the suppression. This is as true for small
angle strabismics (Joosse et al., 1997) as it is for large
angle strabismics (Joosse, Simonsz, van Minderhout,
Mulder, & de Jong, 1999). It is thought that the age at
which the strabismus rst occurs may be the critical
factor. A future objective will be to assess the correlation
between the degree of suppression (Mansouri et al.,
2008) and the amount of HRF delay in the amblyopic
population.
Implications for fMRI studies of amblyopia
Our results have important implications for future fMRI
studies of amblyopia, particularly those using event-
related designs. Specically, the present ndings suggest
that using the canonical HRF in the analysis of fMRI data
in studies of amblyopia (i.e., studies comparing cortical
responses to normal as compared to amblyopic eye) is
intrinsically biased against nding activations in
response to amblyopic eye stimulation, particularly if
measured under dichoptic viewing conditions (e.g., Lerner
et al., 2003). It follows that reduced t-contrasts in
comparisons of normal to amblyopic eye responses may
be due to a mismatch between the canonical HRF and the
amblyopic eye HRF. Future studies should try and mitigate
this difference by either estimating HRFs for the dominant
and normal eyes independently or by employing correc-
tion terms such as the HRF temporal derivatives.
The correlation of relative acuity and HRF delay as
observed in Experiment 1 and its absence in Experiment 2
suggest that some of the effects observed in Experiment 1
are due to differences between the sensory capacities of
the amblyopic and dominant eyes. Experiment 1 did not
control for differences in visual acuity or contrast sensi-
tivity. Therefore, some of the differences seen between the
response of the dominant eye and the amblyopic eye may
have been due to these uncontrolled factors. In contrast,
responses measured in Experiment 2 are always to
stimulation of the amblyopic eye, thus relative acuity
between the two eyes would not be a strong predictor of
performance, unless the opening or closing of the dominant
eye were to have a direct inuence on the acuity of the
amblyopic eye.
In summary, we observed a difference in the HRF
amplitude and delay when the amblyopic and dominant
eyes were stimulated monocularly. We then observed that
the response in the amblyopic eye can be reduced and
delayed as a function of suppression by the dominant eye.
Our results have important methodological implications
for future fMRI studies of visual processing in amblyopia
and also lead to an interesting possibility for the source of
the HRF delay as observed in many fMRI studiesVthat
the HRF delay may serve as an index of local suppression.
Future studies employing higher resolution imaging
methods are needed to directly test this possibility.
Acknowledgments
This research was supported by an operating grant from
the Canadian Institutes of Health Research (MOP-53346)
to Robert F. Hess.
Commercial relationships: none.
Corresponding author: Reza Farivar.
Email: farivar@nmr.mgh.harvard.edu.
Address: Athinoula A. Martinos Center for Biomedical
Imaging, Department of Radiology, Massachusetts General
Hospital, 149 13th Street, Charlestown, MA, USA.
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