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The Journal of Neuroscience, August 15, 1998, 18(16):6411-6424
Neuronal Correlates of Amblyopia in the Visual Cortex of Macaque
Monkeys with Experimental Strabismus and Anisometropia
Lynne
Kiorpes1,
Daniel
C.
Kiper2,
Lawrence P.
O'Keefe1,
James R.
Cavanaugh1, and
J. Anthony
Movshon2
1 Center for Neural Science and 2 Howard
Hughes Medical Institute, New York University, New York, New York 10003
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ABSTRACT |
Amblyopia is a developmental disorder of pattern vision. After
surgical creation of esotropic strabismus in the first weeks of life or
after wearing  10 diopter contact lenses in one eye to simulate
anisometropia during the first months of life, macaques often develop
amblyopia. We studied the response properties of visual cortex neurons
in six amblyopic macaques; three monkeys were anisometropic, and three
were strabismic.
In all monkeys, cortical binocularity was reduced. In anisometropes,
the amblyopic eye influenced a relatively small proportion of cortical
neurons; in strabismics, the influence of the two eyes was more
nearly equal. The severity of amblyopia was related to the relative
strength of the input of the amblyopic eye to the cortex only for the
more seriously affected amblyopes.
Measurements of the spatial frequency tuning and contrast sensitivity
of cortical neurons showed few differences between the eyes for the
three less severe amblyopes (two strabismic and one anisometropic). In
the three more severely affected animals (one strabismic and two
anisometropic), the optimal spatial frequency and spatial resolution of
cortical neurons driven by the amblyopic eye were substantially and
significantly lower than for neurons driven by the nonamblyopic eye.
There were no reliable differences in neuronal contrast sensitivity
between the eyes. A sample of neurons recorded from cortex representing
the peripheral visual field showed no interocular differences,
suggesting that the effects of amblyopia were more pronounced in
portions of the cortex subserving foveal vision.
Qualitatively, abnormalities in both the eye dominance and spatial
properties of visual cortex neurons were related on a case-by-case basis to the depth of amblyopia. Quantitative analysis suggests, however, that these abnormalities alone do not explain the full range
of visual deficits in amblyopia. Studies of extrastriate cortical areas
may uncover further abnormalities that explain these deficits.
Key words:
visual development; visual cortex; amblyopia; anisometropia; strabismus; macaque monkeys
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INTRODUCTION |
Visual function in adulthood depends
on an individual's visual experience in infancy. The work of Wiesel
and Hubel (1963 , 1965) established that the first stage of visual
processing affected by visual experience is in the primary visual
cortex, and a large body of subsequent work has shown that various
forms of anomalous visual experience modify the development of the
functional properties and architecture of cortical neurons (for review,
see Movshon and Van Sluyters, 1981; Movshon and Kiorpes, 1990). It is
no surprise that changes in visual cortical function are associated
with changes in visual performance assessed in behavioral tasks (for
review, see Kiorpes and Movshon, 1990).
Following Wiesel and Hubel, most work on the effect of visual
experience on development has concentrated on the effects of complete
or partial deprivation of visual input, which leads to more or less
wholesale loss of effective inputs from the deprived eye to neurons in
the visual cortex. Such deprivation is rare in humans, who more
commonly experience abnormal early vision as a result of either
strabismus (a misalignment of the visual axes that prevents concordant
stimulation of binocularly corresponding points in the two retinas) or
anisometropia (a difference in refractive state between the eyes that
leads one retinal image always to be blurred). These two conditions are
strongly associated with the development of amblyopia, a reduction in
visual acuity without an obvious organic cause. Amblyopia is
characterized by a constellation of deficits in spatial vision, as
indexed by visual acuity, spatial contrast sensitivity, and other tasks
(for review, see Von Noorden, 1980; Levi and Carkeet, 1993). Some
reports on humans suggest that anisometropia and strabismus lead to
different forms of amblyopia, although this is by no means a universal
finding (Hess et al., 1978; Levi and Klein, 1982; McKee et al., 1992;
Movshon et al., 1996). In recent years, we and others have studied the
characteristics of amblyopia in macaque monkeys raised with
artificially created forms of strabismus and anisometropia.
Psychophysical studies show that the amblyopia that follows this
rearing closely resembles the condition described in humans (Harwerth
et al., 1983; Smith et al., 1985; Kiorpes et al., 1987; 1989;
Kiorpes and Movshon, 1996).
The neural basis of amblyopia has been less thoroughly explored.
Changes in the degree of binocular interaction have been documented in
amblyopic monkeys (e.g., Movshon et al., 1987; Crawford et al.,
1996; Smith et al., 1997), but it seems unlikely that changes in
binocular interaction alone can explain the abnormalities of amblyopic
vision. There is also a substantial, although inconsistent, literature
on developmental visual abnormalities in cats, but this literature is
of uncertain value for understanding amblyopia, because it is not clear
that cats develop the condition as primates do (for review, see Movshon
and Kiorpes, 1990; Daw, 1995).
We have shown previously that the amblyopia that follows one particular
form of abnormal early experience, unilateral blur created by atropine
instillation, is associated with a pattern of physiological and
anatomical changes in visual cortex quite different from that seen
following monocular deprivation. Instead of a wholesale loss of
input, we found changes in the function and architecture of the
visual cortex that were more subtle, suggesting a selective
rearrangement, but not a complete loss, of effective inputs from the
amblyopic eye (Hendrickson et al., 1987; Movshon et al., 1987).
The interpretation of these results is complicated, because unilateral
atropine instillation is a relatively uncontrolled technique for
modifying early visual experience. We have therefore raised and studied
two new groups of experimentally amblyopic monkeys. To simulate
strabismus, we misaligned the visual axes by surgical modification of
the extraocular muscles. To simulate anisometropia, we used
extended-wear contact lenses with different powers in the two eyes.
Just as humans vary in their response to early visual abnormalities, so
do monkeys. In this paper, we report the effects of these two rearing
regimens in a selected group of animals in whom the rearing created a
relatively modest visual loss in the amblyopic eye. Our results show
that this amblyopia is usually associated with deleterious changes in
the spatial properties of neurons driven by the amblyopic eye in the
visual cortex, and in some cases, also with a loss of effective inputs from the amblyopic eye. These changes are associated, on an
animal-by-animal basis, with the depth of amblyopia. We did not observe
distinctively different results in neuronal properties or visual
behavior between the strabismic and anisometropic animals.
Quantitatively, the changes in cortical neuron properties are smaller
than those seen behaviorally, suggesting that the neural basis of
amblyopia begins, but does not end, in the primary visual cortex.
In addition to previous publications of some of the behavioral
data (specifically noted below), a brief report of some of these
physiological results has appeared previously (Kiorpes and Movshon,
1996).
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MATERIALS AND METHODS |
Subjects. Six amblyopic pig-tailed macaques,
Macaca nemestrina, were used in this study. They were
hand-raised from infancy in our primate nursery or in the nursery of
the Washington Regional Primate Center, where they were born. Three
monkeys were raised with unilateral esotropia, and three were raised
with unilateral defocus. These six animals were selected for this study
from larger groups of strabismic and anisometropic animals on the basis
of their degree of amblyopia. Data from three other strabismic monkeys that belong to another study (Fenstemaker et al., 1997) are briefly presented in Figure 3. Control data were obtained from eight monkeys raised normally. Care of the animals was provided in accordance with
established approved protocols, which conform to the NIH Guide
for the Care and Use of Laboratory Animals. Experimental histories
for the monkeys are presented in Table 1,
in which onset age corresponds to the age at which the experimental
condition was begun. Refractive data from some of these animals have
been presented elsewhere (Kiorpes et al., 1989; Kiorpes and
Wallman, 1995).
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Table 1.
The experimental subjects, treatment histories,
psychophysical and physiological parameters, and significance of
differences
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Experimental strabismus. Esotropia was induced by
transection of the lateral rectus muscle and resection of the medial
rectus muscle of the left eye. The medial rectus was, in addition,
advanced to the limbus. Surgery was performed under
ketamine-hydrochloride sedation using sterile surgical techniques. The
resulting esotropia was typically moderate, ranging from 10 to 25 prism
diopters estimated by the Hirschberg method from photographs; this
method is accurate to 5 prism diopters (see Kiorpes et al.,
1989).
Experimental anisometropia. Anisometropia was simulated by
inserting a 10 diopter extended-wear soft contact lens in the right
eye and inserting a zero-power lens in the left (Kiorpes et al., 1993).
The monkey wore the lenses beginning 10-25 d after birth for 7-10
months. The status and condition of the lenses were checked frequently
through each day; missing lenses were infrequent and were replaced
immediately. The lenses were routinely changed and cleaned weekly.
Regular ophthalmic examinations were performed to ensure the health of
the eyes. Eye alignment was evaluated casually by inspection daily and
by the Hirschberg method twice during rearing. No strabismus was
obvious during the rearing period in any of the lens-reared animals;
however, we would not have detected a tropia or phoria of <5 prism
diopters. One animal (monkey LF) developed a large exotropia following
the rearing period.
Behavioral testing
The animals were trained to perform an operant two-alternative
forced-choice discrimination task. Our training and testing procedures
used have been detailed previously (Williams et al., 1981; Kiorpes,
1992a; Kiorpes et al., 1993). The animals were placed in a testing cage
from which they viewed the stimuli and responded by pulling one of two
grab bars located within their reach. The monkeys were rewarded with
0.25 cc of apple juice for correct discriminations; errors were
followed by a time-out period, usually 5-10 sec in duration, that was
signaled by a tone. Each eye was tested independently for each animal.
Optical correction was provided as needed based on behaviorally
established best refraction (Kiorpes and Boothe, 1984). The
animals were all visually mature at the time the measurements reported
in this paper were made; age at test ranged from 1 to 7 years. We began
operant visual assessments between 6 months and 1 year; in some cases,
testing on a variety of visual spatial tasks detailed elsewhere
continued for many years thereafter (for additional behavioral data,
see Kiorpes et al., 1989, 1993; Kiper, 1994; Kiper and Kiorpes, 1994; Kiper et al., 1995).
To measure spatial contrast sensitivity, sinusoidal gratings were
generated under computer control on one of two types of display
systems. One system consisted of a pair of Joyce Electronics DM-2
displays (white phosphor) controlled by a PDP-11 computer. The
luminance of the displays was 250 cd/m2. Each screen
was visible through a circular aperture that subtended 6-12°
depending on the viewing distance, which ranged from 0.9 to 1.8 m
depending on the animal's visual acuity. The other system consisted of
a Mitsubishi Diamondscan HL6605 (mean luminance, 60 cd/m2) controlled by a personal computer with a
Vista graphics board (True Vision, Inc.). The monitor screen
subtended 12-40° depending on the viewing distance, which ranged
from 0.5 to 2 m. The stimuli in this case were patches of
sinusoidal grating vignetted by a two-dimensional spatial Gaussian ( value, 0.75°, except for very low spatial frequencies in which was increased to keep at least three grating cycles visible).
The animal's task was to discriminate the grating from a homogeneous
field matched in space-average luminance; the stimuli were displayed
steadily for as long as the animal wished on any given trial. For most
contrast sensitivity functions, five contrast values for each of four
to six spatial frequencies were presented in pseudorandom order. Each
contrast sensitivity estimate is based on at least 40 trials per
stimulus condition. Threshold was defined as the contrast-supporting
discrimination by the subject at the 75% correct level. Threshold
values and SEs of estimate were obtained by probit analysis of the log
transformed data sets (Finney, 1971) using a maximum likelihood fitting
technique.
Electrophysiological recording
Surgical preparation and maintenance. Animals were
prepared for acute single-unit recording using methods we have
described in detail elsewhere (Levitt et al., 1994); age at recording
ranged from 8 to 11 years. They were premedicated with atropine (0.25 mg) and acepromazine (0.05 mg/kg) or diazepam (Valium; 0.5 mg/kg). After induction of anesthesia with intramuscular injections of ketamine
HCl (Vetalar; 10-30 mg/kg), cannulas were inserted into the
trachea and the saphenous veins, the animal's head was fixed in a
stereotaxic frame, and surgery was completed under intravenous anesthesia with sufentanil citrate (Sufenta; 4-8 µg/kg/hr). Infusion of the surgical anesthetic continued throughout the recordings.
To minimize eye movements during recording, paralysis was maintained
with an infusion of pancuronium bromide (Pavulon; 0.1 mg/kg/hr) or
vecuronium bromide (Norcuron; 0.1 mg/kg/hr) in lactated Ringer's
solution with dextrose (5-20 ml/hr). Animals were artificially ventilated with room air or a mixture of 50-70% N2O in
O2. Peak-expired CO2 was maintained near 4% by
adjusting the tidal volume of the ventilator. Rectal temperature was
kept near 37°C with a thermostatically controlled heating pad.
Animals received daily injections of a broad-spectrum antibiotic
(Bicillin; 300,000 units) to prevent infection, as well as
dexamethasone (Decadron; 0.5 mg/kg) to prevent cerebral edema.
Electrocardiogram, EEG, autonomic signs, and rectal temperature were
monitored continuously to ensure the adequacy of anesthesia and the
soundness of the animal's physiological condition.
Physiological optics. The pupils were dilated and
accommodation was paralyzed with topical atropine, and the corneas were protected with +2 diopter gas-permeable hard contact lenses. When necessary, supplementary lenses were chosen by direct ophthalmoscopy to
make the retinas conjugate with the display screen. The power of the
lenses was then adjusted as necessary to optimize the visual responses
of recorded units. At least once a day, the locations of the foveas
were recorded using a reversible ophthalmoscope.
Recording. Tungsten-in-glass microelectrodes (Merrill and
Ainsworth, 1972) were introduced vertically by a hydraulic microdrive into the primary visual cortex through a small craniotomy and durotomy.
Electrodes were angled tangentially to the cortical surface to sample
from several eye-dominance columns. Most recordings were made from the
foveal portion of V1. In one animal, additional recordings were made
from portions of V1 representing the peripheral visual field 15-25°
from the fovea. In a second animal, additional recordings were made
from foveal portions of V2. After the electrode was in place in the
cortex, the exposed dura was covered with warm agar. Action potentials
were conventionally amplified, displayed, and played over an
audiomonitor.
To provide reasonably even and unbiased sampling of the distribution of
cortical neuron properties, we used methods adapted from those of
Stryker and Sherk (1975). After recording a neuron, we moved the
electrode at least 50 µm before accepting another unit for analysis.
If we failed to isolate a unit within 100 µm of the previous
recording site, we recorded the properties of the unresolved multiunit
background activity; this was necessary at between 5% and 10% of the
recording sites in each experiment.
Characterization of receptive fields. We initially mapped
receptive fields by hand on a tangent screen using black and white geometric targets. We drew the location and size of the minimum response fields of the neuron and determined its selectivity for the
orientation, direction of motion, and size of stimuli. Ocular dominance
was assessed qualitatively using the seven-point scale of Hubel and
Wiesel (1962). Units were classified as ocular dominance group 4 if we
could not distinguish any difference between the responses to
stimulation of the two eyes. They were classified as groups 3 or 5 if
they responded well to both eyes but with a discernible preference for
the contralateral or ipsilateral eye, respectively, classified as
groups 2 or 6 if they responded predominantly to the contralateral or
ipsilateral eye with a weak response to the other eye, and classified
as groups 1 or 7 if they responded only to the contralateral or
ipsilateral eye.
We then used a mirror to place the receptive field of the preferred eye
on the face of a display monitor (Barco 7351 or Nanao T560i;
frame rate, 107 Hz) that subtended 10° at the animal's eye; for some
strongly binocular units, we studied the two eyes separately.
Achromatic sinusoidal gratings with a mean luminance between 40 and 80 cd/m2 were generated on this display by a computer.
For most neurons, we determined neuronal selectivity for the
orientation, direction, spatial frequency, temporal frequency, and
contrast of continuously presented drifting gratings by adjusting these
parameters while listening to the discharge over the audiomonitor. This
gave estimates of the preferred orientation and direction, the
bandwidth of orientation selectivity, the preferred and high-cutoff
spatial frequency, and the preferred and high-cutoff temporal
frequency; we also estimated contrast threshold using targets optimized
for the other parameters. For approximately one-fifth of the neurons,
we also assessed these tuning parameters quantitatively using methods described elsewhere (Levitt et al., 1994).
Reconstruction of recording sites. During recording, small
electrolytic lesions were produced at locations of interest along the
electrode tracks by passing DC current (2 µA for 2-5 sec, tip
negative) through the electrode. At the end of the experiment, the
animals were killed with an overdose of Nembutal and perfused through
the heart with 2 l of 0.1 M PBS, followed by
2 l of a solution containing 4% paraformaldehyde in 0.1 M PBS. The first liter of the fixative contained 4%
sucrose, and the second liter had 12% sucrose added. Blocks containing
the region of interest were stored overnight in the cold in a post-fix
solution of 4% paraformaldehyde plus 30% sucrose, after which
40-µm-thick sections were cut on a freezing microtome. Sections were
stained for Nissl substance with cresyl violet. In most cases, we were
able to reconstruct the course of the electrode penetration with
sufficient confidence to assign the recorded units to either the
supragranular, granular, or infragranular layers of the cortex.
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RESULTS |
Psychophysical observations
Figure 1 shows spatial contrast
sensitivity functions for a normal monkey (Fig. 1A)
and for the six experimental monkeys (Fig. 1B,C). The data for each eye are
well described by the double-exponential function
in which  is spatial frequency, S is
contrast sensitivity, and a, b, and c
are fitted parameters. In the normal monkey, contrast sensitivity was
very similar in the two eyes. In the amblyopic monkeys, both contrast
sensitivity (the peak height of the function) and spatial scale (its
position on the abscissa) were reduced. Table 1 shows the values of
peak contrast sensitivity and of the spatial frequency at which the
peak occurred, as well as the spatial resolution deduced from the
high-frequency intercept of the function with a sensitivity of 1. We
also calculated a dimensionless amblyopia index by taking the area
between the fitted contrast sensitivity function for the treated eye
and the function for the untreated eye and dividing it by the area
under the function for the untreated eye; this index ranges from 0 (no
deficit) to 1 (no measurable sensitivity in the treated eye) and
captures losses in both contrast sensitivity and spatial resolution.
The value of the index for each monkey is printed at the bottom
left of each panel in Figure 1. The severity of the amblyopia for
the experimental monkeys varied somewhat from animal to animal but fell
within the range that we and others have reported (Harwerth et al.,
1983; Smith et al., 1985; Kiorpes, 1992b). Within Figure 1,
B and C, the animals are shown in order of the
severity of their amblyopia at the most recent test age. Figure
2 plots the severity of amblyopia as the
amblyopia index for each of these monkeys at all ages for which we have
data. Filled symbols in Figure 2 indicate strabismic
monkeys, open symbols indicate anisometropic monkeys, and
solid lines connect repeated measures for the same monkey.
The extent of amblyopia in this group was relatively stable over time
despite variations in test stimuli and luminance; this is consistent
with our data in other amblyopic animals. Note that monkeys GH, HC, FT,
and FP were tested extensively between the initial and final contrast
sensitivity measurement, suggesting that concentrated psychophysical
experience does not diminish the amblyopia. Figure 2 also indicates the
age at recording for each animal. The isolated symbols to
the right of Figure 2 are plotted at the recording age; the
y-axis positions for these points are the amblyopia index
values from Figure 1.
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Figure 1.
Spatial contrast sensitivity functions for a
normally reared control monkey (A) and for six
amblyopic monkeys (B, C). In each panel,
data from the nonamblyopic eye are represented by filled
symbols, and data from the amblyopic eye are represented by
open symbols. The smooth curves represent the function
described in the text; these curves were used to estimate the optimal
spatial frequency, peak contrast sensitivity, and spatial resolution
(the spatial frequency at which extrapolated sensitivity falls to 1).
The number at the bottom left of each
panel is the value of an amblyopia index, calculated by taking the area
between the two fitted functions (plotted on linear frequency and
logarithmic sensitivity coordinates) and dividing it by the area under
the function for the nonamblyopic eye. The data shown for LF and OC
were collected at a luminance of 250 cd/m2; the
other data were collected at 60 cd/m2.
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Figure 2.
Amblyopia index as a function of age for the six
amblyopic monkeys. Each monkey is represented by a different symbol
(filled, strabismics; open,
anisometropes); points connected by solid lines are
repeated measures for the same monkey. Isolated points
on the right show the age at recording for each animal;
the amblyopia indices for these points are those shown in Figure 1,
which are from the age closest to recording.
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The ranges of severity of amblyopia for the two treatment groups
overlap, although the anisometropic subjects were on average more
severely affected than the strabismics. The two least amblyopic animals
were both strabismic (GH and HC); the most amblyopic animal was
anisometropic (OC). In other cases, we have observed a wide range of
severity in the amblyopia that develops following strabismus or
anisometropia, so these data do not represent the full range of effects
seen (Kiorpes, 1992b; Kiorpes et al., 1993). Because of this wide
variation in response to similar rearing treatments, we elected to
include in this study only those animals showing a reliable amblyopic
deficit that was not so profound that the animals were unable to
perform all of our routine psychophysical tasks. We have briefly
reported elsewhere on some cortical data from a group of more severely
affected strabismic animals (Fenstemaker et al., 1997); the relevant
portions of this data set will be discussed briefly below.
Neurophysiological observations
We studied the responses of 751 isolated neurons and 46 multiunit
sites in the six experimental monkeys. In the strabismic animals, we
made recordings in both hemispheres of each animal; in the
anisometropic animals, we recorded only in the hemisphere contralateral
to the treated eye. Because there were no important differences between
data obtained from the two hemispheres, we have pooled the results.
In general, cortical activity was brisk and reliable, with most units
responding well and exhibiting approximately normal degrees of stimulus
selectivity. The majority of our recordings were made from the
supragranular layers of the cortex, but we did not notice any
particular tendency for units in any layer to be different in their
response to strabismus or anisometropia.
Eye dominance
In agreement with previous reports (e.g., Crawford and Von
Noorden, 1979; Wiesel, 1982), we found that strabismus virtually eliminated excitatory binocular convergence onto visual cortical neurons. Perhaps unexpectedly, binocularity was also sharply reduced by
anisometropia. Figure 3 shows
eye-dominance distributions for a control group of eight normal monkeys
(Fig. 3A), for the strabismic and anisometropic monkeys
(Fig. 3B,C), and for the six
animals individually. When recordings were obtained from both
hemispheres, they have been flipped, combined, and presented as though
all recordings were made from the hemisphere contralateral to the treated eye; in Figure 3, T and U indicate the
treated and untreated eyes, respectively.
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Figure 3.
Distributions of cortical eye dominance from eight
control monkeys (A) and from the six amblyopic
monkeys (B, C). Eye dominance is
represented using the seven-point scale of Hubel and Wiesel (1962). For
the control monkeys, group 1 represents dominance by the contralateral
eye (C), and group 7 represents dominance by the
ipsilateral eye (I). For the amblyopic
monkeys, data collected from the two hemispheres are combined so that
group 1 represents dominance by the treated eye
(T) and group 7 represents dominance by the
untreated eye (U). The top
histograms in B and C show distributions
pooled across the three monkeys in each group; the bottom
small histograms show the individuals' data. Only neurons with
receptive fields representing the central visual fields are included;
76 units recorded from the representation of the peripheral visual
field in monkey FT are excluded. In monkey FP, 35 units recorded in V2
are included; these were statistically indistinguishable from 62 other
units recorded in V1. All other recordings were from V1.
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In all the amblyopic monkeys, units were very sharply divided into
clusters, 0.5-1 mm in extent, that were strongly dominated by one eye
or the other. These clusters are presumably the physiological manifestations of the very distinct anatomical ocular-dominance columns
seen in strabismic animals. These clusters were also strongly apparent
in recordings made inadvertently from V2 in one monkey. In a number of
cases, we noticed narrow zones, 50-100 µm wide, at the borders of
these eye-dominance clusters in which units were difficult to isolate
or to drive visually. We suspect that these transition zones, which in
normal monkeys contain the most strongly binocular units, are
particularly affected when cortical binocularity is lost; we have also
reported anatomical evidence for abnormalities in the border regions of
ocular-dominance columns in strabismic monkeys (Fenstemaker et al.,
1994, 1997).
In normal monkeys, our results on the overall distribution of eye
dominance are in general agreement with previous reports (e.g., Hubel
and Wiesel, 1968), although in our hands binocular neurons were
somewhat more common. Most neurons (70%) were binocularly activated,
and 85% responded to some degree to stimulation of one eye or the
other.
In all of the amblyopic monkeys, cortical binocularity was sharply
reduced. The proportion of binocularly activated units in the three
strabismic monkeys ranged from 18 to 27%; in the anisometropes, the
range was from 15 to 50%. It is noteworthy that the anisometropic
monkey with the smallest number of binocularly activated units (LF) had
developed an exotropic strabismus after the end of the lens-rearing
period.
In the three strabismic monkeys, eye dominance was approximately evenly
balanced, with the amblyopic eye dominating between 49 and 54% of the
units. In the three anisometropes, the amblyopic eye dominated a
smaller fraction of neurons (21-32%), suggesting that this eye had
suffered a competitive disadvantage in its effectiveness in driving
cortical neurons. The lack of an eye-dominance shift in the strabismics
was characteristic only of this group of relatively mild strabismic
amblyopes. Other strabismics with more profound amblyopia often show
eye-dominance shifts as great or greater than those seen in this group
of anisometropes (see below) (Eggers et al., 1984). Conversely, some
monkeys, found to be amblyopic after being raised with unilateral
instillation of atropine in an earlier simulation of anisometropia, did
not show the eye-dominance shift evident in this group of anisometropes
(Movshon et al., 1987).
Perhaps a more informative indicator of the change in the cortical
representation of the amblyopic eye is the proportion of units that
responded at all to stimulation of that eye. In normal monkeys, 84% of
units responded to stimulation of the contralateral eye.
In the three strabismic monkeys, the fraction of units responding to
the treated eye ranged from 57 to 67%. In the three anisometropes, this fraction was between 40 and 59%. Thus, in both groups of amblyopes, the combination of reduced binocular interaction and shifted-eye dominance substantially reduced the representation of the
input of the amblyopic eye across the cortical neuron population.
To compare these eye-dominance distributions with behavioral
sensitivity losses, Figure 4 plots the
proportion of units in each monkey dominated by the amblyopic eye
(i.e., the total units in eye-dominance groups 1-3 plus half of those
in group 4, as a fraction of the total) against the amblyopia index
described above. In Figure 4, circles indicate animals in
the two experimental groups, and crosses indicate data from
three strabismic animals not otherwise described in this paper; these
monkeys were tested behaviorally, allowing calculation of the amblyopia
index, and their cortical eye dominance was assessed in connection with
a separate series of anatomical experiments (Fenstemaker et al., 1997).
Figure 4 reveals that some animals had substantial degrees of amblyopia
even when the amblyopic eye dominated a normal proportion of cortical
units. There was, however, a covariation between cortical eye dominance
and amblyopia; the most severely amblyopic animals had the smallest
fraction of units dominated by the amblyopic eye. Finally, although the
data shown in Figure 3 give the impression that anisometropes and
strabismics showed characteristic differences in cortical eye
dominance, including the three additional animals (all strabismics with
substantial shifts in cortical eye dominance away from the amblyopic
eye) (Fig. 4, crosses), reveals that all the amblyopes of
either etiology seem to lie on a continuum.
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Figure 4.
The proportion of units dominated by the amblyopic
eye is plotted against an amblyopia index (a measure of the severity of
amblyopia that is described earlier). The normal situation is
indicated by the open square; the value of the amblyopia
index for three normal monkeys was 0.024, 0.061, and 0.074. Data from
the strabismic monkeys in this study are shown by filled
circles; data from anisometropic monkeys are shown by
open circles. Also included are data from three more
profoundly amblyopic monkeys in which we measured cortical eye
dominance (crosses) (Fenstemaker et al., 1997).
Substantial amblyopia can evidently occur with or without a shift in
cortical eye dominance, but the most severe amblyopes experienced a
loss of effective input from the amblyopic eye.
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Spatial properties and contrast sensitivity of
cortical neurons
We wished to know how the losses in spatial resolution and
contrast sensitivity seen behaviorally (Fig. 1) were reflected in the
properties of visual neurons. We and others have shown previously that
the spatial properties of afferent neurons in the lateral geniculate
nucleus are little affected, even by complete visual deprivation
(Blakemore and Vital-Durand, 1986; Levitt et al., 1989). We therefore
chose to study the properties of neurons in the visual cortex.
We made quantitative measurements of orientation, spatial, temporal
frequency tuning, and contrast response in 131 neurons from five
monkeys. Figure 5 shows quantitative data
obtained from both eyes for a binocularly activated unit recorded in an
anisometropic monkey (OC). Each panel in Figure 5 plots the response
for the amblyopic eye with open symbols and the response for
the nonamblyopic eye with filled symbols. Apart from the
obvious fact that this particular neuron responded more vigorously to
stimulation of the nonamblyopic eye, its properties were similar when
tested in either eye with respect to orientation and direction
selectivity, temporal frequency tuning, and contrast response (Fig.
5A,C,D). There was,
however, a distinct difference in the spatial frequency tuning measured
through the two eyes (Fig. 5B). When tested through the
nonamblyopic eye, the best response of the unit was obtained for
gratings of 3 c/deg, and the spatial resolution was ~8 c/deg. Tested
through the amblyopic eye, the preferred spatial frequency was ~1
c/deg, the spatial resolution was ~4 c/deg. We observed this pattern
of interocular difference in spatial tuning, favoring the nonamblyopic
eye, in most of the eight cases in which we tested units binocularly
with quantitative methods; this was true for units regardless of
whether the amblyopic or the nonamblyopic eye generated stronger
responses.
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Figure 5.
Data from a complex cell recorded in an
anisometropic monkey (OC). For this binocularly activated unit,
quantitative data were measured with stimulation of each eye. Data
taken through the amblyopic eye are shown by open
symbols, and data taken from the nonamblyopic eye are shown by
filled symbols. A, Orientation and
direction selectivity measured with high-contrast drifting gratings
whose orientation was orthogonal to the direction plotted; the spatial
and temporal frequencies were optimal for the eye being tested.
B, Spatial frequency tuning measured with high-contrast
gratings of optimal orientation, direction, and temporal frequency.
C, Temporal frequency tuning measured with high-contrast
gratings of optimal orientation and spatial frequency.
D, Contrast response measured with gratings of optimal
orientation and spatial and temporal frequency. Error bars indicate SE
of the mean spike count per stimulus cycle. Dashed lines
indicate spontaneous activity.
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Although we occasionally encountered and quantitatively tested
binocularly driven units like the one shown in Figure 5, most of our
data came from units that strongly preferred one eye or the other (Fig.
3). Our main conclusions are therefore based on population comparisons
rather than cases like the one in Figure 5. Quantitative tests of such
populations did not reveal decisive differences between the amblyopic
and nonamblyopic eyes with respect to response magnitude, orientation,
direction, spatial or temporal tuning, or contrast response. Because
our quantitative data came from a relatively small subpopulation of the
recorded neurons, this is not particularly surprising. In fact, our
main rationale for collecting quantitative data was to provide
independent verification of the accuracy of measurements made with
qualitative techniques.
For all 797 recording sites (isolated neurons and multiunit sites), we
made qualitative assessments by listening to the unit response over the
audiomonitor while we adjusted the parameters of the grating being
displayed. From this qualitative assessment, we established orientation
preference and selectivity, optimal spatial frequency and spatial
resolution, optimal temporal frequency, and threshold contrast for an
optimal grating; we also rated the responsiveness of the cells. For the
131 cases tested quantitatively, we were able to compare the two sets
of measurements. In general, the validations were excellent. For the
key parameters of optimal orientation and direction, optimal spatial
frequency, optimal temporal frequency, and contrast threshold, the
correlations between qualitative and quantitative measures were between
0.54 and 0.96; in no case was the slope of the relationship between
measures significantly different from 1. For spatial frequency,
temporal frequency, and contrast measures, the difference between
qualitative and quantitative measures rarely exceeded a factor of 2 and
was typically much less. We observed the lowest correlation when
comparing contrast thresholds judged by ear with those established
using a quantitative statistical technique (Tolhurst et al., 1983;
Levitt et al., 1994); we also found this judgment to be the most
difficult to make reliably, as well as to be the one on which multiple
qualitative observers had the most difficulty agreeing.
Using the qualitative data, we compared the properties of units driven
by the two eyes. In most respects, the populations did not differ
significantly. Units driven by the amblyopic and nonamblyopic eyes were
indistinguishable in all six animals with respect to their
responsiveness to optimal visual stimuli, frequency and degree of their
orientation and direction selectivity, and their preference for
temporal frequency. Because amblyopia is a disorder of spatial vision,
we suspected that comparisons of the spatial tuning properties of
neurons in the two eyes might be more informative.
Figures 6 and
7 summarize our data on the spatial
frequency tuning and contrast sensitivity of units from the strabismic
and anisometropic monkeys. In Figures 6-8, data in
red relate to the amblyopic eye, and data in
green relate to the nonamblyopic eye. The data in these
figures are presented in the same order as they were in Figure 1, so
that the least severe amblyope in each group is at the top
and the most severe is at the bottom. The scattergrams in
Figures 6A, 7A, and 8A
display the locations of the peaks of the spatial frequency tuning for
all units; note that the axes are isomorphic to those used for the
behavioral data in Figure 1. The distributions in Figures
6B, 7B, and 8B show
frequency histograms for each of the parameters shown, as well as for
spatial resolution. It is evident that the spatial and sensitivity
properties of neurons in all monkeys are quite widely dispersed, with
all parameters showing at least a 10-fold range of variation; this is
not different from previous reports in normal monkeys (e.g., DeValois
et al., 1982) and from our own unpublished observations.
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Figure 6.
Spatial frequency tuning and contrast sensitivity
data for neurons recorded from the three strabismic monkeys. Data for
the amblyopic eye are shown in red, and data for the
nonamblyopic eye are shown in green. A,
Scatter diagrams in which each neuron is represented by a point plotted
at its optimal spatial frequency and contrast sensitivity (i.e., the
inverse of its threshold contrast). Bars on the abscissa
and ordinate indicate the interquartile ranges (i.e., the bounds of the
central 50% of the observed values) for each eye. B,
Distributions of optimal spatial frequency, contrast sensitivity, and
spatial resolution for neurons tested through each eye. The boundary
between adjacent pairs of bins represents the center of the class
interval. The three monkeys' data are ordered vertically in the same
way as in Figure 1B. For monkey FT, only data
obtained from foveal recordings are included.
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Figure 7.
Spatial frequency tuning and contrast sensitivity
data for neurons recorded from the three anisometropic monkeys. Data
for the amblyopic eye are shown in red, and data for the
nonamblyopic eye are shown in green; the format is
identical to Figure 6. The three monkeys' data are ordered vertically
in the same way as in Figure 1C. For monkey FP, 35 units
recorded in V2 are included; these were statistically indistinguishable
in their properties from the 67 other units recorded from V1.
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Within this variation, however, it is possible to discern interocular
differences that seem to be related to each animal's depth of
amblyopia. Strabismic monkeys GH and HC (Fig. 6) and aniso metropic
monkey LF (Fig. 7) whose amblyopias were the most modest, showed only
subtle interocular differences for any of the reported measures. For
monkey GH, only the interocular difference in contrast sensitivity
achieved statistical significance (t test; p < 0.01), and this difference was in the "wrong" direction, with units in the amblyopic eye being more sensitive. For monkey HC, none of
the interocular differences was significant. For monkey LF, the
interocular difference in contrast sensitivity was significant (t test; p < 0.01) and in the
"correct" direction, with the amblyopic eye showing lower
sensitivity. But the differences in optimal spatial frequency and
resolution were not significant.
Consider now the three most severely amblyopic cases: strabismic monkey
FT (Fig. 6) and anisometropic monkeys FP and OC (Fig. 7). In all three
of these cases, the interocular differences in both spatial resolution
and optimal spatial frequency were large, robust (t test;
p < 0.001 in all cases), and in the direction expected; the spatial performance of the amblyopic eye was inferior to
that of the nonamblyopic eye. Curiously, in none of these cases was the
interocular difference in contrast sensitivity significant.
In humans, strabismic amblyopia is primarily a deficit of central
vision (Sireteanu et al., 1981; Hess and Pointer, 1985). We have also
found this to be true in some, but not all, monkey amblyopes (L. Kiorpes and D.C. Kiper, unpublished observations). To explore the
neural basis of this variation with visual field location, we studied
the properties of 76 units from the representation of the peripheral
visual field in FT, the most severely affected of our three strabismic
amblyopes. The receptive fields of the neurons were located in the
inferior quadrant, between 16 and 23° from the fovea. Data from this
peripheral sample are shown in Figure 8,
using the same format as in Figures 6 and 7. This monkey's foveal data
showed clear interocular differences in spatial resolution and optimum
frequency (Fig. 6), but the data from the periphery show no interocular
difference; none of the three pairs of distributions in Figure
8B differs significantly.
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Figure 8.
Diagrams in the format of Figure 6 and 7
representing data from units recorded in strabismic monkey FT from the
representation of the peripheral visual field in V1. The receptive
fields of these units were located in the lower visual quadrant,
between 16 and 23° from the fovea.
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To compare the physiological data presented in Figures 6 and 7 with the
behavioral measurements in Figure 1, in Figure
9 we plot the amblyopia index against a
measure of the interocular difference in three spatial properties for
each of the experimental monkeys. As in Figure 4, filled
circles represent data from strabismics and open
circles represent data from anisometropes. The ordinate in each
panel is the ratio of the geometric mean values of the distributions
shown in Figures 6B and 7B, with the value
for the amblyopic eye in the denominator. In accordance with the
impression derived from Figures 6 and 7, there was a reasonably clear
relationship between the amblyopia index and the interocular ratios of
spatial resolution and optimal frequency (Fig. 9, top two
panels). There was, however, no clear relationship between the
interocular ratios of contrast sensitivity and the depth of an
animal's amblyopia (Fig. 9, bottom panel).
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Figure 9.
A comparison of interocular differences in spatial
frequency tuning and contrast sensitivity with the severity of
amblyopia. Filled symbols indicate data from the
strabismic monkeys, and open symbols indicate data from
the anisometropic monkeys. The ordinate in each plot is the ratio of
the geometric population means of the values of the listed parameter
for units tested through each of the eyes, with data from the
nonamblyopic eye placed in the numerator.
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The analysis in Figure 9 suggests a correlation between physiological
measures of spatial vision and the depth of an animal's amblyopia.
Figure 10 poses the question of whether
this relationship is quantitatively precise. The ratio of the geometric
means of the physiological measures is plotted again on the ordinate of each panel in Figure 10; the abscissa now shows the interocular ratio
of the homologous psychophysical measure derived from the curves fitted
to the spatial contrast sensitivity data in Figure 1. If the
interocular differences in physiological properties documented in
Figures 6 and 7 represented a perfect quantitative correlate of the
behavioral changes shown in Figure 1, then these ratios should be
exactly proportional, and the data for the six animals should lie along
a diagonal of unit slope. It is evident instead that for both of the
spatial measures (Fig. 10, top two panels), the
physiological ratios were related to, but consistently smaller than,
the psychophysical ratios; the bottom panel in Figure 10
reveals no clear relationship between interocular ratios of contrast
sensitivity determined psychophysically and physiologically. For
spatial resolution and peak contrast sensitivity (Fig. 10, top and bottom panels), all six animals showed a
smaller ratio of physiological than psychophysical values; this
difference is significant in each case (binomial sign test,
p = 0.016). The comparison for optimal spatial
frequency (Fig. 10, middle panel) eludes significance
only because one monkey's data fall slightly above the diagonal.
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Figure 10.
A comparison of behavioral and neurophysiological
assessments of interocular differences in spatial frequency selectivity
and contrast sensitivity. The ordinate of each graph plots the same
ratio of population geometric means shown on the ordinate of Figure 9.
The abscissa indicates the ratio of the same values from the behavioral
measurements of spatial contrast sensitivity shown in Figure
1.
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DISCUSSION |
The results of these experiments show that experimental amblyopia
produces a number of changes in the properties of neurons in the visual
cortex. Moreover, the changes we observed depended in an orderly way on
the severity of the amblyopia measured behaviorally. All amblyopic
animals showed a substantial reduction in cortical binocularity, with
strabismics having the smallest number of binocularly activated
neurons; more severely affected animals also showed a shift in cortical
eye dominance away from the amblyopic eye and significant differences
in the spatial properties of cortical neurons driven by the two eyes.
The particular method used to create amblyopia (strabismus or
anisometropia) did not lead to obviously different results. Thus, it is
the severity, not the etiology, of the visual losses that seems related
to the nature of the physiological changes we found.
These results are in good agreement with our previous studies on
monkeys raised with unilateral atropinization to create unilateral blur. In these animals, moderate amblyopia was also accompanied by
differences in the spatial properties of neurons driven by the two
eyes, as well as by a loss of binocularity and (in some cases) a shift
in cortical eye dominance toward the untreated eye (Kiorpes et al.,
1987; Movshon et al., 1987). Interestingly, the shift in eye dominance
in these animals was apparently only among neurons preferring high
spatial frequencies, and ocular dominance was more balanced among
neurons preferring low spatial frequencies. This trend was evident in
the anisometropic, but not the strabismic, amblyopes in the present
study. Our eye-dominance data may appear to be at odds with earlier
data from strabismic monkeys (Baker et al., 1974; Crawford and von
Noorden, 1979), which show a complete shift of eye dominance away from
the deviating eye. However, the monkeys in those studies had very poor
acuity in their deviating eye, which was comparable with acuity in
monocularly deprived animals in most cases. Their results represent the
extreme of the continuum and are thus not out of line with the results presented here (Fig. 4).
The literature on human amblyopia suggests that strabismic and
anisometropic amblyopes differ in their visual capacities. Anisometropic amblyopes appear to show contrast sensitivity deficits over a wide range of visual field locations, whereas the deficits of
the strabismic amblyopes are confined to the central visual field (Hess
et al., 1980; Sireteanu et al., 1981; Hess and Pointer, 1985; but see
Sireteanu and Fronius, 1990). Furthermore, strabismic amblyopes have
been reported to have severe deficits in positional acuity, whereas the
deficits of anisometropic amblyopes are comparatively mild (Levi and
Klein, 1982; Hess and Holliday, 1992; but see McKee et al., 1992;
Kiorpes and Movshon, 1996). We have not, however, been able to discern
consistent differences between these two types of amblyopia in monkeys
(Kiorpes et al., 1993; Kiorpes and Movshon, 1996). Our main concern in
this paper is with spatial resolution and contrast sensitivity;
behaviorally, we find a wholly overlapping range of contrast
sensitivity deficits among our anisometropic and strabismic amblyopes.
Thus, it is not surprising that we find similar physiological deficits
in spatial resolution and contrast sensitivity in these two
populations.
Of course, there may be differences between strabismic and
anisometropic amblyopia that are not reflected in the kinds of measurements we made in this study. It is, however, important to note
that the classification of human amblyopes is typically based on the
presence of strabismus or anisometropia at the time of clinical
evaluation or psychophysical testing, whereas our classification is
based on the particular visual abnormality that we created in early
life. The difference is important because both strabismus and
anisometropia can develop in amblyopes after the end of the critical
period. For example, anisometropic monkey LF in this study became
strabismic after the period of lens-rearing had ended, and strabismic
monkey FT became mildly anisometropic (1.0 diopter) after an extended
period of amblyopia (Kiorpes and Wallman, 1995). These monkeys might
all have been classified as strabismic and anisometropic had they first
been studied in maturity. However, within the limits of our
measurements, we are confident that none of these monkeys was both
strabismic and anisometropic during the first postnatal year, which
represents the primary period of spatial visual development in monkeys
(Kiorpes, 1992a; Boothe et al., 1989).
Mechanisms of developmental abnormality in amblyopia
It is widely believed that cortical neurons respond adaptively to
the visual environment during early development, in the sense that
activity-dependent mechanisms of plasticity act to bring the
selectivity of cortical neuron responses into a rough match with the
visual input received in early life (see Daw, 1995; Katz and Shatz,
1996). In accordance with this idea, some of the physiological
manifestations of amblyopia seem to be clearly related to the factors
that created the condition. For example, it is intuitively reasonable
for strabismic animals to lose binocularity; strabismus abolishes
correlated visual experience at corresponding locations in the two
eyes, and it has long been accepted that this decorrelation could
change cortical binocular interaction by any of several
activity-dependent mechanisms (e.g., Hubel and Wiesel, 1965). It
is also relatively easy to understand how persistent retinal image blur
in one eye might represent a form of visual deprivation for neurons
that respond to high spatial frequencies, because effective retinal
image contrast is sharply reduced at those frequencies. By analogy with
the response of the visual system to more severe forms of deprivation
(Wiesel and Hubel, 1965), the reduction in effective stimulation might
prevent the development of high-frequency neurons. This could happen
either because these neurons were in effect monocularly deprived and adaptively selected their inputs from the untreated eye, or because the
lack of stimulation prevented them from developing their full spatial
resolving power, sensitivity, and selectivity. Our data do not allow us
to distinguish between these two possibilities.
On the other hand, some of the cortical changes in amblyopia seem quite
puzzling. There is no obvious reason why neurons driven by the
amblyopic eye in some strabismic amblyopes should have degraded spatial
properties. These neurons should have been exposed to reasonably clear
retinal images throughout early development and would therefore appear
to have no reason to fail to develop normal spatial properties. It is
also unclear why anisometropic animals should show such a stark
reduction in cortical binocularity. The alignment of the eyes was not
discernibly affected by the contact lenses and was well enough
preserved during rearing that corresponding retinal points should have
received correlated visual inputs, at least at low spatial frequencies,
providing binocular stimulation. Yet the proportion of binocularly
driven units was similar among neurons preferring low and high spatial
frequencies for both strabismic and anisometropic monkeys; this is
consistent with our previous results of amblyopia following unilateral
atropinization (Movshon et al., 1987). However, it should be noted that
our tests would not have detected the residual binocular interactions
demonstrated by simultaneous binocular stimulation in strabismic and
anisometropic monkeys by Smith et al. (1997).
The physiological basis for amblyopia?
Our goal is to understand the biological basis of amblyopia.
Because amblyopia is a disorder of spatial vision, we concentrated our
efforts on measuring and comparing the spatial properties of cortical
neurons driven by the two eyes. In the more severely affected
amblyopes, we found clear interocular differences in spatial resolution
that could, in principle, explain the visual deficit in amblyopes (Fig.
9). Yet quantitative analysis shows that this effect is probably an
incomplete explanation of the deficits shown behaviorally. Figure 10
compares the interocular differences in behavioral and physiological
measures of optimal spatial frequency, spatial resolution, and contrast
sensitivity. If the physiological differences were to account for the
whole of the amblyopic loss, these differences should have been equal. Instead, in nearly all cases, the magnitude of the physiological differences was less than those found behaviorally. This is clearly manifested in the fact that many cortical neurons driven through the
amblyopic eyes of the more severely affected monkeys responded to
spatial frequencies that the animals could not see. For example, a
comparison of Figure 1 with Figures 6 and 7 shows that in monkeys FT,
FP, and OC, we recorded significant numbers of neurons driven by the
amblyopic eye whose spatial resolution exceeded the animal's spatial
resolution; we almost never encountered such neurons driven by the
nonamblyopic eye.
It is also notable that we failed to detect reliable differences in the
contrast sensitivity of neurons driven by the two eyes despite the
substantial differences in contrast sensitivity measured behaviorally
(compare Fig. 1 with Figs. 6 and 7). As noted in Results, it is
conceivable that our measurements of contrast sensitivity were not
sufficiently precise to detect a subtle difference between the two
eyes. Although we measured no difference in the absolute responsiveness
of neurons driven by the two eyes, it is also possible that the
interocular differences in behavioral contrast sensitivity are
explained by the reduced number of neurons driven by the amblyopic
eye.
Together, these considerations suggest that the changes we have
observed represent only a partial explanation of the visual losses in
amblyopia and that some additional factors must be involved. Although
it has been suggested that abnormalities in the pattern of correlated
firing among striate cortical neurons driven by the amblyopic eye might
cause amblyopia (Roelfsema et al., 1994), it seems equally reasonable
to suppose that some aspects of amblyopia reflect changes in the
properties of cortical neurons at processing stages beyond the primary
visual cortex. For example, amblyopes may show abnormalities in
long-range feature-linking tasks that seem unlikely to be subserved by
striate cortical neurons alone (Hess et al., 1997; but see Levi and
Sharma, 1998). A full explanation of the amblyopic deficit should
therefore be cast in terms of a cascade of deficits in several
processing areas of the cerebral cortex. The effects we have observed
in striate cortex represent only the first stage of that cascade.
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FOOTNOTES |
Received March 18, 1998; revised June 3, 1998; accepted June 5, 1998.
This research was supported by National Institutes of Health Grants
EY05864, EY02017, and RR00166, and by an investigatorship to J.A.M.
from the Howard Hughes Medical Institute. D.C.K. was supported in part
by a fellowship from the Fonds National Suisse pour la Recherche.
Michael Hawken and Chao Tang participated in some of these experiments.
We thank Suzanne Fenstemaker, Jasmine Allen Siegel, Michael Gorman, and
Patricia Adler for their assistance, and Drs. Howard Eggers and Melvin
Carlson for their expert strabismus surgery.
Correspondence should be addressed to Lynne Kiorpes, Center for Neural
Science, New York University, 4 Washington Place, Room 809, New York,
NY 10003.
Dr. Kiper's present address: Institut de Biologie Cellulaire et
Morphologie, Faculté de Medecine, Université de Lausanne, CH-1015 Lausanne, Switzerland
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Abstract
Introduction
