(Investigative Ophthalmology and Visual Science. 2002;43:686-691.)
© 2002
by The Association for Research in Vision and Ophthalmology, Inc.
Slow Target–Directed Eye Movements in Ataxia-Telangiectasia
Richard F. Lewis1,2 and
Thomas O. Crawford3,4
1 From the Departments of Otolaryngology and
2 Neurology, Harvard Medical School, Boston, Massachusetts; and the
3 Departments of Neurology and
4 Pediatrics, Johns Hopkins Medical School, Baltimore, Maryland.
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Abstract
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PURPOSE. To analyze the slow eye movements that shift the direction of gaze in
patients with ataxia-telangiectasia (A-T).
METHODS. Eye and head movements were recorded with search coils in three
patients with A-T during attempted gaze shifts, both with the head
immobilized and free to move.
RESULTS. Gaze shifts frequently included both saccadic and slow components. The
slow movements were recorded after 42% of saccades and had an average
peak velocity of 6.1 deg/sec and a mean amplitude of 2.0°. They
occurred with the head stationary and moving, could be directed
centripetally or centrifugally, had velocity waveforms that were
relatively linear or exponential, and always moved the eyes toward the
visual target.
CONCLUSIONS. The slow movements appear to differ from pursuit and vestibular eye
movements and are not fully explained by the various types of abnormal
eye movements that can follow saccades, such as gaze-evoked nystagmus
or postsaccadic drift. Their origin is uncertain, but they could
represent very slow saccades, due to aberrant inhibition of burst cell
activity during the saccade.
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Introduction
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Minimal eye motion typically occurs before or after
saccades.1
When the head is stationary, postsaccadic eye
movement is usually attributed to a mismatch between the phasic (pulse)
and tonic (step) components of the saccade command.2
When
the head is moving, slow gaze shifts are generally ascribed to partial
cancellation of the vestibulo-ocular reflex (VOR).3
In the
head-fixed cat, however, slow postsaccadic eye movements have been
described that shift the direction of gaze toward the visual
target.4
5
These movements are not characteristic of
either a pulse–step mismatch or cancellation of the VOR, and their
basis is uncertain.
We have observed that some patients with the genetic disorder
ataxia-telangiectasia (A-T) shift gaze with a combination of saccadic
and slow eye movements, both of which direct the eyes toward the visual
target.6
These slow eye movements have not been described
in other human subjects, but appear qualitatively similar to those
recorded in the cat. To characterize these movements and to determine
their interaction with head motion, we recorded eye and head movements
in several patients with A-T during head-fixed and head-free gaze
shifts.
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Methods
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Eye and head movements were recorded with the magnetic search
coil technique, with coils placed in one eye and in the center of the
forehead. The head coil was calibrated by passively orienting the head
to the horizontal 0° and right 10° positions, and the eye coil was
calibrated by having subjects fixate targets at 0° and right 10°
with the head centered. Data were filtered at 90 Hz, sampled at 500 Hz,
and stored in a computer for off-line analysis.
Coil recordings were made in three patients (age range, 15–23 years)
in whom A-T was diagnosed according to standard criteria.7
The consent of the patients and their parents was obtained according to
the Declaration of Helsinki, and all experimental procedures were
approved by the Johns Hopkins Committee on Clinical Investigation.
Gaze shifts were tested with the head immobilized on a bite bar and
with the head free to move. Patients viewed an array of light-emitting
diodes 125 cm in front of the head and made gaze shifts along the
horizontal axis for target jumps from 0° to right 10°, right 10°
to 0°, 0° to left 10°, and left 10° to 0°. Pursuit movements
were also recorded with the head immobilized. The pursuit target was
back projected onto a translucent screen and moved to the right and
left at a constant velocity of 20 deg/sec.
Data were analyzed off-line with an interactive computer program. The
position of the eye and head coils was determined with a linear
calibration. The coils gave direct measurements of gaze position
(defined as eye position in space = eye coil) and head position
(head coil). Eye position in the orbit was calculated as gaze minus
head position. Gaze, eye, and head velocity signals were obtained by
digitally differentiating the position signals and by filtering them at
30 Hz with a seven-point Gaussian filter. The beginning of the rapid
gaze movement (gaze saccade) was defined as the point where gaze
velocity first exceeded 20 deg/sec, and the end of the movement was
defined as the point where gaze velocity declined to less than 45
deg/sec. The amplitude and peak velocity were determined for the
initial gaze saccade in each gaze shift.
For head-fixed gaze shifts, the amplitude, duration, and peak velocity
of the slow postsaccadic movements were quantified for centrifugal
saccades. Similar measurements were not made for centripetal saccades,
because all three patients had impaired gaze holding that resulted in
centripetal slow phases. The onset of the slow movement was defined as
coincident with the end of the saccade and the end of the slow movement
as the point at which gaze velocity returned to a steady value of zero.
Although slow movements could also precede the initial saccade, such
presaccadic movements were infrequent and therefore were not analyzed
quantitatively. Head-free gaze shifts were analyzed by separating the
slow postsaccadic movements into components that were due to VOR
cancellation and components that were independent of head motion, as
described in the Results section.
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Results
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Gaze saccades were markedly hypometric in the three subjects, but
their peak velocities were appropriate for the amplitude of the gaze
shift (Fig. 1)
. In the head-fixed condition, many gaze shifts consisted of a
combination of saccades and slow movements (Fig. 2)
. The slow movements typically followed saccades without a detectable
latency, but could also precede the initial saccade. These movements
were always corrective, because they moved the eyes toward the visual
target. They were recorded for both centrifugal and centripetal gaze
shifts and had velocity profiles that were either relatively linear or
velocity-decreasing. The characteristics of the slow eye movements that
followed centrifugal, head-fixed saccades are summarized in Table 1
. These movements occurred after 42% of initial saccades in the
three subjects, and had an average amplitude of 2.0° and an average
peak velocity of 6.1 deg/sec. A small fraction of the head-fixed eye
movements had dynamic characteristics that fell between saccades and
the typical postsaccadic slow movements. For example, the second eye
movement in Figure 3
had an amplitude of 5° but its peak velocity was relatively low
(approximately 70 deg/sec).
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Figure 1. Amplitude and peak velocity of the initial gaze saccades in head-fixed
( ) and head-free (•) conditions. All target displacements were
10°. Solid lines: mean values measured in a population
of normal subjects in the same laboratory.20
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Figure 2. Gaze position and velocity profiles for two head-fixed gaze
shifts. Saccade velocities are clipped at the upper and lower
extremes of the figures.
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Figure 3. Head-fixed, centrifugal gaze shift. The second saccade, which slowed
and then reaccelerated, had a peak velocity of approximately 70
deg/sec.
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The head movements recorded during head-free gaze shifts were generally
smaller than the size of the target displacement (Fig. 4) and averaged 2.3° to 5.8° in the three subjects. The temporal
relationship between head motion and the gaze shift was variable,
because the head movement could precede (Fig. 4A) or follow (Fig. 4B)
the primary gaze shift, or both could occur concurrently. When the head
movement and gaze shift did not coincide, the VOR appeared to function
normally with a gain near unity. For example, in Figure 5
A the head movement was completed before the initial gaze saccade, and a
comparison of head and gaze velocity (Fig. 5B)
demonstrates that after
the saccade, gaze shifted slowly to the left while the head velocity
oscillated around zero. This uncoupling between head and gaze velocity
indicates that the VOR had a gain near unity after the saccade and that
cancellation of the VOR was not responsible for the prolonged slow gaze
shift. In contrast, when the head movement and gaze shift occurred
concurrently (Fig. 6A
), head and gaze velocity were clearly linked (Fig. 6B) , indicating
that the VOR was partially canceled.
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Figure 4. Examples of head-free gaze shifts. (A) Target jumped from
right 10° to 0°, and the head movement was completed before the
initial saccade. (B) Target jumped from 0° to right 10°,
and the initial gaze saccade occurred before the head movement.
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Figure 5. (A) Head-free gaze shift with the head movement largely
completed before the initial gaze saccade. (B) Gaze velocity
(black line) and head velocity (gray line).
Although the gaze shift was centripetal, the majority of the slow eye
movement was centrifugal in the orbit (portion below the dotted
line in the eye trace (A) because the head was deviated
away from center.
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Figure 6. (A) Head-free gaze shift with the head movement and gaze
shift coinciding. (B) Gaze velocity (black line)
and head velocity (gray line).
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To quantify the dependence of the postsaccadic gaze shifts on VOR
cancellation, instantaneous (desaccaded) gaze velocity was plotted
against head velocity, and the slope and y-intercept of a
linear regression of the data were calculated (Fig. 7)
. If VOR cancellation was complete during the slow postsaccadic
movement (i.e., VOR gain was zero), then head and gaze velocity should
be linked, and the regression slope of the data should have a value of
unity (Fig. 7
, dashed line). If the VOR functioned normally during the
gaze shift (i.e., its gain was unity), then head and gaze velocity
should be independent and the regression slope should have a value of
zero. With this approach, the VOR gain during the nonsaccadic portions
of the gaze shift can be estimated as (1 - regression slope).
Gaze movements that were not dependent on VOR cancellation (and hence
were unaffected by head motion) should shift the data points away from
zero along the y (gaze velocity) axis. The average velocity
of this VOR-independent component was therefore estimated by
calculating the y-intercept of the regression plot.
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Figure 7. Instantaneous head velocity plotted against (desaccaded) gaze velocity,
sampled every 2 ms. (A) Gaze shift shown in Figure 5
;
(B) gaze shift shown in Figure 6
. Solid line:
linear regression of the data points; dashed line: equal
head and gaze velocity.
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Figure 7
illustrates this analysis for the gaze shifts shown in Figures 5
and 6
. When the head movement and gaze shift did not coincide (Fig. 5)
, the regression line had a slope of -0.03 and a
y-intercept of -2.5 (Fig. 7A)
, indicating that the VOR gain
was approximately 1.03 and that gaze shifted leftward independently of
head motion with a mean velocity of 2.5 deg/sec. This analysis was
applied to 20 gaze shifts in which the head movement and gaze shift did
not coincide and yielded an average VOR gain of 1.04 ± 0.08 (SD)
and an average VOR-independent component of 3.1 ± 1.3 deg/sec
(SD). In contrast, when the head movement and gaze shift coincided
(Fig. 6)
, the regression slope was 0.66 (indicating a VOR gain of 0.33)
and the y-intercept was -2.6 deg/sec (Fig. 7B)
. Analysis of
20 similar gaze shifts yielded an average VOR gain of 0.42 ± 0.21
and an average VOR-independent component of 2.8 ± 1.5 deg/sec.
Eye movements were also recorded in the three patients with A-T
while they attempted to track a pursuit target moving horizontally at a
constant velocity of 20 deg/sec. These visually guided movements,
recorded with the head immobilized, were markedly impaired in all
subjects, and were characterized by smooth movements of low velocity
(gain ranged from 0.12 to 0.37) interrupted by frequent corrective
saccades (Fig. 8)
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Figure 8. Eye movements during attempted tracking of a pursuit target (moving to
the right and left at 20 deg/sec). Dotted lines:
position and velocity of the visual target.
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Discussion
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The principal finding in this study is that patients with A-T
shift the direction of gaze with a combination of saccades and slow
movements. The slow movements could precede the initial saccade, but
more typically followed both the initial and corrective saccades.
Similar slow movements were observed in a prior study of A-T, but were
not analyzed in detail and were attributed to vestibular slow
phases.8
In our subjects, however, these movements clearly
occurred in the absence of vestibular nystagmus, could be centrifugal
or centripetal, occurred with the head stationary or moving, and always
directed the eyes toward the visual target. The dynamics of these
movements are similar to the slow eye movements that have been
described in the head-fixed cat.4
5
The mechanism underlying the slow gaze movements in A-T is uncertain.
Because these movements were frequently recorded when head motion was
minimal, VOR cancellation clearly cannot be their sole underlying
mechanism. Unlike normal subjects9
or patients with
congenital defects in saccade initiation,10
however, the
patients with A-T canceled the VOR to a variable degree during
small-amplitude gaze shifts when the gaze shift and head movement
coincided. It is interesting to note that the three subjects had
markedly impaired pursuit and could not significantly reduce their VOR
gain during passive, whole-body, sinusoidal rotation.6
This suggests that the VOR cancellation evident during active,
head-free gaze shifts may depend on a mechanism that uses the efferent
command sent to the neck11
or proprioceptive afference and
may be largely independent of the pursuit system.12
Postsaccadic drift can shift the direction of gaze and occurs if the
step command is not accurately matched to the pulse.2
Because patients with A-T have several eye-movement deficits that are
associated with dysfunction in the cerebellar flocculus,6
the brain region responsible for minimizing postsaccadic
drift,13
it is likely that a pulse–step mismatch
contributes to the slow, postsaccadic movements. The dynamic
characteristics of these movements, however, are not typical of
postsaccadic drift, because they often had a prolonged duration and a
relatively linear velocity profile. Postsaccadic drift, in contrast,
has an exponential velocity profile with a time constant close to that
of the oculomotor plant (approximately 200 ms).2
Normal subjects can generate slow eye movements to step displacements
in target position, which is considered a form of anticipatory
pursuit.14
The patients with A-T had abnormal visually
guided pursuit, however, and anticipatory pursuit has not been observed
in patients with cerebellar disease who have a similar degree of
pursuit impairment.15
Neural integration is abnormal in
A-T6
and produces centripetal drift of the eyes during
attempted eccentric gaze. Although these movements would augment
centripetal slow movements, they would serve to attenuate the
centrifugal movements that were frequently recorded. Finally, although
the recordings presented herein were monocular, physical examination of
these subjects demonstrates that the slow eye movements were
approximately conjugate6
and hence were not due to
vergence.
In sum, the slow gaze shifts in A-T probably have components that are
the result of VOR cancellation (when the head is moving), postsaccadic
drift, and impaired neural integration (for centripetal movements). An
additional undefined mechanism also appears to contribute to these
movements. It has been suggested that a slow eye movement pathway
projects directly to the motor neurons, bypassing the saccadic pause
cell–burst cell system,16
and there is limited evidence
of such a pathway in the cat.5
In the patients with A-T,
if the burst cell activity responsible for the rapid portion of the
saccade were prematurely terminated,6
the remainder of the
gaze shift could in theory be generated by this slow pathway.
Furthermore, the saccade abnormalities evident in A-T (increased
latency, hypometric amplitude)6
suggest aberrant
suppression of burst cell activity during attempted gaze shifts. If the
burst cells were partially inhibited during the saccade or at its
onset, pre- or postsaccadic eye movements of markedly reduced velocity
could result, driven by the subset of burst neurons that remain
active.6
This mechanism, which suggests that the slow
movements are actually low-velocity saccades, is supported by the
observation that burst cell activity continues in the cat during slow,
postsaccadic gaze shifts.17
Because the velocity of some
gaze shifts in the patients with A-T were between normal saccades and
the typical slow movements (Fig. 3 , for example), it is plausible that
the fast and slow components of the gaze shifts may represent different
ends of a spectrum of movements generated by the same saccade
mechanism.
Although slow saccades historically were thought to be pathognomic for
disease in the burst cells, there is considerable experimental and
clinical evidence that dysfunction at higher levels, such as the basal
ganglia18
and superior colliculus,19
can
result in slowing of saccades. As does Huntington disease, A-T may slow
saccades by disturbing the saccade generating mechanism at a level
above the burst cells. Patients with A-T may also generate a spectrum
of saccade velocities, however, ranging from those with essentially
normal dynamics to extremely slow movements that cannot be readily
identified as saccadic.
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Acknowledgements
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The authors thank David Zee and Kathleen Cullen for
comments on the manuscript, and Dale Roberts and Adrian Lasker for
technical assistance.
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Footnotes
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Supported in part by the Ataxia-Telangiectasia Children’s Project, the
Pediatric General Research Center at Johns Hopkins Hospital, and the
National Institutes of Health.
Submitted for publication June 15, 2001; revised November 2, 2001;
accepted November 27, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Richard F. Lewis, Massachusetts Eye and Ear
Infirmary, 243 Charles Street, Boston, MA 02114;
richard_lewis{at}meei.harvard.edu
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Abstract
Introduction
