VESTIBULO-OCULAR RESPONSES TO VERTICAL TRANSLATION
by
Ke Liao
Submitted in partial fulfillment of the requirements
For the degree of Doctor of Philosophy
Thesis Adviser: Richard John Leigh M.D.
Department of Biomedical Engineering
CASE WESTERN RESERVE UNIVERSITY
August, 2008
CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES
We hereby approve the thesis/dissertation of
Ke Liao
candidate for the Ph.D. degree *.
(signed) Robert F. Kirsch Ph.D (chair of the committee) R. John Leigh M.D. John Stahl M.D. Ph.D Louis F. Dell'Osso Ph.D Miklos Gratzl Ph.D
(date) May 20th, 2008
*We also certify that written approval has been obtained for any proprietary material contained therein.
Dedication
To my parents
献给我的父母
And my wife
和我的妻子 Table of Contents
Table of Contents 1
List of Tables 7
List of Figures 8
Acknowledgements 10
Abstract 11
Chapter 1
Introduction to Eye Movements during Natural Behaviors 13-40
1-1. Eye movements, visual acuity and motion parallax 13
1-2. Advantages of Studying Eye Movements 15
1-3. Eye movements during locomotion 17
1-4. Binocular vision and eye movements during locomotion 20
1-5. Prior Studies of translational vestibulo-ocular reflex (tVOR) 22
1-5-1. Methodological Considerations 22
1-5-2. Summary of tVOR Properties Reported to Date 24
1-6. Reference List 35
Chapter 2
Methodology 41-57
2-1. Summary of current eye movement recording techniques 41
2-1-1. Clinical observation and ophthalmoscopy 42
2-1-2. DC Electro-oculography (EOG) 43
1 2-1-3. Ocular electromyography (EMG) 44
2-1-4. Infrared reflection (IR) technique 44
2-1-5. Purkinje image tracker 45
2-1-6. Video-based systems (tracking pupil and reflected corneal images) 45
2-1-7. Magnetic search-coil systems 46
2-2. Rationale for using the magnetic search coil technique in the present study 48
2-3. Vestibular and visual stimuli selected for this study 49
2-4. Reference List 55
Chapter 3
Performance of the translational vestibulo-ocular reflex (tVOR) in normal human subjects 58-86
3-1. Introduction 58
3-2. Methods 60
3-3. Results 66
3-3-1. tVOR Responses during binocular viewing in ambient illumination 66
3-3-2. Comparison of tVOR responses during different viewing conditions 68
3-4. Discussion 70
3-4-1. Comparison with Prior Studies of tVOR 70
3-4-2. What mechanisms determine tVOR responses? 73
3-4-3. Possible role of tVOR during natural activities 74
3-5. Reference List 82
2 Chapter 4
Factors determining tVOR performance 87-105
4-1. Introduction 87
4-2. Methods 88
4-3. Results 91
4-3-1. Comparison of cancellation of tVOR and smooth visual tracking 91
4-3-2. Effect of moving visual background on tVOR 92
4-4. Discussion 93
4-5 Reference List 104
Chapter 5
Potential application of this study to clinic disorders---First Example: Progressive
Supranuclear Palsy (PSP) 106-130
5-1. Introduction 106
5-2. Methods 109
5-2-1. Vestibulo-Ocular Testing 109
5-2-2. Vestibulo-Spinal Testing 111
5-3. Results 112
5-3-1. Responses to Translating while Rotating 112
5-3-2. Responses to Click-Induced Stimulation 114
5-4. Discussion 115
5-5 Reference List 125
3 Chapter 6
Potential application of this study to clinic disorders---Second Example: Cerebellar
Ataxias 131-141
6-1. Introduction 131
6-2. Methods 132
6-2-1. Stimuli 132
6-2-2. Measurement of Eye and Head Movements 133
6-3. Results 134
6-3-1. Translational VOR 134
6-3-2. Rotational VOR 135
6-4. Discussion 135
6-5. Reference List 141
Chapter 7
General Discussion and Future Research of the Translation Vestibulo-Ocular Reflex
142-167
7-1. History of a scientific journey 142
7-2. Development of a new device to test tVOR 143
7-3. Safety procedures 148
7-4. Remaining engineering considerations 148
7-5. Evolution of findings and hypotheses for tVOR 149
7-5-1. The first finding: tVOR does not maintain foveal foveation of visual targets
149
4 7-5-2. The second finding: tVOR responsivity is determined by binocular visual
cues, but not vergence angle or visual tracking mechanisms 152
7-5-3. A hypothesis to account for visual influences on tvor and a test of the
hypothesis 154
7-5-4. Applying present findings to interpret the effects of disease 155
7-6. Concluding Remarks 157
7-7. Reference List 165
Appendix 1
Three dimension transformation algorithm 168-174
A1-1. Head three dimension rotation 168
A1-2. Eye three dimension rotations 169
A1-3. Required three dimension eye rotations 171
A1-4. Reference List 174
Appendix 2
Details of instrumentations 175-195
A2-1. Summary of system Infrastructure 175
A2-2. Control of Moog™ motion platform 176
A2-2-1. Introduction to the Moog™ motion platform 176
A2-2-2. Procedure to generate command to move the Moog™ platform 178
A2-2-3. Operation and maintenance of Moog™ 179
A2-3. Operation of Vicon™ infrared tracking system 181
5 A2-3-1. Introduction to Vicon™ infrared tracking system 181
A2-3-2. Calibration of Vicon™ 181
A2-3-3. Collecting data from Vicon™ 184
A2-4. Operation of the magnetic search coil system 184
A2-4-1. Introduction to the magnetic search coil system 184
A2-4-2. Calibration of 3-D coil system 185
A2-5. Synchronization of coil system and Vicon™ system 189
A2-6. Transformation of raw data to eye movement measurement 190
Bibliography 196-213
6 List of Tables
1-1 Fnctional classes of human eye movements 30
1-2 Summary of prior studies of tVOR 31
2-1 Methods available for measuring eye movements 54
5-1 Summary of clinical information of patients studied 123
6-1 Summary of Cerebellar Ataxia Patients Studied 140
7 List of Figures
1-1 Geometry of motion parallax 27
1-2 Geometry of the angular vestibulo-ocular reflex (aVOR) 28
1-3 Geometry of the translational vestibulo-ocular reflex (tVOR) 29
3-1 Representative eye movement records from one subject 78
3-2 Summary of tVOR responsivity and aVOR gain from all 20 subjects 79
3-3 (A) Comparison of direct and prism viewing on tVOR responsivity 80
3-3 (B) Comparison of vertical smooth-tracking and tVOR 80
3-4 Retinal image speed (RIS) as a function of target distance 81
4-1 Representative records of one subject during viewing far, near target and mirror viewing 97
4-2 Summary of tVOR responses to bob at 2.0 Hz 98
4-3 Representative records comparing direct versus prism viewing 99
4-4 Representative records of the effects of illumination on tVOR 100
4-5 Comparison of measured CanR and estimated CanR 101
4-6 Effects of tVOR with a moving background 102
4-7 Geometry of peak retinal image speed (RIS) as a function of target distance 103
5-1 Comparison of VOR for a normal subject and a PSP patient 120
5-2 Comparison of aVOR (A) and tVOR (B) responsivity ratio 121
5-3 Amplitudes of the VEMPs in PSP patients and healthy controls. 122
6-1 Representative responses to vertical translation in one normal subject and three patients 138
6-2 (A) Responsivity and vergence angle in normal subjects and patients 139
6-2 (B) Comparison of tVOR responsivity and rVOR gain in each subject 139
7-1 Temporal installation of Moog platform in office space 159
8 7-2 Close view of Moog base 160
7-3 Early photographic records of human locomotion 160
7-4 Chair and coil frame for Moog 161
7-5 tVOR during viewing targets at optical infinity 162
7-6 Moog with magnetic field coils, skate-board helmet and safety rails installed 163
7-7 Visual background on a large flat-screen monitor 164
A1-1 Vectors of coil frame and coils on the eye ball 173
A2-1 Moog motion platform 193
A2-2 Coil frame, helmet and the head rest mounted on the moog platform 193
A2-3 Magnetic search coil after inserted to human eye 194
A2-4 Front panel of the moog computer 195
9 Acknowledgements
Studying in USA and getting a Ph.D degree has long been my dream. Now I am
very close to it. I want to thank Dr. R. John Leigh for his years-long support. Without his help, I wouldn’t have been able to come to the United States. He kept the position and tried his best to help me after my visa was checked for one year. Without his help, my journey to pursue Ph.D degree would have also been much longer and harder.
I also want to thank my committee members, Drs. Louis F. Dell’Osso, Robert F.
Kirsch, Miklos Gratzl, and John Stahl for giving their insightful comments and guidance
during the course of my research. Their suggestions have helped me to develop a more complete and robust research project.
Many thanks to my colleagues at the Lab, from whom I got great help every time
and learned a lot during our conversations and discussions. Special thanks to our
secretary, Ms. Ann Rutledge, who has provided not only the office supplies but also wisdom of life with which I am able to live more comfortable in a new environment and
a different culture.
Finally, I want to thank my family including my parents and my wife. They have
always been supportive to me in my life. My wife gave up her career in China, and came
to United States to accompany me. Without her, I wouldn’t be able to focus on study and
do the research as I did.
10 Vestibulo-Ocular Responses To Vertical Translation
Abstract
by
Ke Liao
The Vestibular-ocular reflexes (VOR) generate eye movements to compensate for
head perturbations, and thereby safeguard vision during the head perturbations that occur
during locomotion, which consist of rotations and translations. In response to rotational
head perturbations, the angular VOR (aVOR) can generate oppositely directed eye
rotations that hold images of near and distant components of the visual world steady on the retina, a requirement for clear vision. In response to linear head perturbations, geometry dictates that the translational VOR (tVOR) can generate eye movements to hold either near or distant objects steady on the retina, but not both. Prior studies suggested that the purpose of tVOR is to minimize image slip of a visual target on the fovea (central retina), but without supportive evidence. We studied tVOR in human subjects, who sat on a moving platform that applied vertical head translations at 2 Hz, which is similar to the frequency of movements occurring during locomotion. We found that tVOR consistently generated eye movements that were only 60% of those required to keep the fovea pointed
at a visual target, irrespective of the viewing distance. Nonetheless, during viewing of a
near target, eye movements generated by tVOR increase by an order of magnitude
compared with viewing a target at optical infinity. We proposed that the main factor
governing tVOR responses was motion of the visual target with respect to the
background; this motion parallax signal provided information on the relative distance of
11 objects. We applied this knowledge to investigate tVOR function in patients with two types of neurological disease that commonly cause falls: progressive supranuclear palsy
(PSP) and cerebellar ataxia. Neither group of patients could modulate tVOR appropriately as a function of the target's viewing distance, implying abnormal otolith- mediated reflexes, which might also contribute to their frequent falls. Future studies of the human tVOR using moving platforms seem likely to elucidate other important properties in normal subjects and patients with postural instability.
12 Chapter 1 Introduction to Eye Movements during Natural Behaviors
1-1. Eye movements, visual acuity and motion parallax
Vision is our most important sense. One necessity for clear vision of the world is
that images of the environment must be held steadily on the retina. For visual objects
with high spatial frequency texture, such as printed text in books, retinal image slip must
not exceed 5 deg/s in order to achieve a clear and stable vision (Burr & Ross, 1982;
Carpenter, 1991). Since the eyes (and retinas) are attached to heads, head movements,
especially those during locomotion, pose a direct threat to clear vision (Grossman et al.,
1988; Pozzo et al., 1990). One important demand made of eye movements is to compensate for head perturbations during locomotion so that vision remains clear.
The retina of the human eye contains photoreceptors (rods and cones), which are
not uniformly distributed. A specialized area of the retina, called the fovea or macula, has
the highest concentration of cone photoreceptors and corresponds to the region with
greatest visual acuity. The area of fovea has a diameter of only about 1.0 mm, and
corresponds to a visual angle of about 0.5 deg. In order to achieve clear vision of a
feature of interest in the environment, its image must to be brought to the foveal region of
the retina (Jacobs, 1979). A second important demand made of eye movements is to point
the fovea at features of interest.
13 In general, the purpose of eye movements is to aid vision by controlling the direction of gaze. Gaze is defined as the angular direction of the eyes in space and corresponds to the foveal line of sight. One class of eye movements holds gaze steady, especially during locomotion, so that images of the world are still enough to be seen clearly. This type of eye movements includes reflexes that mainly use vestibular and visual sensory inputs. They are present even in animals that do not have a well developed fovea, such as fish and rabbit (Walls, 1962; Carpenter, 1988).
Another class of eye movements shift gaze from one point to another, so that the image of the target is brought to the fovea. There are three main types of these
“targeting” movements (Leigh & Zee, 2006): (1) Saccades, the rapid conjugate eye movements that shift gaze; (2) Visual tracking, conjugate eye movements that holds the image of a small moving target on the fovea, or holds the image of a small near target on the retina during linear self-motion; (3) Vergence, disjunctive (oppositely directed) eye movements, are in responses to shifting gaze between targets located at different distances, so that images of a single object are placed on both foveae simultaneously to acquire a clear single vision. Table 1-1 summarizes the purpose and properties of each functional class of eye movements.
Although vision is clearest when the images of the visual world are held steady on the retina, it is not possible to achieve this comprehensively if the subject’s head moves linearly (translates) and the visual scene contains objects at different distances (Fig. 1-1 and 1-3). In this situation, relative motion of retinal images (motion parallax) provides
14 the brain with information about the relative distance of different objects (Howard &
Rogers, 2002). As discussed in later sections of this thesis, sometimes it is advantageous to generate eye rotations that do not hold the image of one object steady on the retina, but rather minimize retinal image motion of several objects lying at a range of different distances. This would be the case, for example, as we walk through a forest.
The present research especially concerns vestibular and visual-tracking eye movements such as occur during locomotion, which are described in more detail in section 1-3.
1-2. Advantages of Studying Eye Movements
The eyes can rotate with three degrees of freedom, but for practical purposes, they do not translate in the orbit. Rotations of each eye are controlled by six extra-ocular muscles, consisting of a pair of horizontal rectus muscles (which mainly rotate the eye horizontally), a pair of vertical rectus muscles (which mainly rotate the eye vertically) and a pair of oblique muscles (which mainly rotate the eyes around the line of sight – torsion). The geometry of eye rotations have been the subject of considerable research interest (Haslwanter, 1995; Tweed et al., 1998; Wong, 2004).
The distinctive properties of eye movements provide several opportunities to
study the underlying brain control mechanisms. One advantage is that they are easily accessible to precise measurement in each rotational plane (methods of measurement are discussed in Chapter 2), which provides a foundation for further quantitative analysis and
15 modeling. A second advantage is that, unlike movements of the limbs or trunk, the eye
muscles move the globe against an unchanging mechanical load, and may lack a
monosynaptic stretch reflex (Keller & Robinson, 1971). This means that it is possible to
mathematically relate the amount of eye rotation to the discharge properties of ocular
motoneurons by simple, linear differential equations (Robinson, 1970). A third advantage
is to define the classes of eye movements by distinguished properties suited to carry out a
specific task, such as gaze-holding and gaze-shifting movements (Carpenter, 1988). In
addition, each type of established functional eye movement has a well identified
anatomical substrate.
Clinically, abnormal eye movements are often very helpful to neurologists in diagnosing a range of common neurological disorders, including stroke, multiple sclerosis (MS), as well as degenerative disorders (e.g., the parkinsonian syndromes, including progressive supranuclear palsy, PSP) (Leigh & Zee, 2006). Taking all these advantages together, the study of eye movements provides a powerful approach to better understand normal motor control systems and how malfunctions of such control systems due to certain diseases can cause impaired behavior disorders. For example, the research
summarized in this thesis uses eye movements as an experimental tool to better understand why patients with PSP or cerebellar ataxia fall.
16 1-3. Eye movements during locomotion
During locomotion, perturbations of the head occur with each step. These
perturbations consist of rotations and translations. Prior studies have defined the
frequency and amplitude of head movements as normal subjects walk or run. An
important property of head perturbations during locomotion is their frequency, which
ranges 0.5 – 5.0 Hz (Grossman et al., 1988). Typically, vertical perturbations (either
rotation – pitch, or translation – bob) are twice that of horizontal perturbations, because
the head goes up and down with each step, but turns from side to side during a pair of
steps. A generally accepted principle is the brain generates eye rotations to “compensate”
for head perturbations, so that vision remains clear during locomotion. How is this
achieved?
The vestibulo-ocular reflexes (VOR) are the main guardians of clear vision during
locomotion. The evidence for this is that individuals who have lost all vestibular function cannot see clearly during locomotion; for example, they cannot read street signs (J.C.,
1952). This means that visual tracking mechanisms are incapable of generating compensatory eye movements alone. Specifically, visual tracking responds to stimuli above ~ 1 Hz with increasing phase lag causes slip of images of the world on the retina
(Lisberger et al., 1981). The phase lag of visual tracking at frequencies > 1 Hz is due to
delays in the visual system of >70 ms (Gellman et al., 1990). In contrast, the
vestibulo-ocular reflexes are generated at a latency of < 25 ms (Maas et al., 1989;
Bronstein & Gresty, 1988; Ramat & Zee, 2002), and phase lags of eye rotation with
17 respect to head rotation are small over the frequency range 0.5 – 5.0 Hz (Wilson &
Melvill Jones, 1979). There are two kinds of VOR, suited for the two kinds of head
perturbations.
1) The angular VOR (aVOR) compensates for rotational head movements by
rotating the eyes in the opposite direction to the head rotation. It is conserved
through evolution (Walls, 1962), and can be found in animals like fish, and
has received extensive research during the past 30 years.
2) The translational VOR (tVOR) compensates for translational head movements
by rotating the eyes in the opposite direction to head translation. It is only well
developed in humans and non-human primates with frontal vision (Bronstein
& Gresty, 1988; Israël & Berthoz, 1989; Paige, 1989; Paige et al., 1998;
Angelaki, 2004).
It is helpful to consider the geometric demands of the aVOR and tVOR (Fig. 1-2
and 1-3), especially as a human subject views either a distant or near object. If a subject views a distant object and rotates the head, then the required eye rotation to hold the line of sight (direction of foveal vision, or gaze) is equal and opposite to the head rotation. If the viewed environment is at optical infinity, all images on the retina will be held still
during the head rotation, permitting clear vision of the entire surroundings. However, if
the subject views a near object, the situation is different because the eyes do not lie at the
center of rotation of the head, and translate with the head rotation. Thus, during viewing
of a near target, eye rotations need to be larger than head rotations, by more than 30% for
18 targets at 15 cm or nearer (Viirre et al., 1986). Nonetheless, difference in retinal image
motion on the fovea versus the peripheral retina will differ by only about 30%.
Now consider tVOR (Fig. 1-3). If the subject views a target at optical infinity,
and bobs the head up and down (translation in vertical or Z axis), no eye movements are
required to be generated to hold images steady on the retina (required peak eye velocity =
0 deg/s). As the object moves closer, increasingly large eye movements are required, as
described by the tangent function:
−1 A θ = tan D When one considers the situation while viewing an object at 15 cm, large eye
rotations are required to hold the foveal line of sight on target. For example, if the head
bobs up and down by 3 cm (peak-to-peak), which may occur during locomotion, then the
required eye rotation is over 11 deg. If the frequency of these bob movements is 2 Hz,
then the required peak eye rotation is over 70 deg/s. These geometric considerations
indicate that it is impossible to simultaneously compensate for retinal image motion due
to objects located at optical infinity and at near. This fundamental fact has been ignored
in prior studies of tVOR, in which it is assumed that this reflex acts to hold the foveal
image of a near target stationary and ignore motion of images of the background that lie
at some distance. A major consideration in the present research is that tVOR in humans is set at values to minimize motion of foveal image (near target) with respect to peripheral retinal image motion (distant background).
19 Thus, we postulated that the apparent goal of the tVOR is to minimize the
velocities of the relative retinal image motion between objects in different
planes. Specifically, during subject translation, relative motion of near and distance
objects is inevitable and can not be reduced by vestibular or visual-tracking eye
movements. Relative image motion occurring during subject translation provides an
important cue to the relative distances of objects. Motion discrimination of relative
motion is better at low than at high velocities of retinal image motion (Howard & Rogers,
2002). Thus, motion parallax signals should be optimized when the retinal velocities that
result during subject translation are low.
1-4. Binocular vision and eye movements during locomotion
So far, this review has considered movements only of a single eye. However, our
two eyes are separated horizontally in our heads by several centimeters. This means that
while each eye’s view of a distant visual world will be similar, during viewing of a near target, each eye will receive a different signal. Moreover, there must be independent control of the eyes so that the fovea of each eye can be aimed at a near target, and this is achieved by vergence movements. Two main types of vergence movements are recognized, depending on the stimulus that drives them (Leigh & Zee, 2006): (1) fusional vergence movements are generated when there is a disparity between the location of images on the retina of each eye; (2) accommodative vergence occurs in response to the blurred images on the retina and needs to adjust the accommodation of the lens and
20 pupillary constriction appropriate for the nearness of the object. Both fusional and
accommodative vergence are important for depth perception.
Accommodative effort alone can produce vergence movements. For example, if
one eye changes fixation between two objects at two distances while the other eye is covered, accommodative vergence eye movements occur in the eye under cover
(Carpenter, 1988). The accommodative vergence during monocular viewing is open-loop response because its purpose is to adjust accommodation appropriate for the object
distance thus focus the image of the object on the fovea of the viewing eye, the vergence movement of the other eye does not affect the final output. Without appropriate feedback,
the vergence during monocular viewing are always less than that during binocular
viewing, and may vary from subject to subject for the target at same distance. In
comparison, fusional vergence generates eye movements to minimize the retinal disparity
between two eyes so that both lines of sight of the eyes are pointed at the target. Hence,
fusional vergence uses negative visual feedback to minimize the retinal disparity.
During head rotations, if the subject views a near target (Fig. 1-2 , then the eyes must be converged and one eye may rotate more than the other depending on the relative distance between each eye and the visual target (Viirre et al., 1986). Similarly, during head translations, if the subject views a near target, rotations of one may be greater if it is nearer to the target (Fig. 1-3).
During locomotion, the different views of near objects provided by each eye
(disparity-based stereopsis) contribute to the subject’s ability to localize the distances of
21 objects in the visual environment (Howard & Rogers, 2002). Thus, stereopsis and motion parallax work together to provide 3-D percept of the environment that can be used for
navigation.
1-5. Prior Studies of translational vestibulo-ocular reflex (tVOR)
1-5-1. Methodological Considerations
Whereas the human aVOR has been the subject of intensive research, especially
over the past half-century (Wilson & Melvill Jones, 1979; Leigh & Zee, 2006), tVOR has
been less frequently studied in humans. Part of this discrepancy reflects technical
difficulties posed in studying tVOR. Thus, on the one hand, aVOR can be tested as
subjects actively or passively rotate their head on shoulders, or during passive en-bloc
rotation in a swivel chair. On the other hand, head translations are hard to achieve
manually without also inducing head rotations. In addition, en-bloc translations generally require large devices such as sleds or moving platforms, which have been expensive
(Paige, 2002). Head translations occur naturally during locomotion, including bob movements due to the bouncy nature of erect human posture (Massaad et al., 2007).
However, both head rotations and translations occur during natural locomotion (Moore et al., 1999; Hirasaki et al., 1999). Recently, less expensive moving platforms have become available that make it possible to study tVOR due to translations in one plane without accompanying rotations. The present study uses one such platform, which is described further in Chapter 2. An alternative is application of devices that seek to translate the
22 head through small amplitudes on the trunk (“head sled”) (Ramat & Zee, 2005; Kessler et
al., 2007).
When the human tVOR has been previously tested, precise methods for
measuring eye movements have seldom been used. Thus, although DC
electro-oculography (which measure the corneal retinal potential) can signal larger
horizontal eye movements with some reliability, it may not provide useful measurement
of the small eye movements that occur during viewing of distant targets (Gianna et al.,
1997). In the current research, 3-D eye rotations were measured with precision using the
magnetic field/scleral search coil method, which is also summarized in Appendix 1.
A third limitation of prior studies of the human tVOR is that the visual
conditions employed were unlike those during natural locomotion. Thus, subjects usually
viewed small targets, such as light-emitting diodes (LEDs) in otherwise dark rooms
(Ramat et al., 2005). As will become evident in the present thesis, tVOR responses are
greatly influenced by viewing conditions and illumination. Specifically, visual cues such as motion parallax and relative size are not available when subjects view a LED in an otherwise dark room, but it was found that such visual cues are very important for determining tVOR behavior.
Finally, although tVOR has been studied using precise methods in squirrel and
rhesus monkey (Paige & Tomko, 1991a; Paige & Tomko, 1991b; Schwarz & Miles, 1991;
Angelaki, 2004), species differences may well exist due to the erect, straight-legged gait
23 of humans that causes more prominent bob translations during walking (Massaad et al.,
2007).
1-5-2. Summary of tVOR Properties Reported to Date
Prior studies of tVOR in human subjects are summarized in Table 1-2. Although
there have been attempts to measure tVOR since late 1960s (Benson, 1974), modern
studies of tVOR started when Geoffrey Melvill Johns and colleagues tested it with a
vertical flight simulator and during aircraft flight (Melvill Jones et al., 1980); they used
electro-oculography (see Chapter 2 for a description of the limitations of this technique)
to measure the eye movement, and reported very low response in darkness. Several other
groups (Buizza et al., 1980; Berthoz et al., 1987; Bronstein & Gresty, 1988; Baloh et al.,
1988; Israël & Berthoz, 1989) also studied tVOR responses during 1980s, but either used
weak translational stimuli or did not require subjects to view a near target, or even tested
in darkness. Gary D. Paige was among the first to realize that tVOR is modulated by the
viewing distance of the target, and to apply stimulus frequencies corresponding to natural
head perturbations, such as occur during locomotion (>2 Hz). However, he also tested his
subjects while they viewed optotypes in otherwise dim illumination, and reported that
tVOR compensated for only about 45% of that required for foveal fixation, when the
target was at 36cm. Subsequently, several other labs have studied interaural or surge
tVOR in response to transient stimuli, and all reported that compensation gain (defined as
eye rotational velocity / required eye rotational velocity to maintain foveal fixation of the
visual target) was ~ 0.5 (see Table 2) (Busettini et al., 1994; Gianna et al., 1997; Gianna et
24 al., 2000; Ramat & Zee, 2003; Ramat et al., 2005; Crane et al., 2003; Tian et al., 2006).
Similarly, attempts to measure tVOR during locomotion have reported either large amounts of retinal slip (Crane & Demer, 1997) or oscillopsia (Moore et al., 1999) during near viewing, implying that compensation gain was inadequate to hold the fovea on target. The otolith-ocular reflexes have also been tested along with the canal-ocular reflexes by rotating subjects about an eccentric vertical axis (Anastasopoulos et al., 1996; Gianna-Poulin &
Peterka, 2008), or an axis tilted from vertical, such as barbecue-spit rotation (Paige, 2002).
The finding that tVOR appears not to be able to compensate for head translations
so that clear foveal vision is maintained has led to a number of theoretic considerations of
how tVOR performance might be optimized when head rotations accompany head
translations, which occurs during locomotion. However, these hypotheses have not been
tested by applying controlled translation and rotation stimuli, during viewing of near
visual stimuli in ambient illumination. The deficiencies of prior studies of human tVOR
and the new opportunities offered by affordable moving platforms and magnetic search
coil technology motivated a series of experiments that constitute this thesis. These studies
defined properties of tVOR that led to a re-examination of the purpose for which it
evolved. Specifically, the hypothesis is that tVOR cannot simultaneously stabilize images
of far and near objects on the retina, and rather than stabilizing only foveal images, tVOR
is set at a compensation gain that minimizes all retinal image motion – from objects far or
near – and thereby optimizes motion parallax information, which is vital for judging the
distances of objects in the path of locomotion. This hypothesis is then taken further in
25 studies of patients with neurological disorders that fall. A loss of the ability to modulate tVOR responses to viewing distance was discovered, which constitutes a new type of central vestibular disorder.
26
P1 P1
P2 P2
D
(A) (B)
Figure 1-1. Geometry of motion parallax. (A) Information about the distance of two points is absent when they are viewed from one location. (B) When an observer moves in a direction that is orthogonal to objects lying in one depth plane, relative motion of the near object with respect to the far object (motion parallax) provides information to the visual system about the relative positions of the two objects in the environment.
(Redrawn from Howard and Rogers, page 412, Figure 25.1)
27
Figure 1-2. Geometry of the angular vestibulo-ocular reflex (aVOR). During viewing of far targets, aVOR must generate eye rotations that are equal and opposite to head rotations to hold gaze (the foveal line of sight) on the visual target. However, since the eyes do not lie at the center of rotation of the head, during near viewing, eye rotations must exceed head rotations to hold the eyes on target. The equations at top describe the relationship between the radius of head rotation (R), the viewing distance (D), head rotation (φ) and required eye rotations (θ) of the right and left eyes to hold the eyes on target. During viewing of targets as close as 15 cm, eye rotations may exceed head rotations by over 30% (Viirre et al., 1986).
28 D θ A θ A θ = tan −1 D A
B
Figure 1-3. Geometry of the translational vestibulo-ocular reflex (tVOR). (A): During vertical
head translations (in the Z-axis, bob), vertical eye rotations are required to hold the eyes on target.
The magnitude (θ) of eye movements required to hold the foveal line of sight on the target is given by the equation at bottom, where D is the target distance, and A is the amplitude of the head translation. (B): Note that during viewing a near target, larger eye rotations are required. It follows that tVOR cannot generate eye rotations that hold images of far and near targets simultaneously still on the retina.
29 TABLE 1–1. FUNCTIONAL CLASSES OF HUMAN EYE MOVEMENTS*
Class of Eye Movement Main Function Vestibular Holds images of the seen world steady on the retina during brief head rotations or translations
Visual Fixation Holds the image of a stationary object on the fovea by minimizing ocular drifts
Optokinetic Holds images of the seen world steady on the retina during sustained head rotation
Smooth Pursuit Holds the image of a small moving target on the fovea; or holds the image of a small near target on the retina during linear self-motion; with optokinetic responses, aids gaze stabilization during sustained head rotation
Nystagmus quick phases Reset the eyes during prolonged rotation and direct gaze towards the oncoming visual scene
Saccades Bring images of objects of interest onto the fovea
Vergence Moves the eyes in opposite directions so that images of a single object are placed or held simultaneously on the fovea of each eye * (Leigh & Zee, 2006)
30
31
32
33
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40 Chapter 2 Methodology
2-1. Summary of current eye movement recording techniques
To fully realize the advantages offered by studying eye movements, it is
necessary to make reliable measurements. A number of methods are currently available,
each offering certain advantages and disadvantages (Young & Sheena, 1975; Carpenter,
1988; DiScenna et al., 1995; Leigh & Zee, 2006). A decision on which method to use
depends on the question to be addressed in the experiment (which often specifies the precision required), as well as human factors. Thus, some individuals will not tolerate the
discomfort present with more precise methods (e.g., wearing a contact lens), and simpler
methods, or even observation is sometimes all that is possible. Thus, a judgment must be
made in the case of each subject as to whether the methods available will answer the
question posed. Here are several key parameters based on which the judgment will be
made:
• Spatial resolution (e.g. 1 part in 4096; or the angular width of one retinal
photoreceptor, 0.02 deg to the full range of eye-head gaze movements, 180
deg)
• Temporal resolution (e.g. a bandwidth of 0-50 Hz is satisfactory for
measuring the VOR, but 0-150 Hz is required for saccades).
• Need to record vertical as well as horizontal eye movements; or 3-D rotations
41 • Reliability and speed of calibration: Can subjects be relied on to look at visual
stimuli? Should the system be pre-calibrated before the subject arrives?
• Noise: Does the ocular motor behavior under study (e.g., microsaccades)
require a sensitive noise-free measurement?
• Cost: Silver electrodes and scleral search coils are expensive, but a
video-based monitoring system has no need for “supplies.”
A good system for eye movement recording should have a spatial resolution of 1 part in 4096 or better that can be adjusted to the movement range under study; a bandwidth of 100 Hz or higher in temporal resolution; be able to record the vertical and, if necessary, 3-D movements; noise should be less than 0.1 deg (and be capable of being reduced further if needed); setup and calibration should be fast and reliable. Contactless methods are preferred, but most subjects can also tolerate skin electrodes and even contact lenses. In the sections that follow, key features of currently available methods for recording eye movements and their performance will be reviewed by referring to the key parameters listed above. Methods available are summarized in Table 2-1.
2-1-1. Clinical observation and ophthalmoscopy
The most frequently used method by clinicians is simply to observe the subject make each of the different functional classes of eye movements (Table 1-1) (Leigh & Zee,
2006). While observation provides no permanent record, a careful and systematic examination, especially when directed to testing a specific hypothesis, has often provided
42 important clues that guide subsequent quantitative studies. The sensitivity of observation may be extended by viewing with the ophthalmoscope, by which it is possible to detect eye movements as small as 0.1 deg. Making a video record may often capture important qualitative features that can provide an adjunct to interpretation of quantitative measurements.
2-1-2. DC Electro-oculography (EOG)
The electro-oculography works by measuring the potential difference between cornea and retina (the corneal-retinal potential), which changes as a function of horizontal eye position (Carpenter, 1988). By placing skin electrodes at the temporal and nasal borders of the orbit, horizontal eye rotations can be measured, since the relationship between horizontal eye rotations and the corneal-retinal potential is quite linear.
Electrode placed above and below the orbit can be used to signal blinks but are unreliable for measuring vertical eye rotations because of a large artifact due to the eyelid (Barry &
Melvill Jones, 1965). The advantages of EOG are that it is noninvasive, causes minimal discomfort, operates over a large range of rotation (+ 40 deg) with reasonable linearity, a potential sensitivity of about 1 deg, and it is inexpensive. It is also possible to measure eye movements during eye-head movements using EOG (head movements are measured using a separate sensor). In addition to being applicable to children, EOG is also widely used by clinicians to test vestibular function in patients complaining of dizziness. A major disadvantage of this method is the predisposition to contamination of the eye
43 movement signal with electrical, electromyographic or biological noise and lid artifacts.
Further, spontaneous baseline drifts and changes of calibration occur with any changes in room light, and require repeated calibration.
2-1-3. Ocular electromyography (EMG)
Ocular electromyography uses needle electrodes that are inserted through the skin into the extraocular muscles to measure the electrical activity of muscle fibers during eye movements. It is an uncomfortable procedure and is used only in selected individuals to answer specific issues about activity in extra-ocular muscles. As a research procedure, it has provided important information about the “division of labor” between the different types of extraocular muscle fibers (Scott & Collins, 1973).
2-1-4. Infrared reflection (IR) technique
This technique works by quantifying the difference of infrared light reflected from the sclera between a pair of sensors (phototransistors). Infrared light is used so that one can test subjects in darkness. It is mainly used to measure horizontal eye position
(Young & Sheena, 1975). The differential signal from the emitters provides a representation of horizontal eye rotation relative to the emitter over a range of approximately + 20 deg. The bandwidth of this method is broad enough for all eye movements (0 - 200 Hz) with a resolution of 0.1 deg, and a low noise level. This method causes little or no discomfort, and is well suited for measurement of children and patients
44 who do not want to wear contact lenses. Vertical eye movements can be recorded by this
methodology, but the linear range is smaller (+ 10 deg). The main disadvantages of the
technique are its limited linear range, and the need to hold the subject’s head still (head
movements with respect to the sensor will signal artifactual eye movements). The
accuracy of calibration depends on the ability of the subject to sustain steady fixation of
an array of visual targets.
2-1-5. Purkinje image tracker
Purkinje eye tracker measures the relative displacement of the images formed by
the reflection of a light source at the anterior corneal surface and the posterior lens surface (known as the 1st and 4th Purkinje images, respectively) to determine eye position. The advantages of this method are that discomfort is minimal and resolution is <
0.5 deg. However, the method requires that subject’s head be rigidly immobilized on bite bar, and is not suitable for experiments that permit relatively free movement by the subject (Young & Sheena, 1975). Motion of the lens of the eye during rapid eye movements causes an artifact for all saccades. In addition, this device is expensive to buy and maintain.
2-1-6. Video-based systems (tracking pupil and reflected corneal images)
Several video tracking systems (VTS) are currently available. Some use multiple
infrared light sources and small video cameras to simultaneously measure the positions of
reflected corneal images and the center of the pupil (DiScenna et al., 1995). By
45 measuring relative movement of the cornea and pupil, which rotate on different circles, it
is possible to calculate a signal proportional to eye rotation that is relatively free of
translational artifacts (due to head motion). Such devices may have a linear range of
approximately + 40 deg horizontally and + 30 deg vertically. Sampling rate can be as
high as 250 Hz with the head fixed, and system noise with standard deviation of < 0.04
deg (determined by the resolution and digitization rate of the camera). The video-based
eye tracker is noninvasive, with minimal discomfort and a high resolution. In comparison
with the magnetic search-coil technique (described below), the VTS generally provides
reliable measurements of horizontal and vertical eye position (DiScenna et al., 1995);
some systems also provide torsional eye position. Eye velocity is typically noisier than corresponding coil signals, but can be improved with appropriate filters (Das et al.,
1996).
2-1-7. Magnetic search-coil systems
Invented by D. A. Robinson in 1963, the scleral search-coil technique is based
upon the magnetic induction of a small coil which is embedded in a flexible ring (silastic
annulus) of silicone rubber which adheres to the limbus of the eye concentric with the
cornea (Robinson, 1963; Collewijn et al., 1975; Ferman et al., 1987). The subject sits in
the “field coils” – magnetic fields that are alternating spatially and temporally in
quadrature; either two or three magnetic fields, each oscillating at a different, non-harmonic frequency can be used. The field coils induce an electric current in the
46 search coils when the eyes rotate. With a standard search coil, which has loops of wire in
the frontal plane, after amplification and phase-locked detection, two analog voltages are
obtained which are proportional to the horizontal and vertical eye position. With a 3-D
coil, which, in addition, has a second coil wound in the sagittal plane, it is possible to measure horizontal, vertical and torsional eye position (Ferman et al., 1987). At present, the magnetic search-coil technique is generally regarded as the most reliable and versatile approach that can be applied to both animal and human studies. This method, which is sensitive to ~ 0.02 deg, and has a potential linear range of ±180 deg, is able to measure all kinds of eye movements, including miniature eye movements such as tremor, drift and microsaccades. The system bandwidth is potentially 0-1 KHz. When a search-coil is attached to the forehead of the subject, it can be used to measure head positions. The eye position relative to the head can be achieved by subtracting head position from the gaze position. This method has wide applications ranging from neurophysiology to clinical studies. The only disadvantage is that subjects are required to wear scleral annulus
(contact lens) on the eyes after topical anesthetic drops are applied, and the recording time is usually limited to 30 minutes. A minor scratch may occur on the cornea during the experiment in < 1% of subjects, which usually resolves in a few hours. The scleral search coil/magnetic field method has been applied to approximately 1,000 subjects in the
Daroff-Dell’Osso laboratory over the past quarter-century, without adverse effects.
47 2-2. Rationale for using the magnetic search coil technique in the present study
At present, the magnetic search coil technique is still widely regarded as the “gold
standard” for measuring eye movements of human, including patients. No other method
allows precise measurement of 3-D eye rotations over a large range of movement with a
high bandwidth. Nonetheless, and even though this facility is available in the
Daroff-Dell’Osso laboratory, a justification for its use in the current experiments is
appropriate.
It was of crucial importance to measure 3-D eye rotations with accuracy in the
proposed experiments for several reasons. First, the experiments combined vertical
translations (bob) with horizontal rotations (yaw) while subjects viewed a far or near
target. Thus, subject’s eyes were variably converged, and rotated in both horizontal and vertical directions. To extract reliably responses due to translational and rotation stimuli,
3-D signals were essential; from these, rotation vectors could be calculated, as described
in Appendix 1. Second, the eye rotations induced by translation during viewing of a far
target are small and call for a sensitive method with low noise. Third, it was important to
be able to measure the latency of response of vestibular reflexes, and for this a broad
system bandwidth (0-150 Hz) and a high digitization rate (500 Hz) were necessary. The
thresholds for measuring the onset of these movements (some as low as 1.5 deg/s)
necessitated the use of a low-noise, high-precision recording method. Fourth, movements of the subject’s head with respect to the platform helmet were always a concern. A head coil could easily detect rotational components of such movements. Fifth, some of our
48 patients – especially those with progressive supranuclear palsy (PSP) could not be relied upon to look at visual targets for calibration, since they have a vertical saccadic gaze palsy. It is possible to pre-calibrate the search coil in the magnetic field prior to placing the search coil (contact lens) on the patient’s eyes; in this way, we could be sure of our calibration. The magnetic search coil system answered all of our experimental needs, and no other available system or methodology could do so. Thus, the magnetic search coil technique was the method of choice for the measurement of eye and head rotations in experiments described in this project.
2-3. Vestibular and visual stimuli selected for this study
After reviewing the literature (see Table 1-2), we found that prior attempts to measure tVOR behavior commonly suffered from three main deficits in experiment design. First, many studies employed low-frequency stimuli or low acceleration step movements, even though natural head movements have a frequency range of 0.5 – 5.0 Hz
(Grossman et al., 1988; Pozzo et al., 1990). Moreover, if tested in ambient illumination, tVOR can only be distinguished from visual tracking responses only above about 1.5 Hz
(Lisberger et al., 1981). Second, some prior studies have only test tVOR during visual fixation of distant targets. As described in Chapter 1, when the target is at infinity, geometry dictates that there is no need to move the eyes even when head is perturbed in a translation; and during viewing of a near target are eye movements required. As shown in
Chapter 3, eye movements induced by head translation may increase by as much as 10
49 times from viewing a target at 2m versus 15cm. Therefore, it was important to select a near target so a significant amount of tVOR response could be measured. A third problem with concerns the level of illumination. Most prior studies of tVOR were performed as subjects viewed a small target, such as a light-emitting diode, under dim illumination or even in complete darkness. If tVOR is to be adjusted appropriately to visual needs, it seems important to provide adequate illumination of the environment, including the surrounds, such as occurs during normal day-time activities.
More generally, we want to design the stimuli in our experiments to simulate
daily activity, especially locomotion. During locomotion, the head rotates vertically
(pitch) with each step, but rotates from side to side (horizontally – yaw) with every two
steps (Grossman et al., 1988). The head also translates vertically at 2Hz, and rotates (yaw)
at 1Hz (Pozzo et al., 1990). Therefore we design our stimuli to have 2 Hz vertical
sinusoidal translation and 1 Hz horizontal rotation, either in combination (to simulate
locomotion) or separate (in control experiments).
Our subjects sat in a chair on a Moog 6DOF2000E electric motion platform (East
Aurora, New York) that could move with six degrees of rotational and translational freedom
through a range of + 20 deg and + 20 cm, with peak rotational acceleration of 400 deg/s2
and peak linear acceleration of 5 m/s2 (0.5 g). Belts were used to secure the subject’s torso
and a snugly fitting skate-board helmet, inlaid with foam, was used to stabilize the subject’s
head. We specified the following stimuli. Each experimental run, which lasted 90 s, started with 3 cycles of bob at 0.2 Hz (typical amplitude + 5.6 cm) followed, after a pause of 3 s, by
50 3 cycles of yaw at 0.2 Hz (typical amplitude + 6 deg). We assumed that our normal subjects
could continuously view the visual target during these 0.2 Hz stimuli (due to normal smooth
pursuit) and used their eye movements as one index of “ideal” responses. Then, we applied
bob translations at 2 Hz (typical amplitude + 1.5 cm) for 12 s to test tVOR. After a 3 s pause,
we applied yaw rotations at 1.0 Hz (typical amplitude + 5 deg) for 12 ss, to test aVOR.
Finally, after a 3 s pause, we applied combined bob at 2 Hz and yaw rotation at 1 Hz
(starting at zero phase difference) for 12 s (combined vertical translation and horizontal rotation).
The visual target was presented with all room light on, and therefore all the visual
cues were available for the subjects to make the best estimation of the target distance. There
were two main visual conditions to compare tVOR performance for normal subjects. (1)
Subjects binocularly viewed a laser spot projected on a wall at a distance of 2m (“far target”). (2) Subjects binocularly viewed a “near target” (reflective ball, diameter 1 cm) suspended at a distance of ~ 17 cm in front of their left eyes.
In order to investigate visual factors that might determine tVOR behavior, we
presented different visual stimuli by manipulating some of the visual cues. (1) 20 normal
subjects were asked to view the near target monocularly (right eye occluded), to abolish
binocular cues. (2) Six subjects viewed targets binocularly at 2m, 40 cm and 17 cm first
directly and then with a 15- or 10-diopter base-out prism placed before the right eye to
induce a larger vergence angle. Thus, each stimulus was viewed binocularly at one
distance with two different vergence angles. (3) In two subjects, we turned the room
51 lights out for periods of 2-4 s, as subjects attempted to fix upon the remembered location
of the near target (no visual cues available), which they had previously viewed
binocularly. (4) These two subjects also binocularly viewed the near target under
conditions of strobe illumination, in order to minimize retinal image slip information
(Melvill Jones & Mandl, 1981). The strobe illumination was achieved using an array of
bright light-emitting diodes, which were illuminated at a flash rate of 4 Hz, with a 30 ms
flash duration.
A special visual stimulus was presented for us to measure the “visual
cancellation” of tVOR. Subjects viewed a small mark on the bridge of their own nose
through an earth-fixed mirror at a distance of ~ 8.5 cm (Han et al., 2001). When the
subject was translated by the platform, the image in the mirror moved with the subject, therefore subject had to cancel their tVOR response to fixate their eyes on the target.
We also tested smooth pursuit in 13 subjects to determine whether tVOR behavior
in ambient lighting could be explained simply by the contribution of visual tracking.
They were seated in a stationary chair, and asked to follow a moving visual stimulus
(Amsler grid), subtending 25.6 deg horizontally and 18.6 deg vertically with a central dot, at a target distance of 110 cm. The movement of the grid replicated the movement of the target relative to the subject during the platform’s translational movement.
For our patients with progressive supranuclear palsy (PSP) and cerebellar ataxia,
we also present a picture of face that subtended ~ 50 deg at 15 cm to help. Such a
52 stimulus provides a more compelling visual stimulus than the reflective ball we used as a
near target, especially to patients who have difficulties fixating upon a small near target.
To summarize: In contrast to prior studies of tVOR, we applied head movements
corresponding to those occurring during locomotion under ambient illumination of targets that were similar to near and distant features of the natural visual environment.
53 TABLE 2-1 METHODS AVAILABLE FOR MEASURING EYE MOVEMENTS*
METHOD ADVANTAGES DISADVANTAGES Simple No discomfort; detects qualitative No record, unless video is observation, behaviors; ophthalmoscope made; observations are ophthalmoscopy, sensitive to 0.1 deg qualitative video D.C. Electro- Non-invasive, minimal discomfort; Electrical and oculo- graphy can record horizontal movement electromyographic noise, lid (EOG) ranging + 40 deg; resolution of ~ 1 artifact; unstable baseline, deg; applicable to children. Widely requiring repeat calibration used in clinical vestibular labs and adaptation to level of ambient lighting. Unreliable for vertical eye movements. Infrared Non-invasive, minimal discomfort; Limited range (+ 20-30 deg differential resolution 0.1 deg; little noise. horizontally and + 10 deg reflection vertically) technique Purkinje image Non-invasive; resolution < 0.5 Lens motion artifact with tracker (lens and deg; little noise. saccades; subject’s head cornea) must be immobilized; expensive to buy and maintain. Video-based Non-invasive, minimal discomfort; Subject required to wear systems (tracking resolution < 0.5 deg; noise head-gear; digitization noise pupil or reflected depends on camera resolution and of system may limit analysis corneal images) digitization rate. of slow eye movements. Magnetic search Sensitive to <1 minute of arc; Subject required to wear coil technique precise; potential linear range of + scleral annulus (contact using scleral 180 deg; capable of measuring lens); 3-D scleral annulus is annulus horizontal, vertical, and torsional expensive. rotations of eyes and head. Ocular A research tool that provides Uncomfortable; technically electromyography information about extraocular difficult. (EMG) muscle activity
* Table modified and updated from (Leigh & Zee, 2006)
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57 Chapter 3 Performance of the translational vestibulo-ocular reflex (tVOR) in normal human subjects
3-1. Introduction
During natural activities, such as locomotion, head perturbations occur that have both rotational and linear (translational) components (Grossman et al., 1988; Pozzo et al.,
1990). The vestibulo-ocular reflexes generate eye rotations to compensate for such head perturbations at short latency. The angular vestibulo-ocular reflex (aVOR) has been shown to produce eye rotations that compensate for angular head perturbations, thereby guaranteeing clear vision during natural activities (Grossman et al., 1989; Moore et al.,
1999). The translational vestibulo-ocular reflex (tVOR) has also received study, mainly using fore-aft and side-to-side head perturbations (Israël & Berthoz, 1989; Schwarz &
Miles, 1991; Gianna et al., 1997; Ramat & Zee, 2003; Ramat et al., 2005; Angelaki,
2004). Although its latency is short – about 19 ms in humans (Ramat & Zee, 2003) – prior studies have reported that the tVOR typically generates eye rotations that are less than 60% of that required to hold the eye on target (Hirasaki et al., 1999; Ramat & Zee,
2003). This behavior predicts that vision will be degraded during linear head motion, particularly when viewing near objects. Yet why this should be the case is poorly understood.
58 It is possible that the performance of the tVOR is better during locomotion and
other natural head movements than has been measured in the laboratory. First, in most prior studies, the tVOR has been measured in darkness or in a very limited visual
environment. In contrast, daylight vision is rich in information about the
three-dimensional location of objects. It might be that this additional visual information
can be used by the brain to generate a more nearly compensatory tVOR. Second, during
locomotion, pure head translation is rare. It has been suggested that under natural
conditions, combining head translations with rotations may improve gaze stability
(Ramat and Zee 2003).
Thus, one goal of this study was to determine whether full ambient illumination
and simultaneous rotation causes the tVOR to hold the eyes on target. A second important goal was to characterize in detail responses to vertical (bob) translations, because these are prominent during locomotion, due to the straight-legged gait of humans
(Massaad et al., 2007), and because they have only rarely been studied in humans (Paige,
1989). For the rotational stimulus, we chose horizontal head rotations (yaw) because they were easier to control with our apparatus. We selected frequencies of bob (2 Hz) and yaw
(1 Hz) that were similar to those reported to occur naturally during walking (Grossman et al., 1988; Pozzo et al., 1990). We found that neither a full visual environment, nor simultaneous head rotation improved the vertical tVOR: it still only generated eye rotations that were about 60% of those required to hold the eye on target. This finding led us to our final goal: to investigate the nature of the visual cues used to set the magnitude
59 of tVOR responses and to re-evaluate the role of tVOR during natural activities.
Preliminary findings are reported in an abstract (Liao et al., 2007b).
3-2. Methods
Subjects: We studied 20 healthy human subjects (8 female) age range 25-72 years
(median 55 years). No subject was taking medicines with effects on the nervous system or wore a refractive correction greater than 4 diopters. Refractive corrections were not worn during testing, and all subjects reported that they could easily see the visual targets, including the near targets. Experiments were performed in ambient light, so that natural visual cues, such as motion parallax and relative size, were available, and the safety of the subject on the platform could be monitored by one of the investigators who stood by the platform with an emergency stop switch. All gave informed, written consent, in accordance with the Declaration of Helsinki and the Institutional Review Board of the
Cleveland Veterans Affairs Medical Center.
Vestibular Stimuli: Subjects sat in a chair on a Moog 6DOF2000E electric motion platform (East Aurora, New York) that could move with six degrees of rotational and translational freedom through a range of + 20 deg and + 20 cm, with peak rotational acceleration of 400 deg/s2 and peak linear acceleration of 5 m/s2 (0.5 g). Belts were used to secure the subject’s torso and a snugly fitting skate-board helmet, inlaid with foam, was used to stabilize the subject’s head. Any head movements that were decoupled from chair or platform motion were measured, as described below.
60 Visual Stimuli: There were two main visual conditions to compare tVOR performance during bob versus combined bob-yaw under ambient illumination. (1)
Subjects binocularly viewed a laser spot projected on a wall at a distance of 2 m (“far target”). (2) Subjects binocularly viewed a “near target” (reflective ball, diameter 1 cm) suspended at a distance of ~ 17 cm in front of their left eyes. All twenty of our subjects, including more elderly individuals, were easily able to view these visual stimuli without refractive correction. The actual positions of the near target, for each subject, were measured directly as described below.
In order to investigate visual factors that might determine tVOR behavior, 20 subjects also viewed the near target monocularly (right eye occluded). Since convergence decreased during monocular viewing, six subjects viewed targets binocularly at 2m, 40 cm and 17 cm first directly and then with a 15- or 10-diopter base-out prism placed before the right eye (prism power selection was based on each subject’s ability to fuse the visual stimulus). Thus, each stimulus was viewed binocularly at one distance with two different vergence angles. In two subjects, we turned the room lights out for periods of
2-4 s, as subjects attempted to fix upon the remembered location of the near target, which they had previously viewed binocularly. These two subjects also binocularly viewed the near target under conditions of strobe illumination, in order to minimize retinal image slip information. The strobe illumination was achieved using an array of bright light-emitting diodes, which were illuminated at a flash rate of 4 Hz, with a 30 ms flash duration.
Finally, to determine whether tVOR behavior in ambient lighting could be explained
61 simply by the contribution of smooth visual tracking, 13 subjects followed a moving
visual stimulus (Amsler grid), subtending 25.6 deg horizontally and 18.6 deg vertically
with a central dot, at a target distance of 110 cm. The stimulus moved sinusoidally, in the
vertical plane: (A) through + 9.0 deg at 0.2 Hz (peak velocity 11 deg/s); (B) through +5.6
deg at 2.0 Hz (peak velocity 70 deg/s); (C) through + 2.8 deg at 2.0 Hz (peak velocity 35
deg/s). The first two of these moving visual stimuli imposed the same requirements on
eye movements as those imposed by the translation stimuli (see next section), if there were no vestibulo-ocular responses; the last stimulus corresponded to the remaining visual motion if tVOR compensated for half of that required to hold the eye on target.
Experimental Paradigms: Each experimental run, which lasted 90 s, started with 3
cycles of bob at 0.2 Hz (typical amplitude + 5.6 cm) followed, after a pause of 3 s, by 3
cycles of yaw at 0.2 Hz (typical amplitude + 6 deg). We assumed that our normal subjects
could continuously view the visual target during these 0.2 Hz stimuli (due to normal smooth pursuit) and used their eye movements as one index of “ideal” responses. Then, we applied
bob translations at 2 Hz (typical amplitude + 1.5 cm) for 12 s to test tVOR. After a 3 s pause,
we applied yaw rotations at 1.0 Hz (typical amplitude + 5 deg) for 12 s, to test aVOR.
Finally, after a 3 s pause, we applied combined bob at 2 Hz and yaw rotation at 1 Hz
(starting at zero phase difference) for 12 s.
Measurement of Eye and Head Movements: Three-dimensional eye rotations were
measured using the magnetic search coil technique. Three orthogonal magnetic fields,
top/bottom, left/right, front/back oscillating respectively at 60, 90, and 135 KHz, were
62 implemented in a 76 cm cube (CNC Engineering, Seattle WA) rigidly attached to the chair mounted on the platform. Dual scleral search coils capable of measuring 3-D rotations (Skalar, Delft, Netherlands) were calibrated prior to each experimental session.
First, signal offsets were nulled with the coil inside a metal tube that shielded it from the magnetic fields. Next, the relative gains of each channel were determined by aligning the coil with each of the three fields and recording the corresponding maximum signal. These gains are used to normalize the raw coil signals when calculating rotation vectors.
Following calibration, a scleral coil was placed on each eye following application of topical anesthesia. A coil was also taped to the subject’s forehead to detect any rotations due to incomplete head stabilization. Linear and rotational movements of the chair frame and subject’s head were monitored by an infrared reflection system (Vicon Motion
Systems, Los Angeles, CA). Six reflective markers were attached by adhesive tape to the subject’s forehead and skin over the zygomatic malar processes (cheeks). Rotational and translational movements of the coil frame were monitored by attaching 4 reflective markers on the coil frame. For each subject, before experiments were started, two extra reflective markers were attached over the subject’s eyelids so that we could calibrate the geometric relationship of the subject’s eyes to the facial markers. In addition, the position of the near target was measured. Six cameras allowed head and coil frame movements to be measured with a resolution of 2 mm and 0.1 deg.
Data Analysis: Coil signals were digitized at 500 Hz with 16-bit precision after
Butterworth filtering (0-150 Hz) to avoid aliasing and were saved on computer disk for
63 subsequent analysis. Raw coil signals were normalized by the recorded gains and converted to rotation matrices and then 3-D rotation vectors in degrees (Haustein, 1989), using a straight-ahead reference position at a distance of 2 m; 3-D angular velocity vectors were calculated from the rotation vectors (Hepp, 1990). Both eye and head rotations were expressed in the same earth-fixed coordinate system (see Appendix 1).
The horizontal vergence angle was calculated as the difference in the horizontal components (left eye - right eye) of the eye orientation vector; because the Haustein
(1989) correction was applied, this measure took into account the effect on horizontal gaze position of an ocular rotation about the head-fixed torsional axis, when the eye was looking up or down. Because reference positions were recorded at a target distance of 2 m, not at optical infinity, the vergence angle corresponding to this distance and each subject’s interpupillary distance was added to the calculated values. Positive values correspond to leftward, downward, and clockwise rotations from the subject’s viewpoint
(Steffen et al., 2000; Straumann et al., 2003), and divergence. Position signals from the infrared reflection system were digitized at 120 Hz, and used to calculate the movements of the subject’s head, the coil frame, and “required eye rotations” to hold gaze
(corresponding to the line of sight) on the visual target (see Appendix 1). A linear accelerometer (Crossbow Technologies) was mounted on the platform to measure the vertical acceleration induced by a step movement at the beginning of each trial, and thereby synchronize coil system signals with those from the Vicon system.
64 Measurement of Subjects’ Responses: Complete head stabilization during these
experiments was difficult to attain (even with a bite bar which, in preliminary studies,
subjects could not tolerate during the head perturbations). Therefore, we used the infrared
motion detection system to measure actual head perturbations. Most subjects’ head
movements were small with respect to the coil frame (typically < 1 deg rotations and < 2
mm translation in each plane). We computed eye-in-head movements as rotation vectors,
and desaccaded records using a manually selected velocity threshold for each eye movement
session. We computed head rotations and translations in space using the infrared motion
detection system (see Appendix 1). We then carried out Fourier transforms of eye and head
velocity, measuring the response at the frequency of the stimulus. The responses around the
stimulated frequency were also examined, but no significant values were found, i.e.,
responses were limited to the frequency of the applied stimulus.
We quantified the responses in two ways. First we measured gain of aVOR as
eye-in-head rotational velocity / head rotational velocity, and responsivity of tVOR as eye rotational velocity / head translational acceleration. Note that aVOR gain has no units but
tVOR responsivity has units of deg/s of eye rotation per m/s2 of head translation (hereafter
stated as deg*s/m). The utility of aVOR gain and tVOR responsivity are that they provide a
direct measure of changes in the absolute magnitude of the responses as a function of target
distance. We also calculated the ratio: eye rotational velocity / required eye rotational
velocity to maintain foveal fixation of the visual target (far or near), hereafter referred to as compensation gain, similar to prior usage (Ramat & Zee, 2003; Ramat et al., 2005). This
65 measurement allowed us to relate measured responses to the ideal response (when equals to
1.0), assuming that the goal of tVOR is to hold the eye on target. The gain and phase lag of
smooth tracking with respect to visual target motion were calculated by desaccading eye
velocity data, and computing Fourier transforms.
3-3. Results
3-3-1. tVOR Responses during binocular viewing in ambient illumination
Representative records from one subject while viewing the near or far targets
during either bob or combined bob-yaw are shown in Fig. 3-1; note that, apart from vergence, individual traces have been offset to aid clarity of display. Both tVOR responsivity (indicated at bottom) and aVOR gain (indicated at top) increased during
viewing of the near target (17 cm) versus the far target (2 m). In addition, tVOR
responsivity increased slightly during combined bob-yaw compared with during bob.
Results from all 20 subjects are summarized in Fig. 3-2. This shows a large
increase of tVOR responsivity during binocular viewing of the near target at 17 cm
(diamonds) versus the far target at 2 m (circles), although less than the ideal calculated
response (gray line). The aVOR also showed gain increases during binocular near viewing.
Paired comparisons of all data (Wilcoxon signed rank test) indicated a statistically
significant increase of tVOR responsivity (p = 0.003) during combined bob-yaw versus bob
(12% median increase in responsivity). There was also a small but significant (p = 0.001) decrease in aVOR gain during yaw-bob versus yaw (2% median decrease in gain).
66 Phase lags for tVOR (with 0 deg being ideal) were similar for different viewing
conditions being 18.9 deg (+ 12.7) during far viewing and 18.7 deg (+ 10.9) during
binocular near viewing. Phase lags of aVOR with respect to ideal response were small,
being 1.6 deg (+ 4.8) during binocular far viewing and 2.7 deg (+ 4.2) during binocular
near viewing. Phase lags of tVOR for combined translation-rotation versus pure
translation were similar, with median differences being < 2.6 deg for each viewing
condition.
How much did the increases in tVOR responsivity during combined bob-yaw
contribute to generating eye rotations to hold the eyes on target? When subjects viewed
the target at 2 m, compensation gain increased from a median of 0.52 during bob to 0.59 during combined bob-yaw (p<0.01). When subjects viewed the target at 17 cm, compensation gain increased from a median of 0.58 during bob to 0.60 during bob-yaw
(difference not significant; average value: 0.57). Thus, the tVOR changed only slightly
during translation-rotation versus pure translation, and our subjects’ ocular rotations remained at about 60% of those required to point the eyes at the target. The compensation
gain of aVOR or tVOR for the ten subjects aged 25-55 years did not differ statistically, for
any visual test condition, from subjects aged 56-72 years; furthermore, vergence angles
were similar under the same viewing condition in each age group.
Since the magnitude of the increase in responsivity from far to near was large (a
median factor of 8.7 for combined bob-yaw), this suggested that the brain was controlling
tVOR behavior so that eye velocities were about 60% of those required to hold the eyes
67 on target. This prompted us to approach tVOR differently, and investigate which visual
factors contributed to this response.
3-3-2. Comparison of tVOR responses during different viewing conditions
First, we asked whether monocular viewing conditions would affect tVOR behavior during viewing of the near target. Fig. 3-2 summarizes responses of all 20 subjects (squares) and shows that both tVOR responsivity and aVOR gain were reduced compared with during binocular viewing. As a group, the subjects showed a significant
drop of tVOR responsivity (p=0.019, Wilcoxon signed rank test), but not aVOR
responsivity, from binocular to monocular viewing of the target at 17 cm. However, also apparent in Fig. 3-2 is a decrease in vergence angle from 17.7 + 2.8 deg during binocular
viewing to 12.2 + 7.8 during monocular viewing, which was significant (paired t-test, p <
0.005). Accordingly, we compared six subjects’ responses when they viewed targets at 2
m, 40 cm, or 17 cm either directly or with a base-out prism before their right eye; data are
summarized in Fig. 3-3A. For each of the three target distances, tVOR responsivity
values clustered in a discrete range, even though vergence angle varied according to
whether viewing was direct or through a prism (Fig. 3-3A). Paired comparison (Wilcoxon
signed rank test) of tVOR responsivity for each target distance of each subject, either
directly or through a prism, showed no significant difference. This result suggested that
the effects of monocular viewing on tVOR could not be simply attributed to change of
vergence angle, but might reflect attenuation of visual cues.
68 We studied this possibility further by measuring the effects of switching to
darkness, and strobe illumination (to minimize retinal slip information) in two subjects as
they attempted to view binocularly the near target. After switching to darkness, both
subjects gave consistent and similar responses that are summarized in Fig. 3-2 (inverted
black triangles); tVOR and aVOR both declined substantially. The same was the case
during strobe illumination (Fig. 3-2, upright gray triangles). Thus, either switching to
darkness, or minimizing retinal slip information by strobe illumination reduced aVOR
and tVOR responses during attempted viewing of a near target, even though vergence
angle remained greater than 18 deg.
Finally, we addressed the possibility that greater tVOR responsivity in ambient light was due simply to improved smooth visual tracking. Mean (± SD) of tracking gain
for smooth pursuit for the full amplitude stimulus was 0.25 (±0.08) with phase lag of 58.6
±15.6 deg for measured eye velocity with respect to ideal eye velocity required to follow the target; for the half amplitude stimulus, gain was 0.16 (±0.06), with a phase lag of 56.4
(±13.7) deg. We compared these responses with tVOR behavior when responses were largest – during binocular viewing of the near target. Fig. 3-3B is a polar plot comparing
smooth tracking gain and tVOR compensation gain. Note how phase lags were smaller, and gain values larger, during tVOR than during visual tracking, with no overlap of data.
Thus, smooth visual tracking could not account for tVOR during near viewing, indicating
that other mechanisms must modulate tVOR during these visual test conditions.
69 3-4. Discussion
We set out to determine how well tVOR responded to vertical head translations
during combined bob-yaw movements under conditions of ambient illumination. Our test
frequencies corresponded to those of head perturbations that occur during locomotion
(Grossman et al., 1988; Pozzo et al., 1990; Moore et al., 1999). In 20 subjects spanning
almost 5 decades in age, we found that tVOR generated eye movements that were only
about 60% of those required to hold the line of sight on the target, whether it be located
far (2 m) or near (17 cm). In contrast, aVOR generally compensated for head rotations and held the eyes on far and near targets. This led us to re-evaluate the purpose of tVOR,
noting that geometry makes it impossible for tVOR to adequately stabilize images of both
near and far objects within the visual scene during head translations. We found that the
best responses occurred during binocular vision in ambient illumination, when natural
visual cues, such as motion parallax, were available. Our findings raise a number of
issues. First, how do our results compare with prior studies of tVOR? Second, what
factors seem most important for adjusting tVOR responses? Third, what could account
for the apparent inadequacy of tVOR to compensate for translational head perturbations?
3-4-1. Comparison with Prior Studies of tVOR
Prior studies have thoroughly documented how aVOR compensates for yaw head
perturbations during viewing of distant and near targets (Viirre et al., 1986; Crane &
Demer, 1997; Han et al., 2001). However, to the best of our knowledge, only G. D. Paige
70 has previously studied tVOR in bob in normal human subjects. He studied two subjects who bounced themselves up and down on a spring-suspended stool at ~ 2.7 Hz with a peak excursion of 3.2 cm (Paige, 1989), motion that mainly stimulates the sacculus
(Fernandez & Goldberg, 1976). Movements of only one eye were measured using the magnetic search coil technique (vergence angle was not monitored). The two subjects viewed Snellen optotypes at 424 cm, 142 cm, and 36 cm in dim illumination or in darkness with spot illumination of the optotype; thus viewing conditions were dissimilar from the ambient lighting that we employed. Similar to the present study, Paige found that eye rotation was almost 180 deg phase-shifted with respect to head displacement, i.e., compensatory in direction, and increased as target distance decreased, but fell short of what was required to maintain target fixation. When his two subjects viewed a head-fixed target at 36 cm, tVOR decreased by 56% and 80% of values with an earth-fixed target, and Paige concluded that “no visual following or motion detection mechanism exists which could have accounted for the major proportion of eye movement responses observed during vertical linear oscillations, even when visual inputs were available.”
Our present study essentially confirms Paige’s finding in a large number of subjects. In addition, by making binocular eye movement recordings, we were able to show (at least under our experimental conditions) that target distance was an important determinant of tVOR responses. Furthermore, by also testing smooth tracking of a large visual display moving at a frequency and amplitude corresponding to the visual demands imposed by platform motion, we confirm that visual tracking mechanisms contribute only
71 modestly to the response to bob motion during near viewing. Thus, similar to visual
modulation of aVOR (Huebner et al., 1992; Das et al., 1998), mechanisms other than
superposition of visual tracking appear to contribute.
Other studies have measured human tVOR in response to transient (Gianna et al.,
1997; Ramat et al., 2003; Ramat et al., 2005), or sinusoidal (Paige et al., 1998), interaural
motion. At 2 Hz, the interaural tVOR shows a positive slope with increasing vergence
angle and a positive intercept (similar to Fig. 3-2). Studies employing transient stimuli
have reported responses that are influenced by vergence, accommodation, visual cues
such as motion parallax, as well as anticipation of whether the visual target will remain
still or move.
Our study combined rotational and translational head movements. A prior study
on rotation while translating concerned rabbits who translated across a rotating platform
so that Coriolis acceleration was induced due to translation within the rotating frame
(Maruta et al., 2005). Thus, this stimulus was unlike that employed in our study, in which
head rotations occurred around the vertical axis in which head translated. Other studies of
humans and squirrel monkeys have displaced the subject’s head eccentrically from the
axis of rotation in order to induce simultaneous aVOR and tVOR (Bronstein & Gresty,
1991; Anastasopoulos et al., 1996; Telford et al., 1998). When the subject’s head is positioned nose-up and one side of the head is directed outward, then a torsional aVOR and vertical tVOR are stimulated. In squirrel monkey, such orthogonal aVOR and tVOR components were similar to those measured during independent stimulation. In our
72 subjects, both tVOR and aVOR responses showed small changes during combined
rotation-translation versus pure yaw or bob. In the case of the aVOR, the decrease in
responses during combined rotation-translation might have been due, at least in part, to
the small increase in target distance at the extremes of vertical platform translation. On
the other hand, the increase in tVOR responses during combined rotation-translation
cannot be readily attributed to geometric factors and may represent another example of
how vestibular responses are enhanced when coupled with other types of eye movements
(Das et al., 1999). Enhancement of tVOR during combined canal-otolith stimulation
induced by eccentric rotation has been previously reported (Anastasopoulos et al., 1996).
3-4-2. What mechanisms determine tVOR responses?
Our present results suggest that the brain's estimate of target distance, based on
multiple factors including motion parallax and vergence is the key factor that determines
tVOR responses. We performed our experiments in ambient light and presented real near
stimuli, which provided 3-D visual information as well as relative motion between the
near stimulus and background during testing. During binocular viewing, our present responses, measured in terms of percentage of ocular rotations required to hold the eye on
target, were as large as reported in any prior study. However, whenever this percept was
eroded – during monocular viewing or during strobe illumination – tVOR responses
declined (Fig. 3-2), even though some convergence was maintained. Furthermore, during
binocular viewing with a prism placed before one eye to induce convergence, responses
73 were similar to during direct viewing, indicating the relative importance of binocular
information in setting tVOR responses, although convergence may also contribute.
Another important finding was that there was no significant change of the phase
lag of tVOR during the far and near viewing conditions; mean values were ~ 18 deg from
that required for an ideal response. For our 2 Hz stimuli, this phase lag corresponds to a
delay (latency to onset) of about 20 ms for tVOR, which agrees with reported values from
studies that have employed transient stimuli (Ramat & Zee, 2003). If visual tracking eye
movements were supplementing otolith-ocular responses, substantial phase lags would be
expected, and one implication of the constant phase of tVOR is that the response
represents mainly vestibular drives. Thus, it seems that although natural visual cues are
required to modulate tVOR and, specifically, to increase the magnitude of the response during viewing of near targets, visual tracking eye movements do not contribute substantially to this increase.
3-4-3. Possible role of tVOR during natural activities
There are differences between the head perturbations that occur during natural
locomotion and those that we applied in these experiments (aside from our subjects not
moving forward through their environment). For example, during walking, active and
passive vertical head translations are accompanied by pitch rotations (Pozzo et al., 1990;
Moore et al., 1999; Bloomberg et al., 1992), which we intentionally minimized in our
experiments. It follows that hypotheses that invoke interactions between head rotations
74 and translations to explain why tVOR does not adequately compensate for translations
during near viewing (Ramat & Zee, 2003) do not readily account our findings. If tVOR
compensates for only about 60% of translational head perturbations during far and near
viewing (Israël & Berthoz, 1989; Paige, 1989; Gianna et al., 1997; Ramat & Zee, 2003;
Moore et al., 1999), what are the potential visual consequences?
During our testing, subjects noted that the near stimulus appeared to bounce up
and down (oscillopsia), probably due to excessive retinal image motion. Similar
perceptions were reported in subjects during treadmill walking as they viewed a near
target (Crane & Demer, 1997; Moore et al., 1999). A simple experiment may convince
the reader that tVOR fails to stabilize images of near objects. Place a visual acuity test
card on a shelf at eye level at a target distance of ~ 17 cm. First rotate the head in yaw at
1-2 Hz; visual acuity will remain about the same (aVOR). Second, bob up and down by bending the knees at a frequency of 1-2 Hz; visual acuity will deteriorate by several lines,
and oscillopsia may result (tVOR). Thus, aVOR guarantees clear vision of near objects
during head rotations, but tVOR does not guarantee clear vision during head translations.
If one takes the view that tVOR must compensate for head translations
sufficiently to safeguard some aspect of vision then, since the target distance appears to
be the main determinant of the response, at what distance are objects located for which
tVOR will provide clear vision? Knowing the amplitude of head translations, it is
possible to calculate the peak retinal image velocity that will occur as subjects view targets over a range of target distances (Schwarz & Miles, 1991), and then scale this
75 curve by a factor of (1- compensation gain). Fig. 3-4 provides a comparison of such a
curve with measured retinal image speeds in three subjects, whose mean compensation
gain was 0.6. In general, the curve predicts the data well, with smaller values for peak
retinal image speed for visual targets at 40 cm (for which their compensation gain values
were greater). Also shown in Fig. 3-4 is a dashed line corresponding to 5 deg/s, which is
required for clear vision of objects with higher spatial frequencies (Carpenter, 1991;
Demer & Amjadi, 1993). It is evident that tVOR with a compensation gain of 0.6 holds peak retinal image speed below 5 deg/s for target distances greater than 90 cm and, even within arm’s reach (~ 30-50 cm), peak image slip is < 10 deg/s; a similar range for optimal operation of tVOR has been previously noted (Paige et al., 1998). Only for very close viewing does retinal image velocity increase to levels that degrade vision and cause oscillopsia. In Fig. 3-4, we also plot the peak retinal image speed of the background lying at 200 cm that, although defocused, might provide motion parallax information; its speed
is similar to that of the image of the fixation target (although opposite in direction).
Finally, we asked what motion of the background image would be expected if tVOR did
perfectly compensate for head translations; it is evident in Fig. 3-4 that during near
viewing, background image motion would be expected to exceed 50 deg/s. Thus, taken
with evidence from prior studies (Paige et al., 1998), it seems possible that tVOR is set to
optimize viewing of objects that fall between the distance of the target being viewed and
the background (Miles, 1998). More specifically, minimizing the velocity of retinal
image motion of both near and distance objects might aid detection of motion parallax
76 signals that are important for detecting relative distances of objects in the environment.
Thus, the human tVOR may have evolved to maintain compensation gain at a value of ~
0.6 not to keep the eyes on target, but rather to optimize motion parallax estimates of the
locations of objects in the path of locomotion. Further experiments, for example, moving
the visual background with respect to the stationary near visual target, will be discussed
in Chapter 4. This reinterpretation of the purpose of tVOR could also be extended to
patients with abnormal vestibular responses. (Liao et al., 2007a).
77
Figure 3-1 Representative records from one subject showing responses to bob or combined bob-yaw during viewing of far and near targets; note that, apart from vergence, individual traces have been offset in position to aid clarity of display. Both tVOR responsivity (indicated at bottom of panels in units of deg*s/m) and aVOR gain (indicated at top of panels) increase during near versus far viewing. In addition, modest increases in tVOR responsivity occur during combined bob-yaw versus bob. Positive values correspond to leftward, downward, and divergence movements. Required eye movements were calculated.
78
Figure 3-2 Summary of tVOR responsivity and aVOR gain from all 20 subjects, during binocular viewing of the target at 2 m (Far), or the target at 17 cm binocularly (Near –
Binocular) or monocularly (Near – Monocular). Responsivity of both aVOR and tVOR increased with vergence angle; solid lines are linear regressions (intercept A, slope B, in bottom right corners) and dashed lines are 95% confidence region. The gray lines, labeled
“ideal” are based on geometric predictions. The ideal response for aVOR was calculated from: D(D+ R) , for which D is the distance between eye and target, R is the distance from eye to (D22+ I / 4) the center of rotation (assumed average value of 9 cm), I is the inter-pupillary distance (mean
6.4 cm for our subjects). The ideal response for tVOR was calculated from: 1 , for D*2*π *f which D is the distance between eye and target, and f is the frequency of the stimulus in Hz.
Also plotted are data from several trials from two subjects who attempted to view the target at
17 cm either during strobe illumination (Near – Strobe) or after switching to darkness.
79
Figure 3-3 (A) Comparison of direct and prism viewing on tVOR responsivity. Data from six subjects are plotted, showing that for each of the three target distances, tVOR responsivity clustered in a discrete range, even though vergence angle varied according to viewing conditions. (B) Comparison of vertical smooth-tracking and tVOR during binocular viewing of a near target. In this polar plot, numbers on the circumference indicate phase shift and numbers on radii indicate gain for visual tracking and compensation gain for tVOR. Gain values were greater, and phase lags of eye velocity with respect to ideal eye velocity required to follow the target were smaller, during tVOR than during visual tracking, with no overlap of data (indicated by enclosing lines).
80
Figure 3-4 Comparison of geometric prediction of peak retinal image speed (RIS) as a function of target distance for three subjects versus their measured peak retinal image speeds.
The mean bob head displacement in these three subjects was ± 1.5 cm. Their mean compensation gain was 0.6, and the curve defined by the equation shown was accordingly scaled by a factor of 0.4. Squares indicate measured values of RIS of the fixation target at each of the target distances for each subject for either pure bob or combined bob-yaw. There is generally good agreement, except that during viewing targets at 40 cm, peak RIS is lower than predicted due to greater compensation gain values. Circles indicate RIS of the background at
200 cm; although the direction of background image motion is opposite to that of the target image motion, the magnitude is similar. Inverted triangles indicate calculated RIS values of the background if tVOR compensation gain = 1.0; this is substantially increased during near viewing. The dashed horizontal line corresponds to a retinal image speed of 5 deg/s, above which visual acuity for high spatial frequencies will decline.
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86 Chapter 4
Factors determining tVOR performance
4-1. Introduction
In Chapter 3, the behavior of tVOR during vertical (bob) translations in ambient light, and also in combination with horizontal (yaw) rotations is described. Our goal was to determine whether these test conditions, which approximated components of head perturbations during locomotion, would increase the overall tVOR response. We found that tVOR increased only slightly during translation-rotation in ambient light compared
with reported values (Israël & Berthoz, 1989; Paige, 1989; Gresty et al., 1987; Gianna et
al., 1997; Ramat & Zee, 2003; Ramat et al., 2005). Although the velocity of eye
movements increased by almost a factor of 10 between far versus near viewing (Figs 4-1
and 4-2A), compensation gain (eye rotational velocity / required eye rotational velocity to
maintain foveal target fixation) remained at 0.55-0.60 (Fig. 4-2B). Based on responses
during prism viewing (to induce convergence) versus direct viewing (Fig. 4-3), we concluded that binocular signals rather than convergence angle determined tVOR responses. Further, based on responses after switching to darkness, or under reduced
(strobe) illumination (Fig.4-4), we concluded that relative image motion between the target and background was a critical determinant of tVOR behavior.
The goals of this chapter were to investigate further the influence of vision on
tVOR performance during two test paradigms: (1) To compare tVOR cancellation versus
87 smooth visual tracking. (2) To determine whether motion of the visual background
influenced tVOR during viewing of a near target.
4-2. Methods
Subjects: We studied 13 healthy subjects (6 female, median age 60 years, range
25-72). All gave informed, written consent, in accordance with the Declaration of
Helsinki and the Institutional Review Board of the Cleveland Veterans Affairs Medical
Center.
Vestibular Stimuli: Subjects sat in a chair on a Moog 6DOF2000E electric motion
platform (East Aurora, New York) that could move with six degrees of rotational and
translational freedom. Each experimental run started with 3 cycles of bob at 0.2 Hz (typical amplitude + 5.6 cm). Responses to this 0.2 Hz stimulus held subjects’ eyes continuously on
target and served as a calibration check. Then, we applied bob translations at 2 Hz (typical
amplitude + 1.5 cm) for 12 s.
Comparison of Cancellation of tVOR and Smooth Tracking: For the first set of
experiments, for which all 13 subjects participated, there were three visual conditions,
each employed for one experimental run. (1) Subjects binocularly viewed a laser spot
projected on a wall at a distance of 2 m. (2) Subjects binocularly viewed an
earth-stationary near target (reflective ball, diameter 1 cm) suspended at a distance of ~
17 cm in front of their left eye. (3) Subjects viewed a small mark on the bridge of their
own nose through an earth-fixed mirror at a distance of ~ 8.5 cm. The actual positions of
88 the near target and the mirror, for each subject, were measured directly. During these
experiments, room lights were turned on so that natural visual cues, such as motion
parallax and relative size, were available. We compared the cancellation of tVOR during
mirror viewing with smooth visual tracking of a moving visual stimulus (Amsler grid),
subtending 25.6 deg horizontally and 18.6 deg vertically with a central dot, at a target
distance of 110 cm. The stimulus moved sinusoidally, in the vertical plane: (A) through
+5.6 deg at 2.0 Hz (peak velocity 70 deg/s) or (B) through + 2.8 deg at 2.0 Hz (peak
velocity 35 deg/s). The first moving visual stimulus imposed the same requirements on
eye movements as those imposed by the translation stimuli, if there were no
vestibulo-ocular responses; the second stimulus corresponded to the remaining visual
motion if tVOR compensated for half of that required.
Investigation of Background Motion on tVOR: For the second set of experiments,
subjects viewed the near target at ~ 17 cm with a background consisting of horizontal stripes or a photograph of a park, displayed on a large flat screen at 1.5 m, which subtended 50 deg horizontally and 30 deg vertically. Room lights were turned out, but the earth-stationary near target could be easily seen by its reflected light, which emanated from the large screen; however, other background landmarks in the room could not be
seen. The two visual conditions were then (1) near target against the background which
was stationary; (2) near target against the background that moved sinusoidally at 2.1 Hz.
Three subjects took part in these experiments (age range 25-60).
89 Measurement of Eye and Head Movements and Data Processing:
Three-dimensional eye rotations were measured using the magnetic search coil technique;
details of the system and processing of coils signals have been previously described (Liao
et al., 2007). Linear and rotational movements of the chair frame and subject’s head were monitored by an infrared reflection system (Vicon Motion Systems, Los Angeles, CA),
and its signals were used to calculate the movements of the subject’s head, the coil frame,
and “ideal eye rotations” to hold gaze (corresponding to the line of sight) on the visual
target (Liao et al., 2007). We carried out Fourier transforms of eye and head velocity,
measuring the response at the frequency of the stimulus. We quantified the responses with
two parameters, which we term the responsivity and the compensation gain. We define the
responsivity (output/input) of tVOR as eye rotational velocity / head translational
acceleration, which has units of deg/s of eye rotation per m/s2 of head translation (hereafter
stated as deg*s/m). We also calculated compensation gain as eye rotational velocity /
required eye rotational velocity to maintain foveal fixation of the visual target (Ramat et al.,
2005).
In the case of mirror-viewing, ideally, tVOR should be negated. Thus, as an index of
tVOR cancellation, we compared tVOR responses during mirror viewing with responses
during viewing of the near target. The measured viewing distance of the near target (16.9 +
0.9 cm) and virtual image in the mirror (17.7 + 1.0 cm) were similar but not identical and,
accordingly, we made a geometric correction to the near-target responses. We then calculated tVOR cancellation ratio (CanR) from [(near-viewing response –mirror viewing
90 response) / near-viewing response]. The gain (eye velocity/target velocity) and phase lag
of smooth tracking with respect to visual target motion were calculated by desaccading
eye velocity data, and computing Fourier transforms. To test whether smooth tracking
was the only factor that cancelled the tVOR response during mirror viewing, we
calculated the expected response during mirror viewing (MR) by subtracting smooth
pursuit response (SP) from tVOR response during near viewing:
MR= tVOR− SP
The predicted cancellation gain or ratio (CanR) could then be calculated as:
AA− CanR = tVOR MR AtVOR where AtVOR is the measured amplitude of tVOR, and AMR is the calculated amplitude of
the MR. In this way we could compare values of predicted CanR with measured results.
4-3. Results
4-3-1. Comparison of cancellation of tVOR and smooth visual tracking
Representative records from one subject during the three visual test conditions are shown in Fig. 4-1; note that, apart from vergence, individual traces have been offset to aid clarity of display. The magnitude of tVOR (responsivity) increases from far to near viewing, but is largely negated during mirror viewing, although the vergence angle is similar to during near viewing.
91 Results from all 13 subjects are summarized in Fig. 4-5. For the group of subjects during mirror viewing, mean vergence angle was 20.0 deg and median tVOR cancellation gain was 0.81 (range 0.55-0.97). The median gain (range) for smooth tracking for the full amplitude stimulus (located at 110 cm) was 0.27 (0.09-0.42) with mean phase lag of 58.6
±15.6 deg for measured eye velocity with respect to ideal eye velocity required to follow the target; for the half amplitude stimulus, median gain was 0.18 (0.06-0.38), with a phase lag of 56.4 deg (±13.7). As shown in Fig. 4-5, the cancellation gain (CanR) calculated from either full or half amplitude smooth pursuit response is significantly smaller than the measured CanR (p <0.001). Furthermore, a paired comparison for each subject (Wilcoxon rank-sum test) showed a significantly lower value of calculated CanR than measured CanR (p < 0.001). Thus, smooth visual tracking could not account for cancellation of tVOR responses during near mirror viewing.
4-3-2. Effect of moving visual background on tVOR
Representative responses from one subject are shown in Fig. 4-6. As the difference between platform and background motion decreased, tVOR showed consistent changes in responsivity in both subjects that could be related to the difference between retinal image speed of the foveal target and the background. Thus, as relatively motion of the background increased (increasing slip speed of background retinal images), tVOR decreased (increasing slip speed of the foveal image) and thereby tended to equalize retinal image slip of the foveal target with respect to the background. Under natural
92 conditions, a changing relationship between image slip of a near target and the background would occur as the subject traveled forward through the visual environment.
4-4. Discussion
We found that visual cancellation of tVOR, as each subject viewed the bridge of their nose in a near mirror, was achieved much more successfully than could be accounted for by visual tracking mechanisms such as smooth pursuit. These results are consistent with a prior study of visual cancellation of tVOR in bob in two human subjects
(Paige, 1989). Thus, similar to visual cancellation of aVOR (Huebner et al., 1992; Das et al., 1998; Leigh et al., 1989), mechanisms other than superposition of visual tracking appear to contribute. During smooth visual tracking at 2 Hz, large phase lags of the eye occur with respect to the target. In contrast, the phase lag of tVOR at 2 Hz encountered in our prior experiments was about 18 deg, irrespective of the viewing condition (Liao et al.,
2007), which could be largely accounted for by the reported tVOR latency of about 25 ms
(Ramat & Zee, 2003; Gresty et al., 1987). Thus, one conclusion is that although visual stimuli are important for setting tVOR responsivity to an appropriate level, smooth visual tracking (such as smooth pursuit) appears to play little if any role.
Our second experiment addresses the issue: Why should the compensation ratio of tVOR be systematically smaller than the amount of eye rotation that is required to keep the fovea pointed at the near target? During translation of the observer, relative motion of objects located at different distance is inevitable, for which eye movements cannot
93 compensate. This relative motion of retinal images provides a cue to the distance of objects in the environment. Motion detection follows Weber’s law, such that discrimination of relative motion is better at lower velocities of retinal image motion
(Nakayama, 1985; Howard & Rogers, 2002). We have postulated that tVOR responses are set to minimize retinal image speed for both the target and the visual background
(Liao et al., 2007). In this study, we found that motion of the visual background may influence tVOR performance compared with viewing a stationary background. Thus, when the platform and target were moving in opposite directions (180 deg phase shift), assuming the subject’s gaze remained close to the near target, then retinal image due to background motion should be minimized and we postulate that tVOR responsivity should be maximized. Conversely, when the platform and target were moving in the same direction (0 deg phase shift), then assuming the subject’s gaze remained close to the near target, retinal image motion of the background should be maximized, and we postulate that tVOR responsivity should be minimized. The responses shown in Fig. 4-6 generally conform to those predictions.
In our prior study, based on measured tVOR responses during viewing of targets at three viewing distances (2 m, 40 cm, 17 cm), we were able to calculate geometric predictions of retinal image velocity (Schwarz & Miles, 1991), assuming a compensation gain of 0.6, The predictions of this simple geometric model generally fitted the measured values of retinal image speed well (Fig. 4-7 – curve and squares). If tVOR has a compensation gain of 0.6, it will hold peak retinal image speed below 5 deg/s (a threshold
94 for clear vision) for target distances greater than 90 cm. Note that measured peak retinal image speed of the background lying at 200 cm (diamonds in Fig. 4-7), which might provide motion parallax information, is similar to that of the image of the fixation target, although opposite in direction.
Our present finding that background motion may influence tVOR led us to develop a more general optimization function that minimizes retinal slip due to both the visual target and the background. Retinal image speed (RIS), when the eye is stationary, depends on the distance (D) between target and eye, the amplitude of the head movement
(A) and the frequency of oscillations (f) in Hz: A R**IS = f 360 (1) D RIS calculated with the eye stationary also corresponds to the speed of the required eye movement to keep the fovea pointed at the target. To calculate RIS when the eye is moving with velocity θ , then if C=A*f*360,
RIS =θ− C (2) D
We postulate that tVOR is set to minimize the sum of squares of RIS of both the background (RISbk) and the foreground target (RIStar). Then, the optimization function
(Fopt) is:
22 FRISRISopt=+ bk tar (3)
Substituting,
CC22 F(opt =θ− )( +θ− ) and its minimum occurs when DbktDar
95
C1 1 θ= *( + ) (4) 2Dbktar D Taking into account the different effect of background RIS and target RIS, we assign a weight coefficient to each. Then the optimized eye velocity becomes:
KC KC 12+ DD θ= bktar (5) KK12+
Where K1 is the weight for the background, and K2 is the weight for the target. To determine the value of K1 and K2, we fit the model to measured responses from 3 subjects for target distances of 40 cm and 17 cm, and a background distance of 2 m by minimizing the error of predicted eye velocity to the measured eye velocity with a least-squares method. Thus we obtain:
K1 = 0.43, K2 = 0.57.
We then use this optimization model to fit the RIS of targets (black dotted line) and RIS of the background (gray dotted line) in Fig. 4-7. The optimization model generally gave better fits of the measured RIS of subjects for target or background than the curve based on the simple geometric model with a compensation gain of 0.6. This model proposes a new interpretation of the purpose of tVOR: to control retinal image motion of objects at different distances so that motion parallax information is optimized.
96
Figure 4-1 Representative records from the left eye of one subject illustrating typical responses during viewing of the far target, near target and near mirror viewing. Note that, except for vergence, individual traces have been offset in position to aid clarity of display.
Positive values indicate downward and divergence movement. Note how tVOR (vertical eye rotation) increased during near viewing compared with far. During viewing of the subject's own nose in a near mirror (visual target moved with subject), vergence angle remained large, but tVOR was largely cancelled. Required eye rotations were computed from measured head movements (Liao et al., 2007).
97
Figure 4-2 Summary of tVOR responses to bob at 2.0 Hz of 20 normal subjects. (A)
Responsivity plotted as a function of vergence angle. Note that during near viewing
(corresponding to larger vergence angles), responsivity increases substantially compared with far viewing. (B) Compensation gain values during far and near viewing were similar, despite the large changes of responsivity shown in (A).
98
Figure 4-3 Representative records comparing direct versus prism viewing. Note how tVOR is larger during viewing the target at 17 cm versus 40 cm, but is unaffected by vergence angle.
Plotting conventions are similar to Fig. 4-1.
99
Figure 4-4 Representative records of the effects of illumination on tVOR. (A) Switching to darkness. Note how vergence angle and tVOR declined when the room lights were turned off (first vertical dashed line), and then increased when lights were turned on again. (B)
Strobe illumination (flashed indicated by spikes in strobe channel) caused decreases of tVOR compared with viewing in ambient light (in A), and a decrease in vergence. Plotting conventions are similar to Fig. 4-1.
100
Figure 4-5 Comparison of measured CanR during mirror viewing and estimated CanR based on smooth-tracking performance (see text for details); measured CanR values are significantly greater than values calculated from either “full amplitude” or “half amplitude” smooth tracking responses.
101
Figure 4-6 Effects of tVOR as a subject fixed upon a small earth-stationary target at 17 cm against a moving background (horizontal gratings) at a viewing distance of 1.5 m. The subject bobbed sinusoidally at 2.0 Hz and the background moved at 2.1 Hz. The subject’s vertical eye velocity, and the velocity of retinal image motion of the background and of the near target are plotted. Horizontal dotted lines correspond to median values of peak eye velocity while this subject viewed the same near target against a stationary background.
Note how tVOR decreased after background retinal image motion maximized, thereby maximizing target image motion.
102
Figure 4-7 Geometry of peak retinal image speed (RIS) as a function of target distance for three subjects versus their measured peak retinal image speeds. Squares indicate measured values of RIS of the fixation target at each of the target distances for each subject. Diamonds indicate measured values of RIS of the background at 200 cm, which is opposite to that of the target image motion, but is similar in magnitude The black curve defines responses based on a simple geometric model (Schwarz & Miles, 1991) with a mean compensation gain of 0.6. The dotted curves summarize the fit of the optimization model (see text) for RIS of target and background, which generally fit the data better than the simple geometric model. The dashed horizontal line corresponds to a retinal image speed of 5 deg/s, above which visual acuity for high spatial frequencies will decline.
103 4-5 Reference List
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Gianna, C. C., Gresty, M. A., & Bronstein, A. M. (1997). Eye movements induced by
lateral acceleration steps. Exp Brain Res, 114, 124-129.
Gresty, M. A., Bronstein, A. M., & Barratt, H. (1987). Eye movement responses to
combined linear and angular head movement. Exp Brain Res, 65, 377-384.
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Israël, I. & Berthoz, A. (1989). Contribution of the otoliths to the calculation of linear
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suppression, enhancement and cognitive control. J.Neurophysiol., 94, 2391-2402.
Ramat, S. & Zee, D. S. (2003). Ocular motor responses to abrupt interaural head
translation in normal humans. J.Neurophysiol., 90, 887-902.
Schwarz, U. & Miles, F. A. (1991). Ocular responses to translation and their dependence
on viewing distance. I. Motion of the observer. J Neurophysiol, 66, 851-864.
105 Chapter 5 Potential application of this study to clinic disorders
First Example: Progressive Supranuclear Palsy (PSP)
5-1. Introduction
Progressive supranuclear palsy (PSP) is a parkinsonian disorder characterized by frequent falls, dysphagia, and disturbance of vertical gaze (Steele et al., 1964; Litvan,
2005; Leigh & Zee, 2006). PSP is currently attributed to a sporadic genetic abnormality of tau-protein (Myers et al., 2006). Early in the course of the disease, vertical saccades
(rapid eye movements) become slow and then absent; later vertical smooth-pursuit tracking and horizontal saccades are also involved. However, even in advanced stages of the disease, eye movements can still be elicited by turning the patient’s head (although neck rigidity may make this difficult), indicating that the angular vestibulo-ocular reflex is relatively preserved (Das & Leigh, 2000). Thus, there is an apparent paradox: PSP patients show substantial postural instability, suggesting early abnormalities of vestibulospinal reflexes, but some vestibulo-ocular reflexes continue to operate even in advanced disease.
During natural locomotion, two types of head perturbation occur with each footfall: rotations and translations (linear movements). The fundamental frequency of rotational head perturbations during locomotion ranges between 0.5 – 5.0 Hz, with vertical head rotations (around the interaural, pitch or y-axis) being typically twice that of
106 horizontal rotations (around the rostral-caudal, yaw or z-axis) (Leigh & Zee, 2006;
Grossman et al., 1988). The major translational perturbation during locomotion is vertical
(bob), and is similar in frequency to pitch rotations (Pozzo et al., 1990; Moore et al.,
1999).
The vestibular labyrinths contain two types of motion sensors, which detect angular or translational head accelerations (Leigh & Zee, 2006). The angular vestibulo-ocular reflex (aVOR) is mediated by projections from the labyrinthine semicircular canals to the brainstem, and generates eye rotations to compensate for head rotations. The translational vestibulo-ocular reflex (tVOR) is mediated by projections from the otolithic organs of the utricle and saccule to the brainstem, and generates eye rotations to compensate for head translations.
The properties of aVOR and tVOR are influenced by the distance of the object of visual regard. Thus, on the one hand, aVOR generates eye rotations that are approximately equal and opposite to head rotations while subjects view objects located at optical infinity, but eye movements may increase in amplitude as much as 30% while viewing near targets, because the eyes do not lie at the center of rotation of the head
(Viirre et al., 1986). On the other hand, tVOR does not need to generate eye rotations during viewing of distant objects, but during near viewing, the magnitude of required eye movements is inversely related to target distance (Paige, 1989; Schwarz & Miles, 1991;
Liao et al., 2007).
107 Taking this information together, it is possible to formulate laboratory stimuli that will approximate the head movements occurring during natural locomotion under a range of viewing conditions and could be used to test aVOR and tVOR in patients with PSP.
For our experiments, we applied combined yaw rotations at ~ 1.0 Hz and bob translations at ~ 2.0 Hz, and compare responses of aVOR and tVOR during viewing of targets located at far and near.
During locomotion, otolithic inputs are also essential for generating the vestibulospinal reflexes to adjust muscle tone so that stable posture is maintained. Loss of peripheral vestibular function causes postural instability that leads to falls. The otolith-spinal reflexes mediated by the saccule can be tested by presenting a loud click to the ear and measuring sternocleidomastoid muscle electromyographic activity – vestibular-evoked myogenic potentials (VEMPs) (Welgampola & Colebatch, 2005). This method is now widely used to test the saccular otolithic vestibulo-spinal reflexes, and we applied it to patients with PSP.
Thus, the goal of this study was to test, in two ways, the hypothesis that the otolithic reflexes are involved early in the course of PSP. First, we measured vestibulo-ocular responses to combined rotation and translation during viewing of near and far targets. Second, we tested otolith-spinal pathways using click-induced VEMP responses. Our findings indicate that central otolithic pathways are involved in PSP, and raise questions about how this disturbance arises, and how much it contributes to falls.
108 5-2. Methods
Testing of vestibulo-ocular reflexes was performed on a group of nine PSP patients in Cleveland, and testing of click-induced vestibulospinal reflexes was performed on a separate group of ten PSP patients in Munich. At both centers, the criteria for diagnosing PSP were those of NINDS-SPSP (Litvan et al., 1996); clinical details are summarized in Table 5-1; all patients were alert and attentive enough to comply with testing.
5-2-1. Vestibulo-Ocular Testing
Subjects: We studied tVOR in nine patients with PSP (4 women, age range 61 –
75 years, median 68). Nine healthy individuals (3 women, age range 60-72 years, median
67) served as control subjects. Refractive corrections were not worn during testing, and all subjects reported that they could easily see the visual targets, including the near targets. Experiments were performed in ambient light, so that natural visual cues, such as motion parallax and relative size, were available, and the safety of the subject on the platform could be monitored by one of the investigators who stood by the platform with an emergency stop switch. All gave informed, written consent, in accordance with the
Declaration of Helsinki and the Institutional Review Board of the Cleveland Veterans
Affairs Medical Center.
Vestibular Stimuli: Subjects sat in a chair on a Moog 6DOF2000E electric motion platform (East Aurora, New York) that could move with six degrees of rotational and
109 translational freedom through a range of + 20 deg and + 20 cm, with peak rotational acceleration of 400 deg/s2 and peak linear acceleration of 0.5 g (Liao et al., 2007). Belts were used to secure the subject’s torso and a snugly fitting skate-board helmet, inlaid with foam, was used to stabilize the subject’s head. Any head movements that were decoupled from chair or platform motion were measured, as described below. Each experimental run, which lasted 90 s, started with 3 cycles of bob at 0.2 Hz (typical amplitude + 5.6 cm) followed, after a pause of 3 s, by 3 cycles of yaw at 0.2 Hz (typical amplitude + 6 deg). Then, we applied bob translations at 2 Hz (typical amplitude + 2.3 cm) for 12 s to test tVOR. After a 3 s pause, we applied yaw rotations at 1.0 Hz (typical amplitude + 6 deg) for 12 s, to test aVOR. Finally, after a 3 s pause, we applied combined bob at 2 Hz and yaw rotation at 1 Hz for 12 s (a frequency combination similar to that occurring during natural walking). At the end of the experimental session, the patient’s head was released from the helmet and the vertical (pitch) aVOR was tested with impulsive stimuli delivered by hand (“head-thrust” test) (Halmagyi & Curthoys, 1988).
Visual Stimuli: There were three visual conditions, each employed for one experimental run. (1) Subjects binocularly viewed a laser spot projected on a wall at a distance of 2 m. (2) Subjects binocularly viewed a near target (reflective ball, diameter 1 cm) suspended at a distance of 15 cm in front of their left eye. (3) Subjects viewed a picture of a face that subtended ~ 50 deg at 15 cm. All of our control subjects were able to view these visual stimuli without refractive correction. PSP patients also reported that they could see all of the visual targets (and recognize the face), and tracked them with
110 eye movements during slow platform movements (see below), even though they had limited ability to converge, and some reported double vision.
Measurement of Eye and Head Movements: Three-dimensional eye rotations were measured using the magnetic search coil technique (Straumann et al., 2003), and head movements were monitored by an infrared reflection system (Vicon Motion
Systems, Los Angeles, CA) (Liao et al., 2007). Coil signals were digitized at 500 Hz with
16-bit precision after Butterworth filtering (0-150 Hz) to avoid aliasing and positions of the eyes were calculated in rotation vectors and converted to degrees. Head position signals from the infrared reflection system were digitized at 120 Hz (Liao et al., 2007).
Measurement of Subjects’ Responses: Complete head stabilization was difficult to attain but we were able to use the infrared motion detection system to measure the actual head perturbations and calculate ideal eye movements to hold gaze pointed at the visual target (Liao et al., 2007). We then calculated responsivity ratio (RR). Data were tested for normality with the Kolmogorov-Smirnoff test and comparisons between patients and controls used the Mann-Whitney test.
5-2-2. Vestibulo-Spinal Testing
We tested 10 patients with PSP (7 men, age range 60 – 76 years, median 68 years) and 30 healthy age-matched volunteers (19 men, age range 56 – 80 years, median 67 years) as controls.
111 Saccular function was determined by measuring VEMPs. Rarefaction clicks (0.1 ms, 3.2 Hz, 135 dB peak sound pressure level) were presented through headphones monaurally to the right and left ears. During stimulation, subjects lay supine. They were required to lift their heads off the bed to tense their sternocleidomastoid (SCM) muscles.
This standardized procedure was applied to both controls and patients. EMG activity was recorded from the upper half of the SCM muscle with a reference electrode on the upper sternum. EMG activity was recorded (Medelec Synergy, Surrey, UK), amplified, and bandpass filtered. Signals of 50 to 100 stimuli were averaged. The resultant response consisted of an initial positive peak (P1) and a subsequent negative peak (N1). The
P1-N1 amplitude was calculated for each ear and compared between healthy controls and
PSP patients. Data were tested for normality with the Kolmogorov-Smirnoff test. The comparison between patients and controls used the Mann-Whitney test. Statistical testing was performed using Microsoft Excel and the VassarStats statistical computation website.
5-3. Results
5-3-1. Responses to Translating while Rotating
Representative records from a PSP patient aged 74 years are compared with those of a normal subject (NS) aged 72 years in Fig. 5-1; note that individual traces, with the exception of vergence, have been offset to aid clarity of display. In Fig. 5-1A, during viewing of the far target at 2 m, the normal subject generated a horizontal (red) aVOR
112 with RR (which corresponds to a conventional gain measurement) that is close to 1.0; his vertical (blue) tVOR RR was 1.87 deg*s/m. During binocular viewing of the small near target, vergence angle (green) increased by about 20 deg (convergence is negative), aVOR
RR increased to 1.24 (appropriate for near-viewing) and tVOR RR increased to 10.73 deg*s/m. During binocular viewing of the near face image, vergence angle remained above
20 deg, aVOR RR increased to 1.38, and tVOR RR increased to 12.08 deg*s/m.
In Fig. 5-1B, during viewing of the far target at 2 m, the PSP patient had aVOR with RR of 1.04 and his tVOR RR was 1.48 deg*s/m. During binocular viewing of the small near target, vergence angle changed little (he was unable to converge), aVOR RR remained essentially unchanged at 1.05, and tVOR RR increased only slightly to 1.77 deg*s/m. During binocular viewing of the near face image, vergence angle changed little, aVOR RR increased slightly to 1.10, and tVOR RR increased only to 3.33 deg*s/m.
Fig. 5-2 compares all PSP patients with the group of control subjects for each of the three viewing conditions for aVOR (A) and tVOR (B). PSP patients (square symbols) tend to show smaller values of aVOR RR than control subjects (circle symbols), but with some overlap of data. For tVOR, PSP patients’ RR were smaller than controls during far viewing, but with overlap of data. However, during near-viewing conditions, PSP RR values for tVOR were significantly smaller than controls, with no overlap of data. The range of tVOR RR of our control subjects was similar to those previously reported during bob head translations (Paige, 1989), but responses of PSP patients during near viewing were, on average, only 12% of controls. Median convergence for control subjects for the near
113 target was 16.8 deg (range 14.7-20.3), and for the near image was 16.7 (range 15.0-20.4).
Median convergence for PSP patients for the near target was 0.1 deg (range 0.0 – 4.9), and was 1.4 deg for the near image (range 0.0 – 4.6). We also carried out a paired comparison of the tVOR values shown in Fig. 5-2B, which correspond to translation during rotation, versus tVOR during pure translation (bob) using the Wilcoxon sign-rank test; differences were not significantly different for PSP patients and the 9 age matched control subjects (though difference is significant for 20 normal subjects with an age span of 25-72).
The mean RR or gain (+ standard deviation) of the vertical aVOR in response to hand-delivered impulsive rotations was 0.96 (+ 0.12), which is similar to normal subjects
(Walker & Zee, 2005).
5-3-2. Responses to Click-Induced Stimulation
The median P1-N1 amplitude of all 60 ears of the healthy volunteers was 149 µV
(range: 11.6 - 466), that of all 20 ears of the PSP patients 54.3 µV (range: 16.8 - 214; see
Fig. 5-3). The data followed a non-normal distribution (p = 0.02). The difference between patients and healthy controls was significant. P1 and N1 latencies were within the normal range (17ms ± 2.5 and 25ms ± 2.5) in all subjects except for one PSP patient (right ear:
18.8ms/31.1ms; left ear: 20.0ms/30.3ms) and in the right ear of one healthy control (right ear: 19.9ms/27.8ms; left ear: 17.2ms/27.3ms).
114 5-4. Discussion
We present two independent lines of evidence that otolithic reflexes are impaired in patients with PSP. First, the otolith-ocular responses (tVOR) were impaired during near viewing. Second, otolith-spinal reflexes evaluated by vestibular-evoked myogenic potentials (VEMPs) were reduced compared with controls. First, we will discuss each of these findings separately, and then we will interpret their combined implications for the propensity to fall in PSP.
We chose to test vestibulo-ocular responses using combined rotation-translation stimuli at frequencies that correspond to natural head movements during normal walking
(Grossman et al., 1988; Pozzo et al., 1990). We found that during viewing a far target, vestibulo-ocular responses of PSP patients were not greatly different from control subjects. During viewing of a near target or image, responses of PSP patients to horizontal rotation (aVOR) were moderately impaired compared with controls. However, during near viewing, responses of PSP patients to vertical translation (tVOR) were substantially different than those of control subjects, with no overlap of data (Fig. 5-2).
Thus, tVOR did not increase during near viewing in our PSP patients, whereas it did in the age-matched control subjects. Similarly, decreased responses of tVOR were obtained during pure vertical translation without rotation. Nonetheless, our patients had normal responses to vertical (pitch) head rotations, consistent with the clinical observation that even late in the course of PSP, it is still possible to evoke vertical eye rotations by flexing and extending the patient’s head on the neck.
115 Since our PSP patients were unable to converge, it could be argued that this was the reason for their inability to muster tVOR responses during near viewing. The brunt of the early pathology in PSP falls on the midbrain (Steele et al., 1964; Litvan, 2005), and this may interfere with the ability to generate convergence, and thereby hinder the ability to appropriately set tVOR behavior during near viewing. However, apart from convergence, visual cues also play an important role in setting the magnitude of tVOR.
Thus, in a prior study of tVOR in response to lateral (side-to-side) motion, Schwarz and
Miles concluded: “We suspect that the system can use whatever depth cues are to hand, including vergence, accommodation, motion parallax, size, perspective, texture, overlay, etc”(Schwarz & Miles, 1991). Studies of normal subjects in our laboratory confirm the view that target distance is more important than vergence angle in setting tVOR responses (Liao et al., 2007). Therefore, we suggest that an inability to converge is just one component of PSP patients’ difficulty with directing the point of attention at near objects, which appears to be a pre-requisite for increasing the magnitude (responsivity) of tVOR. Furthermore, the vestibular nuclei consistently show loss of neurons in brains of patients who have died of
PSP (Steele et al., 1964), and therefore direct involvement of central pathways mediating otolith-ocular reflexes could be present, although less is known about their circuitry than for canal-ocular reflexes (Newlands et al., 2003; Leigh & Zee, 2006).
The VEMP is an inhibitory potential recorded from the sternocleidomastoid muscle in response to loud sounds (Zhou & Cox, 2004). There is ample evidence from clinical studies and animal experiments that the VEMPs are mediated by the saccule. In
116 the squirrel monkey, in guinea pigs and in cats, acoustically responsive saccular fibers have been identified (Young et al., 1997; McCue & Guinan, 1995; Didier & Cazals,
1989). In patients with gross abnormalities of the bony labyrinth, but intact vestibules on computed tomography, VEMPs have been recorded (Sheykholeslami & Kaga, 2002). The
VEMPs generated in the saccular macula are transmitted via a disynaptic pathway involving Scarpa’s ganglion, the inferior part of the vestibular nerve, the lateral vestibular nucleus, and medial vestibulospinal tract to cervical motor neurons including those innervating the sternocleidomastoid muscle (Murofushi & Curthoys, 1997; Kushiro et al.,
1999; Uchino et al., 1997; McCue & Guinan, 1994).
In PSP patients we found a significant reduction of the amplitudes of VEMPs compared to an age-matched healthy control group; the latencies were in the normal range. This indicates impaired function of the saccular otolithic pathways. Clinical evidence for an impairment of the nuchocephalic reflex in PSP has been described previously (Jenkyn et al., 1975), and EMG responses of the sternocleidomastoid and other muscles to vertical free fall have been shown to be diminished in PSP (Bisdorff et al., 1999).
One may argue that the amplitude of the VEMPs may be reduced in PSP patients due to increased muscular tension in the sternocleidomastoid muscles, since these patients tend to have very rigid necks. However, the opposite is true: Early studies of
VEMPs recorded at the inion showed the amplitude to increase with tension in the neck muscles (Bickford & Jacobson, 1964). More recent studies have confirmed the strong
117 relationship between the VEMP amplitude and the mean level of electromyographic activity (Colebatch et al., 1994; Li et al., 1999; Ochi et al., 2001). To allow for the reduction of VEMP amplitudes with increasing age (Su et al., 2004), we compared the patients’ response to that of an age-matched control group.
Could reduced VEMPs in PSP be due to a general impairment of cranial nerve function in this disorder? An impaired auditory startle reaction (Kofler et al., 2001), and absent orbicularis oculi responses after median nerve stimulation are reported in PSP
(Valls-Sole et al., 1997). However, the mentalis responses to median nerve stimulation and trigemino-facial blink reflexes do not differ between PSP patients and normal subjects (Valls-Sole et al., 1997). Furthermore, impaired startle response in PSP has been attributed to a degeneration of the nucleus reticularis pontis caudalis (Kofler et al., 2001), which is not a part of the VEMP-circuit.
It may further be objected that reduced VEMPs are an unspecific finding caused by widespread neural degeneration. However, VEMPs are well-preserved in other neurodegenerative disorders such as olivo-ponto-cerebellar ataxia (Takegoshi &
Murofushi, 2000). Furthermore, as noted above, although brunt of the disease in PSP mainly affects the upper brainstem, the vestibular nuclei are also consistently affected
(Steele et al., 1964). Since the pathways conveying VEMPs synapse in the lateral vestibular nuclei (Newlands et al., 2003), it seems probable that reduced VEMPs are not an inevitable feature of degenerative brainstem disease but probably a rather specific symptom in PSP.
118 Falls leading to fractures are an early clinical sign and a substantial cause of morbidity and mortality in PSP (Williams et al., 2006), but have remained largely unstudied and unexplained. Our findings implicate abnormal otolith-mediated vestibular reflexes. However, the cause of falls in PSP is likely to be multifactorial. Thus, PSP patients typically show axial rigidity, and parkinsonian patients who fall generate inappropriately directed arm movements in response to postural perturbations (Bisdorff et al., 1999; Carpenter et al., 2006). One of our findings is that PSP patients could not converge their eyes or apparently direct their point of visual attention to near objects.
There is abundant evidence that normal subjects can modulate the performance of their vestibulo-ocular reflexes according to mental set and state of attention (Leigh & Zee,
2006). Thus, it seems possible that one component of the postural defect in PSP, besides degenerative changes found in the motor cortices and the motor thalamus in PSP patients
(Halliday & MacDonald, 2005), is due to loss of the ability to adjust vestibular reflexes so that they are appropriate for forward motion through the environment. Tests of the postural responses of PSP patients to visual stimuli that mimic the optic flow during locomotion might provide further insights into their propensity to fall.
119
Figure 5-1 Comparison of representative records of ocular motor response to translating while rotating by a normal subject (A) and a patient with PSP (B). Each panel comprises the horizontal eye rotation in response to yaw rotations (red), the calculated ideal eye rotation
(dotted red), the vertical eye rotation in response to bob translations (blue), the calculated ideal eye rotation (dotted blue), and vergence angle (green). Positive values indicate leftward, downward rotations, and divergence eye movements. Note that each channel has been offset to aid clarity of display, except for vergence, which was set to a value of 1.8 deg for far target viewing, based on geometric relationships between the subject and visual stimulus. At the top of each panel is the measured responsivity ratio (RR) of aVOR and, at the bottom, tVOR. In
A, compared to viewing the far target, a normal subject is able to generate convergence and increase aVOR and tVOR responses while viewing the near target or near image. In B, during near viewing, PSP can generate only a small increase of convergence, tVOR responses, or aVOR, during viewing of the near target or image.
120
Figure 5-2 Comparison of aVOR (A) and tVOR (B) responsivity ratio (RR) during the three viewing conditions for nine PSP patients (square symbols) and nine control subjects (circle symbols). PSP patients tend to show smaller values of aVOR RR than control subjects, but with some overlap of data. In contrast, PSP patients show no overlap of RR values for tVOR during near viewing conditions, these differences being highly significant.
121
Figure 5-3 Box plot chart illustrating the amplitudes (in µV) of the vestibular evoked myogenic potentials (VEMPs) in PSP patients and healthy controls. Boxes indicate the range of the first and third quartile. Whiskers extend between the 10th and the 90th percentile, cross symbols between the 5th and the 95th percentile. Differences between amplitudes in patients and controls were highly significant.
122 Table 5-1. Summary of Clinical Information of Patients Studied Patient Age/Sex/Duration Medicines* Postural Stability CP1 61/M/48 None Frequent falls CP2 61/W/40 Levodopa- Unsteady gait, occasional falls carbidopa CP3 64/W/64 None Frequent falls CP4 65/W/36 None Unsteady gait with occasional falls CP5 68/M/60 Levodopa- Unsteady gait with occasional carbidopa falls CP6 70/M/60 None Unable to stand without support CP7 71/M/60 Amantidine Unsteady gait CP8 74/M/48 Levodopa- Frequent falls carbidopa CP9 75/M/14 Amantidine Unsteady gait, occasional falls MP1 67/M/6 None Occasional falls MP2 68/W/33 None Unsteady gait, up to 3 falls/week MP3 63/M/60 Amantidine Unsteady gait, frequent falls MP4 60/W/12 Amantidine, Approx. 1 fall/week Amitriptyline MP5 62/M/17 None Unsteadiness of gait MP6 69/M/24 None Occasional falls MP7 68/W/72 Amantidine, Frequent falls Amitriptyline MP8 68/M/132 Amantadine, Unable to walk without support Levodopa- carbidopa MP9 76/M/36 Amantidine, Frequent falls Levodopa- carbidopa
123 MP10 71/M/10 None Occasional falls
CP: Cleveland patient; MP: Munich patient. M: man; W: woman. Duration: duration of disease in months. *Medicines with effects on the nervous system.
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vestibuloocular reflex. Journal of Neurophysiology, 56, 439-450.
Walker, M. F. & Zee, D. S. (2005). Cerebellar disease alters the axis of the
high-acceleration vestibuloocular reflex. J Neurophysiol, 94, 3417-3429.
Welgampola, M. S. & Colebatch, J. G. (2005). Characteristics and clinical applications of
vestibular-evoked myogenic potentials. Neurology, 64, 1682-1688.
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130 Chapter 6 Potential application of this study to clinic disorders
Second Example: Cerebellar Ataxias
6-1. Introduction
Imbalance and gait ataxia are major causes of functional disability and falls in patients with cerebellar ataxia. The mechanisms underlying these deficits remain uncertain, but impaired vestibular reflexes are likely to play an important role, since the vestibular system provides the brain with essential information regarding motion and the body’s orientation relative to gravity.
Most prior studies of vestibular function in patients with cerebellar disease have focused on the rotational vestibulo-ocular reflex (rVOR). Occasionally, the rVOR is absent (Migliaccio et al., 2004); most often it is present, although it may have an abnormal amplitude or direction (Thurston et al., 1987; Walker & Zee, 2005). Responses to linear motion (translation) and gravity, which are mediated by the otolith organs, are likely to be of particular importance to balance and walking. In fact, it has been shown the horizontal (side-to-side) translational VOR (tVOR) is commonly impaired by cerebellar disease (Wiest et al., 2001; Zee et al., 2002). The response to vertical head motion (bob), however, has not previously been studied in ataxic individuals, although this motion is prominent during natural human locomotion (Massaad et al., 2007). In
Chapter 5, we found that the vertical tVOR is impaired in patients with progressive
131 supranuclear palsy (PSP), another neurodegenerative disease, in which gait and balance deficits are prominent and occur early. Here we investigated the vertical tVOR in patients with cerebellar ataxia.
6-2. Methods
We studied vestibulo-ocular reflexes in a group of eight patients (age range 27-79, median 57 years, Table 6-1) who presented with gait ataxia as a component of one of a range of cerebellar disorders. Twenty normal subjects (8 female, age range 25-72, median
55 years) served as the comparison group (Liao et al., 2008b). Experiments were performed in ambient light, so that natural visual cues were available, and the safety of the subject on the platform could be monitored by one of the investigators who stood by the platform with an emergency stop switch. All subjects gave informed, written consent, in accordance with the Declaration of Helsinki, under a protocol approved by the
Institutional Review Board of the Cleveland Veterans Affairs Medical Center.
6-2-1. Stimuli
Experimental methods have been described in detail in Chapter 5. Subjects sat in a chair on a Moog 6DOF2000E electric motion platform (East Aurora, New York). Belts were used to secure the subject’s torso, and a snugly fitting skate-board helmet, inlaid with foam, stabilized the subject’s head. Any head movements that were decoupled from chair or platform motion were measured, as described below. The tVOR stimulus
132 consisted of 2 Hz bob (typical amplitude + 2.3 cm), and the rVOR stimulus was 1 Hz yaw (typical amplitude + 6 deg), each for a duration of 12 s. In one patient (P8), only bob stimuli were applied.
Data from two visual conditions, each employed for one experimental run, are presented here: 1) Subjects binocularly viewed a laser spot that was projected on a wall at a distance of 2 m and subtended 0.5 deg; 2) Subjects viewed binocularly a near target
(reflective ball, diameter 1 cm, with a central aperture that subtended 1.2 deg) suspended at a distance of 17 cm in front of the left eye.
6-2-2. Measurement of Eye and Head Movements
Three-dimensional eye rotations were measured using the magnetic-field search coil technique, and head movements were monitored by an infrared reflection system
(Vicon Motion Systems, Los Angeles, CA). Coil signals were digitized at 500 Hz with
16-bit precision after Butterworth filtering (0-150 Hz) to avoid aliasing, and positions of the eyes were calculated in rotation vectors and converted to degrees. Head position signals from the infrared reflection system were digitized at 120 Hz and were used to calculate the movements of the subject’s head, the coil frame, and “ideal eye rotations” to hold gaze (corresponding to the line of sight) on the visual target (Liao et al., 2008b).
Complete head stabilization was difficult to attain, but we controlled for this by using the infrared motion detection system to measure the actual head perturbations.
133 Eye velocity signals were desaccaded using a velocity threshold selected interactively. The desaccaded signals were subjected to a fast Fourier transform to determine the amplitude of the response at the stimulus frequency (2Hz for tVOR,1Hz for rVOR) as previously described (see Chapter 3). The tVOR was quantified by its responsivity
(deg*s/cm), the ratio of measured eye velocity (deg/s) to translational head acceleration
(cm/s2). The rVOR was quantified by its gain, the ratio of the magnitude of eye velocity to that of head velocity (which is dimensionless). Given the possibility that data in patients are not normally distributed, a non-parametric statistical test (Wilcoxon rank-sum) was used for all group comparisons.
6-3. Results
6-3-1. Translational VOR
Fig. 6-1 shows vertical tVOR responses in a representative normal subject and three subjects with cerebellar disease, illustrating the variety of responses that we observed in ataxic individuals. These responses were recorded during fixation of the near target; each of these subjects was able to converge to view the target binocularly. Despite similar convergence, only one of the three patients (P5) had a response that was close to the normal range. Subject P7 had a very low response amplitude, and P3 had a brisk downbeat nystagmus but no consistent modulation of slow-phase eye velocity with head movement. For the group, there was no consistent effect of viewing distance on nystagmus slow-phase velocity (p=0.55).
134 Responsivity values for all subjects for both target distances are summarized in
Fig. 6-2A. For both far (p < 0.01) and near (p = 10-4) viewing, responsivity was reduced for patients relative to normal subjects. The increase in eye velocity with viewing of the near target was substantially impaired in patients (median responsivity at near 3.3 vs.
14.8), despite more nearly normal convergence (16.6 deg vs. 19.2 deg).
6-3-2. Rotational VOR
Although several patients had reduced responses to yaw rotation, the rVOR was less consistently impaired than was the tVOR. This is illustrated in Fig. 6-2B, which compares the tVOR responsivity to the rVOR gain in each subject, during viewing of the near target. Four patients had rVOR gains within the normal range, but for three of the four the tVOR responsivity was still less than that of all of the normal subjects.
Correspondingly, the response increase with near compared to far viewing was more impaired for the tVOR (median increase of 240% in patients and 640% in normals) than for the aVOR (median increase of 20% in patients and 26% in normals).
6-4. Discussion
This is the first study to investigate the vertical tVOR in patients with cerebellar ataxia. We found that most patients had a reduced vertical tVOR, and they were unable to increase eye velocity when viewing a near target, even though convergence was intact.
Prior studies have implicated the cerebellum in the horizontal tVOR, mainly mediated by the utricules and evoked by interaural translation. Patients with cerebellar
135 ataxia often have a substantially reduced or absent tVOR, even when viewing near targets
(Wiest et al., 2001; Zee et al., 2002). Our data here show that the vertical tVOR, mainly mediated by the saccules, is also under cerebellar control. As is the case for the interaural tVOR, the cerebellum appears to be an obligate part of the central pathways of the vertical tVOR. This finding is consistent with a recent study in monkeys, in which experimental lesions of the cerebellar nodulus and uvula reduced eye velocity in response to vertical translation in both light and darkness (Walker et al., 2008).
The tVOR is highly dependent on the viewing distance (Schwarz & Miles, 1991).
Thus, the patients’ reduced eye velocity during head translation could be due either to a primary defect of the tVOR or to a general loss of the ability to judge the viewing distance. For example, if the target were thought to be much farther away than it actually was, the evoked eye movement might be correspondingly smaller. Our data support a specific tVOR defect for several reasons. First, convergence was nearly normal, even when the tVOR was dramatically reduced (Fig. 6-1 and 6-2A). That the patients were converging appropriately suggests that they were able to use disparity cues to judge the distance to the near target. Second, at least half of the patients were able to increase the rVOR normally for a near target, yet the tVOR gain remained low (Fig. 6-2B). Finally, there were no patients who had a strong tVOR but no modulation with target distance; the patients had reduced responses even for the far target (Fig. 6-2A).
The vertical tVOR is most likely mediated primarily by the vertically oriented sacculi. A clinical test of saccular function is the vestibular evoked myogenic potential
136 (VEMP). We did not measure VEMPs in our subjects, but our studies have shown that patients with progressive supranuclear palsy (Chapter 5) and some patients with cerebellar disease (Takegoshi & Murofushi, 2000) may have abnormal VEMPs. The use of VEMPs to assess vestibulospinal function in these patients warrants further study.
In conclusion, in this study we have shown that cerebellar disease impairs the vertical tVOR, during head motion similar to that experienced with natural locomotion.
This provides further evidence for an important role of the cerebellum in the processing of otolith signals. Moreover, it is likely that disturbed otolith reflexes contribute to imbalance, gait ataxia, and falls in these patients.
137
Figure 6-1 Example responses to 2 Hz vertical translation (near target) in one normal subject
(N) and three patients (see text). Each plot shows the calculated ideal eye velocity (upward is negative), the actual recorded eye velocity, and the vergence angle (verg; note convergence is negative) for a representative 2.5 s (5 cycle) segment.
138
Figure 6-2 (A) Responsivity and vergence angle in normal subjects (Norm) and patients (Pat).
Each box contains the middle two quartiles (the horizontal line indicates the median), and whiskers encompass the rest of the data points, except for outliers (x). (B) Comparison of tVOR responsivity and rVOR gain in each subject, both measured during viewing of the near target.
139
140 6-5. Reference List Liao, K., Wagner, J., Joshi, A., Estrovich, I., Walker, M. F., Strupp, M. et al. (2008a). Why do patients with PSP fall? Evidence for abnormal otolith responses. Neurology, 70, 802-809.
Liao, K., Walker, M. F., Joshi, A., Reschke, M. F., & Leigh, R. J. (2008b). Vestibulo-ocular responses to vertical translation in normal human subjects. Exp Brain Res, 185, 553-562.
Massaad, F., Lejeune, T. M., & Detrembleur, C. (2007). The up and down bobbing of human walking: a compromise between muscle work and efficiency. J Physiol, 582, 789-799.
Migliaccio, A. A., Halmagyi, G. M., McGarvie, L. A., & Cremer, P. D. (2004). Cerebellar ataxia with bilateral vestibulopathy: description of a syndrome and its characteristic clinical sign. Brain, 127, 280-293.
Schwarz, U. & Miles, F. A. (1991). Ocular responses to translation and their dependence on viewing distance. I. Motion of the observer. J Neurophysiol, 66, 851-864.
Takegoshi, H. & Murofushi, T. (2000). Vestibular evoked myogenic potentials in patients with spinocerebellar degeneration. Acta Otolaryngol, 120, 821-824.
Thurston, S. E., Leigh, R. J., Abel, L. A., & Dell'Osso, L. F. (1987). Hyperactive vestibuloocular reflex in cerebellar degeneration: pathogenesis and treatment. Neurology, 37, 53-57.
Walker, M. F., Tian, J., Shan, X., Tamargo, R. J., Ying, H., & Zee, D. S. (2008). Lesions of the cerebellar nodulus and uvula: Effect on otolith-ocular reflexes. Prog.Brain Res., 171, In press.
Walker, M. F. & Zee, D. S. (2005). Cerebellar disease alters the axis of the high-acceleration vestibuloocular reflex. J Neurophysiol, 94, 3417-3429.
Wiest, G., Tian, J. R., Baloh, R. W., Crane, B. T., & Demer, J. L. (2001). Otolith function in cerebellar ataxia due to mutations in the calcium channel gene CACNA1A. Brain, 124, 2407-2416.
Zee, D. S., Walker, M. F., & Ramat, S. (2002). The cerebellar contribution to eye movements based upon lesions: binocular three-axis control and the translational vestibulo-ocular reflex. Ann.N.Y.Acad.Sci., 956, 178-189.
141 Chapter 7 General Discussion and Future Research of the Translation Vestibulo-Ocular Reflex
7-1. History of a scientific journey
Chapter 1 provides the physiology and systems neurobiology behind the vestibulo-ocular reflexes, and Chapter 2 describes some details of methods and instrumentation for studying these reflexes in humans. Chapters 3-6, which correspond to published scientific papers, each contain a discussion of aspects of tVOR behavior in normal subjects and in patients with neurological disorders. However, these papers do not provide a comprehensive review of the engineering challenges posed by the current research which, in this chapter, will be described from a historical perspective. Thus, a biography of the laboratory starting with delivery of the Moog motion platform, installation of magnetic search coil system and Vicon infrared tracking device will be summarized, commenting on each of the engineering problems that have been solved, and those that require further work. In parallel with instrumentation challenges, the conceptual issues posed by new findings will be reviewed in the order that they occurred, illustrating how our knowledge of tVOR grew incrementally. Thus, this chapter comprises the history of my research project, ending with a view of future prospects for research and development.
142 7-2. Development of a new device to test tVOR
As outlined in Chapter 1, a major impediment to studying tVOR in humans has been the lack of availability of affordable platforms that move linearly. A number of labs, worldwide, have developed devices, such as go-carts on tracks or linear sleds mounted on air bearings. Such devices have been expensive to fabricate and are mainly limited to imposing translations in one plane. The only prior study of tVOR in bob used the simple option of a stool mounted on a spring, with a natural frequency of oscillation of 2.7 Hz and generated reliable data by measuring eye movements with the magnetic search coil technique (Paige, 1989).
The development and production by the Moog Corporation (East Aurora, New
York) of motion platforms with 6-degrees of freedom that could be used as flight simulators provided an affordable and flexible means to test both tVOR and aVOR in human subjects. Purchase of a Moog 6DOF2000E electric motion platform was made possible through a grant from NASA and was delivered on September 16th, 2003. A large and heavy piece of apparatus (Fig. 7-1), it initially was installed in temporary accommodation in spare office space, where preliminary preparations and testing were performed.
The Moog 6DOF2000E contains six hydraulically powered motors that can carry a payload of 1,000 pounds (Fig. 7-2). Thus, an immediate concern in operating the platform was stability and safety because it could only be secured with three bolts into a standard hospital floor. Consequently, only vertical (bob) movements were initially
143 considered safe. Fortunately, such bob movements are a prominent component of head movements during locomotion, as first demonstrated by the French pioneer of cinema,
Etienne-Jules Marey (1830-1904). In Fig. 7-3, note how the marker on the head moves up and down during each step.
The next step in installation of equipment to study tVOR involved stable attachment of a chair, suitable for human subjects, to the platform. The chair also provided a mount for the field coils necessary to measure eye movements using the magnetic search coil system. It was important for the subject’s head and the field coils to be rigidly attached to the platform. Preventing decoupling of the field coils with respect to the platform could be achieved using an aluminum base, and chair made of wood and plastic materials (Fig. 7-4). (Note that ferrous metal could not be used as this would distort the magnetic field.) Later, metal braces between the chair and platform have been added to provide stability during lateral platform motion.
A greater challenge was stabilizing the subject’s head with respect to the chair, especially for high-frequency or transient platform movements. Other labs have used a bite-bar that incorporates each subject’s dental impression. However, in preliminary studies, subjects found this uncomfortable, and it was therefore judged unsuitable for use with patients who have neurological disorders. Eventually, skate-board helmets of two sizes (the smaller being more suitable for females), with inlaid foam were judged as providing adequate stabilization for bob platform motion. As described below, we measured any decoupling of the subject’s head from the helmet. In future studies that
144 incorporate lateral or anterior-posterior movements, even better means for stabilization may be necessary. One possible solution might be an orthopedic neck collar, to minimize roll or pitch movements of the subject’s head.
While the Moog platform was housed in temporary office accommodation, it was possible to perform some preliminary experiments, even though it was not yet possible to monitor movements of the platform. After the magnetic search coil system was attached and was operative, it was possible to measure eye movements during bob translations under unique viewing conditions. The subject was able to view, through a window, a church spire at a distance of 200 meters, corresponding to true optical infinity.
(Vestibular testing laboratories are invariably located in relatively small windowless rooms, where the conditions of illumination can be tightly controlled). Under conditions of viewing a target located at optical infinity, there is no need for any tVOR (see Chapter
1). However, as shown in Fig. 7-5A, a response was detected during bob at of 2 Hz, although measurement of phase shift with respect to platform motion was not possible.
When the Moog platform was moved to the Daroff-Dell’Osso laboratory, and head position could be monitored (see below), we attempted to repeat the experiment, this time by asking the subject to look through a mirror at a visual target (a small doll) at a viewing distance of 6 meters. Under these conditions, we also noted a small tVOR response for which eye movements were directed opposite to head translation (Fig. 7-5B).
Thus, even under conditions in which there is no visual need, the brain generates tVOR, which induces a small amount of retinal image motion. These measurements are
145 consistent with anecdotal reports of illusory bobbing (oscillopsia) of numbers on a distant score board during running on an athletic track (David S. Zee, personal observations,
1980). They are also consistent with theoretical predictions of tVOR behavior during viewing targets at optical infinity (Paige et al., 1998).
After the Moog platform was moved and secured with masonry bolts in the
Daroff-Dell’Osso Laboratory on December 30th, 2005, it became possible to set up the
Vicon infrared system for measuring movements of the subject’s head, and the helmet, which moves with the coil frame. Reflective markers were applied to the helmet (Fig.
7-6), and the subject’s cheek bones. In addition, prior to each experiment, the subject wore an air-travel sleep mask, with reflectors placed over each eye; thus, the relative position of the subject’s eyes to the head markers was measured. Six cameras allowed head and coil frame movements to be measured with a resolution of 2 mm and 0.1 deg.
The transformations of measurements between different coordinate frames are summarized in Chapter 2 and Appendices 1 and 2. These measurements allowed us to measure any decoupling of the subject’s head with respect to the helmet, which were typically < 1 deg rotations and < 2 mm translation in each plane. The measurements also allowed us to calculate what the “ideal eye rotations” would be in order to keep the subject’s line of sight or gaze (corresponding to foveal vision) pointed at the visual target.
We verified these measurements by translating or rotating normal subjects at low frequencies, during which they were easily able to hold their gaze on the visual target; we found a close correspondence between calculated and measured values of ideal eye
146 movements. (During higher frequency movements, such as those used in experiments, we could not rely on subjects to hold their gaze on target, and they usually did not for tVOR, which is one of our main finding, as presented in Chapter 3.) The Vicon motion system provided signals at 120 Hz from a dedicated computer system that was independent from a second computer that acquired eye coil signals. We used a linear accelerometer to detect the onset of platform motion, and digitized that signal on the same interface as the coil signals. By commencing each trail with a vertical step, it was possible to synchronize measurements of eye rotations (coil system) and accelerometer with head-helmet-coil-frame movements, measured by the Vicon infrared system.
Most experiments were performed in ambient light, which provided subjects with a rich visual world in three dimensions. The visual stimuli were a laser spot on the wall at
2 m or a near target, consisting of one of the reflective balls that could be detected by the
Vicon system hung in front of the subject at a viewing distance of about 17 cm. The reflective ball was pierced by the suspensory cord, which provided rich 3-D visual cues.
Some control experiments were performed with a background that moved at a different frequency (2.1 Hz) than that of the platform (2.0 Hz). To achieve this, we used a large flat screen with a variety of patterns, including horizontal stripes (Fig. 7-7) in an otherwise dark room (note that room lights were left on for this photograph). We also presented a stationary background at different viewing distances; this consisted of a large white bed sheet on which were drawn many black dots of variable size.
147 7-3. Safety procedures
Throughout our experiments, an important concern was subject and investigator safety. The Moog platform is a powerful device, and subjects who sat on it included frail patients with neurological diseases. To these ends, we implemented several standard procedures: (1) Subjects were securely belted into the chair. (2) Room lights remained on through all but a few control experiments. (3) A safety stop switch (large button) was immediately accessible to the investigator controlling movement of the platform. (4)
Safety rails were fitted to the platform (Fig. 7-6) to prevent the investigators from falling during subject preparation. (5) For patients with neurological disorders who were unsteady when they stood (all patients with PSP or cerebellar ataxia), we built a wooden platform that could be placed in front of the Moog, to which a ramp for wheelchair access was attached. Patients were then belted into a wheelchair and rolled up the ramp onto the platform. They then were released from the wheelchair and stood supported by at least two investigators as they were transferred into the test chair. During this procedure and egress at the end of testing, six or more individuals were on hand to support the patient and wheelchair, and to prevent falls.
7-4. Remaining engineering considerations
The experiments performed in the current research all concerned vertical translations of the subject (bob), which were selected for three reasons: (1) We were able to deliver them reliably and safely. (2) Bob head translations are prominent during
148 locomotion (Fig. 7-3). (3) The binocular human tVOR in response to bob stimuli had not been previously studied, particularly in patients with neurological disorders causing postural instability. The Moog platform can generate moving stimuli with six degrees of freedom, and there is also need and interest in studying tVOR behavior during lateral or forward-backward movements. However, these translations present two new problems: (1)
The chair and coils, sitting on top of the translating platform, tends to develop the movements of a pendulum unless it is rigidly attached. (2) The subject’s head is much more prone to move within the helmet during lateral and for-aft movements than during bob. By attaching metal braces to the sides of the chair, the first problem has largely been overcome. However, we are still searching for better methods to stabilize the subject’s head during platform translation, including the possibility of orthopedic (Philadelphia) neck collars.
As our knowledge advances, new experiments will likely call for more complex visual stimuli than we have used. Developments in flat-screen technology are likely to make it possible to present variety of stimuli, such as sinusoidal gratings with a range of spatial and temporal frequencies, and contrasts. Eventually, video-based devices may make it possible to measure eye rotations with precision and without the need for a contact lens but, at present, the magnetic search coil system remains the “gold standard”.
7-5. Evolution of findings and hypotheses for tVOR
7-5-1. The first finding: tVOR does not maintain foveal foveation of visual targets
149 In our first experiments, it was evident that tVOR in response to vertical translations in ambient illumination was inadequate to hold the image of a far (2 m) or near (17 cm) target on the fovea (Chapter 3). Since head perturbations that occur during locomotion contain both rotational and translational components, it seemed important to test tVOR during with combined translations and rotations, to determine if, under those conditions, tVOR became “compensatory” – with a compensation gain of ~ 1.0. We decided to apply translations in the vertical axis (bob) and rotations about the vertical axis
(yaw), because this combination could be achieved most smoothly, without decoupling head and helmet movements. Furthermore, analysis of results was simpler with this orthogonal combination of rotation and translation. For example, if we had selected bob and pitch (rotation about an interaural axis), then there would have been some uncertainty about what proportion of eye movements was due to rotation, and what proportion to translation. During locomotion, bob and pitch movements occur at the same frequency, whereas yaw rotations are at half the frequency of bob movements (Grossman et al., 1988;
Pozzo et al., 1990). We selected frequencies for bob (2 Hz) and yaw (1 Hz) corresponding to head perturbations reported during locomotion.
We found that head rotations produced a small increase in tVOR when yaw was combined with bob (Chapter 3), but that tVOR did not become compensatory, and compensation gain remained at ~ 0.6. Thus, under conditions of ambient illumination and combined translation-rotation, tVOR could not keep the “eyes on target”. Prior studies can be criticized for employing unphysiological vestibular stimuli under conditions of
150 reduced illumination, or using unreliable recording methods (see Chapter 1 and Table 1-2 for review of these issues). Ours was the first study to correct these deficiencies and make the case that human tVOR could not be regarded as maintaining foveal vision of a target during head translation.
Several thoughtful explanation have been advanced to account for the “enigmatic” finding that tVOR compensation gain typically remains ~ 0.5, irrespective of viewing distance (Ramat & Zee, 2003; Moore et al., 1999). First, natural head perturbation that occur during locomotion comprise both rotations and translations, and the combination of responses might somehow be adequate to keep the fovea on target. For example, vertical head translations are combined with pitch movements, such that the naso-occipital axis of the head tends to remain pointed about 1m in front of the subject (Moore et al., 1999; Pozzo et al., 1990; Bloomberg et al., 1992). Second, it follows that aVOR gain might be adjusted to aid tVOR responses, depending on the viewing distance of the target. For example, if aVOR was under-compensatory, this might allow pitch head movements to supplement a tVOR that only partially compensated for bob translations. Third, during locomotion while viewing a near target, the amplitude of head movements change, and this might mean that smaller demands are made of tVOR. Finally, central integration of translational and rotational signals from the labyrinths might produce tVOR behavior appropriate for any specific set of demands, such that the overall behavior was more than the sum of its part.
Such an effect would be similar, for example, the way that prior smooth-pursuit movements enhance aVOR (Das et al., 1999). As well argued as these suggestions are, we doubt them
151 because in studies of tVOR and aVOR during locomotion on a treadmill, retinal image slip of 7-14 deg/s (Crane & Demer, 1997), and corresponding oscillopsia (Moore et al., 1999) indicate that tVOR cannot maintain foveal image stability, especially of near targets.
7-5-2. The second finding: tVOR responsivity is determined by binocular visual cues, but not vergence angle or visual tracking mechanisms
An impressive finding was that although the magnitude (responsivity) of tVOR increased substantially from far to near viewing (by a factor of nine in our experiments), compensation gain was maintained fairly constant at about 0.6 (Fig. 4-2). It was reasoned that the brain was adjusting tVOR to visual needs, but not for foveal stabilization of images. Thus, the question arose: What visual need was tVOR responding to? A first step towards addressing this question was to identify factors that appeared to influence or
“set” tVOR behavior.
First, drawing on prior suggestions (Paige, 1989; Paige et al., 1998), the possibility of vergence angle was considered. The finding that tVOR responsivity decreased during monocular versus binocular viewing of the near target (Fig. 3-2) supported this possibility (since vergence angle decreased under monocular viewing conditions). However, control experiments using prisms, in which subjects viewed a visual target at one distance but with two vergence angles (Fig. 3-3A), clearly showed that viewing distance was the key determinant. Although vergence angle may still be monitored by the brain, and used to determine tVOR during impoverished visual
152 conditions (such as dim illumination), our data stress the importance of binocular visual cues.
Second, the possibility of visual tracking as the underlying mechanism of tVOR behavior was considered since, during bob in ambient light, retinal image motion is abundant as a stimulus to eye movements. A consistent finding was that tVOR phase lag of eye versus head movement was ~ 19 deg (Fig. 3-3B). This contrasted with phase lags that were three times larger during visual tracking of a large moving target that present similar retinal image motion to that imposed by head translations. In fact, a phase lag of about 20 deg corresponds quite well with what would be predicted from reported values of 18-25 ms delay for tVOR (Bronstein & Gresty, 1991; Ramat & Zee, 2003). Thus, although vision conditions clearly influenced tVOR behavior, visual tracking was not likely to be the underlying mechanism. Further, when the experimental room was transiently switched to darkness, or the subject viewed the target under strobe illumination (which effectively abolished retinal image slip), tVOR responsivity declined
(Fig. 4-4).
Thus, it seemed that although binocular visual cues provided the information necessary to increase tVOR responses during near viewing, neither visual tracking nor convergence was a critical factor. This led us to consider other aspects of binocular vision that might be more important.
153 7-5-3. A hypothesis to account for visual influences on tvor and a test of the hypothesis
Reconsidering the geometry of tVOR, it became clear why holding the image of the visual target steady on the fovea would cause problems: in that case, peripheral retinal images of the visual background would greatly increase (Fig. 3-4). By calculating the retinal image motion of foveal and peripheral images based on our subjects’ data, it was determined that a compensation gain of 0.6 would tend to equate image motion of the target and the surround (Chapter 4). Taken together, these findings led us to postulate that relative motion of the near target with respect to the distant background (motion parallax) was an important determinant of tVOR behavior. Since discrimination of relative motion is better at lower velocities of retinal image motion,(Nakayama, 1985; Howard & Rogers,
2002) we postulated that tVOR responses are set to minimize retinal image speed for both the target and the visual background (Chapters 3 and 4). It might follow from this hypothesis that changing the location of the visual background during bob translation should influence tVOR behavior. In two subjects, we found only a small effect of positioning a stationary background at 50 cm versus 100 cm from the subject. Note that changing the viewing distance of the background in this way imposed static changes to the geometric demands made of tVOR. However, if the background continuously moved vertically at a different frequency (2.1 Hz) than the platform (2.0 Hz), tVOR showed consistent changes in responsivity in both subjects that could be related to the difference between retinal image speed of the foveal target and the background (Fig. 4-6). Thus, as
154 relative motion of the background increased, tVOR decreased (increasing slip speed of the foveal image) and thereby tended to equalize retinal image slip of the foveal target with respect to the background. Under natural conditions, a changing relationship between image slip of a near target and the background would occur as the subject traveled forward through the visual environment. Thus, our current hypothesis is that the responsiveness of tVOR is adjusted as a continuous function of retinal image motion of near target versus distant background, with the goal of minimizing relative motion of one with respect to the other. In fact, for objects lying at greater distance than about 1 m, tVOR compensation gain of 0.6 is all that is required to reduce retinal image motion below 5 deg/s, to permit clear vision (Fig.
3-4).
7-5-4. Applying present findings to interpret the effects of disease
Although the current findings from normal human subjects are novel, their value would be greatly increased if they were used to try to understand the mechanisms underlying certain diseases. We selected patients with two types of disorders that cause unsteady posture and falls. Falls are a major public health problem, especially in individuals with neurological disorders (Williams et al., 2006). Progressive supranuclear palsy (PSP) is a parkinsonian disorder that causes falls during the first year of the illness, and usually leads to a wheelchair existence with three years (Litvan et al., 1996).
Cerebellar ataxias due to a variety of causes, such as genetically mediated degeneration, also cause disabling gait unsteadiness and falls (Leigh & Zee, 2006). We reasoned that
155 both groups of patients would have abnormal tVOR behavior, even though their aVOR function is often normal. Both vestibulo-ocular (tVOR) and vestibulospinal reflexes are mediated by otolithic inputs to the central nervous system. Recall that the otoliths sense linear accelerations, including gravity and, thus, disturbance of the otolith-spinal reflexes seem a prime suspect for falls in these disorders. Although we did not measure vestibulospinal reflexes in this research, we aimed to use tVOR as a probe of otolithic reflexes. We postulated that neurological disorders that commonly lead to falls, presumably by disruption of otolith-spinal reflexes, would also cause abnormal otolith-ocular reflexes.
We found that in patients with PSP, the responsivity of tVOR fails to increase during viewing of a near target during bob translation (Fig. 5-2); note that these patients cannot converge (Chapter 5). In patients with cerebellar ataxia, tVOR also fails to increase during near viewing, but such patients can converge (Fig. 6-2) (Chapter 6); a similar result has previously been reported with translation along the interaural axis
(Wiest et al., 2001). Thus, failure to converge seems unlikely to be the fundamental problem in PSP for two reasons: (1) Normal subjects show modulation of tVOR with viewing distance, not vergence angle (Fig. 3-3A). (2) Cerebellar patients can converge but cannot increase their tVOR responsivity during near viewing (Fig. 6-2). Furthermore, vestibular-evoked myogenic potentials (VEMPS), in which a loud click is used to stimulate the saccular otolithic organ and induce a vestibulospinal reflex, are impaired in
PSP (Chapter 5). Thus, our evidence supports the notion of abnormal otolith-based
156 reflexes in these disorders. Furthermore, our studies of patients suggest a new class of vestibular disorders, which consists of loss of ability to increase tVOR responsivity appropriately during viewing of a near target.
Further studies of tVOR in neurological disorders causing postural instability and falls are called for – such as measurement of tVOR during for-aft movements. Equally important, direct studies of vestibulospinal reflexes and the development of animal models seem necessary before we can understand the pathophysiology of postural instability and falls in these patients. Now that tVOR responses have been better defined in humans, and the means to test tVOR reliably are more accessible, it should prove possible to examine a number of other disorders that impair balance and cause disability.
7-6. Concluding Remarks
In summary, the ability to test tVOR in humans has provided new opportunities to study a reflex vital for vision during locomotion. Our findings indicate that tVOR is best suited to optimize motion parallax information during vertical translations of the head that are the consequence of the upright, bouncy walk of humans, and thereby judge the relative positions of objects in the environment. The implications of these findings for gait stability and navigation in health and disease have only started to be explored with our studies of patients with neurological disorders who are prone to fall. The recent demonstration of neurons in secondary cortical visual areas that are primarily concerned with processing motion parallax signals (Nadler et al., 2008) underlines the importance of
157 visual inputs during locomotion, in health and disease.
158
Figure 7-1. Temporal installation of Moog platform in office space.
159
Figure 7-2. The hydraulically powered motors of the Moog 6DOF2000E are shown with the
platform in an elevated position.
Figure 7-3. Early photographic records of human locomotion by Marey, showing vertical movement (bob) of head (Public domain access provide by Rensselaer Polytechnic Institute).
160
Figure 7-4. Installation of chair on Moog platform (top left), field coils prior to mounting
(bottom) and picture of subject sitting in chair within field coils after installation on platform
(top right).
161
Figure 7-5. Evidence for tVOR during viewing targets at optical infinity. (A) The subject viewed a church spire through a window at a distance of 200 m. Although measurements of platform motion were not available, vertical eye movements occurred at the same frequency as platform vertical translation (2 Hz). (B) The subject viewed a visual target at a distance of
6 m. The vertical tVOR response is directed opposite to the platform motion. Upward or rightward eye rotations (left scale), and upward head translations (right scale) correspond to negative values.
162
Figure 7-6. Fully installed equipment showing Moog platform with magnetic field coils, skate-board helmet (with reflective markers) and safety rails. One of the Vicon infrared motion measurement cameras is visible at top right.
163
Figure 7-7. This shows a subject sitting in the chair on the platform viewing a visual background on a large flat-screen monitor. Note that the photograph was taken with room lights on to provide a clear picture of the subject. During experiments, room lights were out and only the background screen and a near target were clearly visible.
164 7-7. Reference List
Bloomberg, J. J., Reschke, M. F., Huebner, W. P., & Peters, B. T. (1992). The effects of
target distance on eye and head movement during locomotion. Ann NY Acad Sci,
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Bronstein, A. M. & Gresty, M. A. (1991). Compensatory eye movements in the presence
of conflicting canal and otolith signals. Exp.Brain Res., 85, 697-700.
Crane, B. T. & Demer, J. L. (1997). Human gaze stabilization during natural activities:
translation, rotation, magnification, and target distance effects. J Neurophysiol, 78,
2129-2144.
Das, V. E., Dell'Osso, L. F., & Leigh, R. J. (1999). Enhancement of the vestibulo-ocular
reflex by prior eye movements. J.Neurophysiol., 81, 2884-2892.
Grossman, G. E., Leigh, R. J., Abel, L. A., Lanska, D. J., & Thurston, S. E. (1988).
Frequency and velocity of rotational head perturbations during locomotion. Exp
Brain Res, 70, 470-476.
Howard, I. P. & Rogers, B. J. (2002). Depth from Motion Parallax. In I.P.Howard & B. J.
Rogers (Eds.), Seeing in Depth, volume 2 (pp. 411-443). Toronto: I. Porteus.
Leigh, R. J. & Zee, D. S. (2006). The Neurology of Eye Movements (Book/DVD). Fourth
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165 Liao, K., Wagner, J., Joshi, A., Estrovich, I., Walker, M. F., Strupp, M. et al. (2008a).
Why do patients with PSP fall? Evidence for abnormal otolith responses.
Neurology, 70, 802-809.
Liao, K., Walker, M. F., & Leigh, R. J. (2008b). Abnormal vestibular responses to
vertical head motion in cerebellar ataxia. Ann.Neurol., In Press.
Litvan, I., Agid, Y., Calne, D., Campbell, G., Dubois, B., Duvoisin, R. C. et al. (1996).
Clinical research criteria for the diagnosis of progressive supranuclear palsy
(Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP
international workshop. Neurology, 47, 1-9.
Moore, S. T., Hirasaki, E., Cohen, B., & Raphan, T. (1999). Effect of viewing distance on
the generation of vertical eye movements during locomotion. Exp.Brain Res., 129,
347-361.
Nadler, J. W., Angelaki, D. E., & DeAngelis, G. C. (2008). A neural representation of
depth from motion parallax in macaque visual cortex. Nature, 452, 642-645.
Nakayama, K. (1985). Biological image motion processing: a review. Vision Res, 25,
625-660.
Paige, G. D. (1989). The influence of target distance on eye movement responses during
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166 Paige, G. D., Telford, L., Seidman, S. H., & Barnes, G. R. (1998). Human
vestibuloocular reflex and its interactions with vision and fixation distance during
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Pozzo, T., Berthoz, A., & Lefort, L. (1990). Head stabilization during various locomotor
tasks in humans. I. Normal subjects. Exp Brain Res, 82, 97-106.
Ramat, S. & Zee, D. S. (2003). Ocular motor responses to abrupt interaural head
translation in normal humans. J.Neurophysiol., 90, 887-902.
Wiest, G., Tian, J. R., Baloh, R. W., Crane, B. T., & Demer, J. L. (2001). Otolith function
in cerebellar ataxia due to mutations in the calcium channel gene CACNA1A.
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167 Appendix 1 Three dimension transformation algorithm
A1-1. Head three dimension rotation
Head rotation is a key variable in this study. It could not be measured directly with the search coil and magnetic field because the coil frame itself translates and rotates during the experiment. Thus, signals from the Vicon motion tracking system were used to measure head rotation. Four to six reflective tracking markers were attached on the subjects’ head during the experiment, and the 3D positions of these markers were all recorded by the Vicon tracking system. The rotation of the head could then be calculated using a least-square optimization method (Challis, 1995), summarized as follows:
1. X1i´, X2i´ are the mean position (their relative positions to the center of the
head) of the ith marker at time 1 and time 2. Their correlation matrix C is
defined as:
N 1 ' ' t C ≡ ∑ 2i XX 1i (1) N i=1
where N is the total number of markers.
2. Taking the singular value decomposition of C, we get two orthogonal matrices
U and V:
⋅⋅= VWUC t (2)
168 3. The rotation matrix denoting the head rotation from time 1 to time 2 is given
as:
⎡10 0 ⎤ ⎢ ⎥ t RU01= ⎢ 0⎥ V (3) t ⎣⎢00det(UV)⎦⎥
where det(UVt) is the determinant of the orthogonal matrix UVt.
The rotation Vector rheadInSpace can be calculated from its rotation matrix
(Haslwanter, 1995) with equation (4). The coil frame rotation vector rcoilFrameInSpace can also be calculated in the same way as head rotation with 4 markers attached since they rotate with the coil frame during the experiment.
⎛⎞ RR32 − 23 ⎛⎞1 ⎜⎟ rR =−⎜⎟⎜⎟13R 31 ⎝⎠1(RR +++ 11 22 R) 33 ⎜⎟ (4) ⎝⎠RR21− 12
In Equation (4), Rij is ith row and jth column component of the rotation matrix R, r is the corresponding rotation vector.
A1-2. Eye three dimension rotations
For the same reason in section 1, meaningful eye rotations (eye in orbit and eye in space) can not be measured directly with coils, which only measure the eye rotations relative to the coil frame. They have to be derived from both the search-coil signals and
Vicon signal. The eye’s rotation matrix related to the coil frame can be denoted directly by the coil signal as the following:
169 coil zcoily coilx coilx zcoily coil
fieldx fieldx ⎡⎡CX FX ⎤⎡CYFX ⎤⎡CZ FX ⎤⎤ ⎢ ⎥ fieldy fieldy ⎢CX ⎥⎢CY ⎥⎢CZ ⎥ ⎢⎢ FY ⎥⎢ FY ⎥⎢ FY ⎥⎥ ⎢⎢ ⎥⎢ ⎥⎢ ⎥⎥ field z field ⎣⎣CX FZ ⎦⎣CYFZ ⎦⎣CZ FZ ⎦⎦
where x coil is the direction coil, y coil is the torsion coil, and the z coil being the
“ghost coil” calculated from x and y coil (fig. A1-1). The x-field corresponds with the forward-backward direction of the coil frame, the y-field corresponds with the left-right direction, and the z-field corresponds with the bottom-up direction. CXFX is the signal measured from the directional coil in response to the stimulus of forward-backward magnetic field, and is proportional to the cosine value of the angle between the directional coil and the forward-backward magnetic field. The same nomination rule applies to other matrix components. Then the rotation vector of, for example, the right eye with respect to the field-coil frame, rEyeInCoil, can be calculated. From this, the rotation vector of the right eye in the orbit, reyeInOrbit, can be calculated by combining two rotation vectors: first a rotation of the coil frame with respect to the head, which is the opposite to the rotation vector of the head, rheadInCoil, (measured with a same type of dual scleral coil attached on subject’s head), and second, the rotation of the eye with respect to the coil frame (reyeInCoil), with the following equation:
r(r)reyeInOrbit=− headInCoilD eyeInCoil
Where “ο” operator means the combination of two rotation vectors, and can be calculated in the following way:
rrqp++() rr qp × rrqpD = 1rr−⋅()qp
170
Using the same method, the rotation vector of the eye in space, reyeInSpace, can be calculated with the following equation:
rrgaze= coilFrameD r eyeInCoil
A1-3. Required three dimension eye rotations
It is also important to calculate the “ideally required” eye rotation to maintain the eye on the visual target, as this was used in the calculation for VOR compensation ratios.
The 3D position of the orbit can be reconstructed during the data processing with the knowledge of the 3D relationships among the markers on the subjects’ faces. The target position was also tracked during the experiment. The rotation vector of the ideally required eye rotation (rideal) can then be calculated in the following way:
1. The direction of the rideal (n) is perpendicular to the plane that includes the line
of sight and the straight-ahead line (1, 0, 0) (also known as x´ axis).
2. The angle (e) of the rotation is the angle between the line of sight and the x´
axis, and can be calculated as A = cos−1 (Lx / L ) , where L is the vector of the
line of sight from orbit to target, and Lx is L’s projection to x´ axis.
3. The rotation vector of the rideal by definition is: r = A )2/tan( ⋅ n
The ideal rotation of the eye (ridealeio) in the orbit can then be calculated by:
rr(r)idealeio=− headInCoilDD − coilframer ideal
171 Where rheadInCoil is the head rotation relative to the coil frame, and rcoilframe is the coil frame rotation relative to the space which is measured through Vicon™ tracking system.
172
Figure A1-1 Vectors of coil frame and coils on the eye ball. The x-field (FX) corresponds with the forward-backward direction of the coil frame, the y-field (FY) corresponds with the left-right direction, and the z-field (FZ) corresponds with the bottom-up direction. The coordinate directions fixed on the eye ball do not align with the coil frame’s. Therefore the direction coil vector (CX), the torsion coil vector (CY) and the “ghost” coil vector (CZ) which is calculated from the previous two vectors point to different directions than the coil frame vectors. Adapted from Haslwanter (1995).
173 A1-4. Reference List
Challis, J. H. (1995). A procedure for determining rigid body transformation parameters.
J Biomechanics, 28, 733-737.
Haslwanter, T. (1995). Mathematics of three-dimensional eye rotations. Vision Res, 35,
1727-1739.
174 Appendix 2 Details of instrumentations
A2-1. Summary of system Infrastructure
The current studies of the angular and translational vestibulo-ocular reflexes
(aVOR and tVOR) required that we apply and measure head rotations and translations
(the stimuli) and measure 3-D eye rotations (the responses). To apply the stimuli, we used a Moog™ 6DOF2000E electric motion platform (Moog Inc., East Aurora, New York). To measure the stimuli we used a VICON™ motion tracking system (Vicon, Los Angeles,
CA). To measure the response, we used a 3-D magnetic search coil system (CNC
Engineering, Seattle, WA). With the Moog™ motion platform (Fig. A2-1), and a chair mounted on top of it (Fig. A2-2), we are able to move subjects in all 6 degrees of freedom
(DOF) including: vertical translation (heave or bob), lateral translation, or for-aft translation (surge), with maximum acceleration of 5 m/s2; and rotation about a vertical axis (yaw), an interaural horizontal axis (pitch) or rotation about a nasal-occipital horizontal axis (roll), with maximum acceleration of 400 deg/s2. Mounted on top of chair and the motion platform is a 3-D magnetic search coil frame (Fig. A2-2), which can generate a magnetic field, and thus measure the relative rotational movements of the eye/head to platform by our magnetic search coil (Fig. A2-3). The coil system offers the greatest precision and time resolution among currently available measurements for recording eye rotations (see Chapter 2). The Vicon™ system uses infrared tracking
175 technology. Thus, Vicon M2 cameras allow a pixel resolution of up to 1280x1024, and a recording speed of 1000 frames/s to track all the rotational and translational movements of the motion platform and the subject’s head even in complete darkness.
The common operational steps for this system include:
1. Pre-program the Moog stimulus movement.
2. Calibrate Coil and Vicon Systems.
3. Record data.
4. Process data.
The following sections provide detailed operational instructions.
A2-2. Control of Moog™ motion platform
A2-2-1. Introduction to the Moog™ motion platform
The Moog system generates platform motion with six degree of freedom. An internal computer controls six servomotors that are each connected to a piston-like actuator. The internal computer, called the Motion Base Computer, uses the DOS operating system. Alternatively, a host computer running a Windows operating system can be used to remotely control the servos and actuators via the Ethernet connection to the motion base computer. The Moog system has two power supplies; one for the motion base computer, the other is to drive the six actuators. Both operate at 100-120 VAC, however, the Motion Base computer draws 20 A of single phase current, while the actuators draws 20-30 A. The actuators’ power requirements vary with regards to payload,
176 location of the platform’s center of gravity, and rate of acceleration. The maximum payload the Moog platform can safely handle is 1000 kg (2,200 lbs). The max velocity for pitch, roll, and yaw is about 30 deg/s, while the max acceleration is about 400 deg/s2.
Finally, the max velocity for heave, surge, and lateral translation is 12 inches/s, and the max acceleration is 0.6 g.
The motion platform is driven by a position command through a servomotor in each of its six actuators; the position command is transmitted in 60 Hz. This command can be used in ways of controlling each actuator or each DOF (rotation or translation), and it is transmitted in pure ASCII code. This ASCII data file can be generated by programs such as Excel, MatLab, Basic, C++. In this lab, we use Matlab.
A remote controlling method enables us to access the platform’s online feedback
(current position of the platform), although this signal is not very reliable. Its control can be triggered through other systems, and thus integrated to a larger system such as helicopter simulator. However, due to the nature of UDP protocol, such control through a remote computer is not smooth because the data is not transmitted strictly in 60 Hz, and the subject may feel bumpy during the ride. It was essential for our experiments that the stimulus be smooth and reliably timed, and so we choose to run the platform directly, using its embedded computer. However, by running the platform with its own computer, we forfeited the position feedback signal that is available through UDP control mode.
Thus, in our experiments, the Moog control system operated as an open-loop system, and the actual movement of the platform was variable, depending on the load and the
177 movement pattern. Thus, we needed another reliable method to measure platform movement, which was achieved through Vicon tracking system, which will be described explained in a following section of this chapter.
A2-2-2. Procedure to generate command to move the Moog™ platform
The Moog platform is driven by position commands. The Moog system will take
60 position commands in one second, and each command is the position for either each actuator or each DOF. Here we use DOF in our example because it is easy to use, and directly related to the control of our experiments. Here shows the general structure of command file:
Roll1 Pitch1 Heave1 Surge1 Yaw1 Lateral1
Roll2 Pitch2 Heave2 Surge2 Yaw2 Lateral2
Roll3 Pitch3 Heave3 Surge3 Yaw3 Lateral3
The command is organized as a 6 by n array, of which each line is one command, and has n = t * 60 lines, where t is the duration (in seconds) of the command running time.
Each command has position commands for Roll, Pitch, Heave, Surge, Yaw, and Lateral.
For definition of each direction of rotation and translation, see section A2.1.
Each position command is denoted with 16 bits, and thus has a value range of 0 –
65535. For all directions except heave, 0 corresponds to the minimum value of that direction, and 65536 corresponds to the maximum value. Only for heave does 0 correspond to the highest position it can reach, and 65536 correspond to the lowest
178 position (when parked). The value of 32767 corresponds to the neutral position (when all
DOF is at its median value/center position). Please refer to the Moog documentation for details about its motion range and other specifications. All the files need to be saved as joystick.xxx, where xxx is a three digits number, so it can be recognized by the Moog system computer.
A2-2-3. Operation and maintenance of Moog™
To Operate the Moog, please follow the steps here:
1. Turn on both the drive power (peak current: 30 A), control power (AKA low
power, peak current: 10 A) and the SW1 (Battery Enable) as shown in Fig.
A2-4. Then turn on the embedded computer. The computer will start DOS
system, and automatically launch a default program for “remote control”.
2. When the main interface for the Motion Base Computer appears, press key
Q for quit, and a DOS command prompt will appear. At this point enter
the command for the proper paradigm to run. The command to enter is:
170-121 /c /k /###, where ### is the program code. For example, type 608
will run paradigm saved in joystick.608.
3. The command screen then will prompt for the MOOG password. Enter
637546 and push enter at this time. The Motion Base Computer will
validate the commands and register the appropriate programs.
179 4. When the MOOG’s status is Idle, push E to engage the MOOG. A green
light on the motion base computer should turn on at this point. Make sure
that the MOOG has enough clearance to move at this point.
5. When the MOOG’s status is Engaged, push R to run the program in the
MOOG. To stop the MOOG for any reason, push S for stop or press the
Emergency Stop button.
6. Once the program has completed itself, the MOOG will return to the Park
position. Push Q on the keyboard to quit the current program.
7. Turn off Moog computer, two powers, and the battery switch after the
experiment is finished.
The Moog system is virtually maintenance-free, except some regular checks such as:
1. Check for wear, inspect computer fans, test emergency switches, inspect
computer and electrical connections, battery power after each use.
2. Grease actuator fittings (grease gun), inspect fastening (bolts) for fatigue
monthly.
3. Request MOOG Technicians to inspect drive belts, internal circuitry every
one or two years.
180
A2-3. Operation of Vicon™ infrared tracking system
A2-3-1. Introduction to Vicon™ infrared tracking system
The Vicon™ system is currently one of the leading three-dimensional visual tracking systems. By tracking the individual markers attached to the object of interest, it can provide 3-D translation information of the target, and after further processing, it can also provide the rotations of the rigid segment of the object. The M2 cameras used in our lab have spatial resolution of up to 1280x1024 pixels, and frame rate up to 1000Hz. They can also track the markers in complete darkness since they use infrared strobes to illuminate the markers and receive the reflected infrared light.
The Vicon™ system comprises 6 M2 cameras, the 460 data station, and the host computer. Each camera is mounted on the walls in front and on the left side of the motion platform with special wall mounts, and can be rotated in three dimensions to bring the measurement space to the center of the image. The cameras are connected to data station through coaxial cables, and the data station is connected with the host computer with internet cable.
A2-3-2. Calibration of Vicon™
Before using the Vicon system, a calibration is needed to determine the relative location and orientation of all the cameras, and the transforming relationship between the
2-D image of each camera and the 3-D coordinates of the object.
181 There are two main steps for calibration:
Static Calibration: This calculates the origin or centre of the capture volume and determines the orientation of the 3D Workspace.
Dynamic calibration: This involves movement of a calibration wand throughout the whole volume and allows the system to calculate the relative positions and orientations of the cameras. It also linearises the cameras.
Tools needed during the calibration include a 240mm wand and a “L” frame. The
240mm wand is a “T” shape metal rod with three 15mm reflective spheres attached. The
L frame is made from two metal rods fixed at 90 deg. One arm has three reflective spheres attached, the other just one.
To calibrate the Vicon system, the following steps have to be followed:
1) Place the L-Frame in the centre of the coil frame. Align the arm that has 3
markers with the fore-after axis of the coil frame, and the other arm with the
left-right axis.
2) Start the Vicon workstation program, and also turn on the Vicon datastation.
3) In Vicon workstation program, select System | Live Monitors.
4) Check that each camera is viewing only the four markers on the L-Frame.
5) Select System | Calibrate Cameras to open the Calibrate Cameras dialog.
6) Ensure that all 6 cameras are selected.
182 7) Under Reference Object ensure that the correct Calibration Reference
Object file (“Ergocal.cro”) is selected and that the appropriate name of your
calibration object (Ergocal 14mm mkr – 240mm Wand) is specified.
8) In the Calibration panel ensure that Capture is set to "all new data".
9) Click Calibrate.
10) Click Start.
11) After the static calibration is done, remove the L-frame from the volume and
ensure that it is not visible to any of the cameras.
12) Have another operator stand by and with the wand in the coil frame before
starting the dynamic calibration.
13) Click start to start collecting data for dynamic calibration.
14) Have the other operator wave the wand so that all positions in the coil frame
are covered in all orientations.
15) When you think sufficient data has been collected click Stop. Vicon now
performs its calculations and then the Calibrate Cameras dialog reopens,
displaying new residual values.
16) If the Calibration Residuals are satisfactory (see below), click Accept.
How good should the calibration be? There are two numbers we need to check.
1) Residual for each Camera. A residual is a measure of the accuracy of a
single camera. It should be smaller than 2mm in our setting.
183 2) Static Reproducibility. Static reproducibility is the root mean square error of
the L Frame co-ordinates as calculated compared to the .cro file scaled to
the size of the L-Frame. This number should be less than 1%.
If the calibration is not as good as mentioned above, recalibration of the Vicon system is needed.
A2-3-3. Collecting data from Vicon™
Due to the complexity of the operation, please refer to Vicon workstation manual for detailed operation guidance on how to record a trial, reconstruct and label the markers, and finally output the positions of the markers.
A2-4. Operation of the magnetic search coil system
A2-4-1. Introduction to the magnetic search coil system
The principle of the magnetic search coil technique is based upon the magnetic induction of a small coil (Robinson 1963). The induction coil is embedded in a flexible ring of silicone rubber which adheres to the limbus of the human eye concentric with the cornea (see Chapter 2). Around the head of the subject three alternating magnetic fields, orthogonal to each other are generated: top/bottom, left/right, front/back oscillating respectively at 60, 90, and 135 KHz, implemented in a 76 cm cube (CNC Engineering,
Seattle WA). After amplification and phase-locked detection two analog voltages are obtained which are proportional to the sine of the horizontal and vertical eye position. In
184 addition to this coil, which is wound in the frontal plane, a second coil is wound in the sagittal plane (for details, see Chapter 2). This combination coil simultaneously measures horizontal, vertical and torsional eye position.
A2-4-2. Calibration of 3-D coil system
This section describes how to perform the coil calibration for our 3-D coil system.
This applies only to our 3-D human system, and does not apply to other 2-D system, or the animal coil system in other labs.
The calculation of coil direction described in Appendix 1 requires a prior knowledge of relative strength of each coil field, thus the calibration of the coil system is needed, and is recommended to be performed in every 1-2 weeks.
First, we need to eliminate the offset that induced by connectors and wire junctions. To do this, we place the coil in a magnetically shielded environment, currently a thick steel pipe. Then any signal that shows up at the detector output is due to pickup of the magnetic field at other points along the signal path, and also due to offsets within the electronics. The coil should be placed sufficiently far into the pipe so that it is completely isolated from the magnetic fields. Ideally, this should be halfway down the length of the pipe. It is good to verify the isolation of the coil by noting that the coil readings stop changing when waving the pipe within the magnetic fields. Once the coil is in the pipe, the offset knobs on the coil system should be set so that a zero signal is seen on all channels for that coil. To zero all of the signals, it is convenient to have software that will
185 display the coil signals so that the operator can see the values while adjusting the potentiometer knobs. In our lab, open and start the Labview program --- 3dCal.exe, the program will show output from all of the field signals simultaneously.
After nulling out the offset, we need to obtain the gains for each of the 3 orthogonal magnetic fields. The gain of the magnetic field is affected by the type of search coil, the gains of the detector circuitry, the gain and resolution of the analog to digital converters in the computer besides the strength of the magnetic field itself.
However, we can take all of these factors into account by making a single measurement for each search coil relative to each field. For a dual coil contact lens used in a three field system, this would be a total of six measurements for each coil.
The measurement that we need is the maximum possible signal that the coil can pick up, which corresponds to the maximum value of the sine function that is output by the coil system as the search coil is perpendicular to the magnetic field. To find this maximum we use a simple technique. The coil should be mounted on a gimbal or some other assembly that allows it to be easily and stably oriented towards each face of the field cube. The coil should be calibrated while it is as close as possible to the center of the field cube because the center of the cube is the only place that the magnetic fields are
(theoretically) perfectly orthogonal. As the operator moves the coil away from the center of the cube, the strengths and directions of the magnetic fields change. Since the analysis process makes the assumption that the magnetic fields are orthogonal, we should strive to make this as close to true as possible.
186 After putting the coil into the assembly, and move to the center of the coil frame, turn the “calibration” switch to “auto” in our calibration software – 3dCal.exe, and set the tolerance factor to be a value between “0.02 – 0.05” volts depending on the signal to noise level of the system, and then click “start auto calib” button. Calibration is then performed in the sequence of right eye / left eye / head coil. For each coil, the calibration sequence for six channels are: directional X axis / directional Y axis / directional Z axis / torsional X axis / torsional Y axis / torsional Z axis. For each channel, start by facing the desired coil (directional or torsional) roughly into the desired field (X, Y, or Z). For instance, face the direction coil into the X field by orienting the search coil so that it is in the 'straight ahead' orientation, since the positive axis of the X field points forward in space, and the positive axis of the direction coil's direction vector points forward relative to the plane of the coil. This lines up the direction coil's direction vector with the X field positive axis vector. Once the coil is approximately oriented, you must watch the computer signal while making further adjustments to the coil's orientation. Besides of watching the channel that is measured, the operator should also watch the other two orthogonal channels. In this case, it will be directional coil in Y field and Z field (since X field gain is being measured). That is because when X field signal is at its peak, the other two field signals should be at 0 as they should be parallel to the coil. The sine wave is most sensitive at the 0 position and most insensitive at the peak and valley position, so it will be more precise to find the exact maximum value for the X field by making the other two channels’ value equal to 0. In practice, when the two other channels’ signals are less
187 than the preset “tolerance factor” at the same time, the strength of the X filed will be automatically locked and recorded by the software, and then the software will start calibrating the next channel. Also turn the coil by 180 deg to check if the negative maximum value is equal to the positive maximum value of this channel. A significant difference between these two values is an indication of problems, such as failure to offset the null, a measured being made away from the center of the coil frame, or problems in the pre-amplifiers or the phase detectors of the system.
The sensitivity vector of the torsion coil is defined as pointing to the subject's left
(the same direction as the positive Y field axis) when the subject is looking straight ahead with no torsion. Since the coils are typically applied to the subjects' eyes with the wire exiting nasally, the coils on the right and left eyes will be oriented 180 deg opposite, in the torsional sense. That is, the wire on the right eye exits to the subject's left, and the wire on the left eye exits to the subject's right. The operator must make sure that the coils for the right and left eye are mounted on the gimbal/assembly properly (aligned as they will be on the subject's eyes), so that the signs are correct for the torsional coil. This 180 deg torsional rotation does not affect the direction coil signal.
After recording the gains for all channels, remember to click “Accept and Save” button in the software so the software will save the calibration result onto the hard drive for later reference.
188 A2-5. Synchronization of coil system and Vicon™ system
Since we use two independent measuring systems – the magnetic search coil system and the Vicon tracking system – we need a strategy to synchronize the data recorded through these two systems. We installed an accelerometer (CXL04LP3
Crossbow Technology, Inc., San Jose, CA) on the Moog platform to measure the z-axis
(vertical) acceleration of the moog platform. At the beginning of each experiment, we also program the platform to move vertically in a step with an acceleration of 0.5 g. The step edge is detected by the accelerometer and recorded simultaneously with the coil signal by the Labview program. At the same time, the Vicon tracking system also records the platform movement by recording the movement of the markers attached on the coil frame.
After plotting the accelerometer’s signal and the vertical movement of the coil-frame-marker, we can see the timing difference between two systems and also synchronize their time index by matching the step edges recorded by accelerometer and
Vicon respectively. The current method is to match the maximum point of the acceleration measured in each system, and then visually inspect the match during the 0.2
Hz perturbation and 2 Hz perturbation by checking the time difference between the peak positions measured in two systems.
To synchronize the data, call function “synGui” in matlab, then use “load” menu to load the coil data and the Vicon data. Zoom to the area of the step. Click the “Detect
Edge” menu and click on the coil data, right before the peak acceleration of the step, and
189 do the same thing to the Vicon data. The Third panel in the interface will then show the synchronized data. After visually inspecting the match, click “save” menu and save the synchronized data to your hard drive. The synchronization file will have the time index offset for the coil data.
A2-6. Transformation of raw data to eye movement measurement
After acquiring raw data from the coil and Vicon systems, we need to transform them into more meaningful data as described in Appendix 1. The raw data from the measurement includes the rotation of eyes relative to the coil frame, and the translational movement of each marker attached on the coil frame and subject’s face. However, we need to know the rotation of the eye relative to head, relative to space, and also the required eye movement to keep the eye on the target so that we can use them in our research. To transform the raw data, we need to calculate the coil frame rotation relative to the space, head rotation relative to space, required eye movement relative to space from Vicon data, then combine these rotation matrix and the eye rotation relative to the coil frame with the method described in Appendix 1.
The programs that are used in the calculation are listed here in the sequence of usage:
vicon2rot(coilframe,4); Purpose: transform the position matrix of the markers (4 in this case) into rotation vector, given these markers are on the same rigid body.
190 [req_rrot req_rgaze] = eyeInCoil(reor, pTar, Rotcv); Purpose: calculate required eye rotations. In this example the required right eye rotation relative to coil frame is calculated by combining eye in space and coil in space rotation vectors.
[rt_avel rt_acc] = angvel(req_rrot,smpf); Purpose: get the rotation velocity and acceleration from rotation vector.
Here are the matlab commands to transform the rotation vector to the angles and velocity that we can use in our research: smpf = 120; req_rt = req_rgaze(:,1); req_rv = req_rgaze(:,2); req_rh = req_rgaze(:,3); req_lt = req_lgaze(:,1); req_lv = req_lgaze(:,2); req_lh = req_lgaze(:,3); [left_avel left_acc] = angvel(req_lrot,smpf); req_lhv = left_avel(:,3); req_lvv = left_avel(:,2); req_ltv = left_avel(:,1);
[rt_avel rt_acc] = angvel(req_rrot,smpf); req_rhv = rt_avel(:,3); req_rvv = rt_avel(:,2); req_rtv = rt_avel(:,1);
RotGaze = rot2gaze(Rotcv); ht_vicon = RotGaze(:,1); hv_vicon = RotGaze(:,2); hh_vicon = RotGaze(:,3); hvt_vicon = (leor(:,3) + reor(:,3))/2000; hvtv_vicon = derivata(hvt_vicon, 120); hvtv_vicon = remezfilt(hvtv_vicon, 15,20,120); [hd_avel hd_acc] = angvel(Rotcv,smpf); hhv_vicon = hd_avel(:,3); hvv_vicon = hd_avel(:,2);
191 htv_vicon = hd_avel(:,1);
Finally, remember to save all the results to hard drive.
192
Figure A2-1 Moog motion platform
Figure A2-2 Coil frame and helmet and the head rest mounted on the moog platform
193
Figure A2-3 Magnetic search coil after inserted to human eye
194
Figure A2-4 Front panel of the moog computer showing the battery switch, keyboard/monitor port, the emergency stop port.
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