THE HUMAN VESTIBULO-OCULAR REFLEX: THE EFFECT OF VERGENCE ANGLE AND UNILATERAL LESIONS ON

REFLEX DYNAMICS

Tarn Yat Fai Sunny

A thesis submitted in conformity with the requirements for the degree of Master of Science, Graduate Department of Physiology at the University of Toronto

0 Copyright by Tarn Yat Fai Sunny 2000

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ABSTRACT

THE HUMAN VESTIBULO-OCULAR REFLEX: THE EFFECT OF VERGENCE ANGLE AND UNILATERAL LESIONS ON

REFLEX DYNAMICS

Tarn Yat Fiii Sunny

Master of Science, Department of Physiology

University of Toronto, 2000

The vestibuloscular reflex (VOR) stabilizes vision during head rotations. The

closa the target, the bigger the evoked eye movement needs to be. To study how this

gain increase is accomplished, we measured the gain of normal abjects when viewing

nearby and far targets fiom 0.25Hz to 10Hz. Our results show that the target distance

related VOR gain inmases occurs only at fiequencies below S'Hz and is accompanied by

a mal1 increase in phase Iag. We believe this reflects the recniitment of a second, slower,

pathway during near target viewhg. Next, the dynamics of the VOR was studied h m

unilateral vestibular lesioned patients. Gain asymmetry wrn whole body cotation test is

found to be fiequency dependent. Head impulse test results show that eye velocity is

saturated only at high velocity during ipsilesional rotations. The results show that VOR

aiter unilaterai lesion in humaas has fkequency- and velocity- dependent pathways.

ACKNOWLEDGEMENTS

May I take tbis oppomullty to thank the Department of Physiology to give me the

chance to study here, especially to Dr. David Tomlinson who made my study in these two

years smooth and challenging due to his great guidance and teaching. And also to Alan

Blakeman and Sam Musallam for their technical support and enormous help in al1 aspects

of my research. 1 am grateful to Dr. Manohar Bance for introducing me to the operation

of the laboratory.

This acknowledgrnent extends m e r to Dr. Dianne Broussard and Dr. Robert

Harrison for theù valuable advice throughout the supervisory committee meetings.

FinaMy, I would like to thank my parents for providing my daily needs and for the endless

grace firom the One above.

1.1 THE VESTIBULAR SYSTEM MORPHOLOGY AND MECHANTCS ............................................................. 1 ................................................................................................................... 1 . 1 PeRplieral orga ns 1

1.1.1.1 The rnorphology of the sernicircular canals ....................................................................................... 2 1.1.1.2 The hair cclls ...................................................................................................................................... 3 . . ............................................................................................ 1.1.1.3 The dynamics of the smctrcular canals 6

...................................................................................... 1.1.2 Innervation of the peripheral system 7 1.1.2.1 Af'fmnt fibers .................................................................................................................................... 7 1 . 1 2 2 Effmnt fibers ................................................................................................................................... - 8

............................................................................ 1.1.3 Central pathways for the vestibular system 9 ............................................................................ 1.1.3.1 Anatomy and physiology of the vcstibular nuclei 10

................................................................................................. 1.132 E f f m t s h m the vtstibular nuclci 12 1.1.4 The extruocular muscles and the motonewons ..................................................................... 13

................................................................... 12 THE VESTIBULO-OCULAR REFLEX AND ITS PATWAY 14 1.2.1 nehorirontalangularVOR ................................................................................................ I 5

........................................................................................... 1.2.2 Central connections of the VOR 17 1.2.2.1 Position-Vestibular-Pause (PVP) units ............................................................................................ 17 1.2.2.2 Eyc and Hcad Velocity (EHV] units ............................................................................................ 17

.................................................................................................................... 1.2.2.3 Commissural pathways 18 ...................................................................................................... 1.3 PLASTICITY OF THE VOR 2 0 . * ........................................................................................ 3 1 Spectacle-induced VOR plastzcity 2 l

.............................................................................. 1.32 Vergence angle-induced VOR pfariicty 2 2 ........................................................................................... 1.3.2.1 The effect of vergence angle on aVOR -22

1.3.2.2 The neural pathway for vergence angle rclated aVOR ................................................................... 25 ............................................................................................. 1 . 3.3 Lesion-induced VOR plosricity 27

.......................................................................... 1.3.3.1 The cffcct of unilateral vestibular lcsion on aVOR 27 ........................................ 1. 33.2 The cffect of various stimuli on rccovtry of VOR &cf unilataai lesion 29

I . 4 O B J E ~ E ...... ............-........ ........................................................................................................ 34

2.1 S ~ J E C T S ...................................................................................................................................... 35 2.1.1 Part1 ............................... ,.. .............................................................................................. 35 2 . I.2 Part II ................. ....,,,........... ................................................................................................ 35

2.2 WE~~MENTAL PRC)TOCOL ......................................................................................................... 35 2.2.1 part I ..................................................................................................................................... 35 2.2.2 P d Q ................................................................................................................................... 36

2.3 VESTIBUIAR MEASUREMENTS ....................................................................................................... 36 2.3.1 mole body rot<trCon testirtg .................................................................................................. 36

23.1 .1 The~ordingsystcm ..................................................................... ... ............................................... 38 2.3.12 Calib~tionmddatacoIlection ..................................... ................... .........,.. ................................... 39

............................................................................................................. 2.3.2 Head impuke testing 39 ...................................................................................................................... 2.3.3 CaIork testing 40

...................................................................... 2.4 DATA ANALYSE FOR WHO LE BODY ROTATION TEST 41 2.4.1 Saccade removal .. .............................-.. ......................................................................... 41

..................................................................... .................. 2 . 4 Gain and phare calculation ...... 42 2 4 2 1 Cycle by cycle mcihod ............................................. ..................................................... 4 2 2. 4 3 2 Spectral analysis mcthod . ............................... ..................... ........... .... .................... 44

2 4 U . 1 Trend fernoval ............... .. ....-............... - ...... ............ - ....... - ..,..-............-.........val.... ..... 40 . . 242.22 Diptal filtering .. ..-.,....- - ".. .........-........... ...... .............-..-.. ..- ........ ...........-- . .................... 46 2-4.2.23 Powerspcc@danalysis ...-,.. .. .......,...... .... ...ysis.ysis............. . ............ .............................. 47 . . 2-43 Stan~ncs .................................~................~...~................~.....................~.................................. 49

2.5 DATA ANALYSE FOR HEAD LMPULSETEST ......+.............................................................................. 49 2.6 MODELING OF DATA .... -.. ................................................................................................ ...... ...... 50

3 RESULTS mmommmmommmmmmommHomHHoomommmoemoommwmmmHHmmommoomoowommommmmmmommommmmmmmmmmooooooHm*ommoommmomoooommmommoommmmmomommooooooomm"oe 51

........................................................... 3.1 PART k THE EFFECT OF TARGET DISTANCE ON THE VOR 5 1 ..................................................................... 3.1.1 Sample recording of fur and near target VOR 5 1

............................................................................. 3.1.2 Bode plot of the fur and near target YOR 51 3.1.3 ïïteModedelofVOR ............................................................................................................ 56

3.2 PART n: EFFECT OF UNILATERAL LESIONS ON THE VOR ................. ,...... ......................... 59 3.2.1 Calorfc test results ................................................................................................................ 59

...................................................................................................... 3.2.2 Head impulse test results 59 322.1 Raw rcsults ....................................................................................................................................... 59 3.221 Eye and head velocity for various vestibular loss .......................................................................... 62 3.2.2.3 Eyc and head vclocity for far and near targct ................................................................................... 65

3.2.3 Whole body rotation test results ........................................................................................... 67 . 3.2.3.1 Raw results ............-.-........... ..................................................................................................... 6 7

3.2.3.2 Ipsil&onal and contralesional gain ..................................................... .. ..................................... 69 3.23.3 Phase ................................................................................................................................................ 70

............................................................. 3.2.4 Cornparison between calonc and head impulse test 75 3.2.5 Cornparison between calorif test and whole body rotation test ........................................... 77

............................ 3.2.6 Compariron berneen head impulse test and the whole body rotation test 80

4 DISCUSSION m m m m o ~ ~ ~ ~ ~ ~ . ~ m m m m o m m m m o m m o m m m m o o o o o m m o m m m m o o o o m o o ~ ~ m m o o m o m o m m o m m ~ o o o o o e o o o e o o o o o o o o o o o o o e o o o o o o o o 83

..................................................................... 4.1 THE EFFECT OF TARGET DISTANCE ON THE AVOR 8 3 4.2 THE EFFECT OF UNKATERAL tESIONS ON 'RiE AVOR .................................................................... 86

............................................................................ .......................... 4.2.1 Calorie results ...,... 86 .......................................................................................................... 4.2.2 Head impuLriw resu fts 87

.................................................................................................. 4.2.3 Mo[e body rotation test results 90 ............................................................. 4.2.4 Cornparison between caloric test and head impulse test 93

.................................................. 4.2.5 Conrpartkon bewen caloric test und whole body mtution test 95 4.2.6 Cornparison beween heud impuke test and whole body rotation test ........................................ 96

APPENDIX B m~omomo~~m+mmmommommoHHmm~e~mmmoomHmmommmomoommmooo~ommHmm~ooommom~OHHoHmmommOmomommmomooomHmoommoomooooomOmmOmom~Owoo 107

LIST OF FIGURES

Figure 1 . 1 Structure of the bony and membranous labyïinths ............................................ 1 ...................................................... Figure 1.2 Orientation of semicucuiar canal in head 2

Figure 1.3. Structure of the ampulla of a semicircular canal ................... ................ 3

Figure 1.4. Displacement of microvilli on hak ce11 ............................................................ 5

Figure 1.5. The morphology of type I and type II hair cells .............. .... .................... 6 ....... Figure 1.6. The major vestibular nuclei and the main vestibular newes termination 10

........................ Figure 1.7 Horizontal canal excitatory projections .... ........................ 15

......................................... Figure 1.8. Commissural pathways in vestibule-ocular reflex 20

Figure 1.9 The vergence angle increase to fkate &om a far to a near target .................... 23

Figure . 1.10. The relationship of vergence angle and target distance in VOR ................. 24

............................. Figure.l.11. A mode1 of the aVOR as a hct ion of viewing distance 27

.. Figure 1.12. A bilateral mode1 of VOR with commissural pathways ............................ 32

Figure 1.13. A bilateral mode1 of VOR with linear and nonhear pathways ................... 34

Figure 2.1 A diagram of the recording system for the whole body rotation test ............ 38

.... Figure 2.2 An example of a saccade removal and substituted by a quadratic segment 41

Figure . 2.3 Illustration of raw data fitted with a sinusoid ............................................. 4 2

.......... ...... Figure . 2.4 Using half cycle sinusoids to calculate gain for each direction ..... 43

Figure . 2.5 Illustration of trend rmiov al ........................................................................... 45

.................... ...*. Figure* 2.6 The Butterworth filter was used as a low pass filter ...... 47

............................. Figure 3.1 Exaxnpies of near and far target eye and head movements 52

.................... Figure 3.2 Raw gain data h m normal subjects using fa and near target ... 53

Figure 3.3 Raw phase data for normal subjects .................... ... .................................... 54

Figure 3.4a,b. Mean gain and phase values derived from normal subjects ...................... 55

Figure 3.5. A mode1 of VOR with pathways of modified and unmodified units ............. 57

Figure 3.6a,b. Raw &ta for head impulses perfonned on a caloric normal subject ......... 60

Figure 3.7a,b. Raw data for head impulses perfonned on a caloric a b n o d subject ..... 61

.................... Figure 3.84b.c. Head and eye velocities for head impulse tests on patients 64

Figure 3.9a,b. Head and eye velocities for head impulses with a far and a near target ... 66

Figure 3.10a,b. Sarnples of head and eye movements in the whole body rotation test .... 68

........... Figure 3.1 1 a, b. The directional gain of whole body rotation test in the light ........ 7 1

Figure 3.12a,b. The directional gain of whole body rotation test in the dark ............... .... 72 ........ Figure 3.13a,b. The directional gain of whole body rotation test with large lesions 73

Figure 3.14a,bb: Phases of the whole body rotation test with large and small lesions ....... 74

............... Figure 3.1 Sa, b. Correlation between the head impulse test and the d o n c test 76

Figure 3.16a,b: Correlation behveen caloric and whole body rotation test at 1 and 3 Hz 78

Figure 3.16~. The correlation coefficients for caloric test and whole body rotation test . 79

.......... Figure 3.17. Velocities of the whole body rotation test and the head impulse test 81

..... Figure 3.18a,b. Correlation between head impulse test and whole body rotation test 82

LIST OF ABREVLATIONS

AC

LC

PC

SD

DVN

dLVN

vLVN

MVN

SVN

EHV

FTN

PVP

HGVP

ATD

PH

MLF

VCR

VOR

aVOR

aVOR

Anterior Canal

Lateral Canal

Posterior Canal

Standard of Deviation

Descending Vestibular Nucleus

dorsal Lateral Vestibular Nucleus

ventral Lateral Vestibular Nucleus

Medial Vestibular Nucleus

Superior Vestibular Nucleus

E yeHead Velocity ceUs

Floccular Target Neuron

Position-Vestibular-Pause cells

Horizontal Gaze Velocity Purkinje cells

Ascending Tract of Deiten

Pnpositus Hypogiossi

Medial Longitudinal Fasiculus

VestibiilolCoilic Reflex

Vestibula-Ocular Reflex

angdar Vestibdo4Dculu Relkr

Horizontal Vestibui~cular R e m

1 INTRODUCTION

1.1 The vestibular system morphology and mechanies

The vestibular system is composed of five different end organs. The rnorphoiogy

and mechanics descnbed here will be focused on the main pathway that is required for

the anguiar vestibuio-ocular reflex (VOR).

1.1.1 Periphetal organs

The vestibular apparatus is enclosed within a bony labyrinth, cailed the vestibule,

in the petrous portion of the temporal boue in the hier ear (Baloh and Hombia 1990).

The peripheral end organs include the three semicircular canals, each oriented in a

different plane; and two maculae, one roughly in the horizontal plane (the utriculus) and

the other in the vertical plane (the sacculus). The canals are composad of an endolymph-

filled membranous labyrinth (the endolymphatic space), and the whole vestibular

apparatus is contained in the perilymph-filled bony labyruith (the perilymphatic space).

Enda~ymplraiic sac

Supmrior somicircukr Enddymphork ducr dKt utticte

Cochlro

Co~erior rsmicircular Parilymphatk apace duet

Ampullor Soccu lu s Utriculosocculor duct Horizontal semicireukr

duc,

Sapar in OVO! window

Figure 1.1 Structure of the bony and membranous labyrinths. Ody a portion of the cochlea is shown (Adapted h m Willis and Grosman, 1973).

1.1.1.1 The morphology of the semieireular eanals

T'he semicircular canals are used for detection of angular movements of the head.

The cross sectional diameter of the canals is about O.4mm and the canals form two thirds

of a cucle with a diameter of about 6.5m.m (Baloh and Honrubia 1990). There are two

vertical caoals and one horizontal canal. The vertical ones are the anterior (superior)

canai and posterior canai awi are oriented at roughly 45 degrees in relation to the

midsagittal plane. The horizontal canal is tilted upward about 30 degrees antenorly fiom

the horizontal plane.

Figure 1.2 ûrientation of semicircular c d in head. A Horizontal (LC, lateral) canal is tilted 30 degrees upwards from the horizontal plane at its anterior end. B. Vertical canals (AC, anterior; PC, posterior) are oriented at roughly 45 degrees h m midsagittal plane. (Adapted h m Barber and Stockwell, 1976)

The dilated end of each semicircuiar duct is called the ampulla. It conîains the crista and

the cupula The crista is a saddle-shaped, raised section of the wall that extends across the

floor of the ampulla. The cupula is a gelatinous mass (Dohhann 1971) that extends h m

the surface of the cristae to the roof and lateral walls of the membranous labyrinth to

form a tight partition (Rabbit and Damiano 1992).

Figure 1.3. Structure of the ampulla of a semîcircular canal.

1.1.1.2 The hair ceifs

Hair cells are clustered at the ampulla and they are modified columnar epithelial

ceils that have microviili on their apical d a c e s . In the hair cells, many of these

microviili are elongated to form stereodia, which are grouped in an organ pipe-iike

arrangement. Moreover, each hais ceii contains a kinocilium that is longer than the

stereocilia and is eccentrically located. nie hair bundles extend upward into the cupula

It was f o d that adjacent tips of cilia are liaked together. It was mgued that the

mechanical tensionhg and relaxing of these tip-linkages rnight play a fundamental mle in

the opening and closing of ionic channels responsible for controlling hair cell potentials

(Hudspeth 1985). Displacement of the hair bundle towards the kinocilium results as the

increase of the permeability of stereocilia membrane to small cations, particularly

potassium (Corey and Hudspeth 1979). This results in hair ceiis depolarization and the

firing rate of the afferent fibers inmases (Schwarz and Tomiinson 1993). Displacement

of the hair bundle away h m the kinociliu. results in hyperpolarization of the hair ce11

and a decrease in the f i ~ g rate of the afferent fibers (Figure 1.3). For the horizontal

crista, the kinocilia are located on the side of the hair ce11 that is closest to the utriculus.

For the vertical crista, the kinocilia are located on the side of the hair ce11 furthest fiom

the utriculus. This polarized arrangement of the hair cells allows depolarization of ail the

hair cells when the cupula is displaced in one direction and hyperpolarization of al1 hair

cells when the cupula is displaced in the opposite direction.

Mammalian hair cells probably cannot regenerate after birth because hct ion is

pemanmtiy lost when they are damaged. However, it was found in quail and chickens

that supporthg celis differentiate into sensory cens foilowing destruction of hair cells

after acoustic trauma (Baloh and Hoanibia 1990).

S tereocilia

Figure 1.4. Displacement of microvilli on hair ce11 towards the kinocilium results in depolarization and displacement away fiom the kinocilium results in hyperpolarization.

Hair cells are of two types, type 1 and type II, classified according to their

morphological characteristics. Type 1 haïr cells are flask-shaped and have large afEerent

ending called a calyx surrounding the entire ce11 except for the apical surface. A calyx

cm surmund one or more type 1 cells. If a calyx mrrounds one ce11 ody, this is termed a

simple calyx ending. if more than one ceil is mounded by a calyx, it is termed a

complex calyx ending. Type 1 cells are found concentrated in the central portions of the

sensory epithelia, that is, on the crime crests (Schwarz and Tomlinson 1994). Type II

hair cells are cylinder-shaped. Instead of having caiyx ending, their basal surfaces are

contacted by aEerent and efferent synaptic boutons.

- I -

4 t Type ïï Haïr ce11

Basement

U

Figure 1.5: The morphology of type I and type II hair cells. (Adapted fiom Willis and Grossman, 1973)

1.1.1.3 The dynamics of the semiciirular caoals

nie semicircular canais work as hydrododyaaallc systems. Anguler acceleration of

the head generates an inertial force on the mass of the endolymph fluid in the canal duct.

Instantaneous volumetric displacement of the fluid deflects the cupula, which ben& the

rnircoviiii embedded in it. However, iristead of detecting angular acceleration of the head,

head angular velocity is detected. The re!ason is that fluid flow in the canal is opposed by

viscous force proportional to the flow velocity. Hence, the displacement of the fluid

becomes proportional to head angular velocity. In another words, the c d s act as a

mathematical integrator that integrates angular acceleration into angular velocity

(Carpenter 1 99 1).

A torsion pendulum model was suggested by W. Steinhausen, which suggested

that the deflection of the cupula was related to head acceleration, velocity and position:

where O is the moment of inertia of the endolymph, E is the angular displacement of the

cupula, ll is the viscous-damping couple, A is the elastic-restoring couple and a is the

input angular acceleration. However, it was argued that the model could not account for

the response dynamics of the ht-order afferents innervating the semicircular canals

(Goldberg and Femandez 197 1). Also, there are reservations about the conclusion that the

canals act as velocity transducers. This is true only in a limited bandwidth h m

approximately O. 1 to 5Hi (Carpenter 199 1).

1.1.2 Innervation of the peripheral system

Hair cells of the peripheral vestibular system are imewatcd by the afferent and

efferent fibers. These fibers are found in the WIth cranid nerve.

Primary afferents that synapse on the hair cells of the penpheral vestibular system

can be categorized by thei. structures and theu discharge pattems. Structuraiiy, aEerents

diff'er in their fiba diameters and their terminal arborizations. The thickest nbers belong

usually to nmes with calyx endings that innervate type 1 hair cell. These fibers have

irregular discharge pattems and have moderate sensitivity to head rotation. The thinnest

fibers innervate type II hair cells. They have regulat discharge patterns and have low

sensitivity to head rotation. intermediate diameter afferents have dimorphic endings.

Theu discharge patterns are more variable but tend to have a highcr sensitivity and are

more phase-advanced with respect to head movement than thin afferents (Highstein and

McCrea 1988).

The afferents fiom the vestibular end organ gather together to join the Vmth

nerve, which enters the brainstem at its ventrolateral corner in the cerebello-pontine angle

below the cochlear nuclei. Then the fibers travel over the spinal tract of the Vth newe to

enter the vestibular nuclei (Highstein and McCrea 1988).

It was speculated that the response dynamics of primary afTerent neurons could

match the dynamic requirements of each reflex pathway. The vestibulo-ocular reflex

might receive input largely fiom regular afferents and vestibule-collic reflex (VCR) fiom

imgular afXerents (Femhdez and Goldberg 197 1). However, it was recently estimated

that 30% of the rnonosynaptic vestibular nerve inputs to the secondary vestibular neurons

that projected to the oculomotor nucleus amse h m irregular afferents (Highstein et al.

1987).

1.1.2.2 Efferent fibers

The effemt supply to the vestibular receptors has been described in various

animais includhg h g s , chickens, and monkeys (Goldberg and Femhdez 1980; Precht

et al. 1971; Precht 1978). The main effereat group was found to onginate h m ceiis

located between the abducens and the superior vestibular nuclei (Goldberg and Femiindez

1980). Efferent neurons were also found to be activated by sensory stimuli such as

passive and active limb movements and gentle pressure applied to the skin or the eye

(Recht 1978). Several fûnctions have been suggested for the efferent fibers. F h t , it was

suggested that efferent fibers fiuictioned to extend the dynarnic range of the Serents

during the large accelerations accompanying intended head movements (Goldberg and

F-da 1980). Second, they may f'unction as part of the feedback loop that provides

inhibitory signals when strong sensory stimulation occurs, thus acting as an overflow-

prevention mechanism. Thirdly, since efferent neurons are inhibitory and can be activated

by contralateral vestiibular stimulation, the interaction between bilateral recepton may

fiuiction to sharpen unilateral vestibular inputs by suppressing the activity on the other

side (Precht 1978).

1.1.3 Central pathways for the vestibular system

Centrai vestibular neurons or secondsrder (secondary) vestibular neurons make

up the central pathway for the vestibular system. They are located in the vestibular nuclei

and form a voluminous nuclear complex in the brain stem. These nuclei receive

information fiom vestibular and other sensory systems such as somatosensory and visual

systems as well as central motor systems such as cerebellum and various supranuclear

motor centers, Their efferents connect with different centrai brain structures related to

finictions such as posturep locomotion, oculomotion and spatial perception.

1.13.1 Anatomy rad physiology of the vestibular nuclei

The vestibular nuclei are the organizational centers of different afferent signals.

The main input signal to the vestibular nuclei that is of interest to this thesis is the one

fiom the vestibular nerve. The axons of the p h a r y vestibular nerve divide hto

ascending and descending branches that enter the rostral end and caudal end of the

vestibular nuclei respectively (Baloh and Honmbia 1990). The vestibular nuclei are

located just beneath the floor of the fourth ventricle, chiefly in its lateral recess. The

vestibular nuclei are divided into four sections, superior vestibular nucleus (SVN), lateral

vestibuiar nucleus (LVN), medial vestibular nucleus (MVN), descending vestibular

nucleus 0, and some minor ce11 groups (Broda1 et al. 1962).

Superior vestibular nudeus

Media1 vestiiular nucleus

Lateral vestibular nucleus

Superior and horizontal

Posterior canal nerve

Descendhg vestiiiiular nucleus

nerve

Figure 1.6. The four major vestibular nuclei and the main vestiidar nerves termination. (Adapted nom Gavek, 1994)

The superior vestibular nucleus lies at the head of the vestibular complex. SVN

receives flerent inputs h m many different sites, for example, the semicircular canals,

the contralateral SVN and M W , ipsilateral MVN and vestibulo-cerebellum. The SVN is

generally thought to be primarily involved in the vestibule-ocular reflex pathway.

The lateral vesti'bular nucleus can be subdivided into two subnuc lei: the dorsal

lateral vestibular nucleus (dLVN) and the ventral lateral vestibular nucleus (vLVN). The

dLVN receives input mainly fiom the cerebellar anterior lobe, the spinal cord and the

reticular formation, and gives nse to the lateral vestibule-spinal tract. The major aflierents

to vLVN arise fiom the semicircular canals the cerebellum, the ipsi- and contralateral

vestibular nuclei, and the prepositus nucleus. The vLVN gives rise to vestibulo-ocular,

vestiiulo-spinal and vestibule-thalamic pathways.

The medial vestibular nucleus is the largest nucleus of the vestibular complex.

Afferents projections to the MVN &se h m the c d s and otolithic organs, the ipsi- and

contralateral vestibular nuclei, the vestibulo-cerebellum, the faigiai nucleus, the

interstitial nucleus of Cajal, the mstral interstitial nucleus of the medial longitudinal

fasciculus, the prepositus nucleus and the reticular formation.

The descendhg vestiiular nucleus dso receives a variety of inputs and projects to

various regions that are similar to the other vestiidar nuclei. The DVN was found to be

primdy bervated by otolithic organs (Kevetter and Pefachio 1985). There are also

minor ceii groups associated with the vestiiular nuclei, which include group X, Y, 2, and

E. Ce11 gmups Y and E are important fûnctional units of the vestibular nuclei since Y

group projects to the ocuiomotor and contralaterai vestibular nuclei (Highstein 1973) and

E group contains cells that contribute to the efferent pathway from the brain to the

vestibular end organs (Goldberg and Fcmandez 1980).

There are several classes of physiologicaily identified newons within the

vestibular nuclei. They were classifieci on the basis of their h g behavior during the

VOR, VOR caaceilation, smooth pursuit eye movements, fixation, and spontaneous

saccadic eye movement. The classes have been named as vestibular, vestibular-plus-

pause, eye-position, burst-position, gaze-velocity, position-vestibular, position-vestibular-

pause. and eye and head-velocity according to the signals that they convey (Scudder and

Fuchs, 19%; Chen-Huang and McCrea 1999). Horizontal neurons with vestibular

sensitivity are also subdivided into type 1, excited during ipsilateral rotation, and type II,

excited d u ~ g contralateral rotation.

1.1.3.2 Efferents Crom the vestibuiar nuclei

The vestibular nuclei project to various regions in the brah, including the

brainstem, cerebeilum, and the spinal cord. Different sections of the veshiular nuclei

project with different weights to different target regions. The vestibular nuclei also

project to the vesbibular nuclei contralaterally. The major efferent projections h m

medial, superîor and ventral lateral vestiuiar nuclei fonn the mediai longitudinal

fasiculus (MLF) and the ascendmg tract of Deiters (ATD), the major pathway involved in

the VOR AU the vestiôular nucfei except the dLVN project to the cerebellum. The

cerebellar vermis, the flocculonodular lobe, and the fastigial nucleus are vestibular

termination sides in the cerebellurn (Ito 1982).

1.14 The extraocular muscles and the motoneurons

The extraocular muscles are the muscles that move the eye. There are six

principal muscles, the four recti (superior, inferior, medial and lateral) and two obliques

(superior and inferior).

The medial and lateral recti are responsible for the horizontal (yaw) eye

movements. The insertions of these muscles are symmetricaiiy distributcd around the

horizontal meridian on opposite sides of the globe. nius, the medial and lateral recti are

hinctional antagonists that serve as the principal adductor and abductor of the eye

respectively. Superior and inferior recti are primarily responsible for the vertical (pitch)

eye movements. The obliques are primarily responsible for the torsional (roll) eye

movements,

The motor innervation of the extraocular muscles are provided by the extraocuiar

motor neurons: oculomotor, trochlear and abducens. The ocuIomotor nuclei innervate the

ipsilateral medial rectus, Uiferior rectus, and i n f i o r oblique muscles. They also innervate

the contralateral supezior rectus and levator palpebrae superior muscles. The trochlear

nuclei innervate the contralateral superior oblique muscle. The abducens nuclei innervate

the ipsilateral laterai rectus muscles (Spencer and McNeer 1991).

1.2 The Vestibulo-ocular reflex and its pathway

The vestibuloscular reflex (VOR) is a mechanism for stabiiizing vision during

head movements. As the head moves in one direction, the eyes move in the opposite

direction by an appropriate atnount so that images remah stationary on the fovea in spite

of the head movement. The VOR can also be divided into two types: angular VOR

(aVOR) and translational VOR (tVOR). The aVOR responds to angular rotation of the

head and the tVOR responds to Iinear translation of the head (Crane et al. 1997; Paige

1991). The aVOR can be characterized by its gain and phase. Gain is dehed as eye

velocity divided by angular head velocity. Though these are in opposite directions, gain is

generally represented as a positive number. Phase is defhed as the temporal synchrony,

expressed in degrees, between the head and eye velocity.

Though a particular brallistem pathway is responsible for a particular VOR reflex

according to the site in the labyrinth that is activated, the main VOR pathway is a three-

neuron arc: vestibular nerve (primary vestibular neuron), vestiiular nuclei (secondary

vestibular neuron) and extraocular motor neurons. The vestibular nerve carries head

movement signals h m the semicircular canals and otolith organs. The semicircular

canals sense head rotation and the otolith organs sense head translation. The vestibular

nuclei receive the signal h m the vestibular nerves and p a s it to the extraocular motor

nemns. The extraocuiar motor neurons then pass the sipals to the extraocular muscles

that control the eye to give the appropriate eye movements. In particular, the horizontal

aaguiar VOR wili be studied here as it is ditectly related to this project.

1.2.1 The horizontal angular VOR

The horizontal angular VOR involves the horizontal canals that sense horizontal

head rotation and compensatory horizontal eye movements are generated as a result.

Stimulation of one horizontal canal nene causes a pure horizontal deviation on both eyes

toward the contralateral side, which is mediated by a three-neuron reflex arc as

Laterai Medial Medial Lat eral rectus rectus rectw recîus

Oculomotor Nucleus

ducen Nucleus

Nucleus

Horizontal Canal

Figure 1.7 Horizontal canal excitatory projections. ATD: ascending tract of Deiters.

The eye moves in a push-pull fashion, and thus the extraocular motomeurons

require both excitatory and inhibitory inputs. Electric stimulation of the VIZIth nerve or

selective stimulation of the horizontal canal nerve evokes disynaptic inhibition in

ipsilateral, and disynaptic excitation in the contralateral abducens neurona (Baker and

Highstein 1975). The excitatory signal h m the horizontal canal afferents passes mainly

through the rostral pole of the ipsilateral medial vestibular nucleus to the contralateral

abducens nucleus (VI), resulting in excitation of the contralateral lateral rectus muscle.

The medial vestibular nucleus also projects to the ipsilateral medial rectus division of the

oculomotor nucleus (m) via the contralateral abducens internewons md dong the

ascending tract of Deiter, resulting in excitation of the mediai rectus muscle (Baker and

Highstein 1978). Separate pathways are used for the lateral rectus muscles and medial

rectus muscles so that different amounts of contraction can be given to the muscles to

dlow different amounts of movement of the two eyes, inhibitory vestibular neurons

excited by the horizontal canal nerve fom a Uihibitory pathway that projects directiy to

the ipsilateral abducens nucleus and thus causes a relaxation of the ipsilateral lateral

rectus muscle (Wilson and Melvill Jones, 1979).

Besides the main three-neuron arc pathways, there an collaterals that direct the

vestibular signal to other areas, for example the prepositus hypoglossi (PH) nucleus, the

interstitial nucleus of the vestiiular nerve, the ipsilateral and contralaterai vestibular

nucleus and certain portion of the recticular formation. These colhtefal-co~e~ted

structures serve various hctions, such as integration of the signal (Schwarz and

Tomlinsonl994).

1.2.2 Central connections of the VOR

1.2.2.1 Positfon-Vestibular-Pause (PVP) iinits

Evidence has shown that there are two prominent neural pathways underlying the

VOR One pathway involves the position-vestibular-pause (PVP) units (Scudder and

Fuchs 1992; Lisberger et al 1994a). PVP units are beiieved to be the principal secondary

neurons in the VOR. PVP uni& discharge in relation to heaà velocity, eye velocity, eye

position, and cease fire during some saccades (Scudder and Fuchs 1992). Most PVP units

are activated at monosynaptic latency following electrical stimulation of the ipsilaterai

vestibular nerve (Chen-Huang and McCrea 1999). The majority of PVP units are type 1

(Scudder and Fuchs 1992). Also PVP units have been demonstrated to be

monosynaptically connected to motor neurons (McCrea et al. 1980). They showed

increased h g for contraversive (away from the side of recording) eye motion with the

head stationary and for ipsiversive (towards the side of recording) head motion during

VOR cancellation (Scudder and Fuchs 1992; Lisberger et al. 1994a).

1.2.2.2 Eye and Head Veloeity (EEV) units

The other prominent neural pathway for the VOR is the eye and head velocity

(EHV) units (Scudder and Fuchs 1992; Lisberger et al 1994a). EHV units discharge in

relation to eye velocity and head velocity in the same direction and the majority of them

are type 1 (Scudder and Fuchs 1992; McFarLand et al 1992; Chen-Huang and McCrea

1999).

It has been hypothesized that EHV units correspond to another group of

seîondary neumns caUed floccular target neurons (FTN) (Scudder and Fuchs 1992). They

were so called because they were inhibited at monosynaptic latencies by stimulation of

the flocculus and the ventral parafiocculus with single electrical pulses (Lisberger et al.

1994a). Since FTN units were found to respond with longer latencies d e r the omet of

head motion than PVP units, PVP uni& were proposed to cirive the earliest component of

the VOR and FTN units were to drive the longer latency-spectacle modified component

of the VOR (Lisberger et al. 1994a).

1.2.2.3 Commissural pathways

Experimental observations indicate that there are pathways interconnecthg the

bilateral vestibular nuclei (Shimazu and Recht 1966). These pathways are called

cornrnissurai pathways and they allow connection of the vestibular nuclei to the

contralateral labyrinth. Commissural pathways are important for the coordination

between the two vestibular nuclei and are proposed for contnbuting to the recovery of the

vestibular nuclei activity on the lesiomd side after unilateral vestibular lesion (Galiana et

al. 1984).

The normal intm~tion between the vestibular neurons on both sides during

rotation is illustrateci in figure 1.8A. The medial vestibular nucleus (MVN) type 1 n e m m

receive ipsiiaterai afFerent input and are excited by the head rotation towards the

ipsilateral direction. The M W type Il neurons are dnven indirectly via the opposite

labyrinth. Type II neurons are excited by conûaiateral rotation and are inhiibited by

ipsilateral rotation. Type II neurons are inhiibitory neurons so their reduced inhibition

during ipsilateral rotation will enhance the ipsilateral afTerent input to type 1 neurons

(disinhibition). When the head is rotated to the le& primary afferents from the left

horizontal semicVcular canal are activated, whereas the afferents nom the right are

inhibited. The solid lines in the diagram are the cells that are excited and the dotted lines

are the ones that are silenced. As a result, the eyes rotate to the right.

Mer vestibular lesion as in figure 1 AB, the activity of the airent of the

ipsilesional (right) side is gone. nie decrease of activity in the ipsilesional pathway

results in an Unbaiance of resthg activity between the two vestibular nuclei. The nsulting

activity is similar to the case when a healthy subject rotates to the left. Spontaneous

nystagmus (slow phase eye movement) to the tight will appear.

-27 Head Rotation

Figure 1.8. Commissural pathways in vestibule-ocular reflex. 1: MVN type I vestibular neurons; II: MVN type II vestibdar neurons; III: oculomotor nucleus; VI: abducen nucleus; filled hexagon: idbitory neutons; open hexagon: excitatory neurons; solid iines: firing rate of cells increase in the paîhway; dotted lines: h g rate of cells decrease in the pathway (Adapted fiom Curthoys and Halmagyi 1995)

1.3 Plasticity of the VOR

VOR is known to have neurai plasticity and modification of the VOR has ken

shown to occut under different circumstances. For instance, the gain of VOR cm be

increased immediately when viewing a near target (Vke et al. 1986; Hine and Thom

1987). AIso, the use of spectacles can induce gain change in a few days (Ito 1972;

Gonshor and Melviii Jones 1976). Furthermore, VOR gain is reduced aAer vestibuiar

damage but rnay retum to normal after a few days or weeks (Coujon et al. 1977; Paige

1983). Though diEerent types of VOR plasticity have different chatactenstics, the

underlying neural mechanian for the various types of VOR plasticity should have some

cornmon factors. However, there should also be differences between the different

pathways for VOR plasticity. For instance, speztacle-induced VOR plasticity requires a

significant training period, while vergence angle induced VOR plasticity is observed for

the very f h t transient rotation (Synder et al. 1992). Also, there was a difference in VOR

in response to different fkequencies for the spectacle-induced leaming and lesion-induced

learning (Broussard et al. 1999b). Spectacle-induced leaming modified the gain of the

VOR more effectively for rotation at low fiequencies while lesion-hduced leaming

enhanced the gain for rotation at high frequencies more than at low fiequencies.

Nonetheless, understanding of the underlying neuial mechanisrn in one type of VOR

plasticity should be useful for learning more about the mechanism for the other types of

VOR plasticity.

1.3.1 Spectacle-induced VOR plasticity

If the performance of the VOR becomes degraded, images will move on the retina

during head rotations. The msulting conjunction between the visual slip and head

movement will gmdually alter the amplitude of the VOR until the image is stabilized on

the retina. This adaptive process is called motor 1e-g and may take several days to

cumplete (Ito 1972; Gonshor and Melviil Jones 1976).

Motor leamhg of VOR cm also be produced using corrective spectacles.

Experiments showed that the amplitude of VOR in monkeys could be dtered when they

were fitted with magnifjhg or miniminne spectacles. Mer the monkeys were allowed

to adapt to the spectacles for 5 to 7 days, the performance of VOR was tested by head

velocity pulses that reached a plateau of 30 degreedsec. VOR amplitude could become as

large as 1.8 times nomal when the visual scene was magnified or as mal1 as 0.4 h e s

normal when the visual scene was diminished (Miles and Fuller 1974; Lisberger and

Pavelko 1986).

13.2 Vergence angle-induced VOR plasticity

1.3.2.1 The effect of vergence angle on aVOR

Vergence angle is the angle made when one eye moves relative to the other eye.

As the distance of a target in h n t of a subject decreases, the relative angle that the two

eyes makes relative to each other increases (Pa) in order to b t e on the target (Figure

1.9). Since VOR huictions to stabiiize images on the retina during head movements,

adjustment of the compensatory eye movements is necessary when the target distance

from the subject changes (Chen-Huang and McCrea 1999; Synder and King 1992; Viirre

et ai. 1986).

Figure 1.9 The relative angle that the two eyes make relative to each other increases in order to fixate fiom a far to a near target (Pa).

Imagine that a person's head rotates through an angle 8 with the eye fixated on

target A as in figure 1.10, the persoa has to make an eye movement of angle a. Then, the

person is asked to repeat the procedure but is required to hate at a near target B. The

person has to make a bigger eye movement of angle f), Thus, as target distance decreases,

the eye has to make a bigget movement to compensate for the same hed movement. It

means that gain should increase when target distance decreases so as to provide adequate

compensation.

Figure. 1.10. The geometncal relationship of vergence angle and target distance in VOR. A, B: Target; @: angle of head movement; a$: angles of eye movement when fixating at target A and B respectively.

Experiments have shown that the magnitude of VOR gain increases above 1 .O

when target distance decreases (ViVre et ai. 1986; Hhe and Thom 1987; Snyder and

King 1992). The gain was found to increase fiom 1.1 to 1.6 when a target at 90 cm was

replaced by one at 16 cm (ViVre et al. 1986). The gain stayed at its new high value

throughout the fiequency range fiom 0.25 to 2 Hz

However, other experiments with rotation at higher fkquencies showed different

resuits. ûne experiment showed that VOR gain in human subjects using a near target

decrrased when die frequency was increased h m 1.75 to 3 Hi (Hine and Thorn, 1987).

Also, a ment experiment on monkeys showed that the viewing distance related gain

decreased when rotation frequency was increased h m 0.7 to 4 Hz (Chen-Huang and

McCrea, 1999). The near target data lagged behind the far target data by 10 degrees when

frequencies was increased to 4 Hz.

1.3.2.2 The neurai pathway for vergence angle relateâ aVOR

Various observations suggested that the increase in the ga i . of VOR during near

target viewing was rnanipulated by changes in the processing of the vestibular signals in

brainstem VOR pathways rather than by visual mechanisms. During near target viewing,

sudden step changes in head velocity evoked eye movements with an enbanceci gain at

latencies that were shorter than even the shortest visual feedbackdven eye movements

(Crane and Demer 1998; Synder et ai. 1992; Viim et al. 1986). Also, the gain increase

was found to persist in darkness (Chen-Huang and McCrea. 1999; Hine and Thom 1987;

Snyder et al. 1 992).

As PVP and EHV nemns were the most prominent group of secondary neumns

in the vestibular nucleus, experiments were performed to record the f ing rate of PVP

and EHV units in monkeys during viewing distance moduiated aVOR by using electrode

recording technique (McConviiie et al. 1996; Chen-Huang and McCrea 1999). Though,

the resuits showed that PVP seflsitivity increased durhg aVOR when a far target was

replaced by a near target, this inaease was too smaii when compared with other types of

secondary vestibuiar neurons to account for the increase in the aVOR gain. On the 0 t h

hand, the target distance-related change m firing rate of EHV units was sigpificantly

larger than PVP units (Chen-Huang and McCrea 1999; McConville et al- 1996).

With the idonnation gathered nom the single cellular recordings, one model

(Fig. 1.1 1) was proposed on how the different neural pathways are connected to account

for the change in target distance related aVOR (Chen-Huang and McCrea 1988). As

experiments showed that viewing distance-relateâ gain changes in the aVOR could be

attenuated or even abolished by silencing Vregular vestibular nerve aerents using

galvanic cments (Chen-Huang and McCrea 1998), irregular afferents were comected to

the viewing distance related pathway in the model. Besides, due to the observation that

viewing distance-related signals generated by EHV and PVP units typically phase lag

irreguiar aerent signals by around 90 degrees at 1.9 Hz, it was reasoned that the viewing

distance muitiplied irregular af5erent signal input to secondary VOR neurons should be

low-pass filtered or integrated. The site of this action was proposed to take place in the

aVOR velocity-position integrator (NI) as shown in the model.

lhiewing distance

1 g2" VOR

paths R

I l

Figure. 1.1 1. A mode1 of possible central mechanism used to modi@ the aVOR as a function of viewing distance. R, regular vestibular afferents; 1, irregular vestibular afYerents; II, inhibitory imgular afTerent interneurons; NI, neural integrator; MNS, extraocular motor neurons. Dotted lines are the inhibitory pathways (Adapted fiom Chen- Huang and McCrea 1999).

1 .A3 Lesion-iaduced VOR plasticity

1.3.3.1 The effect of unilateral vestibular lesion on aVOR

The loss of vestibular afferent input fiom a labyrinth may occur as the result of

diseases such as acute vestibular neuritis (Wal infection), the progressive growth of a

neuroma (tumor) or the result of surgical procedures such as labyrinthectomy (removal of

the labyrinth) or vestibular neurectomy (excision of the Scarpa's ganglion) (Curthoys and

Halmagyi 1995).

Physiologically, the nomai response of aVOR is due to combined effect of two

sources of activation: excitation h m the ipsilateral side and disinhi'bition h m the

there is only activation h m ipsilateral side for rotation towards the intact side. For

rotation towards the lesioned side, there is only one source of activation: disinhiiition

kom the intact side. Thus, eye movement responses will be smaller Uiaa normal for

rotation towards both directions immediately d e r a unilateral vestibular lesion. Previous

experiments have shown this VOR gain reduction for both directions of rotation,

especiaily for the lesioned side (Paige 1989; Halmagyi et al. 1990; Broussard et al.

L 999a).

The smaller eye movernent responses for rotation towards the lesioned side than

towards the intact side may be due to the low sensitivity and low saturation threshold of

the disinhibition signals fkom the intact side. For instance, ipsilesional gain measured at

the plateau of the head pulse stimulus of 10 to 30 degreeslsec was smaller than

contralesional one in the first thirty days d e r plugging one horizontal canal of cats

(Broussard et al. 1999). Another experirnent on patients 5 days after surpical destruction

of unilateral vestibular afEerent or labyrhth also showed a large gain asymmetry of 26%

at head velocity of 300 degreedsec (Paige 1989).

In addition to gain asymmetry, eye velocity for ipsilesional stimulation did not

saturate but increased linearly as a function of head velocity with a velocity gain of about

0.2 when head stimuli with velocity from 100 to 250 degneslsec and acceleration h m

1500 to 3000 degreedseclsec were given to patients that undement unilateral vestiiular

neurectomy (Halmagyi et al. 1990). These resuIts suggested that this VOR asymmetry

could be explaineci by Ewald's second law. Ewald's second Iaw states that in the lateral

semicucular canal, ampullopetal (excitatory) endolymph flow provokes a larger slow

component eye velocity than arnpullofiigal (inhibitory) flow. Therefore, the low but

h e a r Uiaease in gain for ipsilesional rotation was due to the low sensitivity in response

to ampuilofhgal endolymph flow in the contralesional labyrinth.

However, an experiment on squirrel moakeys with horizontal canal plugged on

one side showed that the eye movement response fiom VOR did not resemble that

predicted by Ewald's second law (Paige, 1983). The eye movement r e s p s e to

sinusoidal rotation at 0.2 Hz and peak head velocity of 240 and 360 degreedsec was

normal and became clipped only when eye velocity reached 160 degmslsec during

ipsilesional turn. Then was no sign of low sensitivity in ampuilofbgal rotation as

predicted by Ewald's 2" Law. Furthemore, the activity of the regularly discharging

vestibuiar afferents of chinchillas undergohg sinusoidal rotation nom 2 to 20 Hz, with

peak velocity of 15 1 degradsec at 6 Hz and 52 degredsec at 20 Hz showed no

asymrnetry between ampullopetal and ampuilofûgal rotation (Hullar and Minor 1999).

Therefore, VOR asymmesymmetry should not have originated h m the srmicucular canal.

1.3.3.2 The efféct of varioas stimuii on recovery of VOR after unUitenl ksion

Recovery of the gain of VOR was seen after a period of days or weeks following

unilateral lesions. Gain improved h m 50% to 70% of the gain before lesions when

measurement at 30 days was compared with the one on the fûst day after unilaterai canal

plugging in cats (Broussard et al 1999). Similariy, gain asymmetry decreased h m 26%

to 18% when measued 4 months after surgical destruction of unilateral vestibular

afTerent or labyrinth in patients (Paige 1989).

One of the ways to reveal the underlying neural mechanism for the VOR is to see

how the system responds to different types of stimulus after a unilateral lesion. There is

evidence that recovery of VOR asymmetry after a unilaterai vestitbuiar lesion is

dependent on the type of stimulus used. For instance, asymmetry in VOR persisted even

at 1 year after unilateral vestibular neurectomy when high-acceleration head impulse was

used as the stimulus (Hahagyi et al. 1990; Aw et al. 1996). Also, asymmetry Ui VOR

gain in unilateral lesioned patients was noted for stimulus with lower acceleration and

fiequency that reached a high peak velocity (Paige 1989). On the contrary, recovery of

asymmetry of VOR did not occur when other stimuli were used. The VOR asymmetry

was gone when tested by small dynamic rotations, such as stimulus with velocity fiom 30

to 60 degreedsec on patients (Fetter and Zee, 1988; Paige 1983). Recently, Iwo

experirnents looked into how various factors in the dynamics of the stimulus contribute to

the asymmetry of VOR after unilateral vestibular Ioss.

ûne experiment attempted to d e t e d e what factors limit the recovery of VOR

symmetry in cats with one horizontal canal plugged (Broussard et al. 1999a). Gain

asymmetry was found to be fkequency dependent. Persistent gain asymmetry was found

ta be signincant only at kquencies above 2 Hz when sinusoida1 rotations with

fkquencies h m 0.05 to'8 Hz at 10 degneslsec were used. With inmasing stimulus

kquency, the ipsilcsional gain did not change signincantly, but the contralesional gain

increased. The ciifference between the ipsi- and contralesional gain was signincant fiom 5

to 8 Hz. On the other hand, the asymmetry was found to be independent of stimulus with

velocity throughout the hown linear velocity range of the primary vestibular afferents

and independent of peak head acceleration over the range of 50 to 500 degrees/sec/sec

when velocity pulse stimuli with plateau velocity of 5 to 50 degreedsec were used.

The observations of the performance of VOR af€er unilaterai canal plugging were

shulated by a bilateral mode1 of the VOR (Figure 1.12). The plugged canal was

represented by a gain and a hi&-pass filter while the normal canal was represented by a

pure delay only. The observation of fiequency-dependent asymmetry after a milateral

canai plug was simulated by the low-pass filters in the recurrent commissural pathways.

The low-pas filters in the commissural pathways pennitted symmetric responses at low

frequencies while preserving asymmeûic responses at high Erequencies. The gains in the

commissure were adjusted d e r lesions since the commissure was proposed to contribute

to the recovery of VOR symmetry. The high-frequency gain enhancernent after recovery

was simulated by increasing the gains in the pathways of the afferents with hi&-pass

filters.

Figure 1.12. A bilateral mode1 of VOR with commissural pathways afkr unilateral canal plugging. H': angular head velocity; Gx: gains; C: cutoff frequency of the vestibular commissure (low pass filter); S1 and S2: gains of secondary n e m s for increases and decreases in firing respectively; d: pure delay; E': eye velocity. (Adapted h m Broussard et al. 1999a)

Another experiment sought to determine the interaction of frequency, velocity,

and acceleration in producing asymmeûies of the horizontal VOR after disniption of

vestibular function nom one labyrinth in the monley. VOR gain improved when

measurements were made at 30 days was compared with that at the fht day after canal

plugging using acceleration steps (3000 degrees/sec/sec; 1 50 degreedsec) and sinusoidai

rotations (O to 15 Hz; 20 degreedsec). Ab, the findings indicated that there was a

fiequency and velocity dependent asymmetry in the horizontal VOR after plugghg. For

sinusoida1 rotation with fiiaciuency h m 0.5 to 15 Hk and velocity of more than 50

degrees/sec, contraiesional gain was signincantly higher than ipsilesional gai . oniy above

4 Hz (Lasker et al. 1999). The asymmetry was due to an increase in the gain of the

contralesional response, whereas ipsilesional gain was unchanged There was no

significant gain asymmetry when the stimulus velocity was Lowered to 20 degreedsec.

A bilateral mode1 of VOR with üaear and nonlinear pathways was developed to

account for the asymmetries in ipsi- and coatralesional response data. A simplified

version of the model was illustrated as in figure 1.1 3. Nomaily, the hear pathway was

responsible for the constant gain across frequencies with low peak head velocity. The

nonlinear pathway accounted for the fiequency- and velocity- dependent noaliaearity in

VOR gain (Lasker et al. 1999).

To simulate the effect of canal plugging, inputs h m the plugged side were

removed fiom the model. Selective increases in the gain for the lhear and nonlinear

pathways predicted the changes in recovery observed after canal plugging. Since there

was no manifestation of a nonlinear increase in gain with velocity for ipsilesional

rotations after plugging, the nonlinear pathway was proposcd to be dnven into Uihibitory

cutoff for low velocity. An increase in gain for contralesional responses to steps of

acceleration and sinusoida1 rotations at higher fiequencies and velocities could be due to

an increase in the centrai gain element (not shown in the diagram) of the nonlinear

pathway. On the other hand, an hcrease in the central gain element (not shown in the

diagram) of the hear pathway could account for the recovery in VOR gain for both

responses at velocity plateau of the steps of acceleration and at low peak velocity of the

sinusoiciai mtations (Lasker et al. 1999).

Since the two eqeriments above were performed on cats and monkeys ody, the

second part of the experiment looked into the effect of unilateral vestiiular lesion on

human VOR.

Head /

ve'ocitY - 7< E Y ~

Velocity

Left

Figure 1.13. Bilateral mode1 of VOR with linear and nonhear pathways after unilateral canal plugging. Ni: neural integrator; Td: time delay. (Adapted h m Minor et al. 1999).

1.4 Objective

The objective of the project is to understand the dynamics of the underlying VOR

pathways under differing conditions in humans. We hypothesize that the gain increase

caused by near target viewing will involve pathways which only opeiate optimally at 1ow

fiequencies. This hypothesis will be tested by comparing VOR gain and phase with near

and far targets and across a range of fkquencies. In addition, we will investigate the

effects of vestiiular disease on VOR dynamics to determine if the low and high

fkquency bands behave differently.

2 METHODS

The experiments were mainly divided into two parts. The first part involveci the

study of the effect of target distance on human horizontal aVOR This was doue by using

a rotating chair system with targets presented to subjacts at dinerent target distances. The

second part of the experiment involved the study of the effect of unilateral vestiibular

lesions on buman horizontal aVOR. It was done by using different vestibuiar testing

methods on patients with unilateral lesions.

2.1 Subjects

2.11 Part1

Recordings were obtained fiom seven human volunteers (age 22-52 years, 6

males and 1 female) with no history of vestiiular or neurological disorders.

2.1.2 Part II

Recordings were obtained fkom 23 patients (age 34-79, 16 males and 7 fernales)

with various degrees of vestibular lesions or symptoms. The period between the onset of

symptoms and time of testing vatied b r n a few months to a few years. No patient has

spontaneous nystagmus.

2.2 Experimental Protocol

2.2.1 Part 1

Human volunteers underwent passive whole body rotation by sitting on a chair

that osdateci at 12 discrete fresuencies: 0.25.0.5. 1,2,3,4,5,6,7,8,9 and 10 Hz. The

subjects were asked to h a t e at two earth-fixed targets at distances 25cm and 23Ocm fiom

the eyes.

2.2.2 Part II

22 patients undenvent some or aU three cüfferent vestibular tests. First, the passive

whole body rotation test was performed on al1 the subjects with 7 discrete fiequencies:

0.5Hz. 1 Hz, 3 HZ, SHz, 7Hz, 9Hz and 11Hz ia the light and the dark. In the Light,

subjects were required to look at an earth-fixed target at a distance of 23Ocm. In the dark,

they instructed to imagine the same target and try to look at it. Then, 13 of them

underwent head impulse tests by fixating on the 230cm target and a near target ofaround

30cm. Calonc tests were performed on al1 patients nght before the head impulse test or

on another day within a week. The percentages of asymmetry for al1 patients are show in

table 1.

2.3 Vestibular measurements

2.3.1 Whole body rotation testlng

Horizontal angular VOR was studied by whole body rotation test. It was achieved by

using a custom built rotathg chair. Sinusoidal rotations up to 10 Hz (1 1 Hz for part II)

were used. Head velocities were less than 150 degreedsec. By using sinusoïdal rotation,

gain and phase could be calculateci h m the head and eye movement signals. Effects of

target distance and vestibdar lesions on the aVOR were studied by this method.

Table 1 : The d o n c and head UnpuIse test results for al1 the patients. Caloric resuits are represented by unilateral weakness percentages. Head impulse redts are represented by regression slope values. L: lef't, R: nght, far. far target, neac near target.

Patient

145 160 1621

CaloricNorrnal CaIoric L Loss

100%

Impulse L (far)

NIA NIA

Impulse R (fat)

N/A NIA

.Calorie R Loss

76%

163 165 168 169 1 70 171

NIA N/A NIA NIA NIA

0.81 0.8

NIA

Impulse L (near) NIA NIA

100%

45%

172 1 74 175 1 76 177 178

1

180 181 182 183 1 84 188 .. 190 191

Impulse R (near) N/A

1

NIA

0.34 1 .O7 1 -05 0.72 0.7

0.89

0.88 0.83 0.78

!

0.48 O .94 0.82

16%

100%

85Oh

NIA NIA

4% dght IOSS

6% left loss 1 1 % left loss

100%

29%

100%

25% 16%

NIA N/A NIA NIA

0.7 0.78

4% teft loss

14% left loss 9% right loss

5% left loss

15% right loss

0.68 NIA

0.38 0.57 -------- 0.64 0.93

NIA 0.62 0.96 0.73 O .85 0.52 1 .O6 0.8

0.76 NIA

0.88 0.47 0.51 0.92

NIA 0.8

1 -05 0.5

- O -76 0.69 0.94 0.83

0.72 0.96 0.42 0.85 O .63 1.12

NIA 0.74 1.36 0.92

- 1 O .62

1.2 0.78

1 .O4 O .O6 0.97 0.75 0.54

1.1 NIA

O .87 1 -43

1

0.44 0.89 0.82 1.16 0.91

23.1.1 The recording system

Eye movements were recorded by placing a scleral contact lens (Scalar) with a

copper coil embedded in it onto one eye of the subject. Anaesthetic was applied to the

eye before the placement to reduce irritation. A phase angle search coil system (CNC

Enginee~g, 6 feet in diameter) was used to generate the fields. A custom-built hydraulic

rotating chair was used to perform whole body rotations of the subjects. The mbjects'

positions in the chair were fixed by clamping both sides of the head and by strapping the

body to the chair. Subjects were asked to bite on a custom-built dental bite bar with a

search coil mounted for recording head rnovements. There was no pause between

düferent fiequencies of the chair as it was changed at zeronossing. The entire

experiment lasted less than 43 S.

Field coil

I

. I

Figure 2.1 A simplifïed diagram to illusirate the recording system for the whole body rotation

2.3.1.2 Calibration and data coiledon

The coil used to measure head position was precaliirated so that a horizontal

rotation o f f 10 degrees gave a reading of 510 degrees. This was done by a calibration

coil fixtwe that was mounted on a wooden block and was held between the head

restraining pads. The chair was then rotated sinusoidally to obtain a peak angular

difiction o f f 10 degrees and the position output of the chai. controller was calibrated to

+IO degrees. This controller signal was then used to fine-tune the head calibration by

matchhg the head signal to the chair signal at the lowest fiequency (0.25Hz). In practice,

these adjusbnents were minor. Eye coils were calibrated before each set of experiment by

askhg the subject to move between two targets that were placed on the lefl and right side

of the 230cm target.

Eye and head movement data were recorded by using a phase detector system

(CNC Engineering, Seattle) and digitized at 400Hz for off-line anaiysis. Head and eye

coils were calibrated before each run.

2.3.2 Head impulse testing

A simiiar recording system for the whole body rotation test was used to record the

head and eye movcment in the head impulse test. The investigator heId the patient's head

by both han& and deliver a rapid, passive, step displacement of head angular position

(head impulse) by guickly rotating the patient's head around its longitudinal axis, through

an angle of 10 to 20 degrees either to the left or to the right. For the far target paradigm,

the patients were asked to fixate an earth-fixed target 230cm h m their head. Fot the near

target paradigm, the target was around 3ûcm h m the head. Fifteen to twenty head

impulses were generated in each direction. The investigator attempted to generate head

impulses of a broad range of velocities. Peak velocity ranged fimm around 100 to 600

degreedsec.

23.3 Caloric testing

The conventional bithemal calonc test was performed on patients by an

expenenced technician. 25ûml of water irrigated the external ear canal of a subject in the

supine position with the head flexed 30°, so that the plane of the laterai semicircular

canals was vertical. Experiments were performed in the dark to avoid visual fixation. nie

temperature of the water was 30°C for the cool irrigation and 44OC for the warm

imgation. Nystagmus was generated as a response. A method called

electronystagmography (ENG) was used to record eye movements by placing electrodes

on the skin around the eye (Barber and Stockwell 1980). The slow phase eye velocities

were recorded for the two temperatures for each ear.

To quanti@ the differmce in caloric response strength of the two ears, the

examiner used the formula:

(RW+RC)- (LW+LC) * 1 O0 = unilateral weakness R W + R C + L W + L C

where RW, RC, LW, LC are the slow phase eye velocity for nght warm, right cold, Ieft

warm and left cold paradigms respectively.

Patients were divided into three groups: i) complete unilateral loss (100% unilateral

weakness), ii) partial unilateral 10s (more than 15% d a t e r a i weakness), iii) normal

(iess than 15 % unilateral weahiess).

2.4 Data onalysis for whole body rotation test

Eye and head movement siguals were sent to a computer terminai to be aaalyzed.

Gain and phase were calcdated by the following steps.

2.4.1 Saccade removal

Saccades are a type of eye movement that moves botb eyes rapidly to a new eye

position so that a visual target can be directed onto the fovea. During off-line analysis,

saccades were marked manually on a graphics temiinal. They were removed and

substituted by quadratic segments with dopes matched before and after the saccades.

This was necessary so that the e m r in gain and phase calculation could be reduced.

Figure 2 2 An example of a saccade removal and substituted by a quadratic segment in the eye position cuve.

Eye and head velocities were then calculated by differcntiation using a 15-rns

central diGerence digital differentiator that calculated the comsponding velocities f (x)

from the position data fi) by using the formula: f (x) = [f(x+h) - Rx-h)] / 2h where x is

the t h e and h = 7.5 ms.

2.4.2 Gain and phase calculation

Gain and phase were calculated by two methods. Firstly, eye and head data were

fitted with sinusoids on a cycle by cycle basis yielding gain and phase estimated nom

each cycle. Secondly, spectral analysis was applied to the same eye and head data to h d

gain and phase. Both methods were perfomed by custom-made software. Gain and phase

for different subjects were averaged vectorially for each experimental paradigm.

2.4.2.1 Cycle by cycle method

The program fitted the rough c w e of the raw data of eye velocity with smooth

sinusoids as iIlustrated in the drawing (Figure- 2.3). The same procedure was repeated on

the head velocity curve.

Figure.

-3 J

2.3 IUustration of raw data (rough curve) final with a sinusoid (smooth curve).

Gain can be calculated fiom the sinusoids of head and eye velocities. To calculate

the gain for one direction of eye movement, every other halfof a cycle of the eye velocity

curve was chosen and fiipped into the other direction to replace the original curve there

(Figure 2.4). Average gain was calculated for each fiequency. The whole process was

repeated similady for the opposite direction. Phase was calculated fiom the time

difference between the head and eye position curves.

Figure. 2.4 Haif cycle sinusoids (thick line) were copied and flippeci to represent the next haif cycle (thin h e ) for calculating gain on each direction of aVOR

2.4.2.2 Spectrai analysis method

Gain and phase were also calculated Grom head and eye velocity power spectra.

Head and eye velocity power spectra were calculated dong with the cross spectnun using

Fast Fourier Transfonn (FFT). To use this method, the original head and eye data went

through several steps, which included 1) trend removd, 2) digital filtering, and 3)

cdculation of power spectra.

2.4.2.2.1 Trend removai

Trends were removed by a cornputer program. A trend in the data was defined as

any frequency component whose period is longer than the record Iength. Trend was

detected as a drift of the data towards a direction as illustrated in figure 2.SA. M e r the

trend removal, the data would be transfomed as in figure 2.5B.

Figute 2.5 Ulustration of trend removal. (A) A sample of data with a trend. (B) Tàe data with trend removed. (C) The dope and the equation estimated to represent the trend.

In our experimental paradigm, trends were mody found in the recording of eye

position in the the domain. Ifa person bas a lower gain in one direction, the eye

movement camot compensate fully h m the head movement in that direction. Hence, the

eye will drift towards the same direction as the side with vestibuiar lesion over îime.

Though the m v a l of trend would wipe out the gain asymmetry in the data, it was

necessary to do so in calculating the gain and phase by the spectral analysis method.

Othezwise, the trend would mistakenly be calculated as a low frequency component in the

power spectnim of the data and would give an incorrect calculation of gain and phase.

A cornputer program was used to perform trend removal. The digitized data was

repmented as XI where I = A, A+l.. .B for some arbitrary A and B with the constra.int

that the number of data points equals N = B - A + 1. Then the data were fitted with a

polynomial f (1. b) where the fiinction f (1, b) is a polynomial of order 3 aad b was

detennined by using p h a l derivatives and matrix equation using Gauss-Jordan

elimination. An example off (1, b) is represented by a simplified equation Û(t) = bo+bi t

as in figure 2.5C. The data after trend rernoval were represented as YI= XI - f (1. b) as in

figure 2.93.

2.4.2.2.2 Digital filtering

As our interest was in the Iow kquency sinusoida1 rotation, a low-pass filter

could remove the unnecessary high fiequency noise. An 8' order Butterworth filter was

used which acted as a low-pass filter for the data. 8" order was chosen because it gave a

sharp roll-off in the stop band, so as to remove the high Spsuency components nearly

completely. A coma fkquency of 12 Hz was used. The filter had zero-phase shift

characteristics and would not result in phase distortions of the data d u h g filtering. An

example of the Butterwortb filter was show as in figure 2.6.

Figure. 2.6 The Butterworth filter was used as a low pass filter

2.4.2.2.3 Power spectral analysis

Gain and phase were calcuiated from the head aml eye veiocity using power

specûa analysis. First of dl , the head and eye velocity data sequmces were tnmcated so

that each sequence has N = 2 data values. Then the redting sequences were tapered by

using a 20 % split- cosine taper whdow to d u c e leakage in the power spectral density

fùnction. The Fourier transfomis were applied to the head and eye velocity data and were

named as Xk and YI respectively.

The power spectnun is defined as

Where Xk is the Fourier transfomi of the head velocity, N is the nurnber of data points

and H is the interval between decimated data points. The data was decimated by taking

every tenth data point and the data points in between were discarded.

The cross spectnun is defiaed as

where Xi ' is the cornplex conjugate of Xi and Yi is the Fourier transfomi of the eye

velocity data.

Gain and phase values were then calculated with:

2.4.3 Statistics

A two-sample T-test was used to detemine whether there were differences

between the means of the far target and near target groups in gain and phase at each

fiequency. By having a null hypothesis that there was no difference between the two

means and an alternative hypothesis that one mean was bigger than the other, a two-

sample T- test was computed by the following formula:

where x was the mean of a group, s was the standard deviation and n was the size of the

group. The degree of freedom was n - 1 where n was the size of the smailer group. The

value of t gave a correspondhg P-value at a particular degree of fieedom. The smaller the

P-value, the stronger the evidence against the nul1 hypothesis. Thenfore, a small P-value

meant that the alternative hypothesis was significant (Le. one group mean is significantly

bigger than the other). It was regarded to be significant when Pc0.05

2.5 Data analysis for head impulse test

Eye and head signais were coilected the same way as the whole body rotation test.

Peak eye and peak head velocities were recorded for each head impulse. It took around

70 to 130 ms aer the onset of head movement for head velocity to reach the peak value.

Peak eye velocity that was generated more than 15 ms &a the peak head velocity was

discarded as the latency of VOR ha9 been found to be mund 7 to 10 ms (Crane and

Demer 1998; Aw et al. 1996). Saccades and blinks sometimes appeared with a Iatency of

around 100 to 150 ms after the onset of head movement. Such eye movements were

identified and discarded.

2.6 Modeiing of Data

The aVOR system was viewed as a control system for eye movements. By using

control system analysis, responses of the aVOR system were approximated and responses

with different input stimuli were predicted. Also, the dynamics of the system could be

identified and estimated. In applying control system anaiysis to the aVOR, the head

movement signal was regarded as the input and the eye movement signal was regarded as

the output. The central pathway between the input and output was described by transfer

hctions. A transfer fùnction is a mathematical h c t i o n that can be defined as the output

divided by the input. Laplacian notation in terms of 's' was used to simplify the

differential equations in the transfer fùnction into algebraic ones. Short prograrns were

written in MATLAB to show the effect of different transfer huictions on the gain and

phase responses.

3 RESULTS

3.1 Part 1: The effeet of target distance on the VOR

3.1.1 Sample recording of far and near target VOR

Examples of eye and head movements at two different hquencies are illustrated

in figure 3.1. Frequencies of O.25Hz and 7Hz wen chosen for cornparison. The

amplitudes for head movement between the far and near target are similar for each of the

two fiequencies. At 0.25Hz, the amplitude of the peak to peak eye movement for a far

target was similar to the one for head movement resulting in a gain that is close to 1 .O.

For a near target at 0.25Hz, the amplitude of the peak to peak eye movement was greater

than the amplitude of the head movement resulting in a gain that was greater than 1 .O. For

the 7Hz data, eye movement amplitude for near and f i targets were similar and both

curves had smaller amplitudes thim the one for head movement, resulting in gains below

1 .O.

3.1.2 Bode plot of the far and near target VOR

Raw gain and raw phase data for the far and near target h m ail the subjects are

plotted in figure 3.2 and 3.3. The mean gain values for near and far targets at various

fkquencies are depicted in figure 3.4a As can be seea, the gain of the VOR while

viewing a near target was significantly (pçO.05) greater than that for a far target at

@uencies h m 0.25Hz to 3Hz. The gain for far and near target decreased as fiequency

increased. Then, both cuwes merged at about 6Hz and contîuued to decrease together up

to 1oHz.

The mean phase values for fat and near targets at various fiequencies are plotted

in figure 3.4b. Both curves show a general declining trend h m O to -20 degrees as

Figure 3.1 Examples of eye and hcad movements at representative fkequencies of 0.25Hz and 7Hz. Note the eye movement amplitudes for near target are bigger than the far target ones at 0.25Hz. But both amplitudes m sunilar at THz.

2 4 6 8 10

Freqency (Hz)

O 2 4 6 8 10

Frequency (Hz)

Figure 3.2 Raw gain data h m 8 normal subjects (S) for far and near target.

1 Far Target I

4 6

Frequency (Hz)

Near Target

0 2 4 6 8 10

Frequency (Hz)

Figure 3.3 Raw phase data for 8 normal subjects (S).

+ Near Target - Far Target 1 1 1 1

O 1 2 3 4 5 6 7 8 9 10 Frequency (Hz)

O 1 2 3 4 5 6 7 8 9 1 O

Frequency (Hz)

Figure 3.4a,b: Mean gain and phase values detived h m 8 normal subjects (+/- SEM). *: Gain of near target at nCquencies that are sigpificantly w . 0 5 ) larger than far target ones. #: Phase of near target at fiequemies that significantiy wO.05) lag far target ones.

frequency increases. This phenornenon is due to the dynamics and the delay of the VOR

pathway and the change of the target distances. From 3Hz to 5Hz, the near target data

lagged the far target data significantly (p4.05). The maximum phase difference between

the two curves was about 8 degrees. Above SHz, the difference in phase between the far

and near target c w e s was not significant.

3.1.3 The Mode! of VOR

Figure 3.5a depicts a mode1 proposed to account for the data for near and far

targets. We suggest the results can be explained by two parallel pathways with different

dynamics, one is modified and the other isn't. These two pathways may correspond to the

FTN and the PVP units proposed in another experiment (Lisberger et al. 1994a). The

summated result is then sent to the plant. In this study, attention was focused on the

modified pathway because it is the pathway that can significantly modify the gain of

VOR (Lisberger et al. 1994a). A variety of different tmsfer fimctions for the modified

pathway were tried. The best fit was obtained ushg 2 poles. Higher order fits yielded no

improvernent. The transfer fûnction with 2 poles and a tune delay was estimatexi for the

modified pathway as follows:

0.4 0.6 0.8 1 2 4 6 1 1 0

Frequency (Hz)

a

0.4 0.6 0.8 1 2 4 6 8 1 0

Frequency (Hz)

Figure 3.5: A mode1 (A) of VOR with pathways of modified and unmodified units. The correspondhg Bode plots (B, C) of the modined pathway with K = 0,4 and 6 were illustrated.

Input

Modified Pathway

Unmodified Pathway ) Output

C*

where TI = 0.0379, r 2 = 0.02s and At = 0.005s. K is the vergence factor that is inversely

proportional to the target distance and the additionai delay of the modified pathway

relative to the unmodifieci pathway is represented by the tem edD in the equation. The

transfer function of the VOR system is modeled as

at s U+H) e 2

(2)

where t2 = 0.008s is the delay of the system. The conespondhg Bode plots of the gain

and phase of the system with K= 4 (a target of 25 cm), K = 6 (a target of 16.7 cm) and

K= O (a target at infinity) are shown in figure 3 Sb. As we an interested in studying the

sole effect of the recnlitment of modified units, the effect of target distance change can be

easily seen as a result of the additional modified pathway when unmodified one was

assumed to be unity. Thus, gain stayed at one for a far target throughout al1 the

6equencies. However, gain increased with target distance at low fiequencies, but it

merged with the far target one at high fiequencies. Phase lag increased with target

distance and the difference of phase lag for various target distances is more apparent

between 2 and 6 Hz.

3.2 Part II: The effect of uniiateral lesions on the VOR

3.2.1 Caloric test results

Among 20 subjects that underwent the calorie test, 8 were nomai, 2 had a partial

ieft loss, 3 had a total left loss, 5 had a partial right loss and 2 had a total right loss.

3.2.2 Head impulse test results

3.2.2.1 Raw results

Samples of head and eye movement of the head impulse test are show for a

subject (non-patient) with a nomial calonc response (figure 3.6). Figure 3.6a depicts the

eye and head position for two consecutive head impulses. Positive and negative y-axes

correspond to the rightward and lehard head impulses, respectively. Direction of eye

position and velocity ûacings was inverted for better presentation. The eye movements

were able to follow the head movement as illustrated in figure 3.6a,b.

Figure 3.7a shows an example of head impulse response of a patient with a 100%

right calonc loss. The eye movements were not able to follow the head movements. Eye

movement amplitudes were smaller than the head movement amplitudes, especially for

rotation towards the right.

- Head I - Eye

Figure 3.6a,b: Samples of typical raw position and the corresponding velocity data of the head and eye movement for two head impulses perfomed on a subject with normal caioric response. Eye position and velocity curves are mverted.

Figure 3.7a,b: Samples of raw position and the corresponding velocity data of two head impulses pdormed on a subject with no calorie response on the right side. The peaks in the eye velocity after the first one in msponse to each head impulse are caused by saccades.

Saccadic eye movements (indicated in figure 3.7a,b) were grnerateci to catch up with the

head movement. The corresponding velocity profile in figure 3.7b shows that eye

velocity had lower amplihide than the head velocity for the head impulses to both sides,

especially towards the right.

3.2.23 Eye and head velocity for various vestibular loss

Typical eye and head velocities for subjects with caloric responses that were

normal (# 182), left d o n c loss (# 175) and xight caloric loss (#183) are plotted in figure

3.8a,b,c respectively. Each dot on the plots reprcsents the response to a single head

impulse. Dots falling on the diagonal of the figure corresponded to a response where the

eye velocity and the head velocity were equal. Positive and negative x-axes represent

right and left head movements respectively. Separate lines of linear regression passing

through the center of the graphs were drawn for rrsponses to left and nght head

movements. The slopes of the regression lines were calculated. For a subject with no

caioric loss (figure 3.8a). the lefi and right eye responses were symmetrical and had

dopes close to one for both directions of head movement. For a patient with an 85%

caloric loss (figure 3.8b), the slope for lehard head movement was distinctively smaller

than normal. Similarly, with a 100% right caloric loss (figure 3.8~). the slope for right

head movements was reduced. The 1eA and right regression siopes for ail patients are

shown in tabIe 1.

Eye movements could not keep up with head movements at high head velocity

(>IO0 degreedsec) for movements towards the lesioned side, and resulted in saturation of

eye velocity with increasing head velocity. Eye movements could fully compensate for

the head movements at Iower velocities nom the few head impulses with velocity of

below 100 degreedsec. Normal subjects' (non-patient group) eye movements could fully

compensate the head movements up to around 400 degreedsec. Asymmetry between the

left and right response for the patients started to appear at head velocities in the range of

100 to 200 degreedsec.

The value for the percentage of head impulse asymmeûy was calculated by the

equation: 100 * (contralesional slope - ipsilesional slope) 1 (contralesionai slope +

ipsilesional slope), where 'slope' was the dope of the regression line and the side of

lesion is defined by calorie unilateral weakness. For the seven normal subjects (subjects'

age and sex did not match to patients) that undement the head impulse test, the head

impulse asymmetries were less than 5% for fat and near target paradigms. 5 out of 19

patients (# 171,178,182. 190 and 19 1) underwent head impulse test had less than 5%

asymmetry and thus were considered to have normal head impulse responses.

-600 -400 -2 0 0 O 200 400 600 Head Velocfty (degls)

-6 O 0 -400 -2 0 O O 200 400 600 H e a d Velocity (deg l s )

6 0 0 -400 -200 O 2 0 0 4 0 0 6 0 0

Head Velocity (degis)

Figure 3 . 8 3 , ~ : The velocities of head and eye for head impulse tests on patiemts with caloric responses that was (a) normal, (b) 85% left loss, (c) 100% right loss. Positive and negative head velocities represent nghtward and lehard head impulses. Each dot represents one head impulse. Linear regression h e s and their slopes were calculated for head impulses on each side.

3.2.2.3 Eye and head velocity for far and near target

A typical example (Patient # 172) of the effect of target distance on the head

impulse test is shown in figure 3.9. Eye velocities when viewing a near target (figure

3.9b) were higher than far target oaes (figure 3.9a) for rotations to both sides. This was

hue for al1 patients (14 in total) except two (Patient #: 177, 183). The near target

paradigm revealed a larger difference for the slopes of the eye and head velocity plot

between the ipsilesioaai and contraiesional side in 7 out of al1 14 patients when compared

with far target paradigm. Besides, both far and near target paradigrns indicated the same

side of lesion in 13 out of 14 patients, except for Patient 171. The side of lesion indicated

by the far target paradigm is opposite to the one indicated by the near target paradigm for

Patient 1 7 1 .

-600 -400 -200 O 200 400 600

Head Velocity (degls)

400 --

zoo ----

-200 --

-600 -400 -20 O O 200 400 600

Head Velocity (degls )

Figure 3.9a,b: An example of the eye and head velocities of the head impulse tests on a patient with 100% Iefi loss with a far target (a) and a near target (b).

3.23 Whole body rotation test results

3.2.3.1 Raw results

Samples of head and eye movements fiom the sinusoidal rotation test in the light

for a normal subject (non-patient) and a patient (# 172) with 100% lefi vestibular loss are

shown in figure 3.1 1. At 1 Hz, the eye movement for the normal subject and the patient

reached the same amplitude as the head movement on both sides of rotation (figure

3.10a). At 3 Hz, the eye movement for the patient had a smaller amplitude than the

normal subject during rotation to both sides. However, the Ieft and nght difference in the

amplitudes of eye movement for the patient is not obvious (figure 3.1 Ob).

- Head - Patient Eye - Normal Eye

Figure 3.10a,b: Samples of head and eye movements at (a) 1 and @) 3 Hz in the whole body rotation test in the light for two subjects. The thinnest line and the line with intemediate thickness are the eye responses of subjects with calonc responses that were normal and 100% Ieft loss respectively. Positive values hdicate right head tum.

3.2.3.2 Ipsilesioaai and contralesionaï gala

The mean ipsilesional and contralesional gain values of the whole body rotation

test in the üght for various levels of caloric loss in the vestibular system are depicted in

figure 3.1 1. Patients were divided into two groups accordhg to caloric testing: normal

(<15%) and abnormal (>15%) caloric unilaterai weakness. Data that were very noisy or

with very srnaII head ampiitudes were discarded. The ipsilesional and contralesional sides

are detemined by the results fiom calonc unilateral weakness. No difference was

observed between the left and right gain for 7 patients with normal calonc results. (Figure

3.1 la) For 1 1 patients with abnormal caloric results, ipsilesional gain was significantly

(pcO.05) smailer than contralesional gain at 3 and S Hz (Figure 3.1 1 b). Both ipsilesional

and contraiesional gains at fiequencies above 7 Hz in the cdoric abnomal group were

not significantly different fiom the ones at same fiequencies in the d o n c nomal group.

Gain asymmetry for 6 patients only with large (BU%) milateral wealoiess (figure 3.13a)

showed similar pattern as the one when patients with partial caloric loss (between 15% to

85%) were included (figure 3.1 1 b).

The above experiments were repeated in darkness and the resuits are plotted in

figure 3.12. niete was no ciifference between the left and right gain at al1 fiequencies for

7 patients with normal caloric unilateral weakness (figure 3.12a). For 10 patients with

abnormal unilateral weakness, the ipsilesional gain was signincantly (pe0.05) smaller

than contralesional gain at 0.5,3 and 5 Hz (figure 3.12b). Gain asymmetry for 5 patients

oniy with large (>85%) datera1 weakness showd similar pattern except that the

ipsilesional gain became sign.ificantiy smaiier than conttalesional gain at 1 Hz (figure

3.13b). Note that bath the ipsilesional and contraiesional gains in the light at below 2 Hz

were higher than those found in the dark. For patients with a unilateral calonc weakness,

the difference between the ipsilesional and contraiesional gain in the dark was larger than

those found in the light at the lower fiequencies.

Asymmetry in ipsilesional and contraiesional gain (directional preponderance):

100 * (contralesional gain - ipsilesionai gain) / (contralesional gain + ipsilesional gain)

was found for each patient at each fiequency of the whole body rotation test. The side of

lesion is deterrnined by results fiom the caloric test. For each patient, averages and

standard deviations of the gain asymrnetry for d l the cycles in each kequency were

caiculated €rom the averages and standard deviations of the contraiesional and

ipsilesionai gain of each hquency. The formula for calcularing the standard deviation of

gain asymmetry is shown in the appendix. Also, pooled averages and standard deviations

of the gain asymmetry at each frequency were calculated fiom 7 nomal subjects. 9 out of

20 patients had at least one directional preponderance value at a particular frequency that

was significantly different (pcO.05) fiom the mean value at that fiequency in the normal

p u p . These patients were considered to have abnormal asymmetry in whole body

rotation test.

3.23.3 Phase

Cornparisons were made for the phase average of whole body rotation test

between patients with cdoric responses that were normal and with total da t e r a l loss

(Figure 3.14). There was no sigaificant diffemce for the phases in the dark and in the

light.

Frequency (Hz)

1.1 - I 1 l I

With normal caloric

Frequency (Hz)

+ Left Gain

0.5 -- - Right Gain

Figure 3.1 la&: The average directional gain at various frequencies of whole body rotation test in the Iight for groups of patients with (a) normal caioric unilateral weakness and (b) abnomial donc unilaterai weakness. *: Ipdesional gain that is signincantly (p4.05) d e r than conîraiesional gain.

I

0.4 1 I

1 3 5 7 9 11

5 7 9 Frequency (Hz)

1.1 I I 1 1

With abnormal caloric (Dark)

C .I -

0.5 -- - lpsilesional Gain + Contralesional Gain

1 3 5 7 9 11 Frequency (Hz)

Figure 3.124b: The average directionai gain at various fiequencies of whole body rotation test in the dark for gcoups of patients with (a) normal caloric unilateral weaknesses and (b) abnormal unilateral weaknesses. *: Ipdesionai gain that is signincantiy @<O.OS) smaller than contralesional grUn.

r 1 1

Large Caloric Loss (Light)

-, - lpsilesional Gain + Contralesional Gain

L I 1

Frequency (Hz)

Frequency (Hz)

Figure 3.13a,b: The average directionai gain at various 6nquencies of whole body rotation test for 5 patients with more than 85% of caloric unilateral weakness: (a) In the Iight and (b) m the dah. *: Ipdesioaal gain that is significantly @Q).05) smaller than contralesional gain.

Dark

,, + Total caloric unilateral weakness .. Normal caloric response

I t I l 1 1 I

1 3 5 7 9 11 Frequency (Hz)

I I Light

Total caloric unilateral weakness + Normal caloric response

3 5 7 9 Frequency (Hz)

Figure 3.14a,b: Cornparison of phases of the whole body rotation test between patients with Iess than 15% (normal) and 100% cdoric unilaterd wdmesses (a) in the dark and (b) in the üght.

3.2.4 Comparison betweeo cdoric and head impulse test

The correlation between the asymmetry for the caMc and head impulse test for

al1 patients is shown in figure 3.15. Each dot on the graph represents one patient. The

absolute value of the caloric unilateral weakness percentage is represented on x-axis. The

head impulse asymrnetry is represented on y-axis and is calculated by the same equation

as used in section 3.2.2.2. By using linear regression with lines that must pass through the

ongin, the correlation coefficients for the far and near target head impulse test with

caloric test art 0.60 and 0.77 respectively. Points with positive coordinates are the nsults

with both caloric and head impulse test detected a lesion on the same side of the head.

The near target paradigm had a better correlation with caloxic test than the far target

paradigm.

However, there were exceptions when the caloric result did not correlate with the

head impulse test. Some of the patients (Patient #: 171, 176, 182, 188 and 191) with less

than a 25% caloric loss exhibited contraclictory results. The sides with unilateral caloric

weakness in those patients were opposite to the sides detected by either near or far target

head impulse tests. In comparing the size of asymmetry, five (Patient #: 165, 170,176,

18 1 and 184) out of eight patients that were detennhed normal in caionc test (less than

15% of caloric los) wem considered to be abnormal (more than 5% left and right

asymmetry) in either the fat or near target head impulse test.

For patients (#: 163,172,174,183) with no caloric response on one side (1 00%

loss), gain (regression dope) for the defective sides in the far target paradigm were 0.34,

0.68,O.W and 0.5 with eye velocities saturated at 100,300,40 and 200 degrees/sec

respectively.

t I I

Far Target w

a a

a m R = 0.60

0

O SV 20 40 60 80 1 O0 15%

Caloric Unilateral Weakness %

I 1

Near Target

I w

Caloric Unilateral Weakness %

Figure 3.15a,b: Correlation between the head impulse test and the caloric test Each dot represents a patient. Head impulses were separatecl into far target (a) and near target (b) and regression iines and correlation coefficients (R) were caiculated for them with calorie results.

3.2.5 Comparison between caloric test rad wbok body rotation test

Cornparisons between the asymmeûy between ipsilesional and contralesional

sides measwed by caloric test and whole body rotation test in the light and in the dark

were made for patients with abnormal (>1S% d a t e r a l weakness) caloric nsponses

(Figure 3.16). Examples of the correlation of the 0.5 Hz and 3 Hz of whole body rotation

test with caloric test are show in figure 3.1 6a,b. Absolute values of the caionc unilateral

weakness p-tage is represented on x-axis. Whole body rotation asymmetry is

represented on the y-axis by the equation: 100 * (contralesional gain - ipsilesional gain) I

(contralesional gain + ipsilesional gain) where contraiesional ancl ipsilesional sides are

the ones determined by the calonc unilateral weakness. Points with positive coordinates

indicated that the results fiom both tests detected a lesion on the same side. Results fiom

each fiequency of the whole body rotation test in the light and in the dark were comlated

with the caloric results and comlation coefficients (R) were caicuiated (figure 3. Mc). In

the light, 3 Hz, 5 Hz and 1 1 Hz data had large positive R. In the dark, data at 0.5,1,3 and

5 Hz showed a large positive R.

Out of the five patients with no caloric response on one side, the gain of the

defective sides at 5 Hz in the dark were 0.68,0.49,0.43,0.73 and 0.17 (light only). These

values were smaller than the average gain (0.75) at 5 Hz for the patients with nomai

caionc resuits. Out of 6 patients with n o d caloric Tespotme, 2 patients (#: 165,184)

bad abnomial asymmetry in the whole body rotation test in the light Out of 12 with

abnonnal caloric response, 6 of them had abnormal asymmetry in the whole body

rotation test in the light.

Caloric Unilateral Weakness %

Caloric Unilateral Weakness %

30

Figure 3.16a,b: Correlation between calorie test and whole body rotation test. Examples of correlation between the dateral weakness of caloric test and gain asymmetry of the whole body rotation test at fkquencies: (a) O.5Hz and @) 3Hk for patients with abnonnal (>15%) caloric unilateral weakness. The result of each patient is repesented by a dot.

2 25 C1

g 20 15

a 10 8 s .œ

-- 3 Hz-Light 1 a i -----

0

c.

3 O O a -5 r, = -10 O

-15 a3 9

O -20 f -25

-30 O 20 40 60 80 100

-

*

I k

Correlation: Abnormal Caloric vs Whole Body Rotation

Freauencv IHzI

0.6

0.4 -

0.2 -

0.0 -

Figure 3.16~. The correspondhg correlation coefncients were caiculated for caioric test and whole body rotation test at each fkquency in the light and in the dark for patients with abnomial caloric response.

-0.2 - ,

I 1 Dark 1 œ Light ,

3.2.6 Cornparison between head impulse test and the whole body rotation test

Typical results of the peak eye and head velocities in the head impulse test and in

every cycle of the whole body rotation test h m a patient with a complete lefi caloric loss

are plotted in figure 3.17. The velocities of the head stimulus in the whole body rotation

test had much smaller amplitudes than in the head impulse test. Consequently, saturation

of the eye velocities on the lef? side was more obvious in the head impulse test than in the

whole body rotation test.

Correlation coefficients (R) were calculated for the correlation between the

asymmetry in the results of the head impulse test and that of whole body rotation test for

patients with more than 15% caloric unilateral weakness (figure 3.18). The results nom

far and near target paradips of the head impulse test and nom each fiequency of the

whole body rotation test were conelated separately. The asymnietries in both tests were

calculated by the same methods mentioned in the previous sections. In the iight (figure

3.1 8a), data at 3 Hz and 5 Hz had large positive R. In the dark (figure 3.18b), R increased

at most of the fiequemies when compared with the ones in the light.

ûut ofthe 11 (Patient #: 168,169,170,171,172,175,181,182,188,190,191)

patients with normal asymmetry results in the whole body rotation test in thc light, 6

(Patient #: 168,170,172,175,181,190) of them were considered abnomai in the head

impulse test. Out of the two patients (#: 177, 184) with abnormal asymmetry resuits in

whole body rotation test in the Iight, neither of them were considered normal in the head

impulse test.

-200 -1 50 -1 O0 -50 O 50 1 O0 150 200

Head Velocity (degis)

-800 -600 -400 -200 O 200 400 600 800

Head Velocitv (derils)

Figure 3.17. Cornparison of the magnitude of velocities between the whole body rotation test and the head impulse test for the same subject with 85% lefi vesti'bular loss. Regression ünes and thek slopes were calcuiated for rotation on each side.

Correlation: Head impulse vs Whole Body Rotation (Light)

0.8 PS w - 0 . 6 - r 0, .- 0 0.4 E 0, 0.2 O

0.0 C O .i; -0.2 m - p) -0.4 L O 0 -0.6 -- œ Far Target

Near Tatget ,

Frequency (Hz)

Correlation: Head Impulse vs Whole Body Rotation (Dark) 1 .O I

-

O 0 -0.2 -4 L

Far Target Near Target

Frequency (Hz)

Figure 3.18a,b: Correlation between head impulse test and whole body rotation test for patients with abnormal calonc response. Comlation coefficients were calcuiated between far and near target paradigrn of the head impulse test and each Spsuency of whole body rotation test: (a) in the light and (b) in the dark

4 DISCUSSION

4.1 The effect of target distance on the aVOR

In this study, we set out to model the neural mechanism that is responsible for the

modification of the VOR gain and phase between near and far targets. As seen in figure

3.4a there is a significantly (p4.05) higher gain at fiequedes fiom 0.25 to 3 Hz for the

near target than for the far target. As the axes of rotation of the eyes are located in front

of the axis of rotation of the head, VOR hm to operate with a gain above 1 in order to

have stable fixation of targets lying near the head (Vürre et al. 1986, Hine and Thom

1987).

However, instead of having two parallel curves for near and far target, the curves

merged together at a frequency around 6Hz This is sirnilar to the nsults in another

experiment on monkeys where the difference of gain between the near and far target

disappeared at around 4Hz (Chen-Huang and McCrea, 1999). To explain this behavior, a

mode1 of parallel VOR pathways was proposed having a low pass filter in the modifiable

pathway (Figure 3%). The model is able to generate results that rnimic the actual VOR

gain and phases data for the near target distance of 25 cm.

The clramatic decrease in the gain c w e for the near target paradigm (K = 4 and 6)

relative to the far target paradigm (K = O) at high fhquencies couid be postulateci by the

poor paformance of the modifieci pathway at high fkquencies. Low p a s behavior has

been shown h m the asymmetricai response of eye movements in cats with unilateral

vestiiar lesions (Broussard and Bhatia 1996). Thus the modifieci pathway is proposed

to bebve as low pass nItas and has been modeled as Equation 1. The contriiution of the

modified pathway to the VOR decreases as the fiequency of head oscillation increases.

Thus, the gains of the model for the 16.7 cm (K = 6) and 25 cm targets (K = 4) gdually

decrease to one as âequency increases (Figure 3 3 ) . As seen in figure 3.4a, the

unmodified pathway becomes the dominant pathway for driving the VOR for both far

and near targets at high fhquencies. Accordhg to the gain c w e s of the model (figure

3 3 9 , the unmodified pathway dominates in ngulating the gain for the far target (K = O),

while the modified units form an additional group responsible for the gain changes for the

near targets (K = 4 and 6) at low frrquencies.

The vergence factor, K in the transfer hction, is a f'unction of target distance.

The iarger the value of K, the shorter the target distance. The mode1 predicts that the

increase of the value of K will increase the gain at the low frequencies, as shown in figure

3.5b. However, it has no effect on gain at hi& fiequencies.

nie phase lag of the system for a far target (M) is due to the delay of 8ms of the

system. Our experimental data for the 25cm target showed that there was a phase

difference of 8 degrees between the near and far target at around 5Hz (Figure 3.4b). This

is similar to another experiment on moakeys where the difference of phase between far

and near targets increased h m 0.7 to 4 Hz (Chen-Huang and McCrea, 1999). This phase

behavior was modeled by our particular choice of the transfer fhction of the modified

pathway and the use of K = 4. By using a low pass nIta (Equation 1) for the modified

pathway, this phase lag can be seen to increase, as target distance decreases (Figure 3.5b).

As the Iow pas behavior of the modined pathway c o n t n i s to the phase lag in the

system, an increase in the value of K (a decrease in target distance) will increase the

weight of the modifieâ pathway and the phase lag of the system. Thus, phase lag

increases when target distance decreases.

We suggested that FTN or EHV cells might form the modified pathway, while

PVP might be the unmodified pathway. Evidence that the EH' and PVP pathway have

frequency response differences sunilar to our mode1 were found (Chen-Huang and

McCrea, 1999). For instance, the sensitivity of EHV uni& to head rotation for a near

target increased h m 2.5 to 2.8 spikedseddeglsec but remained at 1.9 spikes/sec/deglsec

for the sensitivity of PVP as tiequency increased fkom 0.7 to 1.9 Hz. Our results yield

additional evidence that FTN and PVP have different dynamics. Electrode recording of

these secondary neurons at different target distances c m provide M e r confirmation to

our results.

As the above experiment was performed in the light, the pmuit system affecteci

the rneasured response up to around 2Hz. At frequencies below 2 Hz, the VOR system

alone is ineffective which results in a lower gain and a small phase lead. The pursuit

system cornpensates for the retinal slip to give a larger gain and a phase of zero. On the

other han& there was still a gain diffixence in the VOR when abjects were told to fixate C

imaginary targets at different distances in the dark (Hine and Thorn, 1987). ~h&esult

*5%45b -CRO. ththergence signal h m the oculomotor system can be used to modify VOR

gain.

While OUI hypothesis for the target distance-related change in the aVOR mainly

focused in the changes of secondary neurons. others have suggested that target distance

changes in aVOR may nsults h m other parts of the VOR pathway. Irregular vestibular

afferents were found to have target distance-related changes. One experiment attempted

to study the effect of imgular vestibular afferents to target distance-related changes in

aVOR (Chen-Huang and McCrea, 1998). Mer, galvanic currents were used to reversiibly

silence irreguiar Serents, the viewing distance-related changes in aVOR was reduced by

64%. It was suggested that the eye position signal provided the input for the target

distance nlated changes in the irregular Berents. One mode1 of a target distance-related

VOR pathway (as shown in 1.3.2.2) suggested that irregular afferent sent target distance-

related signal to the secondary neurons (Chen-Huang and McCrea, 1999). In addition, a

neural integrator was suggested to relay the target distance-related afferent signal back to

the secondary neurons.

4.2 The effet of uniiriteral lesions on the aVOR

4.2.1 Caloric results

The caioric test was used in this experiment as a standard to show the degree of

v e s t i a r lesions in our subjects. Our resuits in calonc testing should be as diable as

other conventionai caloric tests. We used an open-loop irrigator (for introducing the fluid

into em) which was stated to be more reiiable dian a closed loop irrigator (Hhagyi et

al. 1997). Less than 15% unilaterai wealmess was used in our experiment to define the

normal group, which was smaller than that used in other experiments (Bergenius et al.

1988; Halmagyi et al. 1997). Our use of lws than 15% unilateral wealmess for definiag

the normal group should be reliable since 25% unilateral weakness had to be present to

confidently identify a significant asymmetry (Henry 1999).

4.2.2 Head impulsive results

Head impulse stimuli were detivered with amplitudes of 20 to 30 degrees and

with head velocities between 100 to 500 degreeslsec. These amplitudes were in the higher

range when compared with similar experiments of the head impulse test with head

velocities amund 200 degreeslsec (Halmagyi et al. 1990; Cuahoys et al. 1995; Aw et al.

1996; Cremer et al. 1998). More deviation in the gain value for patients with similar

vestibular loss was found in our experiments when compared with others (Aw et al. 1996;

Cremer et al. 1998; Halrnagyi et al. 1990). For instance, our gain values for 100%

unilateral vestibular loss ranged h m 0.06 to 0.68 for the lesion side, while it was found

to be 0.2 to 0.3 in another experiment (Cremer et al. 1998). The main reason for the large

variation was that our way of determinhg the amount of vestitbuiar lesion was not as

accurate as the other experiments. For example, we defined 100% unilateral vestiiular

loss in patients by those who had 100% caioric unilateral weakness while the other

experîment used patients with surgical unilaterai vestibular deafferentation. As the caloric

test is not a very accurate test, a 1ûû% caloric loss may not correspond to a complete

unilateral loss. We also used a Mixent method to calculate gain. ûther experiments

determineci gain at certain head amplitude or tirne a f k head initiation, e.g. 80 ms (Aw et

ai. 1996; Halmagyi et al. 1990). We defhed gain by the bear regression dope of the

entire range of peak eye and head velocities. As saturation of eye velocity is not as

apparent at low head velocities as at high velocities (Halmagyi et al. 1990), regression

slopes at low velocities tended to have a higher value than at high velocities. Thus the

overail slope would be slightly higher than it should be. Furthemore, patients who wore

corrective spectacles can af5ect the VOR gain, resulting in lower gains for myopes and

higher gains for hyperopes (Cannon et al. 1985). Nonetheless. our results still reveaied a

clear ipsilesional and contraiesional gain asymmetry for the determination of the side of

lesion. 14 out of 19 patients had more than 5% difference in the slopes between the

ipsilesional and contraiesional side.

Saturation of the VOR for the rotation towards the ipsilesional side was found at

higher head velocity for our experiment than for other similar experiments. Though one

experiment on patients with complete unilatemi loss showed saturation at a head velocity

of 50 degreedsec or less for the lesioned side (Halmagyi et al. 1990), our results showed

that most of the eye movements fully compensated head movements of less than 100

degreedsec. One nason for the contradiction is that the other experirnent used patients

with complete unilaterai vestîibuiar lesion while our patients, even with 100% caloric

hilateral wealmcss, may have incomplete lesions. The remaining activity of the

ipsilesional vestibular system may help to give an eye movement to help compensate for

a mal1 head stimulus

Gain asymmeûy in our patients is partiy due to the inthsic behavior of the

vestibular afferent discharge rates (Baloh et al. 1995). Though the nsting discharge rate

of vestibdar afferents c m be increased linearly by stimuli in the preferred direction, it

can only be decreased to zero by stimuli in the opposite direction. This asymmetry of

discharge rate is naturaily concealed by the nomai bilateral interaction between the two

iabyrinths, but is revealeà when one labyrinth is nonfhctionai at high stimulus velocity.

Similar saturation for the secondary vestibular neumns can also result in gain asymmetry.

Moreover, gain aPymmetry was found to be velocity dependent and occurred at

around 100 to 200 degreedsec. Velocity dependent asymmetry was found in the past

where gain asymmetry increased with an increase in head velocity h m 50 to 300

degreedsec (Paige, 1989). Similarly, another experiment using sinusoidai rotation

showed that gain asymmetry in unilateral canal plugged monkeys increased as peak head

velocity increased from 20 to 100 degreedsec at 4 Hz and above (Lasker 1999).

The existence of asymmeûy in head impulse test can also be due to the behavior

of the commissural pathway. The commissural pathway is thought to contribute to the

recovery of gain asymmetry after unilateral lesions and behave as a low pass filter

(Broussard et al 1999a). As the responses of VOR intemeurons on the lesioned side

depend in part on the commissure, the commissure wiil LUnit the head impulse signal to

the VOR intemeuroas on the lesioned side as it is a high fkequency stimulus. Thus, gain

asymmetry arises in the head impulse test.

Eye velocity for a near target reached a higher amplitude than that of a far target

due to the geomeeic requirements for target fixation. The results showed that there is no

advantage in chmsing a neat target pai.adigm over the far target one for detecting

asymmetry and the lesioned side has no particular effect on gain increase. Besides, one

reaMn for the patient having contradictory sides of lesion predicted by near and far target

paradigms was that the asymmeûy was mal1 and the result cm be easily aEected by

saccades.

Though the head impulse test is a headsa-body rotation test, ceMcal

proprioceptor and stretch receptor inputs were minimal, as there is no compensatory eye

responses in the head impulse test for patients with bilaterai vestibular neurectornies

(Halmagyi et al. 1990).

in sumrnary, the fhdings indicate that there is a velocity-dependent asymmetry in

the horizontal VOR evoked by head impulse rotations in unilateral vestibular lesioned

patients.

4.23 Whole body rotation test results

Gains of the whofe body rotation test below 2Hz showed that ipsilesional and

contralesional gain ammfnetry was apparent for patients with unilaterd vestibular loss in

the dark. This is different h m results in other experhents. An experiment on cats with a

unilateral canai plug showed no gain asymmetry below 2 Hz (Broussard et al. 1999a).

This rnay due to the use of head stimulus with a low velocity of 10 degnedsec, compared

to our use of stimulus of a r o d 30 degrdsec, which may not be enough to induce gain

asyrnmetry. For instance, one experiment on a patient with d a t e r a l vestibular lesion

showed gain asymmetry at 0.8, 1.6 aud 2.4 Hz in the light and in the dark with head

velocity mund 100 degreedsec (Foster et al. 1997). However, there was no gain

asymmetry at 0.5 Hz even when head stimulus of 100 degreedsec was used in a sùnilar

experiment on monkeys with a unilateral plug (Lasker et al. 1999). Thus, another reason

For the absence of gain aPymmetcy in the other experiments is that the vestibular system

with a canal plug rnay have recovered by adaptation for the low fiequency stimulus. As

we did not know the exact location of lesions for the patients, gain asymmeûy may arise

from lesions of an unknown ongin.

Asyrnmetry below 2 Hz was present only in the dark but not in the light. This is

expected as visual fixation helps to reduce asymmetry in the light. Visual fixation is

fiinctionai only below 2 Hz (Saadat et ai. 1995).

For gains above 2 Hz, experiments performed in the light and in the dark had

similar results. Gain asymmetry was apparent h m 3 to 5 Hz and disappeared for higher

fkequencies in both paradigms. However, experiments performed on cats with a unilateral

loss showed that gain asymmetry was persi*stent h m 2 to 8 Hz (Broussard et al. 1999a).

Also, there was a gain asymmetry when unilateially plugged monkeys were rotated above

4Hz with a head velocity of 50 degreedsec (Lasker et al. 1999). Furthmore, significant

gain asymmetry was found h m 2 to 4Hz in patients with unilateral vestibdar

neurectomy performing active head rotation (Saito et ai. 1991). There are several

possiiilities for the loss of gai . asymmetry above 5Hz in our experiment. First, our

patients had various degrees of vestibular loss, whereas the diagnoses of the subjects in

other experiments included unilateral canal plug, labyrinthectomy and neurectomy.

Therefore, the lack of asymmetry in our data may be due to the maIl diffmnce in the

damage between the ipsilesional and contralesional sides. Second, as the amplitude of

oscillation became smdl at high bequencies, different kinds of noise may conceal the

gain asymmetry from the data at these fiequencies. At fkequencies around 8Hz, the chair

did not generate smooth sinusoidal rotation. Thus, it was hard to calculate a correct gain

and phase fkom those data.

There is no significant difference in the phase between the total loss and the

nomial group. This was similar to other experiments that also showed there was no

significant difference in phase between the nomal and the total loss groups within 0.5 to

8 Hz (Broussard et al. 1999a, Paige 1989; Hess et al. 1985). The phase lead at high

fkequencies from our result in the total unilateral loss group was not seen in another

experiment using patients with vestiibular neunctomy (Tabak et al. 1997b). This is likely

caused by errors in phase estimation at high fiequencies where the stimulus amplitude

was both mal1 and somewhat non-sinusoidal.

Finally, there are a few additional potential sources of emr. Although we think it

is unlikely, the bite bar may slip. There is no better way to work around the problem, as

pasting a coil on the forehead will be a worse alternative. It is possible to glue a coil to

the teeth, but this couid not be done on a mutine basis and slip would likely be

idiosyncratic. We have recorded fbm a subject with dentures and the r e d t was poor.

Besides, the head movement amplitude was very s m d at the highest frequencies. As a

result, the error in the rneasurements at high eequencies was larger than at low

fiequencies.

The result of whole body rotation test showed that vestibular asymmetry cm be

fiequency dependent. Further experiments with a fixeci velocity and patients with defined

lesions are needed to corifim this idea.

4.2.4 Comparison between caloric test and head impulse test

The goal of this part of the study is to find out whether the caloric test and head

impulse test are correlated and whether the head impulse test provides more information

than caloric test. Generally, head impulse test results were found to correlate with calork

results. However, five patients with less than 25% unilateral weakness had contradictory

r e d t s for the side of vestibular loss diagnosed by the caloric and the head impulse test.

One reason for the contradiction is due to unreliability of caloric results when less than

25% unilateral weahess was present (Henry 1999).

Of the eight patients with normal caloric responses, five of them were cousidered

as abnormal 0 5 % asymmetry between ipsilesional and contralesioual sides) by the far

target head impulse test A less than 5% asymmetry was chosen to d e h e as the nomal

head impulse result because al1 of the seven subjects in the nomai group have less than

5% head impulse asymmetry. Ammg the five patients with abnormal head impulse

nsuits, various clinical symptoms were found including Menim's disease, ben@

paroxysmal positional vertigo and head trauma. Al1 of them were suggested to have

peripheral vestiuiar lesions. So, head impulses seemed to be more sensitive tban d o n c

test in detecting asymmetry. However, others found that head impulse test was less

sensitive than caloric test in detecting abnonnality and was sensitive only with a large

vestibular lesion (Harvey et al. 1997; Beynon et al. 1998). The possible reason for the

contradiction is that they defined abnomaiity in head impulse test by the presence of

corrective saccade observed by the clinician, whereas we defined abnonnality by a

greater than nomal gain asymmetry. As mal1 corrective saccade would be hard to detect

by the human eye, a patient with a s m d lesion could be mistaken as normal using this

criterion,

On the O ther hand, different results fiom the two tests may be resulted h m

different aspects of the horizontal semicircular canal fiinction stimulated by the two tests.

The calocic measures the low frequency canai hction, whereas head impulse test

measures the high ffequency hction (Halmagyi et al. 1990).

4.2.5 Cornparbon between caloric test and whole body rotation test

In this part of the study, we set out to compare whole body rotation test and

caloric test. The goal was to see whether the two tests are correlatecl and which test would

provide more information for diagnosing vestibular lesions.

From the correlation of agymmetry found between the two tests (figure 3.1 5 c),

large positive correlation was prcsent for whole body rotation at 0.5 and 1 Hz in the dark

while no correlation was present at those fiequencies in the iight. This is expected as

smooth pumit bctions to reduce the asymmetry of the VOR and it is effective ody

below 2 Hz (Saadat et al. 1995). Thus. gain asymmetry was reduced at 0.5 and 1 Hz in

the Light. There is a strong correlation between caloric test and whole body rotation test

below 5 Hz in the dark, small correlation was found for 7 and 9 Hz, and moderate

correlation for 1 1 Hz. The mal1 correlation at 7 and 9 Hz was due to the noise created at

amund 8Hz. Amuod this fiequency, the data did not look sinusoidal and it could

obliterate the gain and phase calculation. AISO. as calonc test measures the low

fiequency behavior of the canai (Halmagyi et al. 1997). the poor correlation for rotation

at high fkequencies may due to the difXerence in stimulus for the two tests.

Severai experiments on correlation between caloric test and whole body rotation

tests have been performed in the past (Baloh et al. 1984, 1988; Hess et al. 1985). They

showed that patients had no responses to caloric stimulation or to sinusoidd rotation

below 0.2Hz but had nomal mean gain above 0.4Hz. Therefore, they stated that caloric

test correlated with the results of whole body rotation test in darkness at low fiequencies

(below 02Hz) but not at higher fiequencies (above 0.4Hz). One clamied that this is

because calonc test is equivalent to a low fiequency stimulation test of around 0.025Hz

(Halmagyi et al. 1997). Mead of ushg ody patients with no caioric response, we used

patients with various degrees of caloric losses and we showed that there was a good

correlation between the caioric asymmetry and gain asymmetry up to 5Hz.

The calonc test seems to be more sensitive in detecting asymmetry than the whole

body rotation test in the iight as only 6 out of 12 patients with abnormai calonc responses

had abnormal asymmetry in whole body rotation test. Further experiments have to be

performed to find out whether whole body rotation test in the dark is a better method to

diagnose the asymmetry Uian the caloric test.

4.2.6 Comparison between head impulse test and whole body rotation test

From the head and eye velocity data, velocity dependent asymmetry could be

clearly seen in head impulse test but is not obvious in whole body rotation test. Thus,

asymmetry in our head impulse test is mainiy velocity dependent. The asymmetry in

whole body rotation may depend more on other factors, e.g. fiequency.

The correlation between the whole body rotation test and the head impulse test

was better with whole body rotation in the dark. Rotations at low frequencies in the dark

have larger correlation coefficients than that in the light. This is expected since visual

fixation fùnctions to suppress the asymmetry at low frequencies in the Light (Saadat et al.

1995). The mal1 correlation coefficients fiom 7 and 9 Hz in the light was probably due

to the noise created whm the chair was rotated near the resonance fkequency of the chair

(around 8 Hz). The non-sinusoida1 data at those frequencies would obiitemte the correct

calculation of gain and phase* It was shown that head impulse test revealed more VOR

asymmetry than whole body rotation test at 2 Hz with the same head acceleration of 2500

degreedsec (Gilchrist et al. 1998). Similady, patients with abnormal head impulse resuits

were found to have no asymmetry in the whole body rotation test at 0.1 to 0.2 Hz (Foster

et al. 1994).

8 out of 12 patients with normal results in the whole body rotation test were

considered abnomal in the head impulse test. Arnong the eight patients with abnormal

head impulse results, various clinical symptoms were found which included Meniere's

disease, benign pamxysmal positional vertigo. head trauma and vestibular neuroaitis. All

of them were suggested to have peripheral vestibular lesions. nius, head impulse test

seems to be more sensitive than the whole body rotation test in detecting gain asymmetry.

Whole body rotation test resuits in the dark is needed to compare its sensitivity with head

impulse test.

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APPENDIX A

Directional Preponderance:

C - I DP% = * 100

C + I

1: Ipsilesionai gain, C: contraiesionai gain

Variance and standard deviation of direc tional preponderance:

V( ): variance, SD( ): standard deviation

APPENDIX B

The mean gain (G) and phase (P) with theV stankd errors (SE) for fat and near target

The mean gain and standard errors (SE) for calorie normal (Normal) and abnormal groups (Ipsi: ipsilesional; Contra: contralesional) in the Iight. Key: Left (L), nght (R).

viewing at various nequencies:

1 Ftequencyl L Gain[ L SEI R Gain1 R SEI lpsi Gain[ lpsil Contra1 contra(

Frequency Near G

0.5 1 3 5 7

Far G Near G SE Far G SE

Normal 0.99 0.98 0.82 0.79 0.83

Far P

Normal 0.02 0.02 0.05 0.07 0.04

Far P SE

Normal 0.99 0.98 0-84

Near P

Normal 0.02 0.03 0.03

Near P SE

0.98 0.95 0.7

0.79 0.86

0.62, 0.7

0.04 0.09

SE 0.02 0.02 0.03 0.07 0.07

Gain 0.97 O -97 0.79.

SE 0.03 0.02 0.03

0.80 0-67

O .O4 0 .O7

The mean gain and standard m r s (SE) for caloric normal (Normal) and abnormal (Ipsi: ipsilesiond; Contra: contraiesional) groups in the dark. Key: Left (L), right (R).

1 Frequencyl L Gain1 L SEI R Gain1 R SEI l psi1 lpsil Contrai contra]

The mean ipsilesional (ipsi) and contraiesional (contra) gain and standard errors (SE) for patients with more than 85% calorie loss at various frequencies in the light and in the dark:

0.5 1

Normal 0.74 0.81

The rnean phase and standard emrs (SE) for patients with caioric nonnal (N) and total unilateral Ioss (T) in the dark and in the light:

0.5 1 3 5 7 9

11

Frequencyl Phasel SEI Phase( SEI Phase] SEI Phase1 SEI

Normal 0.07 O .O6

Contra Gain

lpsi SE

Contra SE

lpsi Gain

(light) 1

0.98 0.72 0.59 0.74 O .66 0.62

Normal 0.66 0.79

Frequency lpsi Gain

(light) 0.01 0.02 0.04, 0.1 1 O .O6 0 .O9 0.04

Normal 0.09 0.06

Contrar SE

lpsi SE

Contra Gain

(light) 0-99 0.99 0.83 0.85 0.61 O .54 0.73

~ a i n 0.68 0.74

(light) 0.03 0.01

SE 0.06 0.09

(dark) 0.59 0.6

Gain O -85 O .88

SE 0.06 0.04

(dark) O .O8 0.12

0.02 0.04 0.08 0.16 0.1

O .O4 0.07 0.09 0.25 0.12

0.64 0.6 0.8

0.99 0.69

(dark) 0.98 0.96

(dark) 0.05 0-02

0.95 0.87 0.82 0.98 0.81

- 0.02 0.04 0.13 0.29 0.11