23

Chapter Three

Vestibular System

3.1 Introduction

The vestibular, visual, and proprioceptive systems work together to maintain

postural equilibrium and visual stability while stationary and when moving. The

peripheral vestibular apparatus, a component of the inner ear, has the ability to detect a

wide range of angular and linear accelerations of the head, as well as changes in static

head position with respect to gravity. The information obtained from the peripheral

vestibular apparatus is utilized in central pathways to help generate appropriate postural

and eye movement responses to changes in head position.

The vestibulo-ocular pathways produce a number of reflexive eye movement

responses to help maintain clear vision during head movement (see figure 3.1). These

responses include “compensatory” responses to angular head accelerations (generated by

the angular vestibulo-ocular reflex or aVOR) and linear head accelerations (generated by

the linear vestibulo-ocular reflex or lVOR) (Raphan and Cohen 2002). The vestibulo-

ocular pathways also produce “orienting” responses, serving to align the z-axis of the eye

with the gravito-inertial acceleration (GIA) vector (Raphan and Cohen 2002).

Vestibular-evoked eye movements have short latencies following the onset of

head movement, reported to be as low as 5ms in some studies of the aVOR (Tabak et al.

1997). Compensatory smooth eye movements resulting from stimulation of the visual

system or the neck proprioceptors are not seen until ≥80ms after the onset of head

movement (Bronstein and Hood 1986; Carl and Gellman 1987), making the vestibular

system critical for the generation of an early eye movement response to head movement

stimuli. The aVOR has an additional advantage, in that it functions well in response to

short duration, high frequency head movements, ensuring clear vision during commonly

performed activities such as walking and running. The physician J.C. highlighted the

importance of these functions by describing how he continuously experienced severe

24

oscillopsia while walking, following the complete loss of vestibular function after

treatment with an aminoglycoside antibiotic (J.C. 1952).

The anatomy and physiology of the peripheral and central components of the

vestibular system are considered in this chapter. Emphasis is placed on the structure and

function of the peripheral vestibular apparatus and on the central structures and pathways

influencing the aVOR, as relevant to the current study.

Figure 3.1 The vestibulo-ocular pathways produce reflexive eye movements that either

compensate for head movement or change the orientation of the eye so that its z-axis aligns with

the gravito-inertial acceleration (GIA) vector. A. The aVOR produces a rotational eye movement

that compensates for rotation of the head. B. The lVOR produces a rotational eye movement to

compensate for head translation. C. With the head upright, the head and eye z-axes (denoted by

arrows on top of the head and eyes, respectively) align with the GIA, which in turn aligns with the

vector representing acceleration due to gravity. D. When the head is tilted, the eyes roll so that

their z-axes align with the GIA. E. During horizontal linear acceleration (LINEAR ACC), which

tilts the GIA relative to the head vertical, the eyes will again roll to align their z-axes with the

GIA (from Raphan and Cohen 2002).

25

3.2 Anatomy of the Peripheral Vestibular System

The inner ear lies deep within the petrous temporal bone, in a chamber of

communicating ducts and cavities known as the bony labyrinth. The inner ear, or

membranous labyrinth, a fluid-filled membranous structure with a shape similar to that of

the bony labyrinth, is suspended within the bony labyrinth by a supportive network of

connective tissue. The space between the bony labyrinth and the membranous labyrinth is

filled with perilymph, a fluid with a high concentration of sodium ions and a low

concentration of potassium ions (Smith et al. 1954), making it similar in composition to

extracellular fluid. The membranous labyrinth, on the other hand, is filled with

endolymph, a fluid with a high concentration of potassium ions and a low concentration

of sodium ions, making it similar to intracellular fluid in its ionic composition (Smith et al.

1954). The ionic composition of endolymph is vital to the normal functioning of the

sensory cells of the inner ear (Corey and Hudspeth 1979), as discussed below in section

3.3.

The membranous labyrinth may be functionally and anatomically divided into two

main portions: the peripheral auditory apparatus, or cochlea, and the peripheral vestibular

apparatus. The peripheral vestibular apparatus incorporates five structures: the three

semicircular canals (SCCs), and two otolith organs, the utricle and saccule (figure 3.2).

The three SCCs (anterior, posterior, and lateral) are named for their positions in the head.

The anterior SCC is also known as the superior SCC, while the lateral SCC is also known

as the horizontal SCC.

Neural signals from the sensory tissue of the SCCs and otolith organs pass to the

brainstem in the primary (first-order) vestibular afferents, which comprise the vestibular

nerve, one of the two nerves making up the eighth cranial nerve (CN VIII). The vestibular

nerve may be divided into superior and inferior divisions. The primary vestibular

afferents from the anterior SCC, lateral SCC, utricle, and part of the saccule pass to the

brainstem in the superior division of the vestibular nerve, while those from the posterior

SCC and remainder of the saccule pass to the brainstem in the inferior division. The

nuclei of the afferents comprising the superior and inferior divisions of the vestibular

nerve are found in the superior and inferior vestibular ganglia of Scarpa, respectively.

26

Figure 3.2 A line drawing of the left inner ear, viewed from the lateral aspect. The semicircular

canals, otolith organs (utricle and saccule), and cochlea are illustrated, as are the nerves and other

structures closely associated with the inner ear. A narrow channel, the ductus reuniens

(unlabelled), joins the cochlea and the peripheral vestibular apparatus (from Kandel et al. 1991).

3.3 Sensory Epithelium and Vestibular Afferents

The sensory epithelium of the peripheral vestibular apparatus consists of highly

specialized hair cells (Wersäll 1956). Each hair cell has a hexagonal array of 60-100

stereocilia and one kinocilium protruding from its apical surface. The stereocilia are

asymmetrically arranged, gradually increasing in height in a staircase fashion, with the

tallest stereocilia being located near the kinocilium and the shortest being located at the

opposite end of the cell surface. The kinocilium is the longest apical process extending

from the hair cell.

The arrangement of the stereocilia with respect to the kinocilium results in each

hair cell having a morphological axis of polarity (Flock 1964). When the stereocilia of the

hair cell are in their resting position, a certain number of mechanically-gated transduction

channels on the stereocilia are open, allowing potassium ions from the endolymph to

move into the cell and depolarize it. Consequently, the cell has a resting discharge of

transmitter. When the stereocilia are deflected towards the kinocilium, more transduction

27

channels on the stereocilia open by a mechanical process that is mediated by tip links

connecting the stereocilia (Corey and Hudspeth 1983), leading to further depolarization

(Flock 1965) and increased release of transmitter (Corey and Hudspeth 1979; figure 3.3).

Deflection of the stereocilia away from the kinocilium results in the opposite response,

with hyperpolarization of the hair cell (Flock et al. 1973) and decreased transmitter

release (Corey and Hudspeth 1979).

The hair cell receptors show greater sensitivity and linearity of response for small

deflections of the stereocilia away from their resting position (see figure 3.3), with larger

deflections resulting in saturation and non-linearity. The saturation effect is particularly

evident with deflections of the stereocilia away from the kinocilium (see figure 3.3).

Figure 3.3 Intracellular voltage changes (in mV) resulting from displacement/flexion of the cilia

of a hair cell. Flexion towards the kinocilium (positive) results in depolarization, while flexion

away (negative) results in hyperpolarization (from Hudspeth and Corey 1977).

The resting discharge of transmitter from the hair cells results in the primary

vestibular afferents also having a resting discharge. The resting discharge rate of primary

vestibular afferents is about 91Hz in squirrel monkeys, and is thought to be approximately

the same in humans (Goldberg and Fernández 1971a, 1971b). Depolarization of a hair

cell results in an increase in the afferent firing rate due to increased transmitter release

28

from the hair cell, while hyperpolarization of the cell will produce a decrease in the

afferent firing rate due to decreased transmitter release (see figure 3.4). Thus, neural

signals coding deflections of the stereocilia both toward and away from the kinocilium

can be communicated to the central nervous system via the primary vestibular afferents

(Löwenstein and Sand 1940; Money and Scott 1962).

Figure 3.4 The hair cell receptor potential and the firing rate of the primary vestibular afferent

both depend on the orientation of the cilia on the hair cell. Deflections of the stereocilia towards

the kinocilium result in depolarization and increased firing rate, while deflections in the opposite

direction result in hyperpolarization and decreased firing rate (from Kandel et al. 1991).

3.4 Semicircular Canals

The SCCs are tubular structures that are roughly semicircular in shape (Curthoys

et al. 1977a). At one end of each canal is an enlargement known as the ampulla (figure

3.5a). Within each ampulla, a collection of hair cells makes up the saddle-shaped

ampullary crest (also known as the crista ampullaris). The cilia of these hair cells project

towards the centre of the canal lumen into a gelatinous membrane known as the cupula.

The cupula extends across the lumen of the SCC and is adherent to the SCC wall, forming

a watertight seal (Dohlman 1971; Lim 1973).

29

When there is an angular acceleration of the head in the plane of one of the SCCs,

inertial forces acting on the endolymph in that canal result in relative fluid flow

(Steinhausen 1933; Van Egmond et al. 1949; see section 3.4a). The relative movement of

the endolymph produces deviation of the cupula (see figure 3.5b). Since the cilia of the

hair cells of the ampullary crest project into the cupula, deviation of the cupula will

produce depolarization or hyperpolarization of the hair cells, depending on the direction

of deflection of the cilia. The hair cells of the ampullary crest are organized so that their

morphological axes of polarity all point in the same direction along the canal (Löwenstein

and Wersäll 1959). Deviation of the cupula in one direction will thus result in an increase

in the firing rate of all of the afferents, while deviation in the opposite direction will result

in a decrease in the firing rate (Goldberg and Fernández 1971a).

A B

Figure 3.5 A. The components of the ampulla of the lateral (horizontal) semicircular canal (SCC)

are illustrated. The hair cells of the ampullary crest project into the cupula, which extends across

the lumen of the SCC. B. An angular acceleration of the head results in deviation of the cupula,

due to the inertia of the endolymph (from Kandel et al. 1991).

The SCCs from the inner ear on one side are approximately orthogonal to one

another (Blanks et al. 1975; Curthoys et al. 1977b; Reisine et al. 1988), so that together

they can sense any angular head rotation in three-dimensional (3-d) space. The SCCs

from both inner ears are often grouped into three functional pairs: the two lateral SCCs

make up one pair, the left anterior and right posterior SCCs another, and the right anterior

and left posterior SCCs make up the final pair (Blanks et al. 1975; Takagi et al. 1989).

The canals from a pair are anatomically related, since they are approximately aligned in

3-d space. As a result, they are also functionally related, as an angular head acceleration

30

that excites one canal in the pair inhibits the other. The SCCs are therefore thought to act

in a “push-pull” manner.

The normal push-pull functioning of the canal pairs is important, since excitatory

stimuli are better vestibular stimuli than inhibitory ones – a phenomenon first described

by Ewald (1892). Ewald applied positive and negative pressure to each of the canals,

making three observations that are now known as Ewald’s first, second, and third laws.

The first was that compensatory eye movements always occurred in the plane of the

stimulated canal, and always in the direction of endolymph flow. Secondly, he noted that

ampullopetal flow (flow of the endolymph towards the utricle) produced a better response

than did ampullofugal flow (flow of the endolymph away from the utricle) when the

lateral canal was stimulated. The third observation was that ampullofugal flow produced a

better response than did ampullopetal flow when the anterior and posterior canals were

stimulated. The importance of Ewald’s second and third laws becomes obvious when an

organism loses the function of the SCCs on one side, as the remaining labyrinth cannot

always adequately detect vestibular stimuli to compensate for the loss (see section 3.3 and

figure 3.3 above). For example, when there is a rapid angular rotation of the head in the

plane of a lesioned canal, in a direction that would normally excite the lesioned canal, the

aVOR response is inadequate and a stable retinal image cannot be maintained (Halmagyi

and Curthoys 1988; Halmagyi et al. 1990; Curthoys and Halmagyi 1995; Aw et al. 1996b;

Cremer et al. 1998).

3.4a Semicircular Canal Hydrodynamics

Steinhausen (1933) first modelled the hydrodynamic function of the SCCs, with

Van Egmond et al. (1949) and Groen (1957) later making refinements to the model.

Steinhausen (1933) proposed that the SCCs function like a heavily damped torsion

pendulum, so that

θΘ=ξ∆+ξΠ+ξΘ &&&&&

where ξ is the angular displacement of the cupula (ξ& and ξ&& refer to the first and second

derivatives of ξ, respectively), θ&& is the angular acceleration of the head (hence, θ and θ&

correspond to angular displacement and velocity, respectively), Θ is the moment of

inertia of the cupula and endolymph, Π is the moment of viscous drag at unit angular

31

velocity of the endolymph, and ∆ is the elastic restoring couple of the cupula and

endolymph. Within the range of natural head movements, ξΘ && and ξ∆ are very small

compared to ξΠ& , hence

θΘ≈ξΠ &&&

Direct integration yields

θΘ≈ξΠ &

and

θΠΘ≈ξ &

Within the range of natural head movements, instantaneous cupular displacement is

therefore not proportional to the angular acceleration of the head, but rather is roughly

proportional to the angular velocity of the head. Hence, the canals mechanically integrate

head acceleration, producing cupular displacement and a neural signal proportional to

head velocity (Goldberg and Fernández 1971a).

During angular head accelerations, inertial forces acting on the endolymph

initially keep it stationary in space, producing relative fluid flow in the canal. The inertial

force is opposed by the viscous forces incurred by the fluid flow in the canal, and by the

elastic restoring forces of the cupula. After a certain period of constant velocity, the

inertial force is therefore overcome by restoring forces, and the endolymph, too, will

move with a constant velocity during the head rotation. The cupula exponentially decays

back towards its resting position with a time constant of approximately 4-6s (Cohen et al.

1981; Dai et al. 1999).

The lack of semicircular canal response to constant velocity stimuli is partly

compensated for by the velocity storage mechanism in the central nervous system (see

section 3.8). The relationships between cupular displacement and different types of head

rotation stimuli are illustrated below in figure 3.6.

3.4b Canal Afferent Responses

Fernández and Goldberg (1971) measured the primary canal afferent responses in

squirrel monkeys, and presented evidence that the primary vestibular afferents are

32

sensitive to cupular velocity, as well as being sensitive to cupular displacement. The

SCCs could therefore relay both head velocity and acceleration information to the central

nervous system. Indeed, Boyle et al. (1991) found that the majority of afferents arising

from the SCCs had firing rates proportional to angular head velocity, with a minority of

afferents giving a signal proportional to angular head acceleration (see also Rabbitt et al.

1996).

Figure 3.6 The relationships between cupular displacement and three different head rotation

stimuli are illustrated. During periods of acceleration, cupular displacement is approximately

proportional to head velocity. When head velocity is constant, however, the cupula decays back

towards its resting position (from Baloh and Honrubia 2001).

33

3.5 Otolith Organs

The utricle and saccule are the sac-like portions of the membranous labyrinth,

collectively known as the otolith organs. They sense both static head position with respect

to gravity and dynamic changes in head position, such as linear accelerations and head

tilts.

The otolith organs have areas of sensory epithelium known as maculae. Each

macula is covered with a gelatinous membrane, the otolithic membrane, which has

crystals of calcium carbonate (otoliths or otoconia) embedded in it (Carlström et al. 1953;

see figure 3.7). The cilia of the hair cells in the maculae project into the otolithic

membrane (Carlström et al. 1953), just as the cilia of the SCC hair cells project into the

cupula. Therefore, when the head is linearly translated, the otolithic membrane moves

relative to the sensory epithelium due to inertia, resulting in excitation or inhibition of the

underlying hair cells (see Wilson and Melvill Jones 1979, for a review).

Figure 3.7 Structure of the otolithic macula. When the head translates, the otolithic membrane

moves relative to the sensory epithelium due to inertia, resulting in excitation or inhibition of the

underlying hair cells. The otoliths (otoconial crystals) add mass to the otolithic membrane,

therefore enhancing the sensitivity of the maculae to head tilt and linear accelerations (from

Furman and Cass 1996).

34

The utricular macula lies on the floor of the utricle, while the saccular macula lies

on the medial wall of the saccule, making the two maculae approximately orthogonal to

one another (Lim 1969). The utricular macula responds best to lateral/fore-aft tilts and

side-side translations of the head, while the saccular macula responds best to up-down

translations of the head. The macula of each otolithic organ is not perfectly flat and the

morphological axes of polarity of the hair cells constituting each macula point in a

number of different directions. Consequently, each macula can produce excitatory

responses to linear accelerations in more than one direction, unlike the SCCs.

3.6 Vestibular Nuclei

Neural signals from the peripheral vestibular apparatus are passed to the central

nervous system via the vestibular nerve. The components of the central nervous system

involved in the receipt, distribution, and subsequent processing of vestibular information

constitute the central vestibular system.

Upon entering the brainstem, the majority of primary vestibular afferents initially

pass to the vestibular nuclear complex in the caudal pons and rostral medulla, where they

synapse on the cell bodies of secondary (second-order) vestibular afferents (Gacek 1969).

Some primary vestibular afferents pass directly to the cerebellum via the juxtarestiform

body (part of the inferior cerebellar peduncle), to synapse with cells in the flocculo-

nodular lobe and uvula (Gacek 1969). Each primary vestibular afferent synapses with

multiple neurons, resulting in considerable distribution of vestibular information

throughout the central nervous system. For example, an afferent from one of the SCCs

can synapse with up to 15 different neurons in the vestibular nuclear complex.

The vestibular nuclei act as a relay point for the distribution of vestibular

information. They also have a role in further processing of vestibular information, such as

for velocity storage (de Jong et al. 1980; see section 3.8) and velocity-position

transformation (Cannon and Robinson 1987; Cheron and Godaux 1987; Godaux et al.

1993; see section 2.5c). There are four vestibular nuclei on each side of the brainstem,

which are distinguished based on their histological features and connections: the medial

35

vestibular nucleus (MVN), superior vestibular nucleus (SVN), lateral vestibular nucleus

(LVN), and inferior (or descending) vestibular nucleus (IVN) (Brodal and Pompeiano

1957; Brodal 1984; Highstein and McCrea 1988; Suárez et al. 1997). Several smaller

accessory subgroups also exist, including the interstitial nucleus and the y-group.

The MVN and the SVN receive the majority of their input from the SCCs. Many

of the secondary afferents from these two nuclei are involved in the direct pathways of

the vestibulo-ocular reflex (see section 3.7a). The MVN has also been implicated in the

velocity-to-position transformation (see sections 2.5c and 3.7b), and in velocity storage

(see section 3.8).

The rostroventral portion of the LVN receives afferent input from the SCCs and

the utricular macula. The LVN also receives afferent input from the cerebellum and spinal

cord. Secondary afferents arising from this nucleus make up part of the vestibulo-ocular

pathways. The vestibulo-ocular afferents extend to the ipsilateral oculomotor nucleus, in

part, through the ascending tract of Deiters (ATD), which passes lateral to the medial

longitudinal fasciculus (MLF) in the brainstem.

The IVN receives input from both the peripheral vestibular apparatus and the

cerebellum. The IVN is important for the integration of vestibular and cerebellar input.

3.7 Angular Vestibulo-Ocular Reflex Pathways

The aVOR produces an eye rotation response that is opposite in direction but

equal in magnitude to the head rotation stimulus. To compensate for mechanical restoring

forces imposed on the eyeball by the orbital contents, two signals must be sent to the

extra-ocular muscles: an eye velocity signal and an eye position signal (see section 2.4).

The signal encoding eye velocity arises from the “direct” pathway of the aVOR, while the

signal encoding eye position is produced from the eye velocity signal by the neural

integrator (see sections 2.4 and 2.5c) in the “indirect” pathway. The two signals are

combined, and the resulting command is sent to the extra-ocular muscles to rotate the

eyes (Robinson 1975).

36

Szentágothai first described the direct pathway of the aVOR in 1950. The three-

neuron arc he proposed included a primary vestibular afferent, a secondary vestibular

afferent (which sends a signal from a vestibular nucleus to a motor nucleus), and a motor

(efferent) neuron (which sends the eye movement signal to an extra-ocular muscle). The

connections are such that a particular SCC directly influences a pair of extra-ocular

muscles, which generate compensatory eye rotations in the plane of the stimulated SCC

(Cohen and Suzuki 1963; Cohen et al. 1964). The head velocity signal in the primary

vestibular afferents is therefore transformed into a compensatory eye velocity signal, by

nature of these connections.

The neural substrate for the neural integrator or indirect pathway (whose

components include the NPH, MVN, INC, and parts of the cerebellum) was not identified

until many years after the original description of the direct pathway, although the

existence of an indirect pathway had been suspected (Lorente de Nó 1933; Szentágothai

1950). As previously discussed, the indirect pathway is critical for maintaining steady

fixation and for producing normal eye movements (see section 2.4). While there is now

agreement as to which structures are involved in this pathway, there is still debate about

how the neural components of the pathway actually generate the eye position signal from

the head velocity signal (Tweed and Vilis 1987; Schnabolk and Raphan 1994; Tweed et al.

1994a; Raphan 1998; Smith and Crawford 1998; see chapter 4).

3.7a Direct Pathways of the aVOR

The aVOR is driven by signals from the SCCs, resulting in coordinated

contraction and relaxation of the extra-ocular muscles. Both excitatory and inhibitory

pathways exist, so that contraction of agonist muscles and relaxation of antagonist

muscles results from stimulation of a particular SCC (Richter and Precht 1968; Precht

1972; Highstein et al. 1971). Conversely, an inhibitory stimulus acting on a particular

SCC results in relaxation of agonist muscles for that SCC and contraction of antagonist

muscles (Shimazu and Precht 1966; Markham et al. 1977). Excitatory pathways therefore

function to produce the desired eye movement, while inhibitory pathways inhibit the

opposite eye movement response. The vestibular commissures, which connect

homologous regions of the two vestibular nuclei complexes, are thought to further

enhance the “push-pull” relationship of the vestibular nuclear complexes, thereby helping

37

to coordinate the aVOR (Pompeiano et al. 1978; Carleton and Carpenter 1983). The

nuclei, pathways, and extra-ocular muscles involved in bringing about eye rotations in

response to excitation/inhibition of each SCC, via the direct pathways, are summarized in

table 3.1. Furthermore, the actual pathways are displayed in figure 3.8.

Table 3.1 Components involved in the direct pathway of the aVOR (adapted from Leigh and Zee

1999).

Receptor Effect Relay Nuclei Pathways Motor Nuclei Muscle

Lateral SCC Excitation MVN - c-VI c-LR

MVN/c-VI ATD/MLF i-III i-MR

Inhibition MVN - i-VI i-LR

MVN/c-VI Poly/MLF c-III c-MR

Anterior SCC Excitation MVN/LVN* MLF* c-III i-SR

MVN/LVN* MLF* c-III c-IO

Inhibition SVN MLF i-III i-IR

SVN MLF i-IV c-SO

Posterior SCC Excitation MVN/LVN MLF c-III c-IR

MVN/LVN MLF c-IV i-SO

Inhibition SVN Extra i-III c-SR

SVN Extra i-III i-IO

(SCC, semicircular canal; i, ipsilateral; c, contralateral. Relay Nuclei: MVN, medial vestibular

nucleus; LVN, lateral vestibular nucleus; *, other nuclei involved; SVN, superior vestibular

nucleus. Pathways: MLF, medial longitudinal fasciculus; ATD, ascending tract of Deiters; Poly,

polysynaptic pathway outside of MLF; *, other pathways involved; Extra, extra-MLF pathway.

Motor Nuclei: VI, abducens nucleus; III, oculomotor nucleus; IV, trochlear nucleus. Muscles:

LR, lateral rectus; MR, medial rectus; SR, superior rectus; IO, inferior oblique; IR, inferior rectus;

SO, superior oblique).

Stimulation of the lateral SCC results in a predominantly horizontal eye rotation

response, due to adduction of the ipsilateral eye and abduction of the contralateral eye.

When the head accelerates towards the left, the afferents from the left lateral canal are

38

stimulated. These pass to the left vestibular nucleus complex, where they synapse on

excitatory and inhibitory secondary vestibular afferents in the MVN (shown in figure 3.8).

Figure 3.8 Line diagram summarizing the structures involved in the direct pathway of the aVOR.

Excitatory and inhibitory projections from the anterior, posterior, and horizontal (lateral) canals

are illustrated (from Leigh and Zee 1999). (Semicircular canals: AC, anterior SCC; PC, posterior

SCC; HC, horizontal (lateral) SCC. Nuclei: MV, medial vestibular nucleus; LV, lateral vestibular

nucleus; SV, superior vestibular nucleus; V, inferior vestibular nucleus; III, oculomotor nucleus;

IV, trochlear nucleus; VI, abducens nucleus; XII, hypoglossal nucleus; PH, nucleus prepositus

hypoglossi; IC, interstitial nucleus of Cajal. Pathways: MLF, medial longitudinal fasciculus;

ATD, ascending tract of Deiters; BC, brachium conjunctivum; VTP, ventral tegmental pathway.

Muscles: LR, lateral rectus; MR, medial rectus; SR, superior rectus; IO, inferior oblique; IR,

inferior rectus; SO, superior oblique).

39

The excitatory secondary afferents function to produce contraction of the left medial

rectus and right lateral rectus, resulting in a rightward eye movement. The signal for left

medial rectus contraction is carried by afferents passing directly to the medial rectus

subdivision of the oculomotor nucleus via the ascending tract of Deiters. Other signals

serving to produce the same muscle contraction pass indirectly to the ipsilateral

oculomotor nucleus, after synapsing on internuclear neurons in the contralateral abducens

nucleus, to ascend to the oculomotor nucleus via the ipsilateral medial longitudinal

fasciculus (MLF). To produce contraction of the right lateral rectus, secondary afferents

synapse on contralateral abducens motor neurons. The inhibitory pathways function to

relax antagonist muscles, in this case the left lateral rectus and right medial rectus

muscles. Most inhibitory secondary afferents pass to the ipsilateral abducens nucleus,

where they inhibit left abducens motor neurons, relaxing the left lateral rectus, and

internuclear neurons synapsing on right medial rectus motor neurons in the contralateral

oculomotor nucleus, relaxing the right medial rectus. Afferents from the right lateral canal,

which have been inhibited in this example, synapse on excitatory and inhibitory

secondary afferents in the right vestibular nucleus complex. The same pathways as

described above are utilized, producing the same end result, rightward rotation of the eyes.

When an anterior SCC is stimulated, the eye movement response includes both a

vertical and torsional component, with elevation/intorsion of the ipsilateral eye and

elevation/extorsion of the contralateral eye being observed. The pathways are shown in

figure 3.8. Excitatory secondary afferents pass from the vestibular nuclei to the

contralateral oculomotor nucleus via the brachium conjunctivum, where they excite motor

neurons of the ipsilateral superior rectus. Other afferents pass to the contralateral

oculomotor nucleus via the MLF and ventral tegmental pathway to excite motor neurons

of the contralateral inferior oblique. Inhibitory afferents pass to the ipsilateral trochlear

nucleus via the MLF to inhibit the contralateral superior oblique motor neurons. Other

inhibitory neurons pass to the ipsilateral oculomotor nucleus, to inhibit ipsilateral inferior

rectus motor neurons. Coordinated contraction and relaxation of the extra-ocular muscles

thereby produces the eye movement response to anterior canal stimulation.

When a posterior SCC is stimulated, similar pathways are utilized, producing

depression/intorsion of the ipsilateral eye and depression/extorsion of the contralateral

eye. There is contraction of the agonist muscles, the ipsilateral superior oblique and

40

contralateral inferior rectus, and relaxation of the antagonist muscles, the ipsilateral

inferior oblique and contralateral superior rectus. The excitatory and inhibitory pathways

involved are summarized in figure 3.8.

3.7b Indirect Pathways of the aVOR

The indirect pathways of the aVOR generate the eye position command to

produce normal vestibular-evoked eye movements and to help maintain fixation

following them. The indirect pathways are also utilized in generating the eye position

command for other types of eye movements. As previously discussed (see section 2.5c),

the neural substrate for the indirect pathway includes the MVN (Miles 1974; Cannon and

Robinson 1987), the NPH (Baker 1977; Lopez-Barneo et al. 1982; Cannon and Robinson

1987), the INC (King et al. 1980, 1981; Fukushima 1987, 1991; Crawford et al. 1991;

Crawford 1994), and the flocculus and paraflocculus (Takemori and Cohen 1974; Zee et

al. 1981; Waespe et al. 1983).

The mechanisms by which the indirect pathways produce a position command

from the eye velocity command have become controversial (Tweed and Vilis 1987;

Schnabolk and Raphan 1994; Tweed et al. 1994a; Raphan 1998; Smith and Crawford

1998). Recent theories and models of the indirect pathways are described and extensively

discussed in chapter 4.

3.8 Velocity Storage

The velocity storage mechanism improves the performance of the aVOR during

sustained head rotations (Raphan et al. 1979), by storing head velocity information from

the labyrinth and thereby lengthening the time constant of the aVOR (Cohen et al. 1981).

The role of the velocity storage mechanism is well illustrated by considering the

characteristics of the vestibular response to a constant velocity rotational stimulus (see

figure 3.9). In the case of a horizontal rotational stimulus, accelerating rapidly from rest,

the time constant of the mechanical response of the cupula in the lateral canal is thought

to be 4-6 seconds (Cohen et al. 1981; Dai et al. 1999; see section 3.4a). However, the

41

resulting nystagmus has a time constant of about 15 seconds, indicating that the raw

vestibular velocity signal has been prolonged by velocity storage (Raphan et al. 1979).

Figure 3.9 Horizontal eye position recording from a subject undergoing a constant velocity

rotation of 50°/s in the dark. The subject is accelerated rapidly from rest (at arrow), and constant

velocity is quickly achieved. The cupular response to the stimulus is thought to last for about 4-6s

after the onset of the stimulus (Cohen et al. 1981; Dai et al. 1999), however the nystagmus lasts

considerably longer due to velocity storage (adapted from Leigh and Zee 1999).

A number of structures are thought to be important in the regulation of velocity

storage, including the MVN and SVN (de Jong et al. 1980), the nodulus and ventral uvula

(Waespe et al. 1985; Wearne et al. 1998), and the vestibular commissures (Blair and

Gavin 1981; Katz et al. 1991; Wearne et al. 1997). Lesions of these structures have been

shown to result in velocity storage being abolished or enhanced.

3.9 Cerebellar Influences on the Angular Vestibulo-Ocular Reflex

The regions of the cerebellum that influence vestibular function, including the

flocculus, ventral paraflocculus, nodulus, and ventral uvula, together constitute the

vestibulo-cerebellum. Lesions of these structures produce characteristic abnormalities of

vestibular and ocular motor function (see section 8.1). Lesions of the flocculus and

ventral paraflocculus result in abnormalities of aVOR gain (Zee et al. 1981; Waespe et al.

1983) and a loss of the ability to adapt the aVOR (Ito et al. 1982; Lisberger et al. 1984;

see section 3.10). Ablation of these structures also produces a deficient velocity-position

integrator, with gaze-evoked nystagmus being observed clinically (Takemori and Cohen

1974; Zee et al. 1981; Waespe et al. 1983).

40 deg

R

L 5 s

42

Lesions of the nodulus and ventral uvula are well known to produce abnormalities

of velocity storage (Waespe et al. 1985; Wearne et al. 1998; see section 3.8). In addition,

periodic alternating nystagmus (PAN) may be seen with lesions of these structures. A rare

form of nystagmus, PAN is a spontaneous horizontal nystagmus that reverses direction

every 90-120s. Loss of the ability to suppress or cancel the aVOR, when the subject is

fixating on a target that is moving with the head, also results from damage to the

vestibulo-cerebellum. The concept of aVOR suppression is illustrated in figure 3.10.

Figure 3.10 Eye position traces recorded from a subject sitting in an oscillating chair, while the

subject is in total darkness (middle trace), and while fixating a target that is moving with the chair

(lower trace). Suppression, or cancellation, of the aVOR occurs when the subject can fixate a

target that is moving with the head during the oscillations. Lesions of the vestibulo-cerebellum

result in a loss of the ability to suppress the aVOR, producing eye rotations similar to those seen

in normal subjects being rotated in the dark (from Baloh and Honrubia 2001).

3.10 Vestibular Adaptation

The aVOR functions as a feed-forward open-loop control system, as no feedback

information is relayed to the receptors that provide the input for the reflex. When the

aVOR is not performing optimally, manifest by excessive retinal image slip, the aVOR

must be re-calibrated. The process of aVOR re-calibration is known as adaptation.

Gonshor and Melvill Jones (1976) illustrated the remarkable degree to which the aVOR

can be adapted. When human subjects wore “dove” prism goggles, which reverse the left-

43

right relations of the visual world, for a few weeks, they noted that the gain of the

horizontal aVOR was progressively reduced, and the eye movement responses even

reversed in polarity.

Destruction of the cerebellum results in a loss of the ability to adaptively modify

aVOR gain (Ito et al. 1974; Robinson 1976). The flocculus and ventral paraflocculus play

a critical role in aVOR adaptation (see section 3.9), with their destruction resulting in a

loss of the ability to adapt the aVOR (Zee et al. 1981; Ito et al. 1982; Lisberger et al.

1984), while the aVOR itself remains intact. Retinal slip information, thought to be the

stimulus for aVOR adaptation, is relayed to the flocculus via climbing fibres from the

inferior olive. Ito and Miyashita (1975) demonstrated that removal of visual input to the

inferior olive results in loss of the ability to adaptively modify aVOR gain. In addition,

local lesions in the dorsal cap of the inferior olive have been shown to abolish aVOR

adaptation (Haddad et al. 1980). Since both retinal slip information and vestibular inputs

are relayed to the flocculus, Ito (1982) proposed that the flocculus is the structure

responsible for making appropriate changes to the aVOR via its projection to the

vestibular nuclei. Recordings from neurons in the flocculus do not, however, show

modifications in their firing rate appropriate to learned increases or decreases in aVOR

gain (Miles et al. 1980). Therefore, it is possible that the flocculus acts as an input to

another structure where aVOR adaptation actually occurs.

As the aVOR only undergoes adaptation when head movements and image slip

occur simultaneously, Lisberger (1988) argued that the site of adaptation should receive

both visual and vestibular input. Experimental evidence implied that the flocculus was not

the site at which aVOR adaptation took place, so Lisberger suggested that the flocculus

might send an error correction signal to cells in the vestibular nuclei called floccular

target neurons (FTNs). The firing rate of FTNs has been observed to systematically

change depending on whether aVOR gain has been increased or decreased as a result of

adaptation (Lisberger and Pavelko 1988; see figure 3.11). Furthermore, FTNs receive

excitatory input from the primary and secondary vestibular afferents, and inhibitory input

from the Purkinje cells of the flocculus. Thus, FTNs receive both vestibular and visual

input, and since they display appropriate firing responses after changes in aVOR gain, it

is possible that they form the locus for aVOR adaptation.

44

Figure 3.11 aVOR responses from two monkeys who had undergone aVOR adaptation. Head and

eye velocity traces are plotted, as well as the firing rate of a representative FTN. A. The monkey

with the increased aVOR gain showed a high firing rate in response to the head movement. B.

The monkey with the decreased aVOR gain showed a lower firing rate in response to the same

head movement stimulus. The velocity calibration is 30°/s (from Lisberger and Pavelko 1988).

3.11 Summary

The receptors of the vestibular system are located in the peripheral vestibular

apparatus, in the inner ear. Angular accelerations of the head are detected by the three

semicircular canals in each ear, which contain hair cell receptors that have the ability to

respond to movements in both excitatory and inhibitory directions. The canals

mechanically integrate the head acceleration stimulus, so that the signal passed to the

brainstem by afferents in the vestibular nerve is proportional to head velocity.

The neural substrate for the aVOR is found in the brainstem and cerebellum. The

eye velocity and eye position signals required for the aVOR to function normally are

produced in the direct and indirect pathways, respectively. The signals are combined and

the resulting command is relayed to the eye muscles via the neurons in the ocular motor

nerves. The central vestibular system also contains mechanisms for enhancing the aVOR

response during constant velocity head rotations (velocity storage mechanism) and for

modifying the aVOR gain so that retinal image slip is minimized (aVOR adaptation).

The literature describing the 3-d kinematic properties of saccadic eye movements

and the aVOR is reviewed in chapter 4. In particular, eye position-dependent changes in

the eye movement kinematics will be discussed.