ORIGINAL

VERTIGO AND MOTION SICKNESS.

PART I:ARTICLE
VESTIBULAR ANATOMY AND PHYSIOLOGY

Vertigo and motion sickness. Part I:

Vestibular anatomy and physiology
Timothy P. Zajonc, MD; Peter S. Roland, MD

Abstract
Control of the symptoms of vertigo and motion sickness
requires consideration of the neurophysiology of areas
both intrinsic and extrinsic to the vestibular system proper.
We review the essential anatomy and physiology of the
vestibular system and the associated vomiting reex.
Introduction
Vertigo is often accompanied by visceral autonomic symptoms, including pallor, diaphoresis, nausea, and vomiting.
Vertigo is similar to motion sickness in that both can be
caused by vestibular stimulation that does not match an
internal model of expected environmental stimuli. Indeed,
a functioning vestibular system is necessary for the perception of motion sickness.1 For this reason, many of the
same drugs are used to treat both conditions. Selection of
a particular type of drug therapy can be facilitated by an
understanding of the essential anatomy and physiology of
the vestibular system and the associated vomiting reex.
Vestibular pathways
The receptor cells for vestibular stimuli are the hair cells of
the vestibular labyrinth. Type I hair cells are ask-shaped
and connected to a single large aerent nerve ber. Type
II cells are cylindrical, and they are innervated by a series
of bouton-type nerve endings at their base. These sensory
cells are found in the cristae at the ampullated ends of the
semicircular canals and in the maculae of the utricle and
sacculus. Movement of the endolymph in the semicircular
canals, and movement of the otoliths in the case of the
maculae, is translated by the hair cells into an electrical
impulse. This impulse is propagated by the aerent nerves
toward the vestibular nuclei. There are four vestibular nuclei: the superior vestibular nucleus, the lateral vestibular
nucleus, the medial vestibular nucleus, and the descending

From ENT Associates, Johnson City, Tenn. (Dr. Zajonc), and the Department of OtolaryngologyHead and Neck Surgery, University of
Texas Southwestern Medical Center at Dallas (Dr. Roland).
Reprint requests: Peter S. Roland, MD, Professor and Chairman, Department of OtolaryngologyHead and Neck Surgery, University
of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.,
Dallas, TX 75390-9035. Phone: (214) 648-3102; fax: (214) 6482246; e-mail: peter.roland@utsouthwestern.edu
Volume 84, Number 9

vestibular nucleus. Secondary vestibular aerent bers are

responsible for making connections with the contralateral
vestibularnuclei,oculomotorcontrolareas,thecerebellum,
and the spinal cord.
The chief neurotransmitter in the vestibular nuclei is
believed to be the excitatory amino acid glutamate. Electron-microscopeautoradiographydemonstratesglutamate
uptake sites in the lateral and inferior vestibular nuclei of
cats.The number of these sites is signicantly decreased by
previous sectioning of the vestibular nerve, indicating that
glutamate is involved in the transfer of signals from vestibular aerent neurons.1,2 Glutamate actions are mediated
by excitatory amino acid receptors. The four main families
of excitatory amino acid receptors are -amino-3-hydroxy5-methyl-4-isoxazole propionic acid receptors (AMPA),
N-methyl-D-aspartate receptors (NMDA), metabotropic
glutamate receptors, and kainic acid receptors. AMPA,
NMDA, and metabotropic receptors have been found in
the vestibular nuclei.1,3 Glutamate appears to act primarily
on AMPA-type receptors in the vestibular nuclei.4
Acetylcholine has been identied in primary vestibular
aerents of the vestibular nuclei.5 In cat studies involving
measurements of the eld potential of the lateral vestibular
nucleus, the application of acetylcholine produces the
same response as does stimulation of the vestibular nerve.
In addition, the response to stimulation of the vestibular
nerve is enhanced by inhibition of acetylcholinesterase
and blocked by the antimuscarinic drug scopolamine.1,6
Muscarinic receptors are acetylcholine-binding receptors
that have historically been demonstrated to be activated
by muscarine and blocked by atropine.
Knowledge of muscarinic receptor subtypes and their
pharmacologic actions is increasing, and more eective
anticholinergic medications with fewer side eects are in
development.Therearenowveknownstructuralsubtypes
of muscarinic receptors, designated m1 through m5. The
capitalized designations M1, M2, and M3 represent pharmacologic denitions, which are based on the actions of
various drugs that bind muscarinic receptors selectively. It
hasbeenshownthatthestructuraldesignationsm1through
m3correlatewiththepharmacologicdenitionsM1through
M3, respectively. In situ hybridization studies of rat brain
have demonstrated a unique distribution of muscarinic
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ZAJONC, ROLAND

receptor subtypes.7,8 The m1 receptors are abundant in

the cerebral cortex, striatum, and hippocampus. The m2
receptors are very rare in brain tissue; they are found in
signicant quantities only in the medial septum and pons
andinlesseramountsinthethalamus.Thedistributionofm3
receptors is similar to that of m1 receptors, but m3 receptors
are also found in several thalamic nuclei and brainstem
nuclei. The m4 receptors are found in the cortex, striatum,
and hippocampus, and the m5 receptors are found in very
low levels in the hippocampus and some brainstem nuclei.
Bovine brain studies have also revealed that muscarinic
receptors are found in the vestibular nuclei.9 Localization
of receptor subtypes to specic areas of the brain allows
for the possibility of designing drugs that have a more
specic action.
Another regulatory substance in the vestibular nuclei
is histamine. H1, H2, and H3 receptors are present in the
medial vestibular nucleus.1,10 Field-potential recordings
demonstrate that the H1 antagonist diphenhydramine
decreases ring of polysynaptic pathways in the lateral
vestibular nucleus.1,11
Other inhibitory actions in the vestibular nuclei are mediated by -aminobutyric acid (GABA). Two subclasses
of GABA receptorsGABA A and GABA Bare found
in the vestibular nuclei. GABA A receptors are bound by
benzodiazepines for agonist eects. GABA B receptors
bind baclofen for agonist eects. Neurons from the contralateral vestibular nuclei and Purkinje bers from the
cerebellum are believed to exert their inhibitory eects
via this GABAergic system.4

Neurokinin type 1 (NK1) receptors have been found in

some vestibular aerents.4 NK1 receptors bind substance P,
which is a neuroactive peptide. Substance P is thought to
be involved in many actions throughout the body, including the transmission of painful stimuli, but its role in the
vestibular system is unclear at this time.12
Other receptors found in the vestibular nuclei include D2
dopaminergic receptors, 5-HT1A and 5-HT2 (serotoninergic)
receptors, and 2- and 1-adrenergic receptors (table).4,13,14
Norepinephrine, which binds adrenergic receptors, has
been reported to block neuronal ring in the medial vestibular nucleus while it stimulates neurons in the lateral
vestibular nucleus.1,15
The cerebellum
The cerebellum is believed to function as a regulator of
movementandposturebycomparingmovementintention
with movement performance and regulating the actions
of descending motor neurons. Information gathered on
movement intention is called internal feedback. Sensory
information about motor performance is called external
feedback. Vestibular stimuli, representing spatial orientation,arealsoregardedasexternalfeedback.Thecerebellum
compares internal and external feedback signals in order
to regulate performance. The cerebellum is also believed
to contain a conceptual internal model that reects normal
sensory congruities for a given movement or posture.
Whenthecomparisonoftheinternalandexternalfeedback
signals does not fall within the parameters of this internal
model, a sensory mismatch is said to exist. These sensory

Table. Anatomic distribution of receptors25-37

Area
postrema

PCRF/NTS

Cerebellum

Vestibular
nuclei

Cortex

AMPA/NMDA

Muscarinic

Histaminic

H2

H3

H1

H1, H2, H3

H1, H2, H3

GABAergic

GABA A

GABA A

GABA A,
GABA B

GABA A,
GABA B

GABA A,
GABA B

Dopaminergic

D2, D3

D2, D3, D4

D3

D2

D1, D2, D4, D5

Serotoninergic

5-HT3

5-HT1A, 5-HT3

5-HT2

5-HT1A, 5-HT2

5-HT2, 5-HT3

-Adrenergic

-Adrenergic

1, 2

1, 2

Receptor

Key: PCRF = parvicellular reticular formation; NTS = nucleus tractus solitarius; AMPA = -amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid; NMDA = N-methyl-D-aspartate; GABA = -aminobutyric acid.

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VERTIGO AND MOTION SICKNESS. PART I: VESTIBULAR ANATOMY AND PHYSIOLOGY

mismatches can develop as a

Organizational model of the vomiting pathway
result of new environmental
stimuli or erroneous input
caused by disease. Upon the
detection of a mismatch, unVestibular
Nonvestibular
input
sensory input
comfortablesensationssuch
as disequilibrium, vertigo, or
motion sickness occur. The
cerebellumisthoughttoproVestibular
Cortex and limbic system
mote short-term regulation
nuclei
(possible secondary comparator)
and long-term habituation
to compensate for these mismatched signals.16
Inferior olive
Cerebellum
The idea that the cerebel(voluntary motor(primary comparator)
lum functions as a regulator
control information)
of the vestibular system is
supportedbytheobservation
that lesions of the cerebellar
Area postrema
occulusinhibitadjustments
(CTZ)
to the gain of the vestibulo16,17
ocular reex. Also, when
nodulectomywasperformed
Vomiting center
on cats, previously acquired
(PCRF and NTS)
habituation to caloric stimulation was lost. This lesion
Figure. Diagram represents the organization of the key areas and pathways for the production of
also severely interfered emesis secondary to motion sickness and vertigo. (CTZ = chemoreceptor trigger zone; PCRF =
with the cats further ac- parvicellular reticular formation; NTS = nucleus tractus solitarius.)
quisition and retention of
habituation.18 Additionally,
dogs have been rendered immune to motion sickness by nuclei. There are many other cortical and subcortical afablation of the nodulus and uvula of the cerebellum.19,20 ferent connections to the PCRF, but the exact means by
Neurons projecting from the inferior olivary nucleus to the which these pathways are integrated and this information
cerebellar nuclei and cerebellar cortex are also necessary is used to initiate vomiting are not clear.1
The nucleus tractus solitarius is closely related to the
for vestibular compensation. The inferior olivary neurons
are believed to carry information about voluntary motor PCRF. It serves as a major coordinating center for automovements.Destructionoftheinferioroliveinratsprevents nomic functions in the brainstem and undoubtedly plays
a signicant role in the vomiting reex. It receives vagal,
compensation after unilateral labyrinthectomy.1,21
vestibular, area postrema, and limbic inputs.4 The nucleus
tractus solitarius is rich in catecholamine-containing
Vomiting center
The area of the brainstem known as the parvicellular bers, has dense GABA input, and also contains 5-HT1A
reticular formation (PCRF) is believed to function as the receptors.
vomiting center, where the vomiting reex is initiated and
coordinated. Electrical stimulation of this area in cats has Area postrema
been shown to evoke vomiting.1,22 The PCRF is located The area postrema is located laterally along the oor of
ventral to the vestibular nuclei and medial to, as well as the fourth ventricle; it is not protected by the blood-brain
partially coextensive with, the elongated nucleus of the barrier. Early studies in dogs showed that ablation of this
spinal tract of the trigeminal nerve.The PCRF projects bers area prevented motion sickness. Later studies in both cats
to the motor nucleus of the facial nerve, to the hypoglos- and squirrel monkeys, which might have involved more
sal nucleus, and to the parabrachial nuclei, which contain accurate ablation of the area postrema, demonstrated no
some respiratory centers.1 These connections may allow protection from motion-induced emesis.1 The facts that
for coordination of the vomiting reex. Also, the PCRF is stimulation of the area postrema produces vomiting in
traversed by an extensive system of commissural bers that cats and that it is not protected by the blood-brain barrier
interconnect the vestibular nuclear complexes. It has been suggestthattheareapostremacontainsthechemoreceptor
suggested that ne axon collaterals may arise from these trigger zone for the production of vomiting in response to
commissural bers to connect the PCRF to the vestibular noxious chemicals.
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Organizational model
The currently understood model for the production of
vertigo or motion sickness includes a system in which
information is gathered from vestibular, visual, proprioceptive, and cortical activity (gure). This information is
then compared with an internal model of expected input
congruity. Detection of a stimulus mismatch promotes the
symptoms associated with vertigo and motion sickness.
This comparator also serves to promote habituation to new
environmentalstimuliorcompensationforerroneousinput
caused by disease.
It is interesting that some medications that are excellent
antiemetics do not prevent vertigo or motion sickness.
One such medication, ondansetron, is often used for the
prevention of chemotherapy-induced nausea. It acts on
5-HT3 receptors in the area postrema. Activity in this
location would not necessarily prevent stimulation of the
vestibularnucleifromultimatelycausingnauseaandvomiting. However, patients who are particularly susceptible to
motion sickness also demonstrate increased responses to
other vomiting center stimuli. This may provide a rationale
for the use of general antiemetics in vertigo associated
with nausea.23,24
The role of medications in treating vertigo and motion
sickness will be reviewed in part II of this article in an
upcoming issue.
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