March 2017 | Volume 8 | Article 1171
REVIEW
published: 30 March 2017
doi: 10.3389/fneur.2017.00117
Frontiers in Neurology | www.frontiersin.org
Edited by:
Bernard Cohen,
Icahn School of Medicine at
Mount Sinai, USA
Reviewed by:
Shinichi Iwasaki,
University of Tokyo, Japan
Richard D. Rabbitt,
University of Utah, USA
Hans VanDerSteen,
Erasmus University Rotterdam,
Netherlands
*Correspondence:
Ian S. Curthoys
ian.curthoys@sydney.edu.au
Specialty section:
This article was submitted to
Neuro-otology,
a section of the journal
Frontiers in Neurology
Received: 16January2017
Accepted: 14March2017
Published: 30March2017
Citation:
CurthoysIS, MacDougallHG,
VidalP-P and deWaeleC (2017)
Sustained and Transient Vestibular
Systems: A Physiological Basis for
Interpreting Vestibular Function.
Front. Neurol. 8:117.
doi: 10.3389/fneur.2017.00117
Sustained and Transient Vestibular
Systems: A Physiological Basis for
Interpreting Vestibular Function
Ian S. Curthoys
1
*, Hamish G. MacDougall
1
, Pierre-Paul Vidal
2
and Catherine de Waele
3
1
Vestibular Research Laboratory, School of Psychology, The University of Sydney, Sydney, NSW, Australia,
2
Cognition and
Action Group, CNRS UMR8257, Centre Universitaire des Saints-Pères, University Paris Descartes, Paris, France,
3
ENT
Department, Salpêtrière Hospital, Paris, France
Otolithic afferents with regular resting discharge respond to gravity or low-frequency
linear accelerations, and we term these the static or sustained otolithic system. However,
in the otolithic sense organs, there is anatomical differentiation across the maculae and
corresponding physiological differentiation. A specialized band of receptors called the
striola consists of mainly type I receptors whose hair bundles are weakly tethered to
the overlying otolithic membrane. The afferent neurons, which form calyx synapses on
type I striolar receptors, have irregular resting discharge and have low thresholds to
high frequency (e.g., 500Hz) bone-conducted vibration and air-conducted sound. High-
frequency sound and vibration likely causes uid displacement which deects the weakly
tethered hair bundles of the very fast type I receptors. Irregular vestibular afferents show
phase locking, similar to cochlear afferents, up to stimulus frequencies of kilohertz. We
term these irregular afferents the transient system signaling dynamic otolithic stimulation.
A 500-Hz vibration preferentially activates the otolith irregular afferents, since regular
afferents are not activated at intensities used in clinical testing, whereas irregular afferents
have low thresholds. We show how this sustained and transient distinction applies at the
vestibular nuclei. The two systems have differential responses to vibration and sound, to
ototoxic antibiotics, to galvanic stimulation, and to natural linear acceleration, and such
differential sensitivity allows probing of the two systems. A 500-Hz vibration that selec-
tively activates irregular otolithic afferents results in stimulus-locked eye movements in
animals and humans. The preparatory myogenic potentials for these eye movements are
measured in the new clinical test of otolith function—ocular vestibular-evoked myogenic
potentials. We suggest 500-Hz vibration may identify the contribution of the transient
system to vestibular controlled responses, such as vestibulo-ocular, vestibulo-spinal,
and vestibulo-sympathetic responses. The prospect of particular treatments targeting
one or the other of the transient or sustained systems is now being realized in the clinic
by the use of intratympanic gentamicin which preferentially attacks type I receptors.
Abbreviations: ABR, auditory brainstem response; ACS, air-conducted sound; BCV, bone-conducted vibration; Fz, the
midline of forehead at the hairline; GVS, galvanic vestibular stimulation; IO, inferior oblique eye muscle; ITG, intratympanic
gentamicin; MSNA, muscle sympathetic nerve activity; VEMP, vestibular-evoked myogenic potential; cVEMP, cervical
vestibular-evoked myogenic potential; oVEMP, ocular vestibular-evoked myogenic potential; OCR, ocular counterrolling;
PID, proportional–integral–derivative; SCD, semicircular canal dehiscence; n10, the initial negative potential of the oVEMP at
about 10ms latency; SCM, sternocleidomastoid muscle; VIN, vibration-induced nystagmus; VsEP, vestibular-evoked potential.
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Curthoys et al. Sustained and Transient Vestibular Systems
Frontiers in Neurology | www.frontiersin.org March 2017 | Volume 8 | Article 117
KEY CONCEPTS
Vestibular aerents with regular resting discharge constitute a
system for signaling sustained vestibular stimuli, such as main-
tained head tilts.
Vestibular aerents with irregular resting activity constitute a
system for signaling transient vestibular stimuli.
Otolith irregular aerents originate from a specialized region
of the otolithic maculae called the striola and form calyx synapses
on type I receptors which have fast membrane dynamics.
Otolith irregular aerents are selectively activated by high-
frequency (~500 Hz) low-intensity BCV and ACS. Regular
otolithic aerents do not respond to these stimuli at comparable
levels.
Ototoxic antibiotics selectively aect type I receptors and thus
the transient system.
e 500-Hz vibration causes eye movements in humans, and
the preparatory myogenic potentials for these movements are the
ocular VEMPs which index the activity of the transient system.
Vestibular nucleus neurons exhibit transient or sustained
responses, as in the periphery.
INTRODUCTION
e early recordings of the response of cat single vestibular
nucleus neurons to angular acceleration established that dier-
ent neurons had very dierent response patterns to identical
angular acceleration stimuli (
1–3). Some neurons showed a
sustained response to maintained stimuli (termed tonic neu-
rons), whereas others showed a transient response to the same
stimulus (termed kinetic neurons). ese results were conrmed
and extended in later research which also showed a similar
distinction applied to primary semicircular canal (
4–6) and
otolithic neurons (
7–9). at research and later work showed
how these characteristics were associated with the regularity of
resting discharge of primary aerent neurons—neurons with
regular resting discharge showing sustained (tonic) responses
to maintained stimuli, whereas neurons with irregular resting
discharge showed transient (kinetic or phasic) responses to the
same stimuli (
10). ere is a continuum of regularity, and we
will use the terms sustained and transient for convenience to
refer to the ends of this continuum.
is review shows how recent evidence about otolithic
responses to sound and vibration demonstrates the value of
applying this distinction of sustained and transient from the
receptors to the behavioral responses. We suggest it is a valuable
principle for interpreting the results of vestibular functional
tests—focusing attention on dierent aspects of the response
rather than just treating the whole response as uniform. is
is especially clear with the otoliths, but even with the canals it
is useful to distinguish between responses to the onset of an
acceleration, as opposed to responses during maintained accel-
erations. e paper will not cover particular areas in great detail
since it has already been done in many other reviews to which
the reader is referred. Instead, we aim to bring together evidence
from physiology to highlight the relevance of this evidence for
understanding vestibular function testing as used clinically. e
rst part of this review covers physiological evidence and the
second part covers the application of the sustained-transient
principle to vestibular responses.
PHYSIOLOGICAL DATA
Peripheral Vestibular Physiology
e regularity of resting discharge of vestibular primary aerents
is associated with a range of characteristics, such as conduction
velocity, axon thickness, and a range of response dimensions,
such as gain to acceleration, sensitivity to electrical vestibular
stimulation [including so-called galvanic vestibular stimulation
(GVS)—DC or low-frequency electrical stimulation of the sense
organs]. While aerents from all vestibular sense organs are
activated by GVS at approximately equal thresholds (
11) irregular
aerents from each sense organ have a signicantly lower thresh-
old for GVS activation than regular neurons.
Angular and linear acceleration of the whole animal have been
the usual stimuli in studies of vestibular physiology, and it has
been shown in a number of species that regular and irregular neu-
rons have dierent frequency responses—with irregular aerents
(both canal and otolithic) typically having an increased gain and
increasing phase lead with increasing frequency—interpreted as
showing that irregular aerents are responsive to both accelera-
tion and change in acceleration (jerk). e characteristics of regu-
lar and irregular neurons have been summarized by Goldberg’s
denitive review of vestibular aerent diversity (
10).
In summary, rst-order vestibular neurons with regular rest-
ing discharge comprised bouton and dimorphic neurons which
synapse on the barrel-shaped type II receptors mainly in the
peripheral zone of the cristae and in the extrastriolar zone of the
otolithic maculae. ey are characterized by thin or medium-
sized, slow conducting axons and with a low sensitivity to head
rotation and relatively low sensitivity to GVS. Irregular rst-order
vestibular neurons comprised calyx and dimorphic neurons,
which innervate the central cristae and the striolar zones of the
otolithic maculae, synapsing predominantly on the amphora-
shaped type I receptors (Figure 1). ey are characterized by
large- or medium-sized fast conducting axons. eir sensitivity
to GVS is on average six times higher than that of the regular
aerents (
11, 12).
In addition, some vestibular aerents show a sensitive
response to sound and vibration (
13–15). Recent research has
extended this account (16–21). e major result is that the otolith
irregular neurons originating from a special band of receptors
We suggest that it is valuable to view vestibular responses by this sustained-transient
distinction.
Keywords: vestibular, utricular, sound, vibration, otolith, vestibular-evoked myogenic potential, vestibulo-ocular
reex, vestibular-evoked myogenic potentials
FIGURE 1 | (A) Schematic representation of a dorsal view of the whole
guinea pig utricular macula, with the arrows showing the polarization of
receptor hair cells. The dashed line is the line of polarity reversal which used
to be called the striola, but more recently it is recognized that the striola is a
band of receptors as shown in the adjacent whole mount. (B) To show a
corresponding whole mount of a guinea pig utricular macula treated by
calretinin—the band of cells comprising the striola is clearly visible (
54).
Reprinted from Ref. (
21), Copyright (2012), with permission from Elsevier.
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on the otolithic macula called the striola (Figure2) respond to
both air-conducted sound (ACS) and bone-conducted vibration
(BCV) up to very high frequencies (>1,000Hz), while regular
neurons—mainly from extrastriolar areas—show modest or
absent responses to such stimuli (see Figure2).
Detailed analysis of the timing of the action potentials of
irregular aerents evoked by sound or vibration show they are
phase locked to individual cycles of the ACS (up to 3,000Hz) or
BCV stimulus (up to 2,000Hz) (Figure3) (
20). Phase locking
means that the exact timing of the action potential is locked to
a particular phase angle (or a narrow band of phase angles) of
the stimulus waveform at that frequency (Figure3). It does not
mean the cell generates an action potential once per cycle up
to thousands of Hertz, but that the moment when the cell res
is locked to the particular narrow band of phase angles of the
stimulus waveform at that frequency. A vestibular aerent may
miss many cycles, but when it does re it is locked to the phase
angle of the stimulus waveform. e phase locking of vestibular
aerents is similar to the well-documented phase locking of coch-
lear aerents to ACS, known since the study of Rose etal. (
22).
In stark contrast, regular neurons (canal or otolith) are not
activated by ACS or BCV stimuli—at least in response to stimulus
levels used in clinical studies of human otolithic function (see
Figure2B)—and so do not show phase locking. As the example
in Figure 2 shows, regular neurons simply continue to re at
their resting rate during stimuli which are much more intense
than those which cause activation of irregular neurons. Irregular
aerents have very low thresholds to BCV—at or below the levels
needed for auditory brainstem response threshold. McCue and
Guinan (
13, 23, 24) showed that irregular saccular aerents were
activated by ACS, and Murofushi et al. (
14, 25, 26) reported
that saccular aerents could be activated by high intensity ACS
click stimuli. ese results have been conrmed years later (17,
20). Curthoys et al. (18) tested the specic, sensitive response
of irregular utricular neurons to 500Hz BCV in guinea pig and
found that very few utricular regular aerents were activated
by high intensity ACS or BCV stimulation. at has also been
conrmed in rat: where few regular aerents are activated even
by intense ACS, although ACS is an eective stimulus for irregu-
lar neurons (
27, 28). It has been shown that both saccular and
utricular irregular aerents are activated by both 500 Hz ACS
and BCV (21).
is clear phase locking of irregular vestibular aerents to
such high frequencies of ACS and BCV stimulation has posed
questions about how vestibular hair cell transduction mecha-
nisms operate at such high frequencies. Vestibular responses are
usually thought of as being for stimuli to a few tens of Hertz, not
to stimuli of over 1,000Hz. Furthermore, the fact that irregular
and regular aerents have such very dierent responses to sound
and vibration raises the possibility of the use of sound and vibra-
tion to probe the relative contribution of irregular (transient) and
regular (sustained) otolithic aerents to various physiological and
even behavioral responses, and thus the likely functional roles of
these classes of aerents. One other question is of the mechanisms
responsible for the regularity of resting discharge, which is now
clearly established as being due to membrane characteristics of
the aerent neurons (
29–31).
In these studies, the usual result is that in animals with intact
bony labyrinths, aerent neurons (either regular or irregular)
from semicircular canals are not activated or only weakly acti-
vated by very intense stimulus levels of 500Hz BCV and ACS
(
18, 27, 28). However, there are drastic changes in neural response
aer a small hole is made in the bony wall of the semicircular
canal (even just 0.1mm diameter in the case of the guinea pig).
is opening, called a dehiscence or a semicircular canal dehis-
cence (SCD) results in a previously unresponsive irregular canal
aerent being activated by sound and vibration at low stimulus
levels (
32, 33). e evidence is that the SCD decreases the imped-
ance of the labyrinth and so, it is argued, acts to increase the uid
displacement suciently to deect the receptors.
More recently, it has been found that even in animals with
intact bony labyrinths, irregular canal aerents can be activated
by very low-frequency BCV and indeed phase lock to 100 Hz
BCV (
17). However, the response of these irregular canal
aerents declines with increasing BCV frequency, and so these
irregular canal aerents are not activated at 500Hz BCV even
at high stimulus levels (
17, 34, 35). In light of this evidence, we
conclude 500Hz BCV is a selective stimulus for irregular otolithic
neurons. It is probable that this activation of canal aerents by
such low-frequency BCV is the neural mechanism responsible for
the clinical test of vestibular function—skull vibration-induced
nystagmus (
35, 36).
Mechanism
How can vestibular receptors and irregular otolithic aerents
respond to such very high frequencies? Textbook schematic
diagrams of the cristae and otolithic maculae give the impres-
sion that each vestibular sense organ is a uniform structure with
receptor hair cells of similar height. It is now clear that is the very
opposite of what is the case. Each macula and each crista shows
complex anatomical dierentiation across the surface. e recep-
tor types are dierentially distributed with predominantly type I
receptors at the striola (
37). e extrastriolar receptors appear to
be more tightly tethered to the otoconial membrane (38) than are
FIGURE 2 | Resting discharge pattern and response to stimulation of an irregular and a regular afferent. (A) Time series of an irregular otolith neuron
during stimulation by 500Hz bone-conducted vibration (BCV) and air-conducted sound (ACS). The top trace (a) shows the command voltage, indicating when the
stimulus is on. The second trace shows the action potentials by extracellular recording. The three bottom traces (x, y, z) show the triaxial accelerometer recording of
the stimulus. The left panel is an example of response to BCV stimulation and the right of the response to ACS stimulation of the same neuron, showing it is clearly
activated by both stimulus types. Note the scale of stimulus intensity in g at the left margin between traces x and y. The irregular resting discharge is seen before
stimulus onset, followed by a large increase in ring during both BCV and ACS. (B) Time series of a regular semicircular canal neuron during stimulation by BCV and
ACS as above. The regular discharge is seen before the stimulus onset. The stimuli are far stronger than in panel (A), but there is no evidence of activation of this
regular neuron by these strong stimuli. From Ref. (
19), Curthoys and Vulovic, © Springer-Verlag, 2010, reproduced with permission of Springer.
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Curthoys et al. Sustained and Transient Vestibular Systems
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the striolar receptors. Receptors across the maculae (and cristae)
are not of uniform height: at the striola of the maculae and at
the crest of the cristae, the receptor hair bundles are shorter (and
stier) than in the extrastriolar areas. Remarkably, this height
dierence can even be seen in Hunter-Duvar’s scanning electron
micrograph of the whole utricular macula of the chinchilla (
39).
Morphological evidence shows apparently looser tethering of the
hair bundles of striolar receptors to the overlying otolithic mem-
brane in comparison with comparable receptors in the periphery
of the macula (extrastriolar receptors) (38–44).
Most models of otolithic stimulation model displacement of
the gelatinous otoconial membrane with otoconia adherent to
its upper surface in response to linear acceleration stimulation,
e.g., Ref. (
45, 46). In such models, frequencies in the kilohertz
range are beyond the upper mechanical cuto of the system.
Nevertheless, it is clear from the neural recordings that action
potentials in individual neurons do respond and are phase locked
to a narrow band of phases for stimulus frequencies even as high
as 3,000 Hz (Figure 3). Phase locking of irregular vestibular
aerents shows that every single cycle of the stimulus waveform is
the adequate stimulus for the receptor–aerent complex. For this
to happen at kilohertz frequencies, the receptor membrane and
calyx membrane must have extremely fast dynamics, and indeed,
the very fast dynamics of vestibular type I receptors and calyx
membranes have been shown beautifully by the studies of Songer
and Eatock (
47). ey used intracellular recording of receptor
and calyx potentials in response to mechanical displacement of
the hair bundle at very high frequencies and demonstrated the
very fast membrane and synaptic dynamics of type I vestibular
receptors and calyx aerents.
In light of this phase locking up to such high frequencies,
we have suggested that the hair bundles of the striolar otolithic
FIGURE 3 | Showing phase locking of a single utricular neuron.
(A,B)Time series of successive action potentials of the neuron to
bone-conducted vibration (BCV) at 985Hz. Panel (B) shows 142 action
potentials superimposed and the onset of the action potential is shown by
the arrow. The red trace shows the x channel of the 3D linear accelerometer.
Panel (A) shows the circular histogram of the phases of the action potentials
clustered around a mean of 129.1°, with angular deviation 28.7°. The test of
circular uniformity, Rayleigh’s z, is highly signicant showing the probability
of a uniform phase distribution is <0.001. The neuron misses some cycles,
but when it res is locked to the stimulus waveform. (C–F) Histograms of
interspike intervals to show phase locking in the same utricular afferent
neuron in guinea pig at two high frequencies of BCV (C,E) and air-
conducted sound (ACS) stimuli (D,F). The bin width is 0.16ms. The dots
below each histogram show integral multiples of the period for the given
stimulus frequency. The clustering around these integral multiples
demonstrates phase locking at both frequencies. This gure is a replotting
of the histograms of the response of neuron 151011, which has been
published as Figure 10 of Curthoys etal. (
20). Reprinted from Ref. (20),
©2016, with permission of Elsevier.
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Curthoys et al. Sustained and Transient Vestibular Systems
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receptors are deected by each cycle of uid displacement caused
by the stapes pumping into the uid-lled inner ear (
33). is
uid displacement is small but vestibular receptors have great
sensitivity: the maximum sensitivity of the hair bundles of
vestibular receptors is around 0.40° of cilia deection, similar to
the value for cochlear receptors (0.39°) (
48), caused by just a few
nanometers of uid displacement.
We (33) have put forward the following account. Striola
receptors are predominantly amphora-shaped type I receptors
(37) and have short sti hair bundles (44, 49), apparently loosely
attached to the overlying otolithic membrane (
38). is uid
motion within the uid-lled hole in the gel-lament layer of
the otolithic membrane produces a drag force on the hair bun-
dle, causing it to deect. e uid environment is so viscously
dominated (Reynold’s Numbers of 10
−3
to 10
−2
) that bundles
move instantaneously with any uid movement. In other words,
this coupling of uid motion to hair bundle is so strong that the
hair bundle displacement follows the uid displacement almost
exactly (
17). us, uid displacement is synonymous with hair
bundle displacement.
Complementing that anatomical evidence is physiological
evidence from recordings of primary otolithic aerent neurons
originating from striola type I receptors as shown by neurobiotin
labeling (
21) (Figure4A), these aerents have irregular resting
discharge and are activated by ACS and BCV up to very high fre-
quencies. ere is evidence that it is the striolar receptor hair cells
(probably mainly type I receptors) which respond to frequencies
far higher than modeling of canal or otolith mechanics indicates.
is account is indirectly conrmed by the eect of SCD on the
response of irregular canal aerents from the crest of the crista
(
17). Prior to the SCD, these neurons do not respond to ACS or
BCV at the levels used in human clinical testing, whereas aer
the SCD [which acts to increase uid displacement (50, 51)] these
same irregular aerents show strong phase-locked activation to
the same stimulus (33) (Figure4B).
Why is it that regular aerents are not responsive to vibra-
tion and sound at such high frequencies? One possible reason is
that regular neurons synapse on few type I receptors mainly in
extrastriolar areas, whereas their largest number of synapses are
usually on multiple extrastriolar type II receptors with long cilia
apparently more tightly tethered to the overlying gel-lament
layer (
38). In this way, uid displacement would be less likely
to activate type II receptors because, instead of projecting into
holes in the overlying membrane, the hair bundles project into
the gel-lament layer or cupula, which limits the deection of
the receptors.
Mechanism—Summary
ere are two issues: (1) the regularity of resting discharge and
(2) the response to sound and vibration determined by recep-
tor mechanisms. ese are two dierent aspects of the aerent
response, and the evidence is that they are determined by dier-
ent factors.
(1) Recent evidence shows that regularity of vestibular aer-
ent resting discharge is due to membrane characteristics
(
29–31). at has been most convincingly shown by recent