Testing for Tinnitus in Animals
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Testing for Tinnitus in Animals
Henry E. Heffner, Ph.D., Department of Psychology, University of Toledo
2015 SHAV Convention, March 26, Session 25, 3:45-4:45 PM
Introduction characteristics of the tinnitus are (e.g., noise or tonal
and, if tonal, what pitch), and how long it will persist.
A procedure for determining if an animal has tinnitus is
Thus, one cannot always be certain that a particular
essential for testing drug treatments for tinnitus as well
treatment will induce tinnitus in an animal or what the
as for discovering its neurological basis. However,
characteristics of the tinnitus will be.
testing an animal for tinnitus is complicated because the
procedures used to induce tinnitus also cause other The second point is that procedures used to induce
auditory problems, such as hearing loss and tinnitus will affect hearing in other ways (e.g., Davis et
hyperacusis, that can confound the results. The tests al., 1950; Cazals, 2000). Specifically, loud sound and
developed so far can be classified into three types. ototoxic drugs sufficient to cause tinnitus also cause a
significant hearing loss. Another effect of such
First are tests in which animals are trained to
treatments is that they may cause physical sounds to be
discriminate between the presence and absence of a
perceived as distorted. Thus, it is necessary to rule out
physical sound and then tested to determine if a
the possibility that an animal’s responding is affected
tinnitus-inducing agent causes the animals to respond as
by changes to its hearing other than tinnitus.
if a sound is present.
Second are tests that look for an interaction between
tinnitus and physical sounds such as determining if a Tinnitus produced by exposure to loud sound
tinnitus-inducing agent enhances the perception of a There have been three relatively comprehensive studies
sound or degrades the ability to detect a temporal gap in on tinnitus caused by exposure to loud sound (Davis et
an ongoing sound. al., 1950; Loeb & Smith, 1967; Atherley et al., 1968;
Third are tests in which animals are trained in a sound these studies are discussed in Heffner & Heffner, 2012).
localization task to indicate whether a sound comes Their results can be summarized as follows:
from their left or right side. Tinnitus is then induced in 1. Exposure to loud sound sufficient to cause tinnitus
one ear by exposing it to a loud sound and the animals produces an immediate hearing loss; if the exposure
tested to determine which side they go to when no does not cause permanent damage, both the hearing
sound is presented. loss and tinnitus subsides in a few days.
These procedures can be compared on whether they 2. The tinnitus is more likely to have a definite and
would reliably detect tinnitus in humans and whether constant pitch if it is produced by exposure to tones
the results would be confounded by hearing loss and or narrowband noise rather than broadband noise.
hyperacusis. Some tentative conclusions on the neural 3. The exposure may affect the perception of physical
mechanisms underlying tinnitus can be made. stimuli, causing them to sound distorted, at least
In evaluating tinnitus in animals, the first step is to during recovery from the temporary portion of the
determine if the results are similar to what we know hearing loss. (Davis et al, 1950, noted that exposure
about tinnitus in humans. Therefore, we will begin with to loud sound could cause a pure tone to sound
what is known from human studies in which subjects “rough”, “noisy”, or “buzzing”, or to cause a single
were either exposed to loud sound or given salicylate tone to sound like two tones presented in
and their resulting tinnitus evaluated. combination, which they referred to as “doubles”.)
4. It is likely that exposing one ear to loud sound will
Tinnitus in humans cause any resulting tinnitus to be lateralized to that
ear. However, there are rare reports of exposing one
Let us begin with two general points. First, although it
ear causing tinnitus to be reported in the other ear.
is well established that loud sound and ototoxic drugs,
However, this apparently occurs when the other ear
such as salicylate, cause tinnitus in humans, there is
has recently been exposed, suggesting that presenting
significant variability between subjects (McFadden,
sound to the opposite ear may reinstate tinnitus in a
1982). Specifically, humans differ in whether a
previously exposed ear.
particular level or dosage induces tinnitus, what the
2
5. There is considerable individual variation in both the 3. The degree of hearing loss varies with the amount of
hearing loss and the pitch of the tinnitus induced by a salicylate, but the relationship between plasma
loud sound. salicylate levels and hearing loss is not perfect and
6. Pitch of the tinnitus: there is much individual variation (Cazals, 2000).
Some studies indicate that the hearing loss is equal at
Tone-induced tinnitus: The median pitch tinnitus
all frequencies whereas others have found that the
induced by a loud tone is higher than the frequency of
loss is greater at high frequencies (cf., McCabe &
the exposing tone; it is also higher than the frequency
Dey, 1965; Myers & Bernstein, 1965).
of the maximum hearing loss.
4. No relationship between the pitch of the tinnitus and
Noise-induced tinnitus: The median pitch of tinnitus
the hearing loss has been observed, possibly because
induced by a loud noise is usually near or slightly
the audiograms have not been sufficiently detailed, as
higher than the center frequency of the exposing
they are typically conducted in octave steps, or
noise; on the other hand, it is lower than the
because they did not extend to frequencies above 8
frequency of maximum hearing loss.
kHz (McFadden, 1982).
5. Besides inducing tinnitus and hearing loss, salicylate
Side Note: An interesting observation made by Davis has been found to affect the perception of sound, the
et al. (1950) is that while the hearing loss caused by a most prominent example being a hypersensitivity that
particular sound varies between individuals, it does not causes some sounds to be especially irritating, a
vary much within an individual. In other words, a phenomenon also referred to as hyperacusis.
particular sound will cause the same hearing loss in Salicylate also affects other auditory functions such
both ears of a subject. This leads to a research topic: as frequency selectivity, temporal integration, and
Specifically, what are the anatomical, physiological, gap detection (Cazals, 2000).
histological, and biochemical characteristics of the ears 6. Two final points are especially noteworthy.
of individual animals that are resistant to noise-induced
hearing loss as opposed to those that are susceptible. First, the effect of salicylate is highly variable; not
Might there be some treatment that would make ears only do the hearing loss and tinnitus vary between
more resistant to noise-induced hearing loss? individuals with the same blood levels of salicylate,
but the blood levels of salicylate among individuals
given the same dosage may also differ noticeably
Tinnitus produced by salicylate (Cazals, 2000). Thus, animals given the same dose
A number of studies have examined the effect of of salicylate would be expected to vary in their
salicylate on hearing and the auditory system; for tinnitus.
reviews, see McFadden, 1982; Cazals, 2000 (also Second, salicylate crosses the blood brain barrier
reviewed in Heffner & Heffner, 2012). giving it the potential to cause tinnitus by acting
1. The most noticeable effects of high doses of directly on the central auditory system. However,
salicylate, usually administered orally, are tinnitus elderly people with hearing loss resulting from loss
and hearing loss, both of which increase during the of hair cells in the cochlea that encode high
initial days of treatment and then level off, fluctuate, frequencies (presbycusis) do not develop tinnitus
or decrease. The effects are reversible and typically when given salicylate (Schuknect & Gacek, 1993;
disappear a few days after treatment is stopped Mongan et al., 1973). This suggests that it is the
(Cazals, 2000). (However, a college student once told effect of salicylate on hair cells that causes tinnitus.
me that she has a permanent hearing loss caused by
high doses of aspirin that were prescribed by her Animal Tests of Tinnitus
physician, although this could have been caused by
Nearly a dozen behavioral procedures have been used
exposure to loud sound while she was being treated.)
to test animals for tinnitus and their designs are often
2. The pitch of the tinnitus is usually described as a complex. This talk will cover the general types of
high-frequency tone or noise, although it is procedures with a few specific examples, comparing
occasionally lower in frequency. One study found them on the following points:
pitch matches ranging from 14.5 kHz down to 900 Hz
Validity
with the loudness of the tinnitus matched to external
tones of over 60 dB (Day et al., 1989). However, 1. Would the tinnitus-inducing agent used cause
untrained subjects are not always good at making tinnitus in humans?
pitch matches. 2. Would the procedure detect tinnitus in humans?3
3. Has the procedure been tested by simulating tinnitus likely to stop drinking when the noise was turned off
with physical sounds? because they would still hear their tinnitus.
4. Would the test be affected by an accompanying The results showed that animals given salicylate were
hearing loss? less likely to stop drinking when the noise was turned
5. Would the test be affected by hyperacusis or other off than were control animals that were not given
side effects such as diplacusis? salicylate, a result suggesting that the treatment animals
had developed tinnitus (Fig. 1).
Utility
With regard to the criteria:
6. Can the procedure be used to determine the pitch of
tinnitus? 1. The salicylate dosage would be expected to cause
tinnitus in humans.
7. Does the procedure rely on group averages or can
tinnitus be assessed in individual animals? 2. Training subjects to make a response when they hear
a sound is similar to asking human subjects to report
8. Can the procedure follow an animal’s tinnitus over
when they hear a sound.
time?
3. Animals show a positive response when presented
with sounds that simulate tinnitus.
1. Tests requiring animals to discriminate sound 4. Although the test could be affected by hearing loss if
from silence the animals could no longer tell when the sound was
The first tinnitus test to be developed for animals on, control tests in which the amplitude of the noise
consisted of training rats to discriminate the presence of was reduced to simulate the hearing loss ruled out
sound from absence of sound; this was done by having that possibility. In addition some studies exposed one
them drink from a water spout in the presence of ear of the animals, leaving the other ear with normal
broadband noise and training them to stop drinking hearing.
when the noise was turned off by administering foot 5. There is no reason to think that hyperacusis would
shock at the end of a 60-sec silent interval (e.g., affect the results.
Jastreboff et al., 1988; Jastreboff & Brennan, 1994).
6. The procedure has been used to determine the pitch
The rats were then given salicylate to induce tinnitus
of tinnitus by administering salicylate during training
and tested with the idea that the animals would be less
so that the perception of an animal’s tinnitus would
Fig. 1. Effect of exposing one ear of hamsters to10 kHz, 124 dB for .5 to 4 hours. Shaded area indicates range of
unexposed animals. Scores below the range of the unexposed animals suggest that an exposed animal perceived a
sound when the physical sound was turned off, i.e., tinnitus. The effect increased with the duration of the exposure
(From Heffner & Harrington, 2002.)4
become associated with foot shock. Testing consisted exposed in one ear to octave noise centered at 16 kHz
of presenting tones during the silent intervals in (110-120 dB, 1 hr). They were then tested with a 10-
which it was found that the rats were more likely to kHz tone which the rats treated as a safe signal,
stop drinking when high-frequency tones were especially if it was sufficiently loud (e.g., 80 dB). At 8-
presented, suggested that their tinnitus was 10 kHz or 9 weeks post-exposure, the exposed animals showed
higher in pitch. slightly better performance than unexposed control
7. The test requires groups of animals as the results animals to the 10-kHz tone. The explanation of for this
vary from one individual to the next. is that the exposed rats developed tinnitus that was
around 10 kHz in pitch and it interacted with the 10-
8. The test cannot be used to follow an animal’s tinnitus
kHz tone to make it “noiser”.
over time as the foot shock is turned off during
testing allowing the animals to learn that they do not This procedure does not meet the first two criteria.
need to stop drinking when the noise is turned off. With regard to the sound used to induce tinnitus, it is
known that exposing humans to that amplitude of
octave noise will cause tinnitus with a 5-min. exposure
2. Interaction of tinnitus with external tones (Atherley et al., 1968; Loeb & Smith, 1967). Thus, the
In one such test, the animals are trained to press a lever one hour exposure the rats received was probably
to get food while a broadband noise is on and to stop sufficient to cause tinnitus. However, the onset of
pressing when the noise is turned off to avoid foot tinnitus due to exposure to loud sound in humans is
shock (Bauer & Brozoski, 2001; Turner et al., 2006). immediate and, at least at the shorter durations used in
The animals may be exposed to a tinnitus inducing the human studies, is transient. Thus, it is surprising
agent before training begins, in which any tinnitus that the animals did not immediately test positive for
would then be associated with shock. Alternatively, the tinnitus. In addition, there is no convincing evidence of
animals can be exposed after training, in which case humans developing tinnitus months after exposure to a
tinnitus might serve as a signal that it is safe to press sound that initially did not cause tinnitus. Moreover,
the lever. tinnitus in humans is not known to interact with
The test for tinnitus involves presenting various tones physical sounds to produce a “noisier” sound, although
and observing whether an animal’s response to a hyperacusis does. Finally, presenting a tone of the same
particular tone differs from the responses of unexposed pitch as one’s tinnitus is known to suppress the tinnitus
control animals, a result taken to indicate tinnitus with a (e.g., McFadden, 1982). Therefore, the results of this
pitch similar to that of the tone. procedure do not match what we know about tinnitus in
humans and it therefore seems unlikely that this is a
Figure 2 presents the results of a test in which rats were
valid test for tinnitus in animals.
trained to lever press when background noise was on
(safe signal) and to stop pressing when the noise was
turned off (warning signal). The animals were then 3. Startle reflex inhibition gap procedure
The startle reflex inhibition procedure involves
reducing an animal’s startle response to a sudden, loud
sound by presenting a weaker stimulus just before the
startle sound is presented; a reduction in the amplitude
of the startle response indicates that the animal
perceived the preceding stimulus. A common use of
this procedure has been to determine the audibility of
sounds by observing whether they reduce the startle
response. However, in the tinnitus test, the startle
response is reduced not by another sound, but by
preceding the startle stimulus with a brief gap in an on-
Fig. 2. Rats trained to press a lever in the presence of going background sound. The hypothesis is that tinnitus
background noise (safe signal) and to stop pressing during would interfere with detecting the gap if it were similar
silence (warning signal) also responded to a 10-kHz tone in pitch to the background sound.
as a safe signal. Rats exposed to loud sound pressed more In this procedure, an animal is placed in a test cage with
than the unexposed animas 8-9 weeks post-exposure,
a low-level background sound, such as 60-dB
which was taken as the appearance of delayed tinnitus that
made the 10-kHz tone sound noisier. (From Turner et al.,
narrowband noise. A startle sound (e.g., 115-dB, 20-ms
2006.) broadband noise burst) is presented at random intervals5
and the animal’s startle response is measured by a strain human subjects show that it does not (e.g., Fournier &
gauge attached to the test cage. The startle sound is Hebert, 2012; Shadwick & Sun, 2015). Finally, this
either presented alone or preceded by a gap in the procedure overlooks the fact that sounds similar in pitch
background sound, typically a 50-ms gap beginning to a subject’s tinnitus would be expected to suppress the
100 ms before the startle stimulus. A reduction in the tinnitus.
average startle response that is caused by preceding the
startle sound with a gap is used to indicate that the
animal perceived the gap (e.g., Turner et al., 2006).
6. Two-choice sound localization procedure
Thus, by testing animals with different background The sound localization procedure is based on the idea
sounds, typically narrow band noise centered at that exposing one ear to a loud sound will cause tinnitus
different frequencies, it is thought possible to determine in that ear and that an animal trained to report whether a
the pitch of their tinnitus. sound came from its left or right side will, in the
This is a popular procedure because it involves no absence of a physical sound, respond by going to the
training of either the animal or the experimenter. One side of the ear that has tinnitus (Heffner & Koay, 2005;
simply purchases the equipment, puts the animal in the Heffner, 2011).
test box, and the computer does the testing In this test, an animal is trained to make a left or right
automatically (Fig. 3). response to sounds coming from its left or right side,
respectively. Correct responses are rewarded with water
whereas incorrect responses are followed by a mild
shock (Fig. 4). Silent trials, in which no sound is
presented, are interspersed among the sound trials. The
animal receives neither reward nor punishment for its
responses on silent trials and its side preference on
these trials is recorded. Importantly, feedback on the
sound trials is changed so that randomly half of the
sound trials are followed by reward or punishment to
reduce the possibility that an animal will notice that
responses to silent trials are never rewarded or
punished. This permits long term testing of an animal’s
tinnitus.
Fig. 3. Startle Reflex Response System. The rat is placed in a
cylinder sitting on sensors that detect its startle response. A
computer presents the startle sound and records the animal’s
reflexive response.
The gap detection test suffers from some of the same
problems as the previous procedure. First, there is no Fig. 4. Sound localization test cage with a hamster. An
evidence that tinnitus interacts with external sounds, animal is rewarded for going left and right to left and right
including affecting the detection of gaps in sound. sounds, respectively. Trials in which no sound is presented
Hearing loss, on the other hand, is known to affect gap (silent trials) are given and tinnitus is induced in the ear
detection thresholds. Second, it presumes that tinnitus opposite the animal’s preference on those trials. The animal
would interfere with the perception of gaps in sounds is then tested to see if it shifts its responding to the side of
similar in pitch to the tinnitus, but recent studies of the exposed ear.6
The side preference of an animal on the silent trials is 2. Asking subjects to report in which ear they hear have
determined and the animal is exposed to a loud sound tinnitus is a standard procedure with human patients.
in the ear opposite its side preference; it is then tested to 3. Animals show a positive response when presented
see if it shifts responding on silent trials to the side of with sounds that simulate tinnitus.
the exposed ear. This is conceptually equivalent to
4. Hearing loss in one ear is unlikely to cause a positive
human patients reporting the ear in which they hear
response because, if anything, an animal would
their tinnitus. Besides being able to indicate whether an
respond to the unexposed (normal) ear in which they
individual animal has lateralized tinnitus, the two-
hear the incidental sounds of their movements.
choice procedure would not be expected to be
confounded by the hearing loss that accompanies 5. There is no reason to think that hyperacusis would
exposure to loud sound; indeed, a hearing loss in the affect the results as the animals are responding when
exposed ear would be expected to cause an animal to no external sound is presented.
respond to the side of its unexposed ear as any 6. The procedure does not indicate the pitch of an
incidental sounds made by the animal would be animal’s tinnitus.
perceived in that ear. 7. The test uses each animal as its own control so that
Because the animals are never given feedback on the individual results, as opposed to group averages, are
silent trials, and their responses on sound trials are only analyzed, providing for greater statistical power.
given feedback half of the time, responding to their 8. The test can follow an animal over time allowing
tinnitus may not easily habituate, making it possible to recovery to be monitored. However, there is always
follow the time course of the tinnitus. An example of the possibility that an animal will habituate to its
the results of this test are shown in Figure 5. tinnitus.
Side Note: After recovering from one exposure, the
animals were tested by exposing them to another loud
tone, with each exposure requiring the animal to be
sedated. This revealed an unexpected effect of
anesthesia (halothane/nitrous oxide) on tinnitus. That is,
whereas anesthetizing unexposed rats did not cause
them to test positive for tinnitus, anesthesia alone
would sometimes reinstate tinnitus in animals that had
previously been exposed. That is, a rat that was no
longer testing positive for tinnitus would occasionally
shift its responding on the silent trials to the side of its
previous exposure after being anesthetized even though
it was not exposed to any sound at that time (Heffner,
2011).
Neural Mechanisms of Tinnitus
Fig. 5. Rats (A-F) were trained to respond in the direction of There is an on-going debate as to the site of the
left and right sounds. Trials were inserted in which no sound
generation of tinnitus (e.g., Eggermont, 2013). One
was presented and their side preference on those trials
determined. The animals were exposed in the ear opposite
obvious site is the Organ of Corti. Another is the dorsal
their side preference on Day 0 with testing begun 10 minutes cochlear nucleus. And then there is the idea that
afterwards. The exposure (4-kHz tone, 110 dB, 10 min) was auditory cortex may be necessary for the perception of
sufficient to cause all six animals to shift their responding on tinnitus.
silent trials to the side of their exposed ear, indicating The main problem is that electrophysiological studies
tinnitus in that ear. (From Heffner, 2011.) look for an increase in neural activity following either
administration of salicylate or exposure to loud sound.
With regard to the criteria: However, both of these treatments will cause a hearing
1. The sounds used to induce tinnitus were within the loss. The assumption that a hearing loss will reduce
intensity and duration of those that cause tinnitus in neural activity overlooks the fact that most neural
humans (Davis et al., 1950). activity within the central nervous system is inhibitory,
not excitatory. Thus, when auditory neurons cease7
activity, they may release other neurons from Day, R. O., Graham, G. G., Bieri, D., Brown, M.,
inhibition, causing those neurons to increase their Cairns, D., Harris, G., Hounsell, J., Platt-Hepworth,
neural activity. Thus, increased neural activity in the S., Reeve, R., Sambrook, P. N., & Smith, J. (1989).
auditory system following administration of salicylate Concentration-response relationships for salicylate-
or exposure to loud sound is likely a sign of hearing induced ototoxicity in normal volunteers. British
loss, rather than tinnitus. Journal of Clinical Pharmacology, 28, 695-702.
A case in point is the increase in activity in the dorsal Eggermont, J. J. (2013). Hearing loss, hyperacusis, or
cochlear nucleus following exposing an ear to intense tinnitus: What is modeled in animal research?
sound (e.g., 10 kHz, 120 dB, 4 hrs). Although it is Hearing Research, 295, 1404-149.
argued that this increased activity is the basis for Fournier P. & Hebert, S. (2012). Gap detection deficits
tinnitus (e.g., Kaltenbach & McCaslin, 1996), there is in humans with tinnitus as assessed with the acoustic
good reason to think that it is not. Whereas the onset of startle paradigm: Does tinnitus fill in the gap?
tinnitus to a loud sound is immediate, the increased Hearing Research, 295, 16-23.
activity in the dorsal cochlear nucleus does not occur
Heffner, H. E. (2011). Two-choice sound-localization
until many days later. Second, a behavioral study that
procedure for detecting lateralized tinnitus in animals.
took hearing loss into account found that the increased
Behavior Research Methods, 43, 577-589.
activity in the dorsal cochlear nucleus was correlated
with hearing loss, rather than tinnitus (Zhang et al., Heffner, H. E. & Harrington, I. A. (2002). Tinnitus in
2004). hamsters following exposure to loud sound. Hearing
Research, 170, 83-95.
Of all the possible sites for the generation of tinnitus,
the one with the strongest evidence is the Organ of Heffner, H. E. & Heffner, R. S. (2012). Behavioral tests
Corti. In giving high doses of aspirin as a medical for tinnitus in animals. In J. J. Eggermont, F.-G.
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