Testing for Tinnitus in Animals

Testing for Tinnitus in Animals
                                    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
Testing for Tinnitus in Animals
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
  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. 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).
                                                               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.
                                                               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.)
  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 intervals
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

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.
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,

                                                                   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 cease
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.
treatment, physicians often use the rule of increasing          Zheng, A. N. Popper & R. R. Fay (Eds.) Tinnitus.
the dosage until the patient reports tinnitus and then          Springer: NY, pp. 21-58.
reducing it until the tinnitus disappears. However, this      Heffner, H. E. & Koay, G. (2005). Tinnitus and hearing
procedure does not work with elderly patients who have          loss in hamsters exposed to loud sound. Behavioral
a hearing loss resulting from loss of the hair cells in the     Neuroscience, 119, 734-742.
cochlea that encode high frequencies (presbycusis)—           Jastreboff, P. J., Brennan, J. F., Coleman, J. K., &
these patients do not develop tinnitus when given               Sasaki, C. T. (1988). Phantom auditory sensation in
salicylate (Schuknect & Gacek, 1993; Mongan et al.,             rats: an animal model for tinnitus. Behavioral
1973). This observation suggests that it is the effect of       Neuroscience, 102, 811-822.
salicylate on hair cells that causes tinnitus.                Jastreboff, P. J. & Brennan, J. F. (1994). Evaluating the
                                                                loudness of phantom auditory perception (tinnitus) in
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                                                            Research in Otolaryngology, 27, 302.
  Rhinology, and Laryngology, 102, 1–16.
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