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Journal of Otology 9 (2014) 111e116
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Acoustic trauma-induced auditory cortex enhancement and tinnitus

Erin Laundrie, Wei Sun*
Department of Communicative Disorders and Sciences, State University of New York at Buffalo, 122 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA
Received 16 October 2014; accepted 17 November 2014

Abstract

There is growing evidence suggests that noise-induced cochlear damage may lead to hyperexcitability in the central auditory system (CAS)
which may give rise to tinnitus. However, the correlation between the onset of the neurophysiological changes in the CAS and the onset of
tinnitus has not been well studied. To investigate this relationship, chronic electrodes were implanted into the auditory cortex (AC) and sound
evoked activities were measured from awake rats before and after noise exposure. The auditory brainstem response (ABR) was used to assess the
degree of noise-induced hearing loss. Tinnitus was evaluated by measuring gap-induced prepulse inhibition (gap-PPI). Rats were exposed
monaurally to a high-intensity narrowband noise centered at 12 kHz at a level of 120 dB SPL for 1 h. After the noise exposure, all the rats
developed either permanent (>2 weeks) or temporary (<3 days) hearing loss in the exposed ear(s). The AC amplitudes increased significantly 4 h
after the noise exposure. Most of the exposed rats also showed decreased gap-PPI. The post-exposure AC enhancement showed a positive
correlation with the amount of hearing loss. The onset of tinnitus-like behavior was happened after the onset of AC enhancement.
Copyright © 2014, PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier
(Singapore) Pte Ltd. All rights reserved.

Keywords: Auditory cortex; Tinnitus; Startle reflex; Hyperacusis; Noise exposure

1. Introduction intense noise exposure to explore the behavioral manifestation

and the mechanisms of tinnitus (Kaltenbach, 2000).
Tinnitus is a phantom perception of sound in the absence of As it has been demonstrated repeatedly, tinnitus is likely a
external stimuli. Fifteen to seventeen percent of the population result of irregular neural activity emerging from a given level
is affected by subjective tinnitus and approximately 2% in the auditory pathway (Norena and Eggermont, 2005). The
experience severe or disabling tinnitus (Axelsson and level in the auditory system where tinnitus arises remains
Ringdahl, 1989; Cooper, 1994). Although the underlying obscure. Some authors have suggested that the aberrant neural
physiology of tinnitus is unknown, acoustic overstimulation signal may be generated at the peripheral level (Jastreboff,
(Atherley et al., 1968; Axelsson and Hamernik, 1987) and 1990), while other authors have proposed a central origin of
ototoxic drugs (Day et al., 1989; Sun et al., 2009; Yang et al., tinnitus (Eggermont and Roberts, 2004; Roberts et al., 2010;
2007) are common inducers of tinnitus. Since acoustic over- Salvi et al., 2000). The peripheral damage, however, cannot
stimulation is one of the most commonly cited causes of fully explain the audiological symptoms associated with noise-
tinnitus, aside from aging, many animal studies have used induced hearing loss, e.g. tinnitus, reduced speech intelligi-
bility and hyperacusis
There is growing evidence suggests that noise-induced
peripheral damage may cause a plasticity change in the cen-
* Corresponding author. Tel.: þ1 716 8295307.
tral auditory system (CAS), which may give rise to tinnitus.
E-mail address: weisun@buffalo.edu (W. Sun).
Peer review under responsibility of PLA General Hospital Department of However, the correlations of neurophysiological changes in
Otolaryngology Head and Neck Surgery. CAS and onset of tinnitus are not well understood. Central

http://dx.doi.org/10.1016/j.joto.2014.11.001
1672-2930/Copyright © 2014, PLA General Hospital Department of Otolaryngology Head and Neck Surgery. Production and hosting by Elsevier (Singapore) Pte
Ltd. All rights reserved.
112 E. Laundrie, W. Sun / Journal of Otology 9 (2014) 111e116

auditory plasticity changes have been observed following pe- repetition rate of 21 times/second. Sound stimuli were pre-
ripheral damage induced by salicylate (Sun et al., 2009), sented through a high frequency super tweeter (FT28D, Fos-
cisplatin (Salvi et al., 2000) and noise exposure (Sun et al., tex) and the sound level was calibrated using a sound level
2012; Syka, 2002). Both monaural and binaural noise expo- meter (Larson Davis Sound Level Meter, model 824, ½ inch
sure often enhanced the amplitude of the auditory cortex (AC) condenser microphone). ABR was obtained in both ears 5e6 h
responses in awake rats. Even though there has been a cor- following noise exposure and on a daily basis until the rat had
relation between noise exposure and increased AC amplitude recovered to its full potential.
as well as noise exposure and tinnitus behavior, the correla-
tions of neurophysiological changes in CAS and onset of 2.3. AC recording
tinnitus remain unclear.
Previous studies using animal models have allowed re- Rats were anesthetized using 1e2% isoflurane. A silver
searchers to study the physiology of tinnitus. Sun et al. ball electrode was implanted into the right AC, cemented in
revealed that salicylate-induced tinnitus paralleled a substan- place, and the wound was sutured around the electrode
tial increase in the AC amplitude in the first few hours connector. The rats were allowed 2 weeks to recover before
following the 250 mg/kg salicylate injection before recovering testing began.
toward the baseline within a day or so (Sun et al., 2009). Even Sound stimuli were generated using TDT hardware (RP2 D/
though acoustic-trauma evoked tinnitus is one of the most A converted, PA5 attenuator, HB7 headphone amplifier) con-
commonly reported causes of tinnitus, it is unknown to what nected to a loudspeaker. The electrode was connected to a low
extent the AC response of an awake rat will be affected by impedance amplifier (RA16PA Medusa Preamp, TDT) and
acoustic trauma-induced tinnitus. We hypothesize that an in- signals were sampled using an RA16 Medusa Base Station
crease in AC response will be related to tinnitus behavior. To (TDT). Stimulus generation and data acquisition was accom-
test this hypothesis, we investigated the influence of monaural plished using TDT software (BioSigRP).
noise exposure on the AC amplitudes by using a chronically The awake rats were tested in a custom testing apparatus to
implanted silver ball electrode of awake rats before and after restrict rat's movement during the test. Before the test, rats
treatment with a 120 dB SPL narrowband noise centered at were placed in the testing apparatus for 1e2 h per day for 2e3
12 kHz for 1 h. We also monitored tinnitus behavior by days to let the rats get used to the testing environment. The
measuring the startle reflex before and after the monaural sound level was calibrated. Local field potentials were recor-
noise exposure. ded before and after noise exposure. Tone-bursts centered at 6,
12, 16 and 20 kHz were used to elicit AC responses.
2. Materials and methods
2.4. Acoustic startle reflex
2.1. Animals
All startle reflex testing was performed in a sound attenu-
Three Harlan Sprague-Dawley male rats (3e4 months old) ating box. Each box contained a startle reflex platform and a
were used for testing. The rats did not have any diet re- high frequency speaker (FT28D, Fostex) located 20 cm above
strictions. All rats were exposed to 120 dB SPL monaural the rat. All rats were placed in a wire mesh cage (15e20 cm
narrowband noise centered at 12 kHz (1 kHz bandwidth) for long  7 cm wide  5.5 cm high) mounted on an acrylic glass
1 h following a series of reliable AC baseline and ABR base to restrict their movement. The cage rested on top of a
measures. Following the noise exposure, AC responses were piezoelectric transducer (Radio Shack 273-066) within the
obtained at 1 h, 4 h, 1 day, 2 days, 1 week and 2 weeks. Startle calibrated sound field
reflex testing was administered pre noise exposure until a Sound stimuli were generated by a RP2 Real-Time Pro-
stable baseline was obtained. Startle reflex testing was also cessor (TDT) from custom software created in MatLab 6.0.
administered 2e4 h, 1 day, 2 days, 1 week and 2 weeks The rat's body movement elicited from the startle stimuli was
following noise exposure. measured by the sensitive piezoelectric transducer connected
to an A/D converter on an Real-Time Processor (TDT). The
2.2. Auditory brainstem response (ABR) recording output was sent to a low-pass filter set at 1000 Hz (LPF-300,
World Precision Instruments). The root mean square (RMS)
Hearing thresholds were obtained from each subject as amplitude was measured over 100 ms response following the
measured by ABR under isoflurane anesthesia (1e2%). The onset of the startle stimulus using custom software. The startle
ABR recordings were measured using a surgically implanted eliciting stimulus consisted of a broadband noise burst pre-
chronic electrode connected to a preamplifier (RA16LA, TDT) sented at 105 dB SPL (0.5e30 kHz, 20 ms duration, 0.1 ms
using a low noise cable. The preamplifier was then connected rise/fall time).
to a digital signal processing module (RX5-2, Pentusa Base Acoustic startle reflexes were measured on all three rats
Station, TDT) before being processed with software (Bio- before and after noise exposure using two testing procedures:
SigRP) with a band pass filter set at 100e3000 Hz. The sound gap-induced prepulse inhibition (gap-PPI) and noise burst
stimulus was a tone-burst (5 ms duration; 1 ms rise/fall time) prepulse inhibition of startle reflex (NB-PPI). For the gap-PPI,
at 6, 12, 16 and 20 kHz generated by TDT hardware with a the startle reflex was measured in the presence of continuous
 E. Laundrie, W. Sun / Journal of Otology 9 (2014) 111e116 113

noise stimulus presented above threshold at 60 dB SPL with or

without a silent gap. The continuous noise was 1000 Hz wide
centered at 6, 12, 16 and 20 kHz. Within the continuous noise,
a 105 dB SPL (20 ms duration) startle sound was presented
alone or preceded by a 50 ms gap. The gap was expected to
reduce the amplitude of the startle response if tinnitus is ab-
sent. The inter-trial interval was between 17 and 23 s.
For the NB-PPI of the acoustical startle reflex, the startle
stimulus was either presented alone or was preceded by a
60 dB SPL narrowband (1 kHz) noise-burst (50 ms, 5 ms rise/
fall time) prepulse centered at 6, 12, 16 and 20 kHz. The 50 ms
noise-burst prepulse was predicted to reduce the amplitude of
the startle response as long as the rats maintained at least one
Fig. 1. Noise exposed ear (n ¼ 3) and control ear (n ¼ 3) during pretreatment
good hearing ear following noise exposure.
(Pre, mean of 3 days), 2 h (Post, mean of 1 day), 1 day (Post, mean of 1 day), 3
days (Post, mean of 1 day), and 1 week (Post, mean of 1 day) following 1 h of
2.5. Noise exposure monaural narrowband noise centered around 12 kHz at 120 dB SPL (1 kHz
bandwidth). Note the large ABR threshold shift occurring at 2 h post
For monaural noise exposure, a narrowband signal centered treatment.
at 12 kHz at 120 dB SPL for 1 h was generated using TDT
hardware and software. All rats were anesthetized using 1e2% the noise exposure, slightly recovering to a permanent
isoflurane. Noise stimuli were produced by TDT hardware and threshold shift as compared to the control ear at 12 kHz. The
sent to a loudspeaker (GMI Professional Series D-59 Super ABR threshold shifts at 6, 16 and 20 kHz revealed no sig-
Driver) in a sound attenuated booth. The center axis of the nificant changes.
speaker was placed in a lateral position 2 inches from the
external ear canal of the test ear. The monaural ear received 3.2. AC response
the noise exposure and an ear plug was inserted into the
contralateral ear to ensure monaural acoustic overstimulation. Local AC field potentials were also recorded from chroni-
A sound level meter was used to calibrate the sound field at a cally implanted (right) electrode before and after noise expo-
position corresponding to the center of the rat's head. sure in the awake rat. The AC response contains two large
positive peaks (P1, P2) each followed by a negative peak (N1,
2.6. Statistical methods N2) as seen in Fig. 2A. The AC amplitude in high intensity (90
and 100 dB SPL), not the low intensity (70 and 80 dB SPL)
Statistical analysis was carried out using the GraphPad showed a significantly large increase 4 h following noise
Prism version 5.00 for Windows (GraphPad Software, San exposure (Fig. 2B).
Diego, CA). A 2-way ANOVA (Analysis of Variance) was Post/Pre Amplitude Ratio was calculated for each test fre-
used to evaluate significance of ABR, AC amplitudes, gap- quency as a function of post-treatment time in order to
PPI, and NB-PPI before and after noise exposure (P < 0.05). quantify the peakepeak amplitude changes. Fig. 2C and D
Variability was indicated by standard error of the mean. show the Post/Pre Amplitude Ratio as function of post treat-
ment time at 6, 12 and 16 kHz at 100 dB SPL and 90 dB SPL
3. Results respectively. The AC response evoked by tone bursts at
6e20 kHz produced significant enhancements at 4 h post noise
3.1. ABR results exposure and recovered at 1 day post treatment.

Three rats were tested before and after the noise exposure. 3.3. Acoustic startle response
Fig. 1 shows the ABR threshold (dB SPL) in the control ear
and exposed ear pre and post acoustic overstimulation at Noise-induced tinnitus was assessed using the gap pre-
12 kHz. During the pretreatment period (mean data for 3 pulse inhibition of acoustic startle reflex (gap-PPI) behav-
days), the mean ABR threshold was approximately 20 dB SPL ioral paradigm (Turner et al., 2006). Prior to acoustic over-
for the exposed and control ears. After the rats were exposed stimulation, the 50 ms gap suppressed the mean (n ¼ 3)
to noise for a 1 h, the ABR threshold increased significantly in amplitude of acoustic startle response ((STng-STg)/
the exposed ear 2 h following the acoustic overstimulation. STng  100%) by approximately 55% across all four fre-
The average ABR thresholds (n ¼ 3) on the exposed ears quencies. Four hours following acoustic overstimulation, the
increased about 30e45 dB SPL, whereas the unexposed ears average gap-PPI had decreased to 31% at 6 kHz, 28% at
showed less than 10 dB SPL changes. These results suggest 12 kHz, 36% at 16 kHz, and 42% at 20 kHz. A significant
that 1 h of monaural narrowband noise centered around decrease was seen in 16 and 20 kHz. Although the averaged
12 kHz at 120 dB SPL (1 kHz bandwidth) significantly de- gap-PPI remained constant (~15% decrease compared to pre-
creases hearing sensitivity for the exposed ear 2 h following
114 E. Laundrie, W. Sun / Journal of Otology 9 (2014) 111e116

Fig. 2. Monaural noise exposure induced enhancements of AC evoked potentials. (A) Examples of AC response. (B) The average AC amplitudes (n ¼ 3) increased
significantly 4 h following noise exposure at 12 kHz. (CeD) The AC response evoked by tone bursts at 6e20 kHz produced significant enhancements at 4 h post
noise exposure and recovered at 1 day post treatment.

exposure) 2 weeks following noise exposure (Fig. 3A), 16 kHz 6, 12, 16 and 20 kHz before and after treatment ((STng-STg)/
gap-PPI showed a significant decrease in 2 weeks, suggesting STng  100%). Prior to acoustic overstimulation, the mean
a permanent noise-induced tinnitus behavior presumably at a NB-PPI (n ¼ 3) was 79% at 6 kHz, 78% at 12 kHz, 83% at
pitch above the noise exposure stimuli (Fig. 3C). 16 kHz, and 79% at 20 kHz. Four hours following acoustic
In order to eliminate the possibility that the gap-PPI deficit overstimulation, the average NB-PPI had decreased to 50% at
was not the result of hearing loss, NB-PPI was also assessed at 6 kHz, 40% at 12 kHz, 71% at 16 kHz, and 44% at 20 kHz,

Fig. 3. (A) The average gap-PPI (n ¼ 3) induced by 12 kHz narrowband noise (60 dB SPL, 50 ms gap) revealed a 44% reduction in inhibition 4 h post treatment
and stabilized at 33% reduction in inhibition from 3 days to 2 weeks following noise exposure. (B) The average NB-PPI (n ¼ 3, 60 dB 12 kHz) showed a 46%
reduction in inhibition 4 h post noise and then totally recovered 1 day post treatment. (C) The average gap-PPI (n ¼ 3) induced by 16 kHz NBN (60 dB SPL, 50 ms
gap) was significantly reduced from 55% to less than 20% at 4 h post noise exposure. The reduction dropped to <20% after 2 weeks, suggesting a permanent noise-
induced tinnitus behavior. (D) The average NB-PPI (n ¼ 3, 60 dB SPL, 16 kHz) showed a decrease at 1 day post noise exposure and then began to recover at 3 days
post treatment. This suggests the noise-induced gap-PPI reduction may not be due to a hearing loss.
 E. Laundrie, W. Sun / Journal of Otology 9 (2014) 111e116 115

suggesting that hearing loss affected the startle reflex. How- PPI. There was a significant decrease in NB-PPI 4 h post
ever, for all frequencies tested, the NB-PPI fully recovered treatment and recovery after 1e3 days following treatment.
within 1e3 days following treatment (Fig. 3B and D). Since This could indicate a possibility that the decrease of gap-PPI
the 60 dB SPL narrowband noise burst produced robust inhi- at 4 h following the noise treatment was a result of hearing
bition of the acoustic startle response following noise expo- loss. A recent study reported that a persistent increase of
sure, the noise-induced gap-PPI reduction was not likely due acoustic startle reflex can be induced by noise exposure in
to hearing loss. hamsters 1e2 weeks after noise exposure (Chen et al., 2013).
These results suggest that noise exposure may induce a
4. Discussion permanent hyperexcitability of the CAS which may
contribute to tinnitus.
The ABR is a measuring technique used to assess the In summary, the purpose of the present study was to
functional status of the peripheral auditory system and brain- investigate the effects of monaural noise exposure on the
stem. The present study found that exposure to a high fre- auditory cortex amplitudes in awake rats and examine if a
quency narrowband noise (12 kHz at 120 dB SPL) caused a correlation exists between the AC amplitudes and noise-
~30 dB permanent hearing loss at 12 kHz. Interestingly, no induced tinnitus onset. We find that the AC amplitudes
significant decrease of AC response was detected at high in- evoked from the unexposed ear increased significantly 4 h
tensity, suggesting a compensatory effect in the cortical area after the noise exposure. Most of the exposed rats also
after peripheral damage. Noise-induced tinnitus was assessed developed tinnitus-like behavior on gap-PPI 1e2 days after
using the gap-PPI behavioral paradigm (Turner et al., 2006). the noise exposure. Therefore, the onset of tinnitus-like
The present study showed a decrease in gap-PPI that remained behavior was happened after the onset of AC enhancement.
constant two weeks following noise exposure. Previous studies The post-exposure AC enhancement showed a positive cor-
have reported many instances in which traumatic noise relation with the amount of hearing loss.
exposure has caused a tinnitus behavior (Engineer et al., 2011;
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