PROCEEDINGS of the
23rd International Congress on Acoustics
9 to 13 September 2019 in Aachen, Germany

Reversing degraded auditory processing using targeted plasticity
Yuko TAMAOKI1, Jonathan R RILEY1, Michael S BORLAND1, Seth A HAYS1, Crystal T
ENGINEER 1, Michael P KILGARD1
1

The University of Texas at Dallas, United States

ABSTRACTHearing loss is a very common and often debilitating neurological disorder, estimated to affect over 5% ofthe population. A major source of disability related to hearing loss stems from deficits in speech processing.
Assistive devices, such as hearing aids, can yield modest improvements in speech perception, but thesedevices often provide inadequate utility in complex, challenging environments. We have developed a newapproach to drive robust, specific plasticity that substantially enhances recovery after neurological damage.
This strategy uses brief bursts of vagus nerve stimulation (VNS) paired with sound presentation. Like humans,
rats are significantly impaired in their ability to accurately discriminate speech sounds following intensenoise exposure. Additionally, noise trauma results in substantial maladaptive plasticity in multiple auditorystructures. In these experiments, we test the hypothesis that VNS paired with sound therapy, 300 times per
day for 20 days, will reverse maladaptive plasticity and restore auditory processing. Following the last dayof VNS-sound pairing, the reversal of maladaptive plasticity is tested through behavioral discrimination
ability, auditory brainstem responses (ABR), and auditory cortex responses. The successful development ofadjuvant therapies to restore speech processing has real potential to yield tangible benefits for millions
suffering from hearing loss.
Keywords: Vagus nerve stimulation, NIHL, Plasticity

1. HEARING LOSS
1.1 Hearing loss in humans
Hearing loss is the second most debilitating neurological disability. Hearing loss commonly affects
many patient populations, including members of the military, children, and aging individuals (1).
Patients with hearing loss exhibit abnormal neural activation in both cortical and subcortical regionsof the auditory pathway (2–4). The abnormal neural activity seen in the auditory pathway affects
patients’ ability to hear and understand speech sounds (5). Maladaptive plasticity in the auditory
network contributes to the abnormal neural activity that degrades information and impairs speech
perception ability. Fortunately, through recent technologies and innovations, multiple forms oftherapeutic interventions have been made available for individuals with hearing loss. However,devices such as hearing aids can sometimes only provide modest improvement in speech perception
abilities.
1.2 Hearing loss in animal models
Animal models of hearing loss exhibit abnormal neurological activity and a degradation of auditory
discrimination abilities (6–9). In auditory cortex, the normal orderly tonotopic map observed inexperimentally naïve animals is reorganized and degraded in noise-exposed animals (7,10,11). In
primary auditory cortex, rats exposed to intense noise (125 dB 1-octave band noise centered at 4 kHz)had significantly degraded responses to sound compared to non-exposed control animals (Figure 1).
Moderate intensity noise-exposed animals (115 dB 1-octave band noise centered at 16 kHz) did notdisplay significant differences in primary auditory cortex tonotopy compared to non-exposed control
animals (Figure 1). This reorganization is due to maladaptive plasticity that alters neural responses
due to a lack of inhibition. Similar aberrant neural responses have been observed subcortically in theinferior colliculus. These response changes in the inferior colliculus are due to hyperactivity of
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yxt170130@utdallas.edu

neurons, which is an effect similar to the changes observed in auditory cortex (12,13). Maladaptiveplasticity in the auditory network is seen across species with hearing loss.
Hearing loss also affects the ability of animals to discriminate between human speech sounds (7).
Cortical changes and behavioral changes were observed in animals noise-exposed at multiple soundfrequencies and intensities (14). Rats who experienced intense noise exposure were unable todiscriminate between speech sounds differing in consonant or vowel following 2 weeks of re-training.
The moderate noise exposure group, however, had an initial decrease in speech discrimination ability
that was able to recover. The moderate noise exposure rats fully recovered to baseline performancelevels after 2 weeks of re-training. This purpose of the current study is to target maladaptive plasticityin order to recover speech discrimination ability in rats who have been exposed to more intense noise
exposure parameters.

Figure 1. Moderate and intense noise exposure altered the tonotopic organization of responses in theprimary auditory cortex. Each polygon represents a single electrode penetration into the auditory cortex.
The color of the polygon represents the characteristic frequency of each penetration. Sites marked with an“o” were assigned to fields other than A1; sites marked with an “x” were classified as nonresponsive totones. Reproduced with permission from (15).

2. VNS-SOUND PAIRING IMPROVES AUDITORY PROCESSING

Vagus nerve stimulation (VNS) paired with a sensory event releases neuromodulators involved inplasticity, including acetylcholine, norepinephrine, and serotonin, activates the neural regions that
respond to the sensory event (16). For example, when VNS is paired with a tone, the proportion ofprimary auditory cortex that responds to the paired tone frequency is increased (10,11,17–19).
Similarly, when VNS is paired with speech sounds, there is an increase in the A1 response strength tothe paired speech sounds (20). Likewise, VNS paired with fast or slow tone trains can increase or
decrease the primary auditory cortex response strength to rapid sounds (21). VNS can alter both thespectral and temporal aspects of the neural response to sound in primary auditory cortex.
VNS paired with tones has also been examined in a rat model of tinnitus in order to improve thedegraded auditory processing observed in this model (10). These rats were exposed to 16 kHz noiseat 115 dB, and one month after noise exposure, the Turner gap detection method was used to identify
the perceived tinnitus frequency of each rat. VNS was paired with multiple tone frequencies that weredistinct from the perceived tinnitus frequency, 300 times per day for 20 days. Both the behavioral andneural effects of noise exposure were reversed following one month of VNS-tone pairing. This VNStone therapy, which was first tested in a rat model of tinnitus, has recently been shown to provide
long-lasting improvement in tinnitus intensity and tinnitus distress in chronic tinnitus patients (22–24).

3. VNS-SOUND PAIRING IN A RAT MODEL OF HEARING LOSS

Based upon the success of these previous studies, the objective of the current study is to test theability of VNS paired with the presentation of sounds to enhance the precision of spared auditory
inputs and substantially improve speech processing in noise-exposed rats. Rats received an auditory6599

brainstem response (ABR) recording prior to noise exposure to test the hearing (Figure 2). Groups ofrats were noise exposed to different intensity-frequency noise combinations for one hour. The intensityof the noise exposure ranged from 115 to 125 dB SPL and the center frequency of the 1 octave bandpassed noise ranged from 4 to 22 kHz. Following a one-month break, rats received a vagus nerve cuffand ABR to assess hearing loss from noise damage. In short, the VNS implantation procedure involved
placing a chronically implanted bipolar cuff electrode around the left cervical branch of the vagus
nerve. Subcutaneous leads were routed to a stimulator interface on the skull. The rats received 300
VNS-sound pairing presentations per day over 20 days. VNS stimulation parameters for the VNSsound paring sessions were 500 ms bursts of 100 us biphasic pulses with 33 ms between pulses at anamplitude of 0.8 mA. The VNS stimulation occurred at the same time that the sounds were presented.
The sounds paired with VNS stimulation were either speech sounds shifted into the rat hearing range
or tones spanning the rat’s hearing range. Following the last day of VNS-sound pairing therapy, in amanner consistent with prior experiments (15), physiological recordings were acquired from the rightauditory cortex and inferior colliculus of noise induced hearing loss animals. Tungsten
microelectrodes were used to record multiunit responses from the respective fields to a variety ofsound stimuli including tones spanning 1-32 kHz from 0 to 85 dB SPL, speech stimuli (both noveland VNS-paired sounds), and noise burst trains.
The rats’ neural responses and ABRs varied from group to group depending on what noise exposure
they received. Rats who received noise exposure at 115 dB SPL had less cortical reorganizationcompared to rats who received more intense noise exposure at 120 dB SPL and higher (Figure 3). Rats
receiving higher frequency noise exposure preserved more neural responses than the group of rats
receiving lower frequency exposure. Noise exposure intensity and sound frequency influenced thepreservation of cortical responses. A similar pattern of response preservation was observed in theABRs of the different exposure groups (Figure 4).

Figure 2. Study timeline: Auditory brainstem responses (ABR) were collected prior to theinduction of noise induced hearing loss, following noise induced hearing loss, and following VNSsound pairing. Approximately 1 month after noise induced hearing loss, animals received 20 days ofVNS-sound pairing. Following VNS-sound pairing neural responses were collected from the primaryauditory cortex and the inferior colliculus.

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Example A1 Maps
Center Frequency of Noise Exposure (kHz)162232(kH )16842CF(unimpaired)t i ti f115

Ch

Intensity of Noise Exposure (dB)

4120125(deaf)

Figure 3. Example maps from the primary auditory cortex of animals with noise induced hearing
loss. Noise exposures were conducted for one hour to 1-octave band-passed noise centered on 4, 16,or 22 kHz. The intensity of the sound was either 115, 120, or 125 dB SPL. Animals were notexposed to 16 and 22 kHz noise at 115 dB SPL nor to 4 kHz at 125 dB. Each polygon represents asingle electrode penetration into the auditory cortex. The color of the polygon represents thecharacteristic frequency of each penetration. Sites marked with an “x” were classified as
nonresponsive to tones.

Figure 4. Mean ABR thresholds following noise exposure but prior to VNS-sound pairing.

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4. CONCLUSIONS

Noise induced hearing loss degrades both neural and behavioral auditory processing. While
auditory training can improve neural and behavioral auditory processing in some rat models of hearing
loss, it can be insufficient to restore auditory processing in other more intense noise exposure models.
Ongoing work involves pairing vagus nerve stimulation with sound presentation in rat models ofhearing loss to improve both sound discrimination ability and the neural processing of sounds.

ACKNOWLEDGEMENTS

The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD
21702-5014 is the awarding and administering acquisition office. This work was supported by theAssistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through theFY17 Hearing Restoration Research Program/Translational Research Award under Award No.
W81XWH-18-1-0399. Opinions, interpretations, conclusions and recommendations are those of theauthor and are not necessarily endorsed by the Department of Defense. In conducting research using
animals, the investigator(s) adheres to the laws of the United States and regulations of the Departmentof Agriculture.

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