hidden hearing loss? effects of noise on evoked amplitude

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Hidden Hearing Loss? Effects of Recreational Noise on Evoked Potential Amplitude and Other

Auditory Test Metrics

Colleen G. Le Prell, Ph.D.

University of Texas at Dallas

School of Behavioral and Brain Sciences

Overview

• Synaptopathy in Rodents

• Translation to Humans

• Retrospective analyses• Cross‐sectional comparisons

• Prospective (Longitudinal) Data collection

• Prevention

• Where do we go from here, and what can you tell your patients today?

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Long‐Term Post‐Noise Neural Response Depression

• DPOAEs measure OHC function

• ABR is neural response

• DPOAEs intact post‐noise

• ABR amplitude depressed at supra‐threshold levels

From Kujawa, S. G. and Liberman M.C. Adding insult to injury: Cochlear nerve degeneration after

“temporary” hearing loss. J Neurosci, 11:29, 14077‐14085, 2009.

IHC/ANF Connections Decrease Post‐Noise

• Synaptic ribbons (red) connect IHCs and auditory nerve dendrites (green)

• Noise induced decrease in contacts

From Kujawa, S. G. and Liberman M.C. Adding insult to injury: Cochlear nerve degeneration after

“temporary” hearing loss. J Neurosci, 11:29, 14077‐14085, 2009.

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Changes in Neural Connections are Permanent

• Explanation for age/noise interactions?

• What happens in other species?

• What is critical level of TTS?

• Robust TTS may be much more harmful than previously assumed, BUT, what are functional correlates?

From Kujawa, S. G. and Liberman M.C. Adding insult to injury: Cochlear nerve degeneration after “temporary” hearing loss. J Neurosci, 11:29, 14077‐14085, 2009.

Synaptopathy

Le Prell, C.G., and Brungart, D.S. (2016). Potential effects of noise on hearing: supra‐threshold testing using speech‐in‐noise and auditory evoked potentials, Otology & Neurotology, 37: e295‐e302.

Black: control

Red: noise‐exposed

• Noise exposure that induces a TTS CAN result in immediate synapse loss, decreased ABR amplitude, and long‐term spiral ganglion loss

• Kujawa SG, LibermanMC. 2006. J. Neurosci. 26: 2115‐2123.

• Kujawa SG, LibermanMC. 2009. J. Neurosci. 29: 14077‐14085.

• Not every noise is synaptopathic• Hickox AE, LibermanMC. 2014. J. Neurophysiol. 111:552‐64.

• Jensen JB, Lysaght AC, LibermanMC, Qvortrup K, and Stankovic KM. 2015. PLoS One 10:e0125160.

• Fernandez KA, Jeffers PWC, Lall K, LibermanMC, Kujawa SG. 2015. J. Neurosci. 35(19):7509 –7520.

• Critically important to determine dose relationship related to both a single acute exposure resulting in a perceived TTS as well as repeat lower level exposure, and contrast with aging alone

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Where does risk of synaptopathic injury begin?

• Mouse: synapse damage observed with 100 dB SPL OBN x 2 hrs, but not 97 dB x 2 hours

• Guinea Pig: synapse damage observed at 106 dB SPL OBN x 2 hrs, PTS observed at 109 dB SPL x 2 hours

• Rat: synapse damage observed at 109 dB SPL OBN x 2 hrs, but not 106 dB SPL x 2 hours

• Rhesus macaque: synapse damage observed at 108 dB SPL narrow band noise x 4 hours (50 Hz noise band centered at 2 kHz), or, 120 dB SPL OBN x 4 hrs

• Human: We don’t know where risk begins, or how it grows, in humans; active efforts to assess risk using both retrospective and prospective designs

Early Translation to Humans

• Stamper & Johnson, 2015: ABR wave I amplitude decreased as recreational noise exposure in past 12 months increased; follow‐up with control for sex differences revealed differences limited to female participants

• Liberman et al., 2016: Summating Potential (and therefore SP/AP amplitude ratio) smaller in high‐risk young adults (music students) vs low‐risk young adults (communication disorders students); in addition, high‐frequency thresholds poorer, and hearing in noise poorer

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“Confirmation” of noise‐induced synaptopathy in

humans?

• Stamper and Johnson (2015, Ear & Hearing) reported decreased ABR amplitude as function of self‐reported noise exposure in the past 12 months

– Relationship statistically significant for 90‐dB nHL click signal when ABR assessed using mastoid electrodes

– Similar trends detected at lower levels (>70 dB nHL) for clicks and 4‐kHz pure tones and when using an electrode placed on the tympanic membrane

• 40 participants (22F, 18M), 18‐28 yrs of age, with <25 dB HL thresholds from 250‐8000 Hz, with and without diabetes

• Participants with higher noise scores worked in the music industry, attended frequent live shows in Nashville, TN, or were hunters/shooters

• No statistically significant relationships between noise history and:

• Conventional or EHF thresholds• DPOAE or TEOAE amplitude

• ABR amplitude

Spankovich, C., Le Prell, C.G., Hood, L.J., and Lobarinas, E. (2017). Noise history and auditory function in young adults with and without Type‐1 diabetes. Ear Hear. 38(6), 724–735.

Vanderbilt University Cohort

• LAeq8760 = 79 dB represents 24‐hour exposure to 79 dBA sound levels all year long

• Assumed to be equivalent to 8 hrs of exposure to 85 dBA noise within each 24 hour period.

79 dBA

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ABR wave‐1 amplitude versus noise exposure

• Supra‐threshold wave I amplitude

• Wave I amplitude plotted as function of NEB at 27.7 clicks/sec and 77.7 clicks/sec

• Triangles: participants with diabetes; circles: no diabetes controls

• Linear regression analyses were not statistically significant (p’s > 0.05)

Left ears Right ears

27.7 clicks/sec

77.7 clicks/sec

Spankovich, C., Le Prell, C.G., Hood, L.J., and Lobarinas, E. (2017). Noise history and auditory function in young adults with and without Type‐1 diabetes. Ear Hear. 38(6), 724–735.

27.7 clicks/sec

77.7 clicks/sec

University of Florida Cohort

• 60 participants (34F, 26M), 18‐29 yrs of age, with <25 dB HL thresholds from 250‐8000 Hz

• Participants had varied noise histories, non‐occupational/ recreational

Fulbright, A.N.C., Le Prell, C.G., Griffiths, S.K., and Lobarinas, E. Effects of recreational noise on threshold and supra‐threshold measures of auditory function. Seminars in Hearing, 38, 298‐318.

• No relationship between noise history and:• Threshold (250 – 8000 Hz)• DPOAE amplitude• ABR amplitude• Performance on a variety of word‐in‐noise tests and other

temporal resolution tasks

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Noise vs ABR Wave I amplitude: no statistically significant relationships w/earlobe electrodes and clicks

• Supra‐threshold wave I amplitude measured using earlobe electrodes versus NEB in females (top panels) or males (bottom panels)

• 21.1/sec clicks • Linear regression analyses were not statistically significant (p’s > 0.05)


90‐dB nHL 99 dB nHL

4000 Hz Tones


• 4000 Hz, 90‐dB nHL• 27.1/sec rate• Supra‐threshold wave

I amplitude measured using earlobe (left panels) and tiptrode(right panels) electrodes

• Linear regression analyses were not statistically significant (p’s > 0.05) in females (top) or males (bottom) for either electrode type

Earlobe electrodes Tiptrode electrodes

Noise vs ABR Wave I amplitude: no statistically significant relationships at 4000 Hz

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Combined data sets increase sample size and power


• wave I amplitude measured using earlobe/ mastoid electrodes and clicks

• Linear regression analyses were not statistically significant (p’s > 0.05)

• 32 participants (19F, 13M), 21‐27 yrs of age, with <25 dB HL thresholds from 250‐8000 Hz

• Participants had varied recreational noise histories, with no significant occupational exposure to noise

• No statistically significant relationships between noise history and:

• Threshold (250‐8000 Hz)• DPOAE amplitude

• ABR amplitude

Grinn, S., Wiseman, K., Baker, J., and Le Prell, C. G. 2017. Hidden Hearing Loss? No effect of common recreational noise exposure on cochlear nerve response amplitude in humans. Front Neurosci, 11:465; https://doi.org/10.3389/fnins.2017.00465

UT Dallas Cohort

79 dBA

79 dBA

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No reliable relationship between previous 12‐months noise exposure and threshold sensitivity in normal

hearing young adults exposed to loud recreational sound

Grinn, S., Baker, J., Wiseman, K., and Le Prell, C. G. Hidden hearing loss? No effect of common recreational noise exposure on cochlear nerve amplitude in humans. Frontiers in Neuroscience, 11:465; https://doi.org/10.3389/fnins.2017.00465

No reliable relationship between previous 12‐months noise exposure and DPOAE amplitude in normal hearing

young adults exposed to loud recreational sound


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No reliable relationship between previous 12‐months noise exposure and Words‐in‐Noise (WIN) in normal

hearing young adults exposed to loud recreational sound


Statistically significant male vs female difference in ABR wave I amplitude at 80 and 90 dB nHL


• Wave I amplitude was reliably larger in females than in males in for clicks, 2000, 3000, and 4000 Hz tone bursts, at 80 dB nHL and 90 dB nHL.

Click 2000 Hz 4000 Hz3000 Hz

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No reliable relationship between previous 12‐months noise exposure and threshold sensitivity in normal hearing young adults exposed to loud recreational sound

Males Click: R=0.0780, p=0.80952000 Hz: R=0.1096, p=0.73463000 Hz: R=0.0374, p=0.9081 4000 Hz: R=0.0106, p=0.9740

Females Click: R=0.0858, p=0.7269 2000 Hz: R=0.1290, p=0.59873000 Hz: R=0.0877, p=0.72934000 Hz: R=0.1516, p=0.5355


No statistically significant relationship between ABR wave I amplitude and noise history

No systematic evidence of risk “boundary” at LAeq8760=79 dBA for ABR wave I amplitude


• Relationships between Wave I amplitude and noise history assessed within sex

• No reliable relationships between noise (those with less than 100% noise dose and those with 100% or greater noise dose) and amplitude revealed by ANOVA analyses.

Click 2000 Hz 4000 Hz3000 Hz

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Prospective monitoringSubject

IDSex Event

Time (Hrs)

LevelNIOSH Dose (%)

NIOSH TWA

OSHA Dose (%)

OSHA TWA

4 F Movie 2.25 73.1 1.8 67.5 3.5 65.822 F Concert 3 80 11.8 75.7 9.4 72.912 M Bar 3 84.2 31.2 79.9 16.3 76.97 F Concert 3.5 83.3 29.7 79.7 16.6 77

14 F Concert 1.5 89.7 55.6 82.4 18.8 77.916 M Concert 3.75 83.6 33.9 80.3 20.4 78.518 F Concert 3.75 86.8 71 83.5 31 81.59 M Concert 3.5 88.2 91.6 84.6 33 82

28 M Bar 3 91.9 185.2 87.7 49.2 84.920 M Concert 2.5 93.5 204.9 88.1 54.3 85.62 F Concert 2.5 93.5 223.2 88.5 54.3 85.6

32 M Bar 2.5 94.9 308.6 89.9 62.5 86.63 F Concert 5 89.4 173 87.4 62.5 86.6

13 FDance Event

2.25 95.7 330.9 90.2 64.3 86.8

31 FDance Event

4.5 91.8 271.1 89.3 73.8 87.8

5 FBar/Live

Music3 96 476.2 91.8 85.7 88.9

6 MBar/Live

Music3 96 476.2 91.8 85.7 88.9

17 M Concert 3 95.7 441.2 91.4 85.7 88.9

10 FDance Event

3 96.5 535.7 92.3 100 90

19 MBar/Live

Music6 93 476.2 91.8 113.2 90.9

1 F Concert 4.5 97.5 1022.7 95.1 173.1 9429 F Concert 3 102.5 2142.9 98.3 230.8 9621 M Concert 4 101.1 2105.3 98.2 235.3 96.28 F Bar 3 104.2 3157.9 100 272.7 97.2

26 F Concert 3 104 3030.3 99.8 272.7 97.227 F Concert 3.5 103.9 3500 100.4 318.2 98.3

24 F3 day

festival16 101 8000 104 941.2 106.2

23 M3 day

festival16 102.7 12307.7 105.9 1230.8 108.1

• 28 of 31 participants attended recreational event they deemed loud, and returned the day after event for repeat testing.

• Exposure Data:

• < 50% OSHA dose (4 male, 5 female)

• 50‐100% OSHA dose (4 male, 6 female)

• > 100% OSHA dose (3 male, 6 female)

• Event levels of 93.3 ± 7.8 dBA (range 73.1 – 104.2 dBA)

• Event durations of 4.2 ± 3.5 hours (range 1.5 – 16.0 hours)

• Calculated using 29 CFR 1910.95, average noise dose was 168.4% ±276% (range 3.5% – 1,230.8%)

Subject ID

Sex EventTime (Hrs)

LevelNIOSH

Dose (%)

NIOSH TWA

OSHA Dose (%)

OSHA TWA

4 F Movie 2.25 73.1 1.8 67.5 3.5 65.822 F Concert 3 80 11.8 75.7 9.4 72.912 M Bar 3 84.2 31.2 79.9 16.3 76.97 F Concert 3.5 83.3 29.7 79.7 16.6 77

14 F Concert 1.5 89.7 55.6 82.4 18.8 77.916 M Concert 3.75 83.6 33.9 80.3 20.4 78.518 F Concert 3.75 86.8 71 83.5 31 81.59 M Concert 3.5 88.2 91.6 84.6 33 82

28 M Bar 3 91.9 185.2 87.7 49.2 84.9

“Low‐Risk” Cohort (OSHA Dose < 50%)


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Subject ID

Sex EventTime (Hrs)

LevelNIOSH

Dose (%)

NIOSH TWA

OSHA Dose (%)

OSHA TWA

20 M Concert 2.5 93.5 204.9 88.1 54.3 85.62 F Concert 2.5 93.5 223.2 88.5 54.3 85.6

32 M Bar 2.5 94.9 308.6 89.9 62.5 86.63 F Concert 5 89.4 173 87.4 62.5 86.6

13 FDance Event

2.25 95.7 330.9 90.2 64.3 86.8

31 FDance Event

4.5 91.8 271.1 89.3 73.8 87.8

5 FBar/Live

Music3 96 476.2 91.8 85.7 88.9

6 MBar/Live

Music3 96 476.2 91.8 85.7 88.9

17 M Concert 3 95.7 441.2 91.4 85.7 88.9

10 FDance Event

3 96.5 535.7 92.3 100 90

“Mid‐Risk” Cohort (50% < OSHA Dose < 100%)


“High‐Risk” Cohort (OSHA Dose > 100%)

Subject ID

Sex EventTime (Hrs)

LevelNIOSH

Dose (%)

NIOSH TWA

OSHA Dose (%)

OSHA TWA

19 MBar/Live

Music6 93 476.2 91.8 113.2 90.9

1 F Concert 4.5 97.5 1022.7 95.1 173.1 9429 F Concert 3 102.5 2142.9 98.3 230.8 9621 M Concert 4 101.1 2105.3 98.2 235.3 96.28 F Bar 3 104.2 3157.9 100 272.7 97.2

26 F Concert 3 104 3030.3 99.8 272.7 97.227 F Concert 3.5 103.9 3500 100.4 318.2 98.3

24 F3 day

festival16 101 8000 104 941.2 106.2

23 M3 day

festival16 102.7 12307.7 105.9 1230.8 108.1


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No reliable increase in TTS the day after recreational events as noise dose (TWA) increases; all TTS recovers by 1‐wk post

No reliable TTS the following day within OSHA dose > 100% group


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No reliable decrease in DPOAE amplitude the day after recreational events as noise dose (TWA) increases; all changes recover by 1‐wk post

No reliable DPOAE decrease the following day within OSHA dose > 100% group


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No reliable decrease in wave I amplitude the day after recreational events as noise dose (TWA) increases; all TTS recovers by 1‐wk post

90 dB nHL data shown

No reliable change in ABR amplitude the following day within OSHA dose > 100% group


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Temporary noise‐dependent decrease in performance observed for Words‐in‐Noise (WIN) the day after recreational

events; recovery observed at 1‐wk test

1 day post noise 1 week post noise

Reliable noise‐induced decrease in WIN score the following day, within OSHA dose > 100% group


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Review of Acute Changes

No reliable TTS Poorer Words in Noise DPOAEs unchanged? ABR unchanged

Word‐in‐Noise understanding was temporarily compromised, suggesting this was the most sensitive metric for transient noise injury.

Individuals are highly variable even if they have same exposure, and these were not equivalent exposures – are there relationships between max TTS and other changes?

6 kHz DPOAE amplitude reliably related to observed TTS

Words in Noise DPOAEs decreasedvariable across at 6 kHzparticipants

ABR amplitude unchanged


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• Bramhall et al., 2017: ABR wave I amplitude decreased in veterans with high noise exposure and civilians exposed to firearm noise

• Prendergast et al., 2017: No relationship between ABR wave I amplitude and lifetime noise exposure in young adults with normal audiograms; high frequency hearing loss detected

• Yeend et al., 2017: No relationship between hearing‐in‐noise outcomes versus lifetime noise exposure in young adults with normal audiograms; high‐frequency hearing loss detected

• Prendergast et al., 2017: No relationship between lifetime noise exposure and hearing‐in‐noise in young adults with normal audiograms; high‐frequency hearing loss detected

• Grose et al., 2017: No relationship between extreme concert attendance (40 concerts in past two years) vs low concert attendance ( 4 concerts in past two years) and ABR wave I amplitude or hearing‐in‐noise outcomes in young adults with normal audiograms; high frequency hearing loss detected

2017 ‐ “hidden hearing loss” was hot topic

• Skoe and Tufts, 2018: No relationships between ABR amplitude and exposure, but latencies delayed

• Guest et al., 2018: No relationship between self‐reported or lab‐validated hearing‐in‐noise deficits and lifetime noise exposure

• Valderrama et al., 2018: ABR wave I amplitude decreased in association with lifetime noise exposure; longer ABR interpeak latencies and reduced central gain (less growth of Wave‐V amplitude relative to Wave‐I amplitude) was associated with poorer performance on listening in noise test

• Ridley et al., 2018: No relationships between ABR amplitude and exposure, but thresholds in noise varied more than expected after adjusting for threshold and OAE amplitude

2018 ‐ “hidden hearing loss” still a hot topic

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Other data assessing noise and function• 74 participants (14 male, 60 female), 18 ‐ 27 years of age, recruited via advertisements posted throughout campus.

• Hearing not required to be normal, but most participants had thresholds < 25 dB HL, present DPOAEs, and normal WIN scores.

• The two most common exposures included bars and dance clubs, followed by music player use.

• No statistically significant relationships between threshold, DPOAE amplitude, or WIN and individual or composite measures of recreational sound exposure, including preferred listening level, years of music player use, number of reported sound exposures, previous impulse noise exposure, or previous noise‐induced change in hearing.

C.G. Le Prell, H.W. Siburt, E. Lobarinas, S.K. Griffiths, and C. Spankovich. No reliable association between recreational noise exposure andthreshold sensitivity, distortion product otoacoustic emission amplitude, or word‐in‐noise performance in a college‐student population. EarHear, 2018 Mar 14. doi: 10.1097/AUD.0000000000000575. [Epub ahead of print].

Previous TTS (Yes/No) was not associated with threshold, DPOAE amplitude, or WIN threshold

C.G. Le Prell, H.W. Siburt, E. Lobarinas, S.K. Griffiths, andC. Spankovich. No reliable association betweenrecreational noise exposure and threshold sensitivity,distortion product otoacoustic emission amplitude, orword‐in‐noise performance in a college‐studentpopulation. Ear Hear, 2018 Mar 14. doi:10.1097/AUD.0000000000000575. [Epub ahead of print].

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Previous impulse noise (Yes/No) was not associated with threshold, DPOAE amplitude, or WIN

threshold

Can we accurately estimate noise exposure without dosimetry?

• Listening levels vary from person to person, so plugging in a single level for anyone reporting music player use will not be very accurate

C.G. Le Prell, H.W. Siburt, E. Lobarinas, S.K. Griffiths, and C. Spankovich. No reliable association between recreational noise exposure andthreshold sensitivity, distortion product otoacoustic emission amplitude, or word‐in‐noise performance in a college‐student population. EarHear, 2018 Mar 14. doi: 10.1097/AUD.0000000000000575. [Epub ahead of print].

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Do listeners consistently report their preferred

listening level?


• Top: highly consistent level preference across 19 songs

• Middle: the average SD was 4.4 dB SPL

• Bottom: highly variable preferences across 23 songs

• Do Hearing‐in‐Noise tests reveal cochlear synaptopathy and provide a sensitive early warning for effects of noise on the inner ear?

• Most difficult tests appear to have greatest sensitivity

• Is this neural damage? Or, is pathology in humans more likely to be a mixture of OHC loss and neural damage?

• Where does human risk for synaptopathy begin? • “Typical” recreational exposure vs extreme concert goers vs music students vs firearm users

• How does risk grow as a function of repeated exposure?

• Can TTS be prevented?

Important Questions Remain

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Do Hearing‐in‐Noise tests provide a sensitive early warning for effects of

noise on the inner ear?

• Rat data• Synaptopathy model – if you have a permanent reduction in wave I amplitude, and you have a difficult listening task, listening in noise can be compromised

Effect of noise on ABR threshold

106 dB SPL 109 dB SPL

Lobarinas E, Spankovich C, Le Prell CG. Evidence of "hidden hearing loss" following noise exposures that produce robust TTS and ABR wave‐I amplitude reductions. Hear Res. 2017 Jun; 349:155‐163

• Rats exposed to octave band noise, 8‐16 kHz, 2h at 106 or 109 dB SPL

• TTS of 20‐25 dB after 106 dB

• TTS of 30‐40 dB after 109dB

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Effect of noise (109 dB) on ABR Wave I amplitude

• Large TTS (30‐40 dB) resulted in permanent decrease in ABR Wave I amplitude in 75% of exposed animals (4 of 6 animals)


Startle Response

Startle Stimulus (airpuff)

Startle Stimulus (airpuff)

50 ms NBN cue

No prepulse condition

Prepulse condition

Startle Response

BBN Carrier Noise

BBN Carrier Noise

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Baseline Assessment Prior to Noise Exposure

• Pre‐pulse inhibition using an acoustic cue (50 ms, 70 dB) and an airpuffstimulus was used to assess hearing in noise

• At easy (“high”) SNR, the pre‐pulse reduces the startle response

• At hard (“low”) SNR, the pre‐pulse less effectively reduces the startle response

• Once SNR is too difficult, startle no longer affected

“Low” SNR

“High” SNR

No reliable effect


No Effect of Noise Exposure on High SNR performance


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Noise Reduced Performance at 16 kHz at Low SNR


Summary and Conclusions

• Noise exposures that do not result in permanent threshold shift can cause ABR amplitude decrease and “hidden” hearing loss

• Functional deficit only after large TTS (30‐40 dB at 24h in rats)

• This large TTS much greater than expected in most occupational and recreational settings

• But this may be highly relevant to blast over exposure (work by Brungart at Walter Reed, Boston Marathon victims)

• When deficits in noise did occur in rats, it was only at the poorest SNR tested and only at 16 kHz (where greatest TTS was observed)

• These data consistent with the limited deficits in chinchillas after carboplatin

• Data urgently needed in order to provide data‐based on relationship between noise exposure, TTS, neural loss, and functional deficits

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Can TTS be prevented?

• Human TTS paradigm development

• These are much smaller TTS’s, which is necessary for obvious ethical reasons

• Data on TTS prevention

4‐hr iPod exposure induces dose‐dependent TTS

93 dB: N=10 subjects. 98 dB: N=11 subjects. 100 dB: N=12 subjects.

Le Prell, C.G., Dell, S., Hensley, B.N., Hall, J.W.I., Campbell, K.C.M., Antonelli, P.A., Green, G.E., Miller, J.M., Guire, K. 2012. Digital music exposure reliably induces temporary threshold shift (TTS) in normal hearing human subjects. Ear Hear. 33, e44‐58.

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Mouse vs Human at 24 hrs

• Little, if any, TTS at 24 hrs

• This is dramatically different from TTS in animal models in which ABR deficits have been documented

Synaptopathic trauma(Mouse)

Non‐SynaptopathicTrauma(Mouse)

Human

• Randomized placebo‐controlled, double‐blind, between‐subjects design

iPod® studies

Placebo, 3‐4d

Screening

Active Agent, 3‐4d

Baseline 2, exposure, post tests

Baseline 1 1 week post test

1 day post test

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Le Prell, C.G., Fulbright, A., Spankovich, C., Griffiths, S., Lobarinas, E., Campbell, K.C.M., Antonelli, P.J., Green, G.E., Guire, K., and Miller, J.M. (2016). Dietary supplement comprised of β‐carotene, vitamin C, vitamin E, and magnesium: failure to prevent music‐induced temporary threshold shift. Audiology & Neurotology EXTRA, 6: 20‐39.

TTS protection varies with experimental agent

• Co‐inventor on patents owned by the University of Michigan.

• Miller, J.M., Le Prell, C.G., and Yamashita, D. US 7,786,100 B2, Composition and method of treating hearing loss. Awarded August 31, 2010. (Delayed Treatment/Vitamin E, Salicylate)

• Miller, J.M., Le Prell, C.G., Schacht, J., and Prieskorn, D.M. US 7,951,845, Composition and method of treating hearing loss. Awarded May 31, 2011. (ACEMg)

TTS protection varies with experimental agent

Kil J, Lobarinas E, Spankovich C, Griffiths SK, Antonelli PJ, Lynch ED, Le Prell CG. 2017. Safety and efficacy of ebselen for the prevention of noise‐induced hearing loss: a randomised, double‐blind, placebo‐controlled, phase 2 trial. Lancet. 390(10098):969‐979.

• NCT01444846 funded by Sound Pharmaceuticals, Inc.

• NCT02779192, not yet recruiting, will expand enrollment criteria, and includes data collection at multiple study sites

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Human Clinical Trials: Why TTS?

• Most pre‐clinical studies measure reduction of PTS but most human trials have assessed reduction of TTS

Why use TTS models?

• Shorter duration, reduced cost, decreased attrition, no permanent damage expected in any subjects

• DoD has high interest in drugs that prevent TTS – temporary compromise in communication compromises lethality, increases mortality

• “proof of concept” – drug was available in cochlea at concentration that was sufficient to attenuate biological response to noise

• Most (if not all) agents that have reduced TTS (in animals) have also reduced PTS (in animals)

• Confirmatory data in PTS trials will be required for PTS claims• Access to populations in which extent, prevalence, variability, and rate of change are documented is challenging

WIN shift is limited to immediate post‐music tests

TTS after 4‐hours of music player use shown for 19 normal hearing listeners (thresholds from 0.25‐8 kHz < 25 dB HL), tested at the University of Florida; Funded by Sound Pharmaceuticals, Inc.

2‐min

pre24‐hr 1‐wk

1‐way ANOVA, p<0.001pre vs 2‐min: p<0.052‐min vs 1‐day: p<0.05Pre vs 1‐day: NSPre vs 1‐week: NS*Clinically significant change defined as 3.5 dB/SB

*

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WIN shift is ~1.5 words, in most difficult listening conditions

WINT changes after 4‐hours of music player use shown for 19 normal hearing listeners (thresholds from 0.25‐8 kHz < 25 dB HL), tested at the University of Florida; Funded by Sound Pharmaceuticals, Inc.

2‐min

pre

24‐hr1‐wk

1‐way ANOVA, p=0.003pre vs 2‐min: p<0.052‐min vs 1‐day: p<0.05Pre vs 1‐day: NSPre vs 1‐week: NS

*

Where does risk begin?

• Vulnerability:

• Mouse > Guinea Pig > Rat > Rhesus macaque ?? Human

• Within species, risk grows with exposure intensity

• Within species, risk grows with exposure duration

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Reducing noise level decreases TTS

• Octave band noise at 100‐dB SPL for 2h produces 40‐50 dB TTS

• Octave band noise at 91‐dB SPL for 2h produces 30 dB TTS

• Both noise exposures result in TTS, neither resulted in PTS, only the higher level exposure resulted in synapse loss

From Fernandez, K.A., P.W. Jeffers, K. Lall, M.C. Liberman, and S.G. Kujawa. Aging after noise exposure: acceleration of cochlear synaptopathy in "recovered" ears. J. Neurosci. 35: 7509‐7520 (2015).

Increasing noise duration increases damage

• 91‐dB SPL exposure becomessynaptopathic when the exposure duration is extended from 2 hrs to 8 hrs

• We don’t know damage‐risk relationship, but clearly there is a time x intensity trade


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Many unanswered questions

• Final answer will not be as simple as “size of the TTS”

• Panel A shows identical TTS at 22.6 kHz

• Panel B shows pathology is only observed for the group with increasing TTS at higher frequencies


How does risk grow with repeated exposure?

• First exposure results in robust TTS, synapse loss, decrease in wave I amplitude

• Second exposure results in robust TTS, but no additional synapse loss or decrease in wave I amplitude

• Third exposure results in PTS, additional synapse loss, and additional decrease in wave I amplitude

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Repeat Exposure

• Single exposure: 30‐40 dB TTS at 24 hrs, no PTS

• Second exposure: same TTS developed, and recovered

• Third exposure: TTS increased (45 dB TTS at 24 hrs) and PTS developed (~10‐20 dB)

From: Wang Y, Ren C. (2012). Effects of repeated "benign" noise exposures in young CBA mice: shedding light on age‐related hearing loss. J Assoc Res Otolaryngol. 3(4):505‐15.

Repeat TTS/PTS Exposure

• Single exposure: ABR wave I amplitude is reduced

• Second exposure: No additional decrease in ABR amplitude with second robust TTS

• Third exposure: ABR amplitude drops again, in parallel with PTS


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Synaptic decrease observed with both TTS and PTS

• Single exposure: Synapses per IHC decreased

• Second exposure: No additional decrease in synapses per IHC

• Third exposure: Additional decrease in synaptic density after 3rdexposure


Real‐World Guidance

• Deficits hearing in noise may be one of the earliest symptoms of noise injury to the inner ear

• Data from musicians and those with occupational and other exposures are needed

• It is not clear if deficits in noise are related to outer hair cell damage, neural damage, or a combination of these two pathologies

• Some clinicians are now dispensing hearing aids with digital noise reduction algorithms and others are advocating auditory training programs for those with speech in noise deficits

• Multiple pharmaceutical companies are tackling synaptogenesis as a target for improving hearing in noise

• The best advice is to limit exposure to loud sound to prevent hearing loss, hearing in noise difficulties, and other dysfunction

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Funding Sources

• NIH: – U01 DC 008423– R44 DC009106

• Department of Defense: – USAMRMC #W81XH1110454 – USAMRAA #W81XWH1820014

• MaxSound, Inc.• Sound Pharmaceuticals, Inc.• Edison Pharmaceuticals, Inc.

• Emily and Phil Schepps Distinguished Professorship in Hearing Science at UT Dallas

Acknowledgments – Hidden hearing loss

• Student Team• Angela Fulbright, AuD, PhD

• PhD thesis• Jason Baker, AuD

• 3rd year AuD research project

• Sarah Grinn, AuD• 1st year PhD student research project

• Katherine Wiseman, AuD• PhD student rotation

• Faculty Collaborators• Edward Lobarinas, PhD• Christopher Spankovich, AuD, PhD

• Hannah Siburt, AuD, PhD

• Technical Assistance– Kaitlin Palmer, BA– Tess Zaccardi, BA

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Acknowledgments ‐ Clinical Trials

• University of Florida• Patrick Antonelli MD• Edward Lobarinas PhD• Chris Spankovich AuD, PhD, MPH• Scott Griffiths PhD• Leigh Ann Marshall BA

• Data Coordinating Center and Lead Team Members

• Josef Miller PhD (UM)• Ken Guire (UM)• Glenn Green MD (UM)• Kathleen Campbell PhD (SIU)• Sharon Kujawa PhD (Harvard)

• Karolinska Institutet• Ulf Rosenhall, MD• Mats Ulfendahl, PhD• Ann‐Christin Johnson, PhD• Ann‐Cathrine Lindblad, ScD

hidden hearing loss? effects of noise on evoked amplitude

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