The Effects of Salicylate on The Effects of Salicylate on Auditory Evoked Potential Auditory Evoked Potential

Amplitudes from the Auditory Amplitudes from the Auditory Cortex and Brainstem Cortex and Brainstem

Brian SawkaBrian SawkaAuD ProjectAuD Project

TinnitusTinnitusSubjective tinnitus is the sensation of Subjective tinnitus is the sensation of

sound in the absence of an acoustic sound in the absence of an acoustic stimulus. stimulus.

Tinnitus can be induced byTinnitus can be induced by noise exposurenoise exposure

(Axelsson & Hamernik, 1987; Job et al. 2007)(Axelsson & Hamernik, 1987; Job et al. 2007)

ototoxic drugsototoxic drugs (Huang & Schacht, 1989; Day et al. 1989)(Huang & Schacht, 1989; Day et al. 1989)

Tinnitus is usually associated with Tinnitus is usually associated with cochlear damagecochlear damage

(Demeester et al. 2007; Job et al. 2007). (Demeester et al. 2007; Job et al. 2007).

Salicylate Causes Hearing Loss Salicylate Causes Hearing Loss and Tinnitusand Tinnitus

Salicylate causes temporary hearing loss Salicylate causes temporary hearing loss and tinnitus in humansand tinnitus in humans

(Hicks & Bacon, 1999; Halla et al. 1991). (Hicks & Bacon, 1999; Halla et al. 1991).

Tinnitus-like behaviors suggest that animals Tinnitus-like behaviors suggest that animals experience tinnitus with treatment of experience tinnitus with treatment of salicylatesalicylate

(Bauer et al. 1999; Jastreboff et al. 1988; Lobarinas et al. 2004; (Bauer et al. 1999; Jastreboff et al. 1988; Lobarinas et al. 2004;

Yang et al, 2007).Yang et al, 2007). Consequently, tinnitus has been extensively Consequently, tinnitus has been extensively

used in research to study tinnitusused in research to study tinnitus

Salicylate Enhances Auditory Evoked Salicylate Enhances Auditory Evoked Potential Amplitude at the Auditory CortexPotential Amplitude at the Auditory Cortex

Yang et. al (2007) showed enhancement of auditory Yang et. al (2007) showed enhancement of auditory cortex (AC) response amplitude with high intensity 16 cortex (AC) response amplitude with high intensity 16 and 20 kHz tone burst stimuli post salicylate treatmentand 20 kHz tone burst stimuli post salicylate treatment

These frequencies were associated with tinnitus-like These frequencies were associated with tinnitus-like behavior in another set of animals behavior in another set of animals (Yang et al. 2007)(Yang et al. 2007)

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Cochlear/8Cochlear/8thth nerve, Cochlear Nucleus, and Inferior nerve, Cochlear Nucleus, and Inferior Colliculus I/O Functions Pre and Post Noise Colliculus I/O Functions Pre and Post Noise

ExposureExposure Salvi et al. found enhancement at the inferior Salvi et al. found enhancement at the inferior

colliculus with high level 1 kHz tone bursts post colliculus with high level 1 kHz tone bursts post noise exposure using local implants in noise exposure using local implants in chinchillas (2000)chinchillas (2000)

Salvi et al. 2000Salvi et al. 2000

Aim of StudyAim of Study

CochleaCochlear Nucleus

InferiorColliculus8th

AuditoryCortex

Observe if the enhancement of the AC waveform Observe if the enhancement of the AC waveform post salicylate is also present in the ABRpost salicylate is also present in the ABR waveform.waveform. To address this question, four implanted animals To address this question, four implanted animals will be tested pre and post salicylate treatment forwill be tested pre and post salicylate treatment for both:both:

AC responseAC response ABR responseABR response

Observe if the enhancement of the AC waveform Observe if the enhancement of the AC waveform post salicylate is also present in the ABRpost salicylate is also present in the ABR waveform.waveform. To address this question, four implanted animals To address this question, four implanted animals will be tested pre and post salicylate treatment forwill be tested pre and post salicylate treatment for both:both:

AC responseAC response ABR responseABR response

Methods: SubjectsMethods: Subjects

Subjects: Four male Sprague Dawley rats Subjects: Four male Sprague Dawley rats Implanted at 2-3 months of ageImplanted at 2-3 months of age Tested at 6-7 months of ageTested at 6-7 months of age Implants consist of:Implants consist of:

Auditory Cortex electrode (right side)Auditory Cortex electrode (right side) Frontal lobe skull electrode Frontal lobe skull electrode Screw for head restraintScrew for head restraint Affixed to skull with dental cement and stainless steel screws Affixed to skull with dental cement and stainless steel screws

The implant procedure has been described in detail The implant procedure has been described in detail (Yang et al, 2007; Lobarinas et al, 2006). (Yang et al, 2007; Lobarinas et al, 2006).

Methods: Animal RestraintMethods: Animal Restraint

The rats were trained to remain still during The rats were trained to remain still during awake recordings:awake recordings:

Small modified plastic cageSmall modified plastic cageHead restraint using head screw and a mechanical Head restraint using head screw and a mechanical

armarm

Awake recordings:Awake recordings:Required for AC recordingsRequired for AC recordingsChosen for ABR to avoid influences of anesthesiaChosen for ABR to avoid influences of anesthesia

Methods: Auditory StimuliMethods: Auditory Stimuli 4 ms alternating polarity tone bursts of 4, 8, 12, 16 and 4 ms alternating polarity tone bursts of 4, 8, 12, 16 and

20 KHz 20 KHz Created in Tucker Davis Technologies (TDT) Created in Tucker Davis Technologies (TDT)

SigGen RP 4.4 softwareSigGen RP 4.4 software TDT Stimuli Hardware: TDT Stimuli Hardware:

ProcessorProcessor AttenuatorAttenuator Headphone driverHeadphone driver 8 ohm tweeter ~ 2 ¼ inches from ear8 ohm tweeter ~ 2 ¼ inches from ear

Left ear for AC recordings (contralateral to recording electrode)Left ear for AC recordings (contralateral to recording electrode) Right ear for ABR recordings (ispilateral to recording electrode)Right ear for ABR recordings (ispilateral to recording electrode)

The auditory stimuli will be binaural as both ears will The auditory stimuli will be binaural as both ears will remain unrestrictedremain unrestricted

Methods: Recording Hardware and Methods: Recording Hardware and ParametersParameters

TDT Recording hardware: TDT Recording hardware: Four channel head stageFour channel head stage Medusa PreampMedusa Preamp Medusa Base Station Medusa Base Station

Recording Software: TDT BioSig RP 4.41Recording Software: TDT BioSig RP 4.41 BioSig and electrode settings for AC recording:BioSig and electrode settings for AC recording:

Recording electrode placed at the auditory cortex and reference Recording electrode placed at the auditory cortex and reference at the frontal lobe of the skull (contralateral recording)at the frontal lobe of the skull (contralateral recording)

Band pass filter 3 Hz - 1000 Hz and 60 Hz notch Band pass filter 3 Hz - 1000 Hz and 60 Hz notch Stimulation rate 2/second and averaged 100 sweeps for each Stimulation rate 2/second and averaged 100 sweeps for each

waveform. waveform. BioSig and electrode settings for ABR recording:BioSig and electrode settings for ABR recording:

Recording electrode placed at the skull and reference at the Recording electrode placed at the skull and reference at the auditory cortex (ipsilateral recording)auditory cortex (ipsilateral recording)

Band pass 100 Hz - 3000 Hz and 60 Hz notch Band pass 100 Hz - 3000 Hz and 60 Hz notch Stimulation rate 19/second and averaged 512 sweeps for each Stimulation rate 19/second and averaged 512 sweeps for each

waveform. waveform.

Methods: Amplitude Measure for Methods: Amplitude Measure for AC and ABRAC and ABR

AC recordingsAC recordingsLarge positive peak ~ 11-15 msLarge positive peak ~ 11-15 msAmplitude recorded peak to following trough Amplitude recorded peak to following trough

in micro voltsin micro voltsABR recordingsABR recordings

Positive peak ~ 4.5 - 5 ms (estimated latency Positive peak ~ 4.5 - 5 ms (estimated latency of inferior colliculus)of inferior colliculus)

Amplitude recorded peak to following trough Amplitude recorded peak to following trough in micro voltsin micro volts

Results:Results: Auditory cortex response Auditory cortex response enhancement was observed for most conditionsenhancement was observed for most conditions

Auditory Cortex Amplitudes in Response to 20 KHz Tone Bursts for Animal 102607

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Results: Auditory Cortex Statistical Results: Auditory Cortex Statistical AnalysisAnalysis

Paired t test comparisons of pre and post salicylate AC Paired t test comparisons of pre and post salicylate AC amplitudes for all four animals:amplitudes for all four animals:

4k: p = .0474k: p = .047 8k: p = .00458k: p = .0045 12k: p = .03212k: p = .032 16k: p = .06816k: p = .068 20k: p = .03220k: p = .032

Alpha = .05Alpha = .050

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Across Animal Average for 20 KHz Auditory Cortex Amplitude at 90 dB SPL

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Results: ABR results for high intensity stimuli were Results: ABR results for high intensity stimuli were typically smaller amplitude for 2 hours post salicylate typically smaller amplitude for 2 hours post salicylate

compared to baselinecompared to baselineBrainstem Responce Amplitudes in Response to

20 KHz Tone Bursts for Animal 102607

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Results: ABR Statistical AnalysisResults: ABR Statistical Analysis

Paired t test comparisons of pre and post salicylate ABR Paired t test comparisons of pre and post salicylate ABR amplitudes for all four animals:amplitudes for all four animals:

4k: Missing data4k: Missing data 8k: Missing data8k: Missing data 12k: p = .00112k: p = .001 16k: p = .06116k: p = .061 20k: Missing data20k: Missing data

Alpha = .05Alpha = .050

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ConclusionsConclusions

The AC results confirm high intensity The AC results confirm high intensity tone burst enhancement post salicylate tone burst enhancement post salicylate treatmenttreatment

The ABR data suggests that the The ABR data suggests that the amplitudes are overall decreased post amplitudes are overall decreased post salicylate at the inferior colliculussalicylate at the inferior colliculus

Discussion: Comparison of ResultsDiscussion: Comparison of Results

CochleaCochlear Nucleus

InferiorColliculus8th

CochleaCochlear Nucleus

InferiorColliculus

AuditoryCortex

AuditoryCortex

8th

Salvi et al. studies using noise exposureSalvi et al. studies using noise exposure

Current observations for salicylate treatment

Current observations for salicylate treatment

DiscussionDiscussion

This study is useful as a small pilot studyThis study is useful as a small pilot studyThe results suggest that hearing damage The results suggest that hearing damage

and tinnitus from salicylate may have a and tinnitus from salicylate may have a different physiological mechanism than different physiological mechanism than noise exposure. noise exposure.

A follow up study is recommended that A follow up study is recommended that would use local inferior collicului implants would use local inferior collicului implants to verify these results. to verify these results.

RecognitionRecognition

I would like to thank my research I would like to thank my research committee for their advisement and committee for their advisement and assistance for this project:assistance for this project:

Wei Sun, Ph.DWei Sun, Ph.DRichard Salvi, Ph.DRichard Salvi, Ph.DJoan Sussman, Ph.DJoan Sussman, Ph.D

Special thanks to:Special thanks to:Lu Jianzhong, Ph.DLu Jianzhong, Ph.D

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Jastreboff, P.J., Brennan, J.F., Coleman, J.K. & Sasaki, C.T. (1988). Jastreboff, P.J., Brennan, J.F., Coleman, J.K. & Sasaki, C.T. (1988). Phantom auditory sensation in rats: an animal model for tinnitus. Phantom auditory sensation in rats: an animal model for tinnitus. Behav Behav Neurosci,Neurosci, 102, 811-822. 102, 811-822.

Job, A., Raynal, M. & Kosowski, M. (2007). Susceptibility to tinnitus Job, A., Raynal, M. & Kosowski, M. (2007). Susceptibility to tinnitus revealed at 2 KHz range by bilateral lower DPOAEs in normal hearing revealed at 2 KHz range by bilateral lower DPOAEs in normal hearing subjects with noise exposure. subjects with noise exposure. Audiol Neurootol,Audiol Neurootol, 12(3), 137-44. 12(3), 137-44.

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Lobarinas, E., Sun, W., Cushing, R. & Salvi, R. (2004). A novel Lobarinas, E., Sun, W., Cushing, R. & Salvi, R. (2004). A novel behavioral paradigm for assessing tinnitus using schedule-induced behavioral paradigm for assessing tinnitus using schedule-induced polydipsia avoidance conditioning (SIP-AC). polydipsia avoidance conditioning (SIP-AC). Hear ResHear Res, 190 (1-2), 109-, 190 (1-2), 109-14. 14.

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