The gap prepulse inhibition of the acoustic startle response has been used to screen tinnitus in an animal model. Here, we examined changes in the auditory late response under various conditions of gap prepulse inhibition.
We recruited 19 healthy adults (5 males, 14 females) and their auditory late responses were recorded after various stimuli with or without gap prepulsing. The N1 and P2 responses were selected for analysis. The gap prepulse inhibition was estimated to determine the optimal auditory late response in the gap prepulse paradigm.
We found that the gap per se generated a response that was very similar to the response elicited by sound stimuli. This critically affected the gap associated with the maximal inhibition of the stimulus response. Among the various gap-stimulus intervals (GSIs) between the gap and principal stimulus, the GSI of 150 ms maximally inhibited the response. However, after zero padding was used to minimize artifacts after a P2 response to a gap stimulus, the differences among the GSIs disappeared.
Overall, the data suggest that both the prepulse inhibition and the gap per se should be considered when using the gap prepulse paradigm to assess tinnitus in humans.
An auditory evoked response (AER) is an electrical potential evoked by an external auditory stimulus. The AER is thought to provide useful neurophysiological information because of its sensitive temporal resolution. Among the various AER components, the N1 and P2 peaks of the auditory late response (ALR) represent auditory perception and provide information about the psychological state of an individual [
Prepulse inhibition (PPI) is a general neurological phenomenon wherein the magnitude of a response to a principal stimulus is reduced when a certain stimulus precedes it by 30-500 ms [
Advances in the methods of tinnitus assessment in animals have facilitated significant developments in tinnitus research. Turner, et al. [
Previous studies have investigated the relationship between the human startle reflex and PPI in the presence of various levels of background noise; a prepulse sound inhibited the startle response in humans [
Ku, et al. [
We explored the possibility that a “gap” can serve as a stimulus for generating an auditory response at the cortical level. We also examined the feasibility of the gPPI paradigm for ALR measurement and investigated the differences in gPPI values derived using various GSIs between a gap prepulse and the principal pulse. Additionally, we investigated the effects of gap-only stimuli in the gap prepulse paradigm by correcting for the responses evoked by the gap prepulse stimuli. Our results demonstrate how the positioning of the gap prepulse affects the gPPI.
We enrolled 19 adults (5 males, 14 females) with a mean age of 28.68 years (range 21-50 years). None of the participants had any history of tinnitus or neurological disease. Their hearing was normal, as shown by pure tone audiometry at 500, 1,000, 2,000, and 4,000 Hz; all hearing thresholds were below 25 dB HL (hearing level) at all tested frequencies. This study was approved by the Institutional Board of Dankook University Hospital (DKUH 2013-08-009).
The system used to measure ALR is described in
The stimuli used are shown in
All ALRs were measured in a double-walled soundproofed room. Participants were seated in comfortable chairs, and an inspector ensured that they did not sleep or engage in habitual movements. The common mode sense electrode was placed on the ipsilateral ear (reference) and the driven light leg electrode was placed on the contralateral earlobe (ground). Headgear with four channel electrodes (AF3, AF4, F3, and F4) was placed, and measurements commenced when the impedances of all electrodes were ≤5 kΩ. Stimuli were delivered (via the earphone) to the left ear, and the contralateral ear was blocked with a sponge earplug (KE-1100, Moden zone, Seoul, Korea). For each subject, three 5 min measurements at a 128 Hz sampling rate were made. The responses were processed using a software, and the responses to no-gap and with-gap stimuli were displayed as bold and dotted lines, respectively (
EEG signals transferred to the computer were processed using specialized software. Both baseline drift and high-frequency noise were removed using a 1-30 Hz band-pass filter. The responses with or without gap prepulse were averaged. With- and without-gap responses are presented together; the ranges of interest including N1 (first negative peak) and P2 (second positive peak) are highlighted using yellow bars. The amplitudes of with- and without-gap responses were automatically calculated from the N1P2 amplitude, within the region of interest.
Epoch durations of 1,000 ms (which are sufficient to include all responses to the longest GSI) were analyzed. Four peaks developing within 0.4 to 0.8 ms were measured: N1, P1, N2, and P2 peaks. Of these, the N1 and P2 peaks after both no-gap and gap stimuli were automatically identified, and the gPPI was defined using the following equation:
Zero padding was applied to the corrected data. The responses after the zero-crossing points of P2N2 waves after gap-only stimuli were set to zero. Thus, the ALR gap-only response was subtracted from the response after both a gap and a principal pulse. Mean and standard deviation (mean±SD) of all peak amplitudes were compared.
All data were analyzed using the Statistical Package for the Social Sciences ver. 19 (IBM, Armonk, NY, USA). Analysis of variance (ANOVA) with Bonferroni post-hoc and paired t-test were used to determine the effect of GSI on the gPPI.
All responses were averaged, yielding the grand-averaged data. The grand-averaged ALR after an 80 dB SPL (8 kHz) stimulus is shown in
We calculated gPPI values to explore ALR changes at various GSIs. The gPPI values at GSIs of 50, 150, and 250 ms are shown in
The decrease in the N1P2 amplitude when a gap prepulse was applied prior to the principal stimulus is assumed to reflect the PPI of the N1P2 response. Moreover, the gap prepulse-induced auditory response may generate interference. Previously, several studies have reported that the AEPs evoked within 300 ms of multiple stimuli changed if they were overlaid with auditory responses [
The gPPI values after correction are shown in
ALRs can be classified as exogenous and endogenous responses, depending on latency [
All gPPI values associated with gap-only stimuli were subjected to zero-padding correction (
We sought to identify ALR changes after gPPI in humans with normal hearing. First, we investigated gPPI under conditions very similar to those used in animal studies, and found that the ALR was inhibited by a gap prepulse. This was in line with the assumption that an AER can be generated using the gap prepulse paradigm [
The ALR responses obtained using various GSIs showed that gap placement 50 ms prior to the principal stimulus resulted in the greatest inhibition of the response. Previous work on gPPI focused on gap duration; a longer gap prepulse was associated with greater inhibition, both for a simple gap prepulse and a gap following a prepulse when background noise was lacking between the gap and principal pulse [
We found that the GSI of 250 ms also inhibited the response to the principal stimulus, albeit not as markedly as the GSIs of 50 and 150 ms. However, the GSI of 250 ms is clinically relevant, and temporal summation is impossible. Blumenthal [
To identify the pure inhibitory effects of all GSIs, we subtracted the responses evoked by gap prepulsing; such prepulses were not inhibitory at the GSI of 150 ms. This is an interesting finding as it shows that the effect of the gap prepulse on the ALR depends on the GSI, and at some GSIs, the effect is saturated. We considered many other factors that might explain this result. As the AEP is very sensitive to measurement conditions and long measurement times, extreme caution is required during experiments for estimating such potentials. Grand-averaged data indicate gPPI trends. We sought to average all data obtained using the same GSIs; these are the most generalizable results of our study. Although statistical analysis was not possible, the most prominent inhibition was associated with the GSI of 50 ms, and the ALR response after a gap prepulse was more inhibited at shorter GSIs. Previous studies have proposed the use of the gap prepulse inhibition paradigm for tinnitus assessment in clinics [
The N1P2 peak has been used to evaluate cochlear implants [
Multiple or paired stimuli delivered at various GSIs have been used to evaluate the auditory processing capacity [
This study was supported by the Ministry of Science, Information and Communications technology (ICT) and Future Planning grant funded by the Korean Government (NRF-2017R1D1A1B03033219).
The authors have no financial conflicts of interest.
Conceptualization: Ilyong Park and Jae Yun Jung. Data curation: JaeHun Lee and Ilyong Park. Formal analysis: Jae-Hun Lee and Jae Yun Jung. Funding acquisition: Jae Yun Jung. Investigation: Jae Yun Jung. Methodology: Jae Yun Jung and Ilyong Park. Project administration: Jae Yun Jung and Ilyong Park. Resources: Ilyong Park. Software: Ilyong Prak. Supervision: Jae Yung Jung and Ilyong Park. Validation: Jae Yun Jung. Writing—original draft: Jae-Hun Lee. Writing—review & editing: All authors.
Auditory late response (ALR) measurement. Stimuli were generated by the computer and presented via earphones. Responses were recorded using a four-channel wireless electroencephalogram (EEG) acquisition module and sent to the computer for analysis. ch.: channel, RF: radio frequency, DAC: digital-to-analog converter, gPPI: gap PPI, PC: personal computer, DAQ: data acquisition.
The stimuli and auditory late response (ALR). A: Various stimuli including background noise with a principal stimulus, gap-ped background with a prin-cipal stimulus, and gapped back-ground alone. The responses to all stimuli were recorded (white numbers represent intensity of stimulus and black numbers represent latency). B: Acquired responses calculated as gap PPI (gPPI) values. “(A)” indicates “the response from No-gap stimulus”. “(B)” indicates “the response from gap stimulus”. “(C)” indicates "the response from gap-only stimulus”. BGN: background noise.
Auditory late responses (ALRs) with- and without-gap prepulsing. The bold line indicates the response to the principal stimulus (80 dB SPL) and the dotted line indicates the response to a gap followed by the principal stimulus. The background noise was narrow-band noise of 8 kHz with a bandwidth of 1 kHz (60 dB SPL). BGN: background noise.
Gap PPI (gPPI) values (mean±standard error of the mean) elicited by different gap-stimulus intervals (GSIs). There was a statistically significant association between the GSI of 50 ms and the highest gPPI, as compared with the GSIs of 150 ms (*
Auditory late responses elicited by only a gap. The background noise was narrow-band noise of 8 kHz with a bandwidth of 1 kHz (60 dB SPL). Gaps within the background noise evoked auditory responses similar to those evoked by sound stimuli. BGN: background noise.
Corrected gap PPI (gPPI) values (mean±standard error of the mean). After correction (subtraction of the gap-only stimulus), the gap-stimulus interval (GSI) of 150 ms, but not 250 ms, was associated with a near-zero gPPI (*
Corrected grand-averaged gap PPI (gPPI) values after zero padding using different gap-stimulus intervals (GSIs). After zero padding, among the three GSIs evaluated, the GSI of 50 ms was associated with the highest gPPI. Notably, GSIs of 250 and 500 ms resulted in similar degrees of inhibition.
The gap PPI (gPPI) values (mean±standard error of the mean) after zero-padding correction. After correction, the gPPI did not vary according to the gap-stimulus interval (GSI).
N1P2 inter-peak amplitudes (mean±standard deviation) with- and without-gap prepulsing at different GSIs
GSI (msec) | 50 | 15 | 250 |
---|---|---|---|
No-gap response (µV) | 9.77±3.56 | 9.71±3.16 | 10.6±4.88 |
Gap response (µV) | 6.24±2.42 | 8.17±3.00 | 8.39±2.61 |
GSI: gap-stimulus interval
Corrected N1P2 inter-peak amplitudes (mean±standard deviation) and gPPI values with- and without-gap prepulsing at different GSIs
GSI (msec) | 50 | 150 | 250 |
---|---|---|---|
No-gap response (µV) | 9.77±3.56 | 9.71±3.16 | 10.6±4.88 |
Gap response (µV) | 7.53±2.83 | 9.23±3.11 | 7.55±2.84 |
GSI: gap-stimulus interval
Corrected N1P2 inter-peak amplitudes including those obtained after zero padding (mean±standard deviation) with- and without-gap prepulsing at different GSIs
GSI (msec) | 50 | 150 | 250 |
---|---|---|---|
No-gap response (µV) | 9.77±3.56 | 9.71±3.16 | 10.6±4.88 |
Gap response (µV) | 7.71±2.78 | 8.28±2.93 | 8.39±2.61 |
GSI: gap-stimulus interval