Alterations in Peripheral and Central Components of the Auditory Brainstem Response: A Neural Assay of Tinnitus

Abstract

Chronic tinnitus, or “ringing of the ears”, affects upwards of 15% of the adult population. Identifying a cost-effective and objective measure of tinnitus is needed due to legal concerns and disability issues, as well as for facilitating the effort to assess neural biomarkers. We developed a modified gap-in-noise (GIN) paradigm to assess tinnitus in mice using the auditory brainstem response (ABR). We then compared the commonly used acoustic startle reflex gap-prepulse inhibition (gap-PPI) and the ABR GIN paradigm in young adult CBA/CaJ mice before and after administrating sodium salicylate (SS), which is known to reliably induce a 16 kHz tinnitus percept in rodents. Post-SS, gap-PPI was significantly reduced at 12 and 16 kHz, consistent with previous studies demonstrating a tinnitus-induced gap-PPI reduction in this frequency range. ABR audiograms indicated thresholds were significantly elevated post-SS, also consistent with previous studies. There was a significant increase in the peak 2 (P2) to peak 1 (P1) and peak 4 (P4) to P1 amplitude ratios in the mid-frequency range, along with decreased latency of P4 at higher intensities. For the ABR GIN, peak amplitudes of the response to the second noise burst were calculated as a percentage of the first noise burst response amplitudes to quantify neural gap processing. A significant decrease in this ratio (i.e. recovery) was seen only at 16 kHz for P1, indicating the presence of tinnitus near this frequency. Thus, this study demonstrates that GIN ABRs can be used as an efficient, non-invasive, and objective method of identifying the approximate pitch and presence of tinnitus in a mouse model. This technique has the potential for application in human subjects and also indicates significant, albeit different, deficits in temporal processing in peripheral and brainstem circuits following drug induced tinnitus.

Dependence of the Startle Response on Temporal and Spectral Characteristics of Acoustic Modulatory Influences in Rats and Gerbils

“…Only the inhibitory effect of the gap reduced the startle amplitude in a frequency-dependent manner. This is in line with a study in mice (Lowe and Walton, 2015 ), finding also no frequency-dependency of the startle amplitude in no-gap trials but a frequency-dependency of gap-PPI. However, our gerbils showed a clear effect of background frequency on the uninhibited startle amplitude as it decreases with increasing frequency of background noise.…”

Prepulse inhibition of the acoustic startle reflex vs. auditory brainstem response for hearing assessment

“…Therefore it is likely that PPI audiometry could be a useful tool to assess neuroplastic changes in awake behaviorally responsive animals. PPI audiometry would be especially suited for labs that already employ the ASR for other purposes such as tinnitus detection (Turner et al, 2006; Tziridis et al, 2012; Ropp et al, 2014; Koehler et al, 2013, Lowe & Walton, 2015) or psychopharmaceutical studies (Phillips et al, 2000; Davis & Menkes, 1982). It should be noted that PPI tests are performed on multiple animals concurrently with no prerequisite training for the animals or the handlers.…”

Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs

“…These data suggest that there are separate mechanisms behind the two different tasks; that is, the reduction of either evoked neural responses to a startling stimulus in auditory cortex or behavioural startle responses by a preceding gap may not directly relate to absolute gap detection thresholds in auditory cortex. The gap-induced PPI circuit has been attributed to the brainstem (Lowe & Walton, 2015), but is thought to be subject to descending modulation by structures such as the cortex and amygdala (Bosch & Schmid, 2008). Thus, decorticate animals show impairments in GPIAS for gaps of < 50 ms duration (Ison et al, 1991;Threlkeld et al, 2008), suggesting that the cortex still plays a role in gap-induced PPI at shorter gap durations.…”