Using an appetitive operant conditioning paradigm to screen rats for tinnitus induced by intense sound exposure: Experimental considerations and interpretation.

In an effort to help elucidate the neural mechanisms underlying tinnitus in humans, researchers have often relied on animal models; a preclinical approach which ultimately required that behavioral paradigms be designed to reliably screen animals for tinnitus. Previously, we developed a two-alternative forced-choice (2AFC) paradigm for rats that allowed for the simultaneous recording of neural activity at the very moments when they were reporting the presence/absence of tinnitus. Because we first validated our paradigm in rats experiencing transient tinnitus following a high-dose of sodium salicylate, the present study now sought to evaluate its utility to screen for tinnitus caused by intense sound exposure; a common tinnitus-inducer in humans. More specifically, through a series of experimental protocols, we aimed to (1) conduct sham experiments to ensure that the paradigm was able to correctly classify control rats as not having tinnitus, (2) confirm the time course over which the behavioral testing could reliably be performed post-exposure to assess chronic tinnitus, and (3) determine if the paradigm was sensitive to the variable outcomes often observed after intense sound exposure (e.g., hearing loss with our without tinnitus). Ultimately, in accordance with our predictions, the 2AFC paradigm was indeed resistant to false-positive screening of rats for intense sound-induced tinnitus, and it was able to reveal variable tinnitus and hearing loss profiles in individual rats following intense sound exposure. Taken together, the present study documents the utility of our appetitive operant conditioning paradigm to assess acute and chronic sound-induced tinnitus in rats. Finally, based on our findings, we discuss important experimental considerations that will help ensure that our paradigm is able to provide a suitable platform for future investigations into the neural basis of tinnitus.

Variability in the Estimated Amplitude of Vowel-Evoked Envelope Following Responses Caused by Assumed Neurophysiologic Processing Delays.

Vowel-evoked envelope following responses (EFRs) reflect neural encoding of the fundamental frequency of voice (f0). Accurate analysis of EFRs elicited by natural vowels requires the use of methods like the Fourier analyzer (FA) to consider the production-related f0 changes. The FA's accuracy in estimating EFRs is, however, dependent on the assumed neurophysiological processing delay needed to time-align the f0 time course and the recorded electroencephalogram (EEG). For male-spoken vowels (f0 ~ 100 Hz), a constant 10-ms delay correction is often assumed. Since processing delays vary with stimulus and physiological factors, we quantified (i) the delay-related variability that would occur in EFR estimation, and (ii) the influence of stimulus frequency, non-f0 related neural activity, and the listener's age on such variability. EFRs were elicited by the low-frequency first formant, and mid-frequency second and higher formants of /u/, /a/, and /i/ in young adults and 6- to 17-year-old children. To time-align with the f0 time course, EEG was shifted by delays between 5 and 25 ms to encompass plausible response latencies. The delay-dependent range in EFR amplitude did not vary by stimulus frequency or age and was significantly smaller when interference from low-frequency activity was reduced. On average, the delay-dependent range was < 22% of the maximum variability in EFR amplitude that could be expected by noise. Results suggest that using a constant EEG delay correction in FA analysis does not substantially alter EFR amplitude estimation. In the present study, the lack of substantial variability was likely facilitated by using vowels with small f0 ranges.

Uncovering the contribution of enhanced central gain and altered cortical oscillations to tinnitus generation.

Various theories and their associated mechanisms have been proposed as the neural basis of phantom sound perception (tinnitus), including central gain enhancement and altered cortical oscillations. However, it remains unknown whether these cortical changes directly cause tinnitus, or simply coexist with the phantom percept. Using chronically-implanted electrodes and drug delivery cannulae in rats, we examined whether enhanced central gain and cortical oscillations are consistent across different tinnitus induction methods (noise exposure; salicylate), and if directly-inducing enhanced central gain or altered cortical oscillations via pharmacologic manipulation of inhibition along the auditory pathway would cause behavioral evidence of tinnitus. We show that, while there appeared to be no clear link between tinnitus and the presence of enhanced sound-evoked cortical activity or altered spontaneous cortical oscillations, pharmacologic impairment of GABAergic neurotransmission in the auditory cortex was sufficient to cause tinnitus; collective findings which further advance our understanding of the neural basis of tinnitus.