Acoustic deprivation modulates central gain in human auditory brainstem and cortex

Although the adaptive plasticity of behavioral loudness judgments in response to earplugging is likely dependent on higher level (i.e., cortical) gain processes within the auditory system, subcortical evidence of gain-related plasticity has been demonstrated in the brainstem following earplugging. In rats, Clarkson et al. (2016) showed that unilateral earplugging for 10 days lead to poorer ABR thresholds but increased relative gain in the cochlear nucleus and lateral lemniscus, as demonstrated by increased ABR amplitude ratios for waves II/I and IV/I. Notably, following earplug removal and 10-days of recovery, the gain increase persisted in the lateral lemniscus but returned to baseline in the cochlear nucleus. In humans, the acoustic reflex threshold (ART) has been used to document changes in brainstem neural function following auditory attenuation via unilateral earplugs (Brotherton et al., 2017, 2016; Maslin et al., 2013; Munro and Blount, 2009; Munro et al., 2014) as well as following auditory enhancement with monaural amplification (Munro et al., 2007; Munro and Merrett, 2013). The acoustic reflex engages a brainstem pathway that includes ipsilateral and contralateral brainstem nuclei (i.e., CN, SOC) and terminates with bilateral contraction of the stapedius muscle in the middle ear (Borg, 1973; Pascal et al., 1998). Activation of this reflex pathway is measured with an ear canal probe system that detects a brief change in the admittance of the middle ear system and can be elicited with a range of stimuli (e.g., pure tones, broadband noise) and sound levels. The ART corresponds to the lowest sound pressure level that elicits a reliable reflex. The earplugging studies have shown that prolonged acoustic attenuation leads to a decrease in the minimum sound pressure level required to elicit the ART relative to baseline measurements (Brotherton et al., 2017, 2016; Maslin et al., 2013; Munro and Blount, 2009), consistent with an increase in central gain. Conversely, enhanced auditory input via short-term and long-term experience with monaural amplification results in an increase in the ART (Munro et al., 2007; Munro and Merrett, 2013), consistent with reduced central gain. While these changes in ART suggest that central gain changes are detectable at an early processing stage in the auditory pathway, it has not been clearly established in humans whether these effects are maintained or further modulated at higher (i.e., cortical) levels of auditory processing in the same individuals (e.g., Maslin et al., 2013b).

Investigations in animal models have shown that reduced peripheral input due to permanent conductive hearing loss can disrupt cortical function (Xu et al., 2007) without altering brainstem function (Yao & Sanes, 2018). Human subjects with permanent unilateral conductive hearing loss, on the other hand, have shown increased cortical activity (Parry et al., 2019) but reduced or altered hemispheric asymmetry (Maslin et al., 2013a). Moreover, human subjects with temporary, reversible conductive hearing loss from earplugging have shown no change in cortical measures with functional magnetic resonance imaging (fMRI) following treatment (Maslin et al., 2013b). Thus, the cortical effects of peripheral deprivation on central gain modulation in the cortex, in auditory systems with otherwise normal cochlear function, is less than clear, and may be due to differences in measures used to quantify central gain changes across studies.

Some evidence of cortically-mediated gain may be gleaned from changes in auditory middle latency responses (MLRs), reflecting contributions from thalamocortical sources (Musiek and Nagle, 2018), that were measured pre- and post-treatment for mildly hyperacusic hearing-impaired persons using bilateral sound generators over several months (Formby et al., 2017c). In this study, participants simultaneously achieved significant incremental changes in their loudness judgements over the treatment period as well as improvements in MLR latency measures. These promising but limited findings suggest the possibility of identifying neural correlates of central-gain mediated loudness growth in the cortex.

Electrophysiological evaluation of loudness growth in humans has also been investigated using the auditory steady-state response (ASSR), also known as the envelope-following response (EFR). The ASSR has been proposed as a physiological measure that parallels loudness growth (Kubota et al., 2019; Ménard et al., 2008; Van Eeckhoutte et al., 2018a, 2018b, 2016). The ASSR is phase-locked to the envelope periodicity of a modulated tone or noise and can be measured with standard clinical instrumentation with as few as three electrodes or with multi-channel electroencephalography (EEG) systems (Picton et al., 2005, 2003). Clinically, the 80-Hz ASSR has been used to assess brainstem processing as a steady-state alternative to the traditional transient-evoked auditory brainstem response (ABR); however, the utility of this response is manifold. For example, the 80-Hz ASSR has been shown to be a viable method for indexing loudness recruitment resulting from cochlear hearing loss at the level of the brainstem (Kubota et al., 2019) and for indexing loudness perception at higher levels of the auditory system. Ménard et al. (2008) showed that in normal-hearing listeners (i.e., without loudness recruitment) there was a higher correlation between 80-Hz ASSR amplitude growth and behaviorally obtained loudness growth functions than between ASSR amplitude growth and stimulus intensity growth functions. Van Eeckhoutte et al. (2016) also showed that 40-Hz ASSR magnitude growth functions and loudness growth functions were almost identical in shape for normal-hearing and hearing-impaired subjects and that ASSR amplitudes were a good predictor of behavioral loudness scaling results, especially for hearing-impaired subjects. Additionally, the utility of the ASSR has been demonstrated in the animal literature as a potential tool for investigating central gain-related changes in the context of aging and hearing loss in rats. Lai et al. (2017) reported enhanced EFR amplitudes in aged animals (16 to 90 Hz modulation rates) and attributed the increase to a compensatory increase in central gain. Given the results from these studies, the ASSR may be a useful, objective tool for investigating central gain-related changes following both acoustic attenuation and enhancement.

Neural generators of the ASSR are known to exist throughout the auditory pathway; however, contributions from dominant sources can vary depending on the stimulus modulation rate, such that higher modulation rates (e.g., 80 Hz) are thought to reflect dominant activity in the brainstem, whereas slower modulation rates (e.g., 40 Hz) reflect dominant contributions from cortical sources within and beyond the auditory cortex (AC; Herdman et al., 2002; Picton et al., 2003; Luke et al., 2017; Farahani et al., 2017, 2019). As such, the cortically-evoked 40-Hz ASSR would be useful for investigating whether changes in peripheral input (e.g., sound attenuation or enhancement) might alter auditory processing at higher levels of the auditory system, and for further investigating changes in loudness perception that may result from changes in central gain (Formby et al., 2017a).

To identify specific cortical generators of the ASSR, a variety of imaging and source localization techniques have been used to evaluate cortical and subcortical contributions to the ASSR. Reyes et al. (2004) used positron emission tomography (PET) to demonstrate peak activation in the right and left primary auditory cortices, the left medial geniculate body, as well as the right middle frontal gyrus in response to a unilaterally presented (right ear) amplitude modulated (AM) tone. Both EEG and magnetoencephalography (MEG) studies of the ASSR also have demonstrated contributions from the left and right primary and secondary auditory cortices and some non-primary cortical sources (Farahani et al., 2019, 2017; Gutschalk et al., 1999; Herdman et al., 2002; Luke et al., 2017; Pantev et al., 1996; Roß et al., 2005). Luke et al. (2017) used EEG to investigate source localization of the ASSR for acoustic and electric (i.e., cochlear implant) hearing and showed a complex pattern of hemispheric laterality that depended on both modulation rate and ear of stimulation. Specifically, for those with acoustic hearing, a right hemisphere dominance was observed for 40-Hz modulation rates regardless of whether the stimulus was presented monaurally to either ear or diotically to both ears. For those with electric hearing, the hemisphere contralateral to the implanted ear was preferentially activated. Similarly, investigations of permanent unilateral hearing loss have shown hemispheric differences in the distribution of cortical activity depending on the ear of stimulation (Han et al., 2021). If the ASSR is to serve as an index of cortical change in central gain following changes in peripheral input, it is important to evaluate contributions from both right and left hemispheres, especially if the experimental paradigms induce differences across ears.

The present study was designed to investigate effects of short-term, unilateral auditory deprivation via earplugging on central gain changes across the auditory system using both subjective and objective outcome measures. The test battery reflects a combination of outcome measures (Contour test, ARTs) previously used to index auditory changes over time following different acoustic treatments, as well as an electrophysiological correlate of central gain (ASSR). To our knowledge, the latter has not been investigated following continuous acoustic attenuation in humans. If changes are observed in the cortically-evoked ASSR following earplugging, then both the ART and ASSR will inform current perspectives on central gain modulation in the auditory pathway from brainstem to cortex.

Here, we hypothesize that unilateral earplugging increases central gain, resulting in a reduction in the ART in the plugged ear following unilateral auditory attenuation, consistent with previous literature (Brotherton et al., 2019, 2017, 2016; Munro et al., 2014). We also hypothesize that unilateral earplugging modulates central gain in the cortex as reflected in altered loudness judgements and cortically-evoked ASSR measures. It is unknown whether central gain changes in the ART brainstem measures will be mirrored in the cortical ASSR measures or if more complex patterns will emerge. To examine potential effects across the entire system, it is of interest to investigate changes in both the plugged ear and not-plugged ear to determine possible cross-ear effects, as has been reported by Munro et al. (2009, 2014), as well as potential hemispheric asymmetries (e.g., Han et al., 2021; Maslin et al., 2013a; Xie et al., 2019).

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