For patients with severe to profound sensorineural hearing loss, cochlear implants (CIs) can be enormously beneficial, as they often permit spoken language acquisition, particularly when CI implantation takes place early in life (Kral and Sharma, 2012). Nevertheless, the auditory performance achieved by CI users remains variable and falls a long way short of natural hearing.

For example, good speech understanding in the presence of competing sound sources requires the ability to separate speech from background. This is aided by ‘spatial release from masking’, a binaural phenomenon, which relies on the brain’s ability to process binaural spatial cues, including interaural level and time differences (ILDs and ITDs) (Ellinger et al., 2017). While bilateral cochlear implantation is becoming more common (Litovsky, 2010; Conti-Ramsden et al., 2012; Ehlers et al., 2017), bilateral CI recipients still perform poorly in binaural tasks such as sound localization and auditory scene analysis, particularly when multiple sound sources are present (van Hoesel, 2004; van Hoesel, 2012). Indeed, while normal hearing (NH) human listeners may be able to detect ITDs as small as 10 μs (Zwislocki and Feldman, 1956), ITD sensitivity of CI patients, particularly with prelingual onset of deafness, is often poor and sometimes seems completely absent (van Hoesel, 2004; Litovsky, 2010; van Hoesel, 2012; Kerber and Seeber, 2012; Litovsky et al., 2012; Laback et al., 2015; Ehlers et al., 2017).

The reasons for the poor binaural sensitivity of CI recipients are only poorly understood, but two main factors are generally thought to be chiefly responsible, namely: (1) technical limitations of current CI devices and (2) neurobiological factors, such as when the neural circuitry responsible for processing binaural cues fails to develop due to a lack of experience during a presumed ‘critical period’ in early life or when it degenerates during a period of late deafness. These presumed factors could act alone or in combination. Let us first consider the technological issues. The vast majority of CI devices in clinical use operate stimulation, which are variants of the ‘continuous interleaved sampling’ (CIS) method (Wilson et al., 1991). While these technical limitations are substantial, currently few researchers believe that they alone can be fully responsible for the poor binaural acuity observed in CI patients because it is possible to test patients with experimental processors that overcome some of the shortcomings of standard issue clinical devices. When tested with such experimental devices, many postlingually deaf CI users show better ITD sensitivity, with some of the best performers achieving thresholds comparable to those seen in NH peers. In contrast, the ITD performance of prelingually deaf CI users remains invariably poor, with even rare star performers only achieving thresholds of a few hundred microsecond (Poon et al., 2009; Conti-Ramsden et al., 2012; Litovsky et al., 2012; Gordon et al., 2014; Laback et al., 2015; Litovsky and Gordon, 2016; Ehlers et al., 2017). It is this poor performance of prelingually deaf patients even under optimized experimental conditions that led to the suggestion that the absence of binaural inputs during a presumed ‘critical’ period in early childhood may prevent the development of ITD sensitivity (Kral and Sharma, 2012; Kral, 2013; Litovsky and Gordon, 2016; Yusuf et al., 2017).

In this context, it is however important to remember that the terms ‘sensitive’ and ‘critical’ period do not have simple, universally accepted definitions, which may create uncertainty about what exactly a ‘critical period hypothesis of binaural hearing’ proposes. Some authors distinguish ‘strong’ and ‘weak’ critical periods. Both types of critical periods are developmental periods during which the acquisition of a new sensory or sensory-motor faculty appears to be particularly easy. However, after ‘weak’ critical periods, a full mastery of a faculty may still be acquired with a little more effort (Kilgard and Merzenich, 1998), but missing essential experience during a ‘strong’ critical period leads to substantial and irreparable limitations later in life (Knudsen et al., 1984). Perhaps the best studied example of a strong critical period disorder is amblyopia. Amblyopic patients experience an uneven or unbalanced binocular visual stimulation in early life, which leads to a failure of the normal development of the brain’s binocular circuitry. This, in turn, causes sometimes dramatic impairments in the visual acuity in the ‘weaker eye’, as well as in stereoscopic vision. These impairments can only be fully reversed if diagnosed and treated prior to critical period closure, and despite substantial research efforts, no interventions performed after critical period closure can offer more than partial remediation of the deficits (Tsirlin et al., 2015). If we hypothesize that binaural hearing development exhibits a similarly strong critical period, then developing clinical CI processors with better ITD coding might not benefit patients with hearing loss early in life, as it might not be possible to implant these patients early enough to provide them with suitable binaural experience during their (strong) critical period. Their brains would then be unable to learn to take full advantage of the binaural cues that improved CIs provided later in life might deliver.

For neonatally deaf patients, periods of sensory deprivation during development are the norm because profound bilateral hearing loss is hard to diagnose in neonates and measurements of auditory brainstem responses (ABRs) have to be repeated to exclude delayed maturation of the auditory brainstem (Jöhr et al., 2008; Cosetti and Roland, 2010; Arndt et al., 2014). Also, before CI surgery is considered non-invasive alternatives such as hearing aids may be tried first. Finally, risks associated with anesthesia in young babies provide another disincentive for very early implantation (Dettman et al., 2007; Jöhr et al., 2008; Cosetti and Roland, 2010). Altogether, this means by the time of implantation, neonatally deaf pediatric CI patients will typically already have missed out on many months of the auditory input. Consequently, if there is a strong binaural critical period, then this lack of early experience might put near-normal binaural hearing performance forever out of their reach.

Various lines of animal experimentation make such a critical period hypothesis plausible, including immunohistochemical studies that have shown degraded tonotopic organization (Rosskothen-Kuhl and Illing, 2012; Rauch et al., 2016) and changes in stimulation-induced molecular, cellular, and morphological properties of the auditory pathway of neonatally deafened (ND) CI rats (Illing and Rosskothen-Kuhl, 2012; Rosskothen-Kuhl and Illing, 2012; Jakob et al., 2015; Rauch et al., 2016; Rosskothen-Kuhl et al., 2018). Additional studies demonstrate that abnormal sensory input during early development can alter ITD tuning curves in key brainstem nuclei of gerbils (Seidl and Grothe, 2005; Beiderbeck et al., 2018). Furthermore, numerous electrophysiological studies on cats and rabbits have reported significantly lower ITD sensitivity to CI stimulation in the inferior colliculus (IC) (Hancock et al., 2010; Hancock et al., 2012; Hancock et al., 2013; Chung et al., 2019) and auditory cortex (AC) (Tillein et al., 2010; Tillein et al., 2016) after early deafening compared to what is observed in hearing experienced controls.

However, although the ‘strong critical period hypothesis’ of poor ITD sensitivity in CI patients is plausible, it has not yet been rigorously tested. The previous animal studies just mentioned have not investigated perceptual limits of binaural function in behavioral experiments using optimized binaural inputs. Similarly, while we do know that CI patients with NH experience in early childhood usually have a better ITD sensitivity than patients without (Litovsky, 2010; Laback et al., 2015; Ehlers et al., 2017), we do not yet know whether early deaf patients could develop good ITD sensitivity after implantation later in life if they were fitted with CI processors providing with optimized binaural stimulation from the outset. Currently, only research interfaces that are unsuitable for everyday clinical use can deliver the high-quality binaural inputs needed to investigate this question. Consequently, there are currently no patient cohorts who experienced through their CIs the long periods of high-quality ITD information that may be needed for them to become expert at using ITDs, irrespective of any hypothetical critical periods. We cannot at present exclude the possibility that the ND auditory pathway may retain a substantial innate ability to encode ITD even after long periods of neonatal deafness, but that this ability may atrophy after countless hours of binaural CI stimulation through conventional clinical processors which convey no useful ITD information.

Since these possibilities cannot currently be distinguished based on clinical data, animal experimentation is needed, which can measure binaural acuity behaviorally. The first objective here is to examine how much functional ITD sensitivity can be achieved in mature ND animals, which receive bilaterally synchronized CI stimulation capable of delivering ITD cues with microsecond accuracy. Achieving this first objective was the aim of this article. In essence, we attempted to disprove the ‘strong critical period hypothesis for ITD sensitivity development’ by examining whether experimental animals fitted with binaural CIs may be able to achieve good ITD sensitivity without excessive training or complicated interventions, even after severe hearing loss throughout infancy. To achieve this, we used a stimulation optimized for ITD encoding straight after implantation.

We therefore established a new behavioral bilateral CI animal model and setup capable of delivering microsecond precise ITD cues to cohorts of ND rats (early-onset deafness), which received training with synchronized bilateral CI stimulation in young adulthood. These young adult rats learned easily and quickly to lateralize ITDs behaviorally, achieving thresholds as low as ~50 μs, comparable to those of their NH litter mates. We also observed that such ND rats exhibit a great deal of physiological ITD sensitivity in their IC straight after implantation. Our results therefore indicate that, at least in rats, there appears to be no strong critical period for ITD sensitivity.

This study is the first demonstration that, at least in rats, severely degraded auditory experience in early development does not inevitably lead to impaired binaural time processing in adulthood. In fact, the ITD thresholds of our NDCI-B rats (≈50 µs) were as good as the ITD thresholds of NH-B rats Li et al., 2019, and many times better than those typically reported for early deaf human CI patients with thresholds often too large to measure (Litovsky et al., 2010; Gordon et al., 2014; Ehlers et al., 2017). The good performance exhibited by our NDCI-B animals raises the important question of whether early deaf human CI patients might perhaps also be able to achieve near-normal ITD sensitivity if supplied with optimal bilateral CI stimulation capable of delivering adequate ITDs from the first electric stimulation even in the absence of hearing experience during a period what has been thought to be critical for the development of ITD sensitivity. But before we consider translational questions that might be raised by our results, we should address two aspects of this study, which colleagues may find surprising:

First, some studies deemed rats to be a poor model for ITD processing due to medial superior olives (MSOs) with less ITD-sensitive neurons and their limited low-frequency hearing that may result in limited ITD perception (Grothe and Klump, 2000; Wesolek et al., 2010). However, in animals with relatively high-frequency hearing, such as rats, envelope ITD coding through the lateral superior olive is likely to make important contributions (Joris and Yin, 1995). The only previous behavioral study of ITD sensitivity in rats outside of our lab (Wesolek et al., 2010) concluded that rats are unlikely to be sensitive to the interaural phase of relatively low-frequency tones. High-frequency ‘envelope’ ITD sensitivity is also bound to be of great importance in prosthetic hearing given that CIs rarely reach the apex of the cochlea. In Li et al., 2019, we recently demonstrate that NH rats can use ITD cues for 2AFC sound lateralization tasks and thus conclude that, at least to broadband clicks, rats show ITD sensitivity. Here, we focused on broadband acoustic or electrical pulse stimuli that provide plenty of ‘onset’ and ‘envelope’ ITDs and that are processed well even at high carrier frequencies (Joris and Yin, 1995; Bernstein, 2001). That may also explain why our CI rats showed good ITD sensitivity even though our CIs targeted the lower mid-frequency region in each ear, and not the apical region associated with low-frequency hearing. Recent studies in CI patients with late deafness in adults and children have shown that ITDs delivered to mid- and high-frequency cochlear regions can be detected behaviorally (Kan et al., 2016; Ehlers et al., 2017).

Second, electrophysiology studies on congenitally deaf CI cats reported a substantially reduced ITD sensitivity relative to wild-type, hearing experienced cats acutely deafened as adults (Tillein et al., 2010; Hancock et al., 2010; Tillein et al., 2016). These studies recorded neural tuning high up in the auditory pathway (AC and IC); therefore, one cannot be certain whether the reduced sensitivity reflects a fundamental degradation of ITD processing in the olivary nuclei or merely poor maturation of connections to higher order areas, the latter of which may be reversible with experience and training. In the IC of our ND rats, we found significant ITD sensitivity in 91% of recordings sites, compared to only 48% reported for congenitally deaf cats (Hancock et al., 2010) or 62% for ND rabbits (Chung et al., 2019). When tested under optimal stimulation to deliver microsecond precise ITD cues in a naive auditory system, the proportion of ITD-sensitive sites in NDCI-E rats is thus more similar to proportions in adult deafened CI-stimulated cats (84–86%; Smith and Delgutte, 2007; Hancock et al., 2010), rabbits (~75%; Chung et al., 2016; Chung et al., 2019), or gerbils (~74%; Vollmer, 2018). Figure 4 suggests that the ITD STVR seen in our ND-CI rats fall in a similar range of the ITD STVRs previously reported for congenitally deaf CI cats (Hancock et al., 2010). While for cats, the proportion of IC multi-units with large ITD STVR values (>0.5) appears to be reduced in animals lacking early auditory experience, the same does not appear to be the case in our rats. Whether these quantitative differences in physiological ITD sensitivity are due to methodological and/or species differences is not determinable, but we believe that these apparent differences are ultimately unlikely to be important because even the congenitally deaf cats still have a decent number of IC units showing fairly large amounts of ITD sensitivity. In fact, more than 20% of the congenitally deaf cat IC units have STVR values of 0.5 or higher, which indicates rather good ITD sensitivity. It is important to remember that it is unknown how much ITD tuning in the IC or AC is necessary, or whether this is species specific, to make behavioral ITD discrimination thresholds of ≈50 µs possible, as we see in our NDCI-B cohort (Figure 2). However, multi-units such as #3 and #4 shown in Figure 3 change their firing rates as a function of ITD substantially between steps of only 20 µs. These multi-units have STVRs that are not outside the range reported for congenital deaf cats. Thus we cannot conclude from the electrophysiology data alone whether the quantitative differences in ITD sensitivity between these studies would equate to difference in behavioral lateralization performances. The level of physiological ITD sensitivity previously observed in cats (Tillein et al., 2010; Hancock et al., 2010; Tillein et al., 2016) and rabbits (Chung et al., 2019) could be sufficient to enable good behavioral ITD discrimination performance if only these animals could be trained and tested on an appropriate task.

Thus, in our opinion, any previously reported reductions in physiological ITD sensitivity seen in the IC (Chung et al., 2016; Chung et al., 2019) or AC (Tillein et al., 2010; Tillein et al., 2016) of early deaf animals does not seem nearly large enough to fully explain the very poor behavioral ITD thresholds seen in most early deaf humans. And indeed, our own findings that the behavioral ITD sensitivity of our NDCI-B rats compares favorably with that in NH-B animals strongly suggests that the poor ITD sensitivity in human CI patients may well have causes beyond the lack of auditory experience during a presumed critical period.

It is unclear why congenitally deaf cats (Hancock et al., 2010; Hancock et al., 2013) show a modest reduction in neural ITD sensitivity, while NDCI-E rats in the present study seem not to. There are numerous methodological and species differences that might account for this, ultimately relatively small discrepancy. More pertinent for the present discussion is that both preparations exhibit a lot of innate residual ITD sensitivity in their midbrains despite severe hearing impairment throughout their development (Tillein et al., 2010; Hancock et al., 2010; Hancock et al., 2013; Tillein et al., 2016; Chung et al., 2019). We would find it surprising if this physiological ITD sensitivity of IC neurons could not ever be harnessed to inform perceptual decisions in the cats’ and rabbits’ brains. Thus, in light of our new behavioral results in rats, it seems reasonable to expect that, with appropriate rehabilitation and training, neonatally deaf cats and rabbits (and perhaps even humans) might be able to learn to make use of their residual innate physiological ITD sensitivity to perform very well in binaural hearing tasks.

The most striking difference between our results and other previously published work remains that the behavioral ITD discrimination thresholds of our NDCI-B rats are an order of magnitude or more better than those of early deaf human CI patients (Gordon et al., 2014; Litovsky and Gordon, 2016; Ehlers et al., 2017). As mentioned in the introduction, previous authors have proposed that the very poor performance typical of early deaf human CI patients may be due to ‘factors such as auditory deprivation, in particular, lack of early exposure to consistent timing differences between the ears’ (Ehlers et al., 2017), in other words, the critical period hypothesis. However, neonatal deafening and severe hearing loss until reaching developmental maturity did not prevent our NDCI-B rats from achieving very good ITD discrimination performance. Admittedly, there may be species differences at play here. Our ND rats were implanted as young adults, and were severely deprived of auditory input throughout their childhood, but humans mature much more slowly, so even patients implanted at a very young age will have suffered auditory deprivation for a substantially longer absolute time period than our rats. Nevertheless, our results on early deafened CI rats show that lack of auditory input during early development does not need to result in poor ITD sensitivity and is therefore unlikely to be a sufficient explanation for the poor ITD sensitivity found in early deaf CI patients.

Previous studies of the development of the binaural circuitry in animal models also have not provided any strong evidence for a critical period, even if they have pointed to the important role that early experience can have in shaping this circuitry. Most of these studies have focused on low-frequency fine-structure ITD pathways through the MSO, rather than lateral superior olive (LSO) envelope ITD pathways that are likely to be of particular relevance for the CI ITD processing we are studying here. But even if they may not be directly applicable, they are nonetheless somewhat informative for the present discussion. For example, developmental studies in ferrets have shown that the formation of afferent synapses to MSO, one of the main brainstem nuclei for ITD processing, is essentially complete before the onset of hearing (Brunso-Bechtold et al., 1992). In mice, the highly specialized calyxes of Held synapses, which are thought to play key roles in relaying precisely timed information in the binaural circuitry, have been shown to mature before the onset of hearing (Hoffpauir et al., 2006). In both cases, crucial binaural circuitry elements are completed before any sensory input dependent plasticity can take place. However, there are also studies that do indicate that the developing binaural circuitry can respond to changes in input. For example, in gerbils, key parts of the binaural ITD processing circuitry in the auditory brainstem will fail to mature when driven with strong, uninformative omnidirectional white noise stimulation during development (Kapfer et al., 2002; Seidl and Grothe, 2005), which shows that inappropriate or uninformative sensory input can disturb the development of binaural brainstem pathways. A perhaps related finding by Tirko and Ryugo, 2012 shows that inhibitory pathways in the MSO, which are thought to be essential for ITD encoding, are significantly reduced in congenitally deaf cats at postnatal day 90, compared to NH peers, but they can be fully restored with the advent of CI stimulation after only 3 months. Finally, Pecka et al., 2008 demonstrated the importance of glycinergic inhibition and its timing in the MSO in controlling binaural excitation by fine tuning the delay between arrival from the two ears, which could allow ITD pathways to be ‘tuned’, possibly in an experience dependent manner. Overall, these studies point to varying extents of experience dependence of the developing binaural pathway, but none of them would suggest that the absence of stimulation early in life would necessarily prevent the restoration of effective binaural processing after the closure of some presumed critical period. None of the published articles we could find point to a biological mechanism for a critical period that could explain the loss of ITD sensitivity in early deaf CI users merely as a consequence of an absence of input in early life.

It is well known that the normal auditory system not only combines ITD information with ILD and monaural spectral cues to localize sounds in space, it also adapts strongly to changes in these cues, and can re-weight them depending on their reliability (Keating et al., 2013b; Keating et al., 2015; Tillein et al., 2016; Kumpik et al., 2019). Similarly, Jones et al., 2011 demonstrated changes in ITD and ILD thresholds as head size and pinnae grow for up to 6 weeks postnatally in chinchillas. Again this highlights the importance of plasticity of binaural hearing during development. However, no studies have demonstrated that critical periods in the ITD pathways will irrevocably close if sensory input is simply absent, rather than altered. By using the rat model, which allowed us to study ITD sensitivity behaviorally, we were able to show conclusively that the ability to use ITD cues perceptually does not disappear permanently after hearing loss during a presumed critical period.

Given that our results cast doubts on the critical period hypothesis, it may be time to consider other likely causes for ITD insensitivity in CI patients. One possibility that we believe has not been given enough attention is that an innate ITD sensitivity could conceivably degrade over the course of prolonged exposure to the entirely inconsistent and uninformative ITDs delivered by current standard clinical CI processors. This possibility is consistent with the observations by Zheng et al., 2015 and by Litovsky and Gordon, 2016 who note that, even after binaural CI listening experience extending for >4 years or >6 years, respectively, the ITD sensitivity of bilateral CI users still lags well behind that of age-matched controls with NH. If the clinical processors supplied to these bilateral CI users do not supply high-quality ITD cues, then no amount of experience will make these patients experts in the use of ITDs. Contrast this with our NDCI-B rats, which received only highly precise and informative ITDs right from the start with no additional auditory cues, and were able to lateralize ITDs as well as their NH litter mates after only 2 weeks of training. This is admittedly a somewhat unfair comparison. Clincal CI processors are, for good reason, designed first and foremost for the purpose of delivering all important speech formant information in real life settings, and optimizing ITD coding was not a priority in their original design. Nevertheless, our results raise the possibility that incorporating better ITD encoding in clinical processors might lead to better binaural outcomes for future generations of CI patients.

Current CI processors produce pulsatile stimulation based on fixed rate interleaved sampling (Wilson et al., 1991; Stupak et al., 2018), which is neither synchronized to stimulus fine structure nor synchronized between ears. Furthermore, at typical clinical stimulation rates (>900 pps), CI users are not sensitive to speech envelope ITDs, as envelope ITD sensitivity requires peak shaped envelopes (Laback et al., 2004; Grantham et al., 2008; van Hoesel et al., 2009; Noel and Eddington, 2013; Laback et al., 2015). Consequently, the carrier pulses are too fast, and the envelope shapes in everyday sounds are not peaked enough, so that speech processors only ever provide uninformative envelope ITDs to the children using them (Laback et al., 2004; Grantham et al., 2008; Laback et al., 2015). Perhaps brainstem circuits of children fitted with conventional bilateral CIs simply ‘learn’ to ignore the unhelpful ITDs that are contained in the inputs they receive. This would mean that these circuits are adaptive to uninformative ITDs. In contrast, precise ITD cues at low pulse rates were essentially the only form of useful auditory input that our NDCI-B rats experienced, and they quickly learned to use these precise ITD cues. Thus, our data raise the possibility that the mammalian auditory system may develop ITD sensitivity in the absence of early sensory input and that this sensitivity may then be either refined or lost, depending on how informative the binaural inputs turn out to be.

The inability of early deaf CI patients to use ITDs may thus be somewhat similar to conditions such as amblyopia or failures of stereoscopic depth vision development, pathologies that are caused more by unbalanced or inappropriate inputs than by a lack of sensory experience (Levi et al., 2015). For the visual system, it has been shown that orientation selective neuronal responses exist at eye-opening and thus are established without visual input (Ko et al., 2013). If this hypothesis is correct, then it may be possible to ‘protect’ ITD sensitivity in young bilateral CI users by exposing them to regular periods of precise ITD information from the beginning of binaural stimulation. Whether CI patients are able to recover normal ITD sensitivity much later if rehabilitated with useful ITDs for prolonged periods, or whether their ability to process microsecond ITDs atrophies irreversibly, is unknown and will require further investigation.

While these interpretations of our findings would lead us to argue that bilateral CI processing strategies may need to change to make microsecond ITD information available to CI patients, one must nevertheless acknowledge the difficulty in changing established CI processing strategies. The CIS paradigm (Wilson et al., 1991) from which most processor algorithms are derived times the stimulus pulses, so that only one electrode channel delivers a pulse at any one time. This has been shown to minimize cross-channel interactions due to ‘current spread’ which might compromise the already quite limited tonotopic place coding of CIs. Additionally, CI processors run at high pulse rates (≥900 Hz), which may be necessary to encode sufficient amplitude modulations for speech recognition (Loizou et al., 2000). However, ITD discrimination has been shown to deteriorate when pulse rates exceeded a few hundred Hz in humans (van Hoesel, 2007; Laback et al., 2007) and animals (Joris and Yin, 1998; Chung et al., 2016). Our own behavioral experiments described here were conducted with low pulse rates (50 Hz), and future work will need to determine whether ITD discrimination performance declines at higher pulse rates which would make pulse rate an important factor for the development of good ITD sensitivity under this stimulation conditions. Thus, designers of novel bilateral CI speech processors may face conflicting demands: They must invent devices that fire each of 20 or more electrode channels in turn, at rates that are both fast, so as to encode the speech envelope in fine detail, but also slow, so as not to overtax the brainstem’s ITD extraction mechanisms, and they must make the timing of at least some of these pulses encode stimulus fine structure and ITDs. While difficult, this may not be impossible, and promising, research is underway, which either provides fine structure information on up to four apical electrodes while running CIS strategy on the remaining electrodes (MED-EL CIs; Riss et al., 2014), uses a mixture of different pulse rates for different electrode channels (Thakkar et al., 2018), presents redundant temporal fine structure information to multiple electrode channels (Churchill et al., 2014), or aims to ‘reset’ the brain’s ITD extraction mechanisms by introducing occasional ‘double pulses’ into the stimulus (Srinivasan et al., 2018). A detailed discussion is beyond the scope of this article. Our results underscore the need to pursue this work with urgency as we have provided evidence that the absence of auditory input during a critical period does not necessarily mean that early deafened CI users show poor or no ITD sensitivity.

On a final note, we would be remiss if we did not acknowledge that, while the ‘maladaptive plasticity hypothesis’ that we have elaborated over the last few paragraphs is ‘compatible’ with the experimental data we have presented, it would be wrong to assert that our data so far prove that this hypothesis is correct. At present, we have merely managed to shed serious doubts on the popular critical period hypothesis, but at present, the maladaptive plasticity hypothesis is still, apart from others including different etiologies of deafness, just one possible alternative explanation for the observed poor ITD sensitivity of human bilateral CI users. It still needs to be put to the test by measuring the effect of deliberately degrading the quality of ITD cues to varying extent and over various periods. However, the animal model introduced in this study now makes this important task experimentally feasible.

All procedures involving experimental animals reported here were approved by the Department of Health of Hong Kong (#16–52 DH/HA and P/8/2/5) and/or the Regierungspräsidium Freiburg (#35–9185.81/G-17/124), as well as by the appropriate local ethical review committee. A total of 14 rats were obtained for this study from the breeding facilities of the Chinese University of Hong Kong or from Janvier Labs (Le Genest-Saint-Isle, France), and these were allocated randomly to the deafened and hearing experienced cohorts described in Figure 1.

Deafening

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Rats were deafened by daily intraperitoneal (i.p.) injections of 400 mg/kg kanamycin from postnatal days 9 to 20 inclusively (Osako et al., 1979; Rosskothen-Kuhl and Illing, 2012). This is known to cause widespread death of inner and outer hair cells (Osako et al., 1979; Matsuda et al., 1999; Argence et al., 2008) while keeping the number of spiral ganglion cells comparable to that in untreated control rats (Osako et al., 1979; Argence et al., 2008). Osako et al., 1979 have shown that rat pups treated with this method achieve hearing thresholds around 70 dB for only a short period (~p14–16) and are severely to profoundly hearing impaired thereafter, resulting in widespread disturbances in the histological development of their central auditory pathways, including a nearly complete loss of tonotopic organization (Rosskothen-Kuhl and Illing, 2012; Rauch et al., 2016; Rosskothen-Kuhl et al., 2018). We verified that this procedure provoked profound hearing loss (>90 dB) by the loss of Preyer’s reflex (Jero et al., 2001), the absence of ABRs to broadband click stimuli (Figure 5b) as well as pure tones (at 500, 1000, 2000, and 8000 Hz), and by performing histological assessment on cochlea sections of 11 weeks old, ND rats (data not shown). ABRs were measured as described in Rosskothen-Kuhl et al., 2018 under ketamine (80 mg/kg) and xylazine (12 mg/kg) anesthesia each ear was stimulated separately through hollow ear bars with 0.5 ms broadband clicks with peak amplitudes up to 130 dB sound pressure level (SPL) delivered at a rate of 43 Hz. ABRs were recorded by averaging scalp potentials measured with subcutaneous needle electrodes between mastoids and the vertex of the rat’s head over 400 click presentations. While normal rats typically exhibited click ABR thresholds near 30 dB SPL (Figure 5a), deafened rats had very high click thresholds of ≥130 dB SPL (Figure 5b).

Figure 5

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All data generated or analysed during this study are included in the manuscript and supporting files. Data have been deposited to Dryad, under the https://doi.org/10.5061/dryad.573n5tb6d .

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Author details

1. Nicole Rosskothen-Kuhl

   1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
   2. Neurobiological Research Laboratory, Section for Clinical and Experimental Otology, University Medical Center Freiburg, Freiburg, Germany

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Contributed equally with

   Alexa N Buck

   For correspondence

   nicole.rosskothen-kuhl@uniklinik-freiburg.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4724-5550

2. Alexa N Buck

   Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

   Contribution

   Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Nicole Rosskothen-Kuhl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0124-9716

3. Kongyan Li

   Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

4. Jan WH Schnupp

   1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
   2. CityU Shenzhen Research Institute, Shenzhen, China

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   jan.schnupp@googlemail.com

   Competing interests

   No competing interests declared

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