# Auditory cortical plasticity after cochlear implantation in asymmetric hearing loss is related to spatial hearing: a PET H215O study

Chadlia Karoui, Kuzma Strelnikov, Pierre Payoux, Anne-Sophie Salabert, Chris James, Olivier Deguine, Pascal Barone, Mathieu Marx

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## ► To cite this version:

Chadlia Karoui, Kuzma Strelnikov, Pierre Payoux, Anne-Sophie Salabert, Chris James, et al. Auditory cortical plasticity after cochlear implantation in asymmetric hearing loss is related to spatial hearing: a PET H215O study. Cerebral Cortex, 2023, 33 (5), pp.2229-2244. 10.1093/cercor/bhac204. hal-04163651

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Submitted on 17 Jul 2023

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# Auditory cortical plasticity after cochlear implantation in asymmetric hearing loss is related to spatial hearing: a PET H₂¹⁵O study

Chadlia Karoui ID, PhD1,2,†, Kuzma Strelnikov ID, MD, PhD1,2,†,*, Pierre Payoux ID, MD3,4, Anne-Sophie Salabert ID, PhD3,4,

Chris J. James, PhD5,6, Olivier Deguine ID, MD1,2,6, Pascal Barone ID, PhD1,2,†, Mathieu Marx ID, MD, PhD1,2,6,†

In asymmetric hearing loss (AHL), the normal pattern of contralateral hemispheric dominance for monaural stimulation is modified, with a shift towards the hemisphere ipsilateral to the better ear. The extent of this shift has been shown to relate to sound localization deficits. In this study, we examined whether cochlear implantation to treat postlingual AHL can restore the normal functional pattern of auditory cortical activity and whether this relates to improved sound localization. The auditory cortical activity was found to be lower in the AHL cochlear implanted (AHL-CI) participants. A cortical asymmetry index was calculated and showed that a normal contralateral dominance was restored in the AHL-CI patients for the nonimplanted ear, but not for the ear with the cochlear implant. It was found that the contralateral dominance for the nonimplanted ear strongly correlated with sound localization performance (rho = 0.8, P < 0.05). We conclude that the reorganization of binaural mechanisms in AHL-CI subjects reverses the abnormal lateralization pattern induced by the deafness, and that this leads to improved spatial hearing. Our results suggest that cochlear implantation enables the reconstruction of the cortical mechanisms of spatial selectivity needed for sound localization.

**Key words:** deafness; brain plasticity; cochlear implantation; hearing loss; auditory cortex.

## Introduction

### Asymmetric hearing loss

Asymmetric hearing Loss (AHL) is defined as a binaural difference in hearing threshold greater than 15 dB, and is known to disrupt binaural processes, leading to impairments in sound localization and speech comprehension in noise. This has a significant negative impact on an individual's quality of life (Nelson et al. 2019). Studies have measured the extent of these binaural deficits, and in the case of sound localization, this has been expressed as an increase in the angular error of localization (Nelson et al. 2019) and as a right-left confusion in sound source lateralization. In a normal hearing subject, monaural stimulation leads to bilateral activation in the auditory cortex but with much stronger contralateral activation, referred to as contralateral dominance. In patients with AHL, studies have shown that the auditory cortical asymmetry is altered, with a dominance shift from contralateral to ipsilateral with respect to the better-hearing ear (Scheffler 1998; Ponton et al. 2001) in line with animal studies. In children with congenital AHL, this shift is

accompanied by a weaker cortical representation of the deaf ear (Gordon et al. 2015). In a recent fMRI study on adults with acquired AHL (Vannson et al. 2020), the dominance shift was observed in the nonprimary auditory cortex (NPAC), thus suggesting that the plasticity involves cortico-cortical interactions. Interestingly, the extent of this functional reorganization strongly correlated with the deficit in sound localization. We hypothesize that the dominance shift reflects a disruption in spatial hearing in line with the theory that the contralateral dominance seen in normally hearing subjects relates to the representation of the contralateral sound field rather than the contralateral ear input (Eisenman 1974; Middlebrooks and Pettigrew 1981; Phillips and Gates 1982). Our study aims to explore the neural correlates of spatial hearing improvement following cochlear implantation for AHL, and more specifically, the lateralization of brain activity in these patients.

### Spatial hearing

In all species, one of the primary functions of hearing is to detect and locate brief sounds in order to direct

<footnote n="1">¹UMR 5549, Faculté de Médecine Purpan, Centre National de la Recherche Scientifique, Toulouse, France,</footnote>

<footnote n="2">²Centre de Recherche Cerveau et Cognition, Université de Toulouse, Université Paul Sabatier, Toulouse, France,</footnote>

<footnote n="3">³Nuclear Medicine Department, Purpan University Hospital, Toulouse, France,</footnote>

<footnote n="4">⁴ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, Toulouse, France,</footnote>

<footnote n="5">⁵Cochlear France SAS, Toulouse, France,</footnote>

<footnote n="6">⁶Service d'Oto-Rhino-Laryngologie et Oto-Neurologie, CHU Toulouse France, Université Toulouse 3, Toulouse, France</footnote>

<footnote>*Corresponding author: Hopital Pierre Paul Riquet, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France. Place du Dr Baylac - TSA 40031 - 31059 Toulouse cedex 9. E-mails: strelnikov.k@chu-toulouse.fr, kuzma.strelnikov@cnrs.fr.</footnote>

<footnote>†C. Karoui and K. Strelnikov contributed equally in one way; P. Barone and M. Marx contributed equally in the other way. Contributions are equal by pairs but not between the pairs.</footnote>
visual attention and further analyze the sound sources (Heffner and Heffner 1992). The ability to locate sound sources involves detecting stimulus disparities between the right and left ear in terms of the intensity (interaural level difference) and timing (interaural time difference) of the sounds. It is known that the information from each ear converges at an early level in the auditory pathway and the combination of information from the two ears is known as binaural integration. This process enables spatial hearing as well as facilitates speech understanding in noisy environments. Studies have shown several advantages arising from binaural integration, including improved sound detection and identification in noise due to binaural redundancy, binaural unmasking, and head shadow effects (Avan et al. 2015).

In the case of unilateral hearing loss, the binaural response properties of the auditory neurons are strongly affected, as revealed by electrophysiological recordings using animal models of congenital (Kral et al. 2013; Tillein et al. 2016) and acquired unilateral deafness (Popelár et al. 1994; McAlpine et al. 1997). In these studies, it has been found that the neuronal activity shifts towards the hemisphere ipsilateral to the normally hearing ear, with both increased excitability/activity and reduced latency. The binaural responses display altered excitatory and inhibitory interactions (Kral et al. 2013; Tillein et al. 2016), which change the neuronal spatial properties at the cortical level (Clarey et al. 1992; Barone et al. 1996). These modifications induce profound functional reorganization at the areal level, affecting the auditory cortex's interhemispheric asymmetry (Scheffler 1998; Ponton et al. 2001).

Though studies on both humans and animals have established that AHL has a deleterious effect on spatial hearing abilities, which is evident at both the behavioral and the neuronal levels (Keating and King 2013; Gordon et al. 2015; Vannson et al. 2015; Kumpik and King 2019), there is also evidence that some degree of auditory localization is still possible, even when the binaural cues are altered. For example, following early unilateral deafness, sound localization abilities can be developed using monaural spectral cue extraction (Slattery and Middlebrooks 1994; King et al. 2000), specific training (Firszt et al. 2015), and following cochlear implantation (Arndt et al. 2011; Távora-Vieira et al. 2015; Galvin et al. 2019). These results clearly demonstrate the plasticity of auditory spatial processing and show that it can be achieved by means of adaptive strategies or by restoring binaural inputs to the brain (Keating and King 2013).

## AHL rehabilitation with cochlear implantation

Ever since the seminal work of Van de Vermeire and Van de Heyning (2009), patients with AHL have been considered candidates for cochlear implantation (Vermeire and Van de Heyning 2009; Arndt et al. 2011). Although the implants were initially used in these patients to target severe tinnitus, it was reasoned that the patients' binaural abilities could also be improved (Vermeire and Van

de Heyning 2009; Arndt et al. 2011). This would involve combining the electrical cues conveyed by the implanted ear with the natural acoustic hearing in the other ear. It has since been found that the restoration of binaural integration is highly variable, presumably because of the difficulty involved in integrating the two types of information. Nevertheless, it has been found that the bilateral auditory input allows some degree of binaural hearing, as studies have shown improved sound localization (Távora-Vieira et al. 2015) and speech recognition in noise (Mertens et al. 2015; Dorbeau et al. 2018; Legris et al. 2018; Galvin et al. 2019; Arndt et al. 2020). These improvements have been found to relate to various factors, including the pre-implantation performance, the hearing level of the nonimplanted ear, the age at implantation, the duration of deafness and the age at the onset of deafness (Mertens et al. 2015; Távora-Vieira et al. 2015; Galvin et al. 2019; Nelson et al. 2019). We hypothesize that the restoration of binaural skills depends on an individual's brain plasticity to enable the integration of both electrical and acoustical information. So far, except for a few reports in children (Sharma and Glick 2016; Polonenko et al. 2018), studies have not fully explored the functional brain responses in these patients. This present study investigated the behavioral and cortical consequences of adult acquired AHL, which is most likely very different from what is reported in cases of early developmental hearing loss. From the sparse existing literature, EEG studies have shown that the neural responses elicited by electrical and acoustical stimulation share similar latencies (Wedekind et al. 2020), but there is a weaker global auditory response (Legris et al. 2018) compared to normally hearing controls, when both modalities are used.

## Aim of the study

The present investigation was motivated by the scarcity of studies on brain plasticity following cochlear implantation for AHL, and our interest in the recovery of spatial hearing. We used PET brain imaging to study the pattern of brain activation in response to natural auditory stimuli in cochlear-implanted patients with AHL (AHL-CI); the cochlear implant precluded the use of other imaging techniques. We hypothesized that the stimulation of the deaf ear by a cochlear implant could restore, at least partially, the normal pattern of contralateral hemispheric dominance. Furthermore, as spatial hearing in AHL has been shown to relate to changes in hemispheric dominance (Vannson et al. 2020), we proposed that the restoration of contralateral dominance would relate to the improvement of spatial hearing.

## Materials and methods
### Subjects

Twenty subjects were recruited: 10 patients with a unilateral cochlear implant for postlingual AHL (AHL-CI) and 10 normally hearing (NH) controls. The characteristics of the AHL-CI group are shown in Table 1.
<table><caption>**Table 1.** Characteristics of the subjects with a cochlear implant (CI).</caption><thead><tr><th>Code</th><th>Age range (years)</th><th>Sex</th><th>Etiology</th><th>Duration of HL (years)</th><th>CI experience (years)</th><th>CI manufacturer</th><th>CI side</th><th>Contralateral pure tone average</th></tr></thead><tbody><tr><td>P5</td><td>61–70</td><td>M</td><td>PHLEBITIS</td><td>2</td><td>3</td><td>Advanced Bionics</td><td>R</td><td>37</td></tr><tr><td>P7</td><td>51–60</td><td>F</td><td>TRAUMA</td><td>10</td><td>4</td><td>Cochlear</td><td>L</td><td>16</td></tr><tr><td>P8</td><td>51–60</td><td>M</td><td>SUDDEN</td><td>33</td><td>3</td><td>Oticon Medical</td><td>R</td><td>27</td></tr><tr><td>P10</td><td>61–70</td><td>F</td><td>SUDDEN</td><td>9</td><td>3</td><td>Cochlear</td><td>R</td><td>15</td></tr><tr><td>P11</td><td>51–60</td><td>F</td><td>OTOSCLEROSIS</td><td>22</td><td>2</td><td>Med-El</td><td>L</td><td>36</td></tr><tr><td>P12</td><td>41–50</td><td>M</td><td>OTOSCLEROSIS</td><td>13</td><td>4</td><td>Cochlear</td><td>L</td><td>57</td></tr><tr><td>P13</td><td>71–80</td><td>F</td><td>SUDDEN</td><td>8</td><td>4</td><td>Cochlear</td><td>L</td><td>65</td></tr><tr><td>P14</td><td>71–80</td><td>F</td><td>SUDDEN</td><td>1</td><td>0.8</td><td>Advanced Bionics</td><td>R</td><td>32.5</td></tr><tr><td>P16</td><td>51–60</td><td>M</td><td>Menière's disease</td><td>20</td><td>0.4</td><td>Cochlear</td><td>L</td><td>68</td></tr><tr><td>P17</td><td>51–60</td><td>M</td><td>Menière's disease</td><td>5</td><td>0.3</td><td>Med-El</td><td>L</td><td>50</td></tr></tbody></table>

Patients were included if they had had a cochlear implant for at least 3 months in order to ensure a period of adaptation. For the nonimplanted ear, the hearing thresholds ranged from normal (pure-tone average [PTA] < 20 dB HL) to moderate hearing loss (PTA 50–70 dB HL); for the implanted ear, there was profound deafness (PTA > 90 dB HL). The patients demonstrated the longitudinal improvement of binaurality on the basis of the French Matrix test (Karoui 2019). All of the controls had normal thresholds over the range 0.5–4 kHz, with a PTA < 20 dB HL, they were sex and age-matched to the AHL-CI group, thus giving a total of five women and five men in each group, with ages ranging from 46 to 74 years. Our study used a patient group and an imaging technique that are rare. The patients all had cochlear implants to treat asymmetric hearing loss; this is a group for whom rehabilitation evaluations are still exploratory; most patients treated so far have been included in research protocols.

Our study used $H_2^{15}O$ PET imaging, an invasive and radioactive procedure, which imposes limitations on the number of subjects. It should be noted, however, that for PET $H_2^{15}O$ activations studies, by accepting a Type 1 risk $\alpha$ of 0.05 with correction for multiple comparisons and a statistical power $1-\beta$ of 0.90, the sufficient sample size per group is estimated as 10–12 subjects (Andreasen et al. 1996).

The study was approved by the French South West and Overseas ethics committee (approval number: 2016-A01442-49) and conducted according to the Declaration of Helsinki including the signed by all participants informed consent form before taking part in the study.

## Localization task

Among the different audiological evaluations, we selected horizontal localization performance, which reflects more directly the level of binaural integration. An array of 12 loudspeakers was set up in an anechoic chamber, each at a distance of one meter from the subjects, with

an angular separation of 15° (Chan et al. 2008) and located behind the subjects' ears at the same height. We used the same localization protocol as developed by Chan et al. (2008), also used in Aronoff et al. (2012), Dorbeau et al. (2018), Galvin et al. (2019). The stimulus is a broadband (230–11 kHz) impulse sound of 1.474 s duration (gunshot), presented at 65 dB SPL allowing the use of both ITDs and ILDs to localize the sound source. The subjects were asked to indicate where the noise had come from by clicking on one of the loudspeakers on the computer screen. For each run, there were 24 trials where the stimulus was presented randomly from one of the loudspeakers, with two presentations per loudspeaker. To minimize the use of loudness cues for the localization task, the amplitude of the stimulus could randomly increase or decrease by 6 dB from trial to trial (roving) (Galvin et al. 2019). The AHL-CI group completed the localization test under four different conditions: with the cochlear implant activated (CI-ON) or deactivated (CI-OFF), with a roving amplitude of 6 dB from trial to trial, and without a roving amplitude (nonroving). The NH group was only assessed using the roving condition. The localization accuracy was reported as the average root mean square (RMS) error in degrees.

## PET procedure

The subjects were scanned in a shielded, darkened room. The head was immobilized and aligned transaxially to the orbitomeatal line using a laser beam. Regional distribution of radioactivity was obtained using a Biograph 6 TruePoint HiRez (Siemens Medical) PET scanner with full volume acquisition. The duration of each scan was 80 s; approximately 6 mCi of $H_2^{15}O$ was administered to each subject. A measure of auto-attenuation correction was obtained by performing a CT scan before the PET $H_2^{15}O$.

## Sound stimuli during the PET scan

We used an auditory discrimination task during PET scan based on natural environment sounds. The voice/
nonvoice task was chosen because it allows activation of a large auditory cortical network (see Belin et al. 2000). In a previous study, this task enabled us to obtain robust values of auditory lateralization indices in the UHL patients (Vannson et al. 2020). Finally, it was preferred to a linguistic task because it does not involve the adaptive strategies generally developed after hearing loss for speech processing. All of the stimuli were taken from our database developed in previous studies (Massida et al. 2011; Vannson et al. 2020). Subsets of 500-ms-long vocal and nonvocal stimuli were randomly presented using PsychoPy2 (Peirce et al. 2019). Vocal stimuli were 55 different sounds, including speech sounds (words in non-French languages and nonsemantic syllables) and nonspeech sounds (e.g. laughs, coughs). Nonvocal stimuli were different environmental sounds (alarms, car horns, bells...). The subjects were given a two-alternative forced choice task to indicate whether they heard a vocal or a nonvocal sound by clicking on the left or right button of a mouse. The duration of each trial was determined by the subject's response time, but this was limited to a maximum of 8 s.

During the PET scan, the subjects had their eyes covered, and the auditory stimulation began at the descending part of the bolus curve, 10–20 s before the tracer reached the brain. For the NH group, the stimuli were delivered using inserts; for the AHL-CI group, the sound was delivered either directly via a cable connected to the implant, or via an insert in the nonimplanted ear, or via the two systems simultaneously. As patients presented a variable hearing loss in the nonimplanted ear, we systematically corrected the stimulation level according to the PTA. According to the Fig. 6 prescription (Gitles and Niquette 1995), we applied a frequency gain for a 65 dB SPL presentation level to correct for hearing loss in the nonimplant ear. The input signal to the CI sound processor was calibrated to be equivalent to 65 dB SPL. In addition, subjects were asked to balance loudness to obtain a comfortable listening level for both ears. There were four different conditions: (i) a baseline condition, where the subjects were instructed to lie quietly in the scanner, (ii) a binaural condition, where the sounds were presented to both ears, (iii) a right-ear monaural, and (iv) a left-ear monaural conditions. There were two runs for each condition, each lasting 80 s, the order of the runs was randomized for each subject, as was the order of the trials within each run. The total duration of the PET scan was 80 min.

## PET analysis

The PET data were analyzed using SPM12 software and included realignment and spatial normalization to the Montreal Neurological Institute template. The images of the patients with a right-sided CI (4 patients) were flipped so that all of the implants were on the left side in the final images. The global signal was normalized within and between the subjects; overall grand mean scaling scales the global blood flow to a physiologically

realistic value of 50 mL/dL/min as proposed in SPM12. The analyses focused at the early cortical levels (primary [PAC] and nonprimary [NPAC] auditory cortex) based on our findings on UHL patients (Vannson et al. 2020); whole-brain analyses will be presented in a separate article. We used the combined cytoarchitectonically defined auditory areas Te1.0, Te1.1, Te1.2, and Te3.0 as the regions of interest, developed and implemented in the SPM Anatomy Toolbox (Eickhoff et al. 2006). We used the linear mixed-effects model (“lme4” package in R) with repeated measures for the comparisons between groups and conditions.

An asymmetry index (AI) of the brain activity in the auditory regions was calculated to study the lateralization pattern of auditory activity with respect to the baseline: $AI = (\text{Contralateral} - \text{Ipsilateral})/(\text{Contralateral} + \text{Ipsilateral})$. Contralateral and ipsilateral refer to the cortical side contralateral and ipsilateral to the stimulated ear.

In addition, the respective influence of the crossed (opposite) and uncrossed (same side) ear on the auditory activity in each cortical hemisphere was estimated using the aural preference index (API): $API = (\text{Crossed} - \text{Uncrossed})/(\text{Crossed} + \text{Uncrossed})$, where Crossed refers to the activity elicited by the opposite ear and Uncrossed refers to the activity elicited by the ear on the same side as the cortical activity. For each auditory cortex, the values are positive in the case of crossed aural preference and negative in the case of uncrossed aural preference.

## Data availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

## Results

### Auditory test performance

The participants were given a voice/nonvoice discrimination task during the PET scan. Performance was assessed by calculating the hit rate under each condition. Using a linear mixed-effects model with the group and the condition as fixed effects, significant results were found for the group, the condition, and the interaction. Overall, the AHL-CI patients had poorer scores than the controls, with an average hit rate of 63 ± 27% (SD), compared to 93 ± 6% for the controls ($P = 3 \times 10^{-9}$; Fig. 1A). Although the patients’ performance depended on the condition (binaural stimulation, acoustic stimulation or cochlear implant [CI] stimulation), it remained above chance (bootstrap, *P* taken at 0.05). The AHL-CI patients’ hit rates for the CI-only condition (49 ± 27%) were significantly lower than for the binaural and acoustic conditions (77 ± 19 vs 68 ± 28%, respectively, $P < 1 \times 10^{-4}$). We observed a weak difference between the binaural and acoustic conditions ($P = 0.014$), suggesting that the information provided by the implant slightly improved global auditory performance. The level of residual
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Hit rates on the voice/nonvoice discrimination task and spatial hearing scores. Bin—Binaural condition. NI ear—Nonimplanted ear. CI—Cochlear implant stimulation. RMS—Average RMS error in degrees. (A) Patients had significantly lower hit rates than the controls for all of the stimulation conditions; their hit rates for the CI condition were significantly lower than for the binaural and acoustic conditions. A small difference was observed between the binaural and acoustic conditions in the patients. (B) Patients made significantly more errors during the spatial perception task than the controls. Without amplitude roving, there was a significant difference between the CI-ON and CI-OFF conditions, showing that the implant improved spatial localization. However, when amplitude roving was introduced, there was only a trend towards better performance in the CI-ON condition (P = 0.08).</figcaption></figure>

hearing, (PTA values), correlated with the scores for the binaural ($r = 0.61, P = 2.3 \times 10^{-6}$) and the acoustic ($r = 0.63, P = 1.6 \times 10^{-4}$) conditions. We did not find a correlation between the hit rate and CI experience.

The spatial hearing abilities were evaluated just before the PET scan using a free-field sound localization task. Performance was assessed with the cochlear implant on (CI-ON; i.e. a binaural, bimodal condition) and with the cochlear implant off (CI-OFF; i.e. an acoustic, monaural condition). On average, the AHL-CI subjects had poorer sound localization than the controls (P < 0.05; Fig. 1B).

This was observed, as expected, in the CI-OFF condition, where the RMS errors often exceeded the range of 50–60°. When the amplitude of the sounds was constant, performance was significantly better in the CI-ON

condition than in the CI-OFF condition (paired t-test; $P = 0.01$); in the more challenging roving amplitude condition, there was only a trend towards better performance in the CI-ON condition (P = 0.08). However, for this latter condition, seven of the ten subjects had superior sound localization in the CI-ON condition, with a binaural benefit ranging from +9 to +33%. Thus, there was a beneficial effect, albeit limited, of the implant on spatial hearing, similar to the results found for discrimination task.

## PET results

### Average activity in the auditory areas

The auditory activity in the PAC/NPAC regions was assessed for the different stimulation conditions (Fig. 2A and B). A linear mixed effects model was
<table><caption>**Table 2.** The effects of subject group, stimulation condition, and hemispheric side on auditory cortical activity.</caption><thead><tr><th>Effects and interactions</th><th>Chi² (df)</th><th>P</th></tr></thead><tbody><tr><td>Condition</td><td>15.2 (3)</td><td>0.00016</td></tr><tr><td>Side</td><td>259.5 (1)</td><td>&lt;2.2e-16</td></tr><tr><td>Group</td><td>5.03 (1)</td><td>-0.024</td></tr><tr><td>Condition:Side</td><td>14.9 (3)</td><td>0.002</td></tr><tr><td>Condition:Group</td><td>10.4 (3)</td><td>0.016</td></tr><tr><td>Side:Group</td><td>13.09 (1)</td><td>0.0003</td></tr></tbody></table>

used to analyze the differences between the subject groups, the stimulation conditions, and the side of the auditory cortical activity (contralateral and ipsilateral to the stimulated ear). The results showed significant differences for all three (Table 2, Fig. 2A), the activity in the auditory regions being reduced by about 5% in the AHL-CI subjects compared with the controls (group effect; $P=0.024$). The differences between the conditions are about 2–5% of the average activity level in the areas of interest (Fig. 2A).

During acoustic stimulation, there were higher levels of activity in the hemisphere contralateral to the stimulation, both in the AHL-CI patients and the controls (side effect; $P=2.2 \times 10^{-16}$). In contrast, during CI stimulation, the activity was higher in the hemisphere ipsilateral to the implanted ear (condition: side interaction, $P=0.002$), and was found to be higher than the ipsilateral activity to acoustic stimulation (post hoc comparisons $P=4 \times 10^{-5}$). The opposite pattern was found for contralateral activity: the auditory activation levels were higher for the acoustic than for the CI stimulation ($P=2 \times 10^{-12}$). Altogether, these results suggest that the implant only partially restores a normal pattern of contralateral auditory cortical activation.

In addition, we computed a binaural integration index (BII) comparing for each hemisphere the activity derived from the stimuli simultaneously presented to both ears (Bin) with the summed activity obtained after separate stimulation of each ear: Bin/(Crossed + Uncrossed ear). Binaural integration mechanisms occur when the BII is significantly different from 1.0. In both the NHS and the patients, we observed BII values lower than 1.0, reflecting a binaural suppression mechanism. BII values are similar when comparing NHS and patients, whatever the side considered (in NHs, the mean for both hemispheres is $0.50 \pm 0.007$; in patients, $0.51 \pm 0.008$ for the hemisphere ipsilateral to the implant and $0.51 \pm 0.01$ for the hemisphere contralateral to the implant (bootstrap, $P < 0.05$) (Fig. 2A). We carried out further analyses to determine whether the auditory cortical activity relates to the level of residual hearing in the nonimplanted ear. Significant negative correlations with PTA (Fig. 3) were observed, but only for the auditory cortex contralateral to the acoustic stimulation. This was found for both the binaural and the acoustic conditions ($r=0.62$ ($P=1.3 \times 10^{-6}$) and $0.52$ ($P=3.6 \times 10^{-5}$), respectively; Fig. 3A and B), and it implies that the level of hearing loss negatively impacts the level of auditory cortical activity. We also found a

similar negative correlation when the cochlear implant was stimulated, but this was for the cortex ipsilateral to the implant ($r=-0.54$ ($P=8 \times 10^{-6}$); Fig. 3C). This suggests that the level of hearing loss affects the overall cortical excitability and influences the response to peripheral stimulation, whether acoustic or electrical.

We also carried out analyses to determine whether the duration of the hearing loss relates to the cortical activity. We found a weak, negative correlation for the activity contralateral to the implant during binaural stimulation ($r=-0.36$, $P=0.009$) and CI stimulation ($r=-0.37$, $P=0.004$), but not during the acoustic stimulation ($r=-0.13$, $P=0.93$). This implies that a longer duration of deafness weakens the restoration of auditory activity in the hemisphere contralateral to the implant.

The influence of post-implantation experience was also assessed. The duration of CI experience correlated with activity in the cortex contralateral to the implant during binaural ($r=0.32$, $P=0.023$) and acoustic stimulation ($r=0.36$, $P=0.007$), but not during the CI-only condition ($r=-0.08$, $P=0.55$). Thus, there is a slightly higher activity contralateral to the implant with CI experience. Our hypothesis is that the treatment of the profound hearing loss by cochlear implantation affects the overall cortical excitability and influences the response to peripheral stimulation, whether acoustic or electrical. No significant correlations were found for the ipsilateral to CI cortex.

To summarize, the auditory cortical activity was found to be lower, on average, in the AHL-CI subjects than in the controls. This can be attributed to weaker activation from the cochlear implant as well as hearing loss in the nonimplanted ear.

## Auditory activity and test performance

For the AHL-CI patients, we examined whether the auditory activity was related to performance on the sound discrimination task (hit rates). Correlation analyses were run and revealed several significant positive correlations. These were found for the auditory cortex contralateral to the nonimplanted ear during binaural stimulation ($r=0.4$, $P=0.0019$; Fig. 4A), for both the contralateral and ipsilateral to acoustic stimulation auditory regions ($r=0.63$ ($P=1.5 \times 10^{-7}$) and $r=0.54$ ($P=1.7 \times 10^{-5}$), respectively; Fig. 4B and C), and for the ipsilateral to CI auditory cortex during CI-only stimulation ($r=0.40$, $P=0.0017$; Fig. 4D).

A positive relationship between auditory activity and performance levels in all cases indicates that auditory activity in our study is related to the efficiency of auditory perception in patients and not to the task difficulty.

Relationships were also examined between the auditory cortical activity and auditory spatial abilities, expressed by the RMS values on the sound localization task. A significant correlation was only found for the activity in the hemisphere contralateral to the nonimplanted ear ($r=0.31$, $P=0.018$). This was confirmed by a regression analysis at the whole-brain level between
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Auditory cortical activity in patients and controls. (A) Contralateral and ipsilateral sides are indicated with respect to the stimulated ear. AHL-CI—asymmetric hearing loss with cochlear implants. NHS—Normally hearing subjects. NI ear—Nonimplanted ear (patients). CI—Cochlear implant stimulation (patients). The values are arbitrary units (a.u.) of regional cerebral blood flow (rCBF) after the normalization per subject. For the binaural bar chart, the average of both auditory cortices is presented. AHL-CI subjects had significantly lower activity in the auditory regions than the controls. In both patients and controls, during acoustic stimulation, activity was higher on the side contralateral to the stimulation. However, during CI stimulation in patients, activity was higher in the ipsilateral than the contralateral auditory cortex. Binaural integration index (indicated as binaural index) compares for each hemisphere the activity caused by the stimuli simultaneously presented to both ears (bin) with the summed activity obtained after separate stimulation of each ear: Bin/(Crossed+Uncrossed ear). The mean of both hemispheres is presented for NHS. (B) Illustration of activity in patients during binaural stimulation, better acoustic ear stimulation (right ear for this image) and CI (left side) stimulation. It can be seen that the activity during binaural stimulation is similar to the acoustic stimulation. The images have been flipped for the four patients with right CI. T-values of the statistical comparison with the baseline condition are presented.</figcaption></figure>

the sound localization scores and brain activity during binaural stimulation (acoustic and CI stimulation); this pointed to a restricted area located within the contralateral to the nonimplanted (NI) ear auditory cortex (Fig. 5). This result indicates that the auditory cortex (PAC/NPAC) contralateral to the nonimplanted ear is implicated in spatial hearing processing in AHL-CI subjects.

To summarize, the relationship between the performance levels and the auditory cortical activity was mainly driven by the nonimplanted ear during both the acoustic and the binaural conditions. Conversely, the performance levels only related to the CI evoked activity in the auditory cortex ipsilateral to the CI.
<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Auditory cortical activity and deafness. NI ear—Nonimplanted ear. CI—cochlear implant. PTA—Pure tone average. Significant negative correlations were only observed between the PTA and activity in the auditory cortex contralateral to the acoustic ear (i.e. ipsilateral to CI).</figcaption></figure>

## Asymmetries in the auditory activity

The asymmetry index (AI; see materials and methods) indicates which hemisphere is more active according to the side of the auditory stimulation (Fig. 6A). AI values are positive when there is greater contralateral activity, and negative when there is greater ipsilateral activity. We calculated them with respect to the stimulated ear for the monaural conditions. For the binaural stimulation, we calculated the AI with respect to the NI ear in patients and to the right ear in controls. We found that the control subjects had greater contralateral activity for both of the monaural stimulation conditions; during binaural stimulation, the index did not differ significantly from zero, thus indicating similar levels of activity in both the left and the right auditory cortices (Fig. 6A).

In the AHL-CI subjects, there were significant positive AI values when the nonimplanted ear was stimulated (Fig. 6B). This demonstrates that the acoustic stimulation induced a contralateral to the NI ear dominance, as observed in normally hearing subjects. Following stimulation through the cochlear implant, the AI index values also tended to be positive, but this was not statistically significant (bootstrap, P=0.05). The AI differences between the AHL-CI group and the controls were not found to be statistically significant for any of the stimulation conditions. We suspect that is probably

due to the lower responsiveness of the cortical activity to the CI in the contralateral hemisphere.

These results indicate that cochlear implantation restores the normal pattern of interhemispheric asymmetry, with a reactivation of the contralateral auditory cortex in response to stimulation at the nonimplanted ear. This can be attributed to the partial recovery of binaural hearing through cochlear implantation. As discussed previously, UHL patients display ipsilateral to the better-hearing ear activation in response to its stimulation (Vannson et al. 2020). In contrast, the AHL-CI patients displayed contralateral activation that was similar to the pattern seen in normally hearing controls.

We also examined whether the AHL-CI subjects' asymmetry index related to performance on the sound localization task. We found that the AI following stimulation of the nonimplanted ear was highly correlated (rho = -0.8, P = 0.0014) with the localization performance, i.e. RMS errors in the roving condition. Superior spatial performance therefore may be related to the restoration of a normal pattern of interhemispheric asymmetry (Fig. 6C). No correlation of AI with CI experience was found.

## Aural preference indices of cortical activity

The aural preference index (API; see materials and methods) is used to assess the respective influence of the
<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Mean auditory cortical activity and hit rates on the voice/nonvoice task. NI ear—Nonimplanted ear. CI—Cochlear implant. There was a significant correlation between the hit rate and activity in the auditory cortex contralateral to the nonimplanted ear during binaural stimulation. The highest significant correlations with performance were for the acoustic stimulation (for both auditory cortices). Following CI stimulation, there was a significant correlation between the hit rate and activity in the ipsilateral to the CI stimulation.</figcaption></figure>

crossed and uncrossed ear on the auditory cortical activity in one hemisphere (Kral et al. 2013; Fig. 6A).

API values are positive when the crossed ear has a greater influence. For the control subjects, we found that the API were positive for both auditory cortices, with values that differed significantly from zero (P < 0.05; Fig. 6D). For the AHL-CI subjects with a left-sided cochlear implant, there was a significant crossed aural preference for the left auditory cortex (API of about 1%), reflecting a preference for the nonimplanted right ear; for the right auditory cortex, the API values did not differ significantly from zero, thus implying that the implanted ear did not strongly influence the

contralateral hemisphere (Fig. 6D). For the patients with a right-sided implant, the pattern of results was similar, with a significant crossed aural preference for the right auditory cortex, but not for the left auditory cortex (Fig. 6D). These results imply that the hemisphere contralateral to the nonimplanted ear shows a crossed aural preference, similar to that seen in controls.

The API values for the left-implanted and right-implanted AHL-CI patients were pooled into a single group to assess correlations clinical factors. Correlation analyses revealed that the longer the duration of the deafness, the stronger the crossed aural preference for the auditory cortex ipsilateral to the implant (rho = 0.67,
<figure><img src="image_7.png" /><figcaption>**Fig. 6.** Asymmetry and aural preference indices for the auditory cortex in subjects with a cochlear implant and controls. (A) Explanatory schemes of the asymmetry index and aural preference index. Asymmetry index (AI) was calculated for each condition using the formula: $AI = (\text{Contralateral} - \text{Ipsilateral})/(\text{Contralateral} + \text{Ipsilateral})$, where contralateral and ipsilateral hemispheres refer to the ear stimulated. The aural preference index was calculated using the formula: $API = (\text{Crossed ear} - \text{Uncrossed ear})/(\text{Crossed ear} + \text{Uncrossed ear})$. B) AHL-CI—Patients with a cochlear implant for asymmetric hearing loss. AI—Asymmetry index. NI ear—Nonimplanted ear. Bin—Binaural stimulation. CI—Cochlear implant stimulation. RMS rov—Root mean square scores on the roving condition of the sound localization task. AI is calculated with respect to the simulated ear. For binaural stimulation, the asymmetry index in patients was calculated with respect to the nonimplanted ear. In controls the binaural asymmetry index is presented with respect to the right ear. AI is marked with an asterisk when significantly different from zero (bootstrap, *P* < 0.05). AI values are in the range of that observed in similar PET scan studies (see Berman and Weinberger 1990). In AHL-CI patients, there were significant positive (contralateral) AI values for stimulation of the nonimplanted ear, as seen in normally hearing subjects. For stimulation through the CI, the AI index was not significantly different from zero; and for binaural stimulation, the AI index showed a contralateral shift with respect to the nonimplanted ear. (C) The AI for acoustic stimulation correlated highly with the sound localization scores, implying that smaller errors in spatial localization were related to the restoration of contralateral hemispheric dominance. (D) AHL-CI—Patients with a cochlear implant for asymmetric hearing loss. API—Aural preference index. The API is marked with an asterisk when significantly different from zero (bootstrap, *P* < 0.05). In normally hearing controls, a crossed aural preference was seen for both auditory cortices (API values significantly different from zero). In the left-implanted subjects, there was a crossed (right) aural preference for the left auditory cortex; in the right-implanted participants, there was a crossed (left) aural preference for the right auditory cortex.</figcaption></figure>

Phillips and Gates 1982). This hypothesis was originally proposed because of the inhibitory influence of ipsilateral stimulation on auditory cortical neurons (Brugge and Merzenich 1973; Phillips and Irvine 1979, 1981) and the low proportion of such neurons unresponsive to ipsilateral stimulation (7% according to Hall and Goldstein 1968). The theory has been supported by several unilateral lesion studies, which showed that sound localization was mainly impaired in the sound field contralateral to the lesion, irrespective of whether the lesion affected a lower or higher stage of brain processing (see (Thompson and Masterton 1978) for the brainstem; (Sanchez-Longo and Forster 1958) for the temporal lobe; (Clarey et al. 1992) for a review). However, whether it

reflects ear dominance or the sound field, it is clear that the usual pattern of lateralization is disrupted following unilateral and asymmetric hearing loss. The first aim of our study was to determine whether cochlear implantation could restore this functional lateralization in AHL.

The aural preference index (API, see Fig. 6D) is a commonly used quantitative measure to assess functional lateralization. It has been used in both human (Gordon et al. 2015) and animal studies (Kral et al. 2013), and has characterized *Aural Preference Syndrome*, which can occur in unilateral deafness (Gordon et al. 2015). API values reflect the strength of activation resulting from each ear at the level of a single hemisphere. In normally
hearing controls, the API reveals a crossed aural pref-
erence for both hemispheres (Fig. 6D); in unilateral and
AHL, this preference shifts towards the better-hearing ear
for both hemispheres (Kral et al. 2013). In our study, we
showed that crossed aural preference is not restored fol-
lowing cochlear implantation in AHL, as CI stimulation
activates the contralateral auditory cortex as much as
the ipsilateral cortex (see Fig. 6D). These results are in
agreement with a study on AHL-CI children (Polonenko
et al. 2018; Lee et al. 2020), where there was only a slight,
nonsignificant tendency towards a crossed preference for
the implanted ear.

It is important to be aware that the API compares the
level of cortical activation resulting from two auditory
pathways (from the cochlea to the cortex) that differ
in their functional integrity. It is known that deafness
leads to a structural alteration of the anatomical path-
way (Moore et al. 1994; Syka 2002; Eggermont 2017), and
this, coupled with the degraded sound representation
provided by the neuroprosthesis (Sato et al. 2017), could
weaken the efficiency of the cochlear implant, leading
to a weak or absent crossed aural preference for the
implanted ear. However, the crossed aural preference
for the nonimplanted ear is preserved, both before and
after cochlear implantation (present study and Lee et al.
2020). When considering these results, it should be noted
that the API does not reflect functional lateralization
concerning representations of the contralateral sound
field.

Another quantitative index, the asymmetry index (AI;
or lateralization index in Vannson et al. 2020) (see Fig. 6)
is also frequently used to assess auditory cortical pro-
cessing in normal hearing (Jamison et al. 2006; Schön-
wiesner et al. 2007; Stefanatos et al. 2008) as well as
in deafness and its treatment (Lee et al. 2020). The AI
provides a direct comparison of the strength of activation
in the auditory cortical areas of the two hemispheres
following stimulation at a single ear. The lateralization
in normally hearing controls is generally reported to be
contralateral, meaning that the auditory pathways onl
activate weaker the auditory cortex ipsilateral to the
stimulated ear. This weaker ipsilateral activation is partly
due to the small number of projections in the ipsilateral
pathways (Schönwiesner et al. 2007) and partly due to the
various excitatory/inhibitory ipsilateral inputs that reach
the auditory cortex (see Gutschalk and Steinmann 2015.
These neuronal interactions are important because they
lead to contralateral sound field representation (Phillips
and Gates 1982; Clarey et al. 1992; Samson et al. 2000),
which is thereby reflected in the AI values.

In a previous study on adult subjects with AHL
(Vannson et al. 2020), we demonstrated that the AI
shifts towards the ipsilateral to the better-hearing ear
auditory cortex following its stimulation. This leads to
disruption of the neuronal interactions in this auditory
cortex. We found that the AI shift was related to the
deficit in sound localization, thus suggesting that a
change in activation towards the ipsilateral auditory

cortex disrupts representations of the sound field. In the
present study, we present data that mirrors this finding,
showing that the restoration of auditory input to the
deaf ear through the CI re-establishes the contralateral
dominance for the NI ear. The was also a trend towards
contralateral dominance for the implanted ear, although
this was not statistically significant. In addition, the
extent of the contralateral to the NI ear lateralization was
found to be associated with better performance on the
sound localization task, thus suggesting a normalization
of the cortical representation of the sound field. This
strengthens our previous claim that the asymmetry
index can predict the recovery of spatial hearing.

At present, there is no clear evidence concerning the
mechanisms that could underlie the loss and the recov-
ery of contralateral activation in AHL and AHL-CI sub-
jects, respectively. It is possible that there are changes
in the balance of excitatory and inhibitory interactions
between the ipsilateral and contralateral inputs; this
may also affect the spatial receptive fields for auditory
localization (Imig et al. 1990).

Brain plasticity in the primary auditory cortex in deafness
and its rehabilitation

Only a few studies have investigated whether the
reactivation of a deaf ear can counteract the cortical
changes induced by AHL (reviewed by Vanderauwa
et al. 2020). However, none of these studies established
a link between brain plasticity and performance on
auditory tasks, as we have shown here. In addition, some
of the studies only investigated single cases (Firszt et al.
2013; Sharma and Glick 2016), while others had highly
variable data (Lee et al. 2020), thus precluding any robust
conclusions. Most of these previous studies used EEG
to study the neural changes (Legris et al. 2018, 2020;
Polonenko et al. 2018; Lee et al. 2020), which limits the
spatial resolution of any findings. They were therefore
unable to precisely locate the functional reorganization
that takes place, as EEG relies on algorithms of source
reconstruction, which lack accuracy. In our study, the
PET methodology was able to precisely locate the
restoration of functional lateralization to the auditory
cortex (primary and nonprimary) and outside in higher
integrative levels (Strelnikov et al. in preparation).
One of the limitations is the difficulty in obtaining
cortical activation maps through an implant, which
is incompatible with fMRI imaging or creates artifacts
in EEG imaging. On the other hand, PET imaging
provides the unique advantage of being compatible
with stimulation through the cochlear implant. As in
most clinical studies in deaf patients, our results are
relatively variable. Still, positive AI values were obtained
in the vast majority of patients (8 out of 10). This result
makes us confident about the validity of the restoration
of cortical lateralization after implantation and allows
us to show that the auditory cortical activity relates to
sound localization performance. It was also possible to
show that the auditory cortical activity relates to sound localization performance. It was also possible to show, using a whole-brain regression analysis, that the function integrity (capacity to respond) of the auditory cortex is predictive of auditory spatial perception. These data highlight the early stages of auditory processing in the cortex as a key level that links brain plasticity to spatial hearing skills. However, brain plasticity may also take place in areas outside of the auditory cortex, such as when acoustical and electrical information are combined to process nonspatial auditory information (Strelnikov et al. in preparation). Developmental studies in animals or humans have led to the notion of an aural preference syndrome after unilateral deafness. The studies on the impact of sequential bilateral cochlear implantation showed that the restoration of lateralization was more or less complete depending on the age at implantation, the time between each CI, and the duration of CI experience (Sharma et al. 2005; Polonenko et al. 2018; Lee et al. 2020), in line with the notion of critical periods during the development (Kral et al. 2019). Our present results are somewhat striking as they are obtained in adult-acquired deafness, which is supposed to present a lower plasticity potential compared to early developmental stages. However, adult plasticity has been demonstrated in the case of profound deafness, particularly crossmodal plasticity (Strelnikov et al. 2015; Anderson et al. 2017; Stropahl and Debener 2017). Crossmodal plasticity can be reversed by restoring hearing functions through a CI (Rouger et al. 2011), indicating that intra- and crossmodal reversal plasticity can occur in the adult auditory cortex. However, while the recovery of language or spatial functions in children is quite convincing (Polonenko et al. 2018; Illg et al. 2019), the capacity to restore spatial hearing processing in adults SSD-CI is still relatively restricted and mostly relies on behavioral studies (Dillon et al. 2017; Buss et al. 2018). Thus, the relationships between the level of cortical restoration (at the macroscopic level of the lateralization pattern) and the level of functional recovery differ between the adult and the early developmental stages, suggesting the existence of additional age-dependent fine-grained neural interaction processes.

## Conclusion

In this study, we demonstrated that the restoration of binaural stimulation in AHL-CI patients reverses the abnormal lateralization pattern induced by AHL. In addition, the hemispheric dominance contralateral to the nonimplanted ear was found to be associated with superior sound localization. This supports the hypothesis that aural dominance relates to representations of the spatial sound field; this would be disrupted in unilateral deafness and restored in AHL-CI patients. The results suggest that cochlear implantation rehabilitates the binaural excitatory/inhibitory cortical interactions, and

that these enable the recovery of the spatial selectivity involved in sound localization.

## Acknowledgment

We thank all of our subjects for their participation in the study, and the ENT team at Purpan hospital, Toulouse, for their precious help and support. The authors would also like to acknowledge all the technical team of the PET scan platform for their help during the scanning sessions, especially Mathieu Alonso, Kevin Rouchette for the technical development of the PET study, and Dr Anne Hitzel, Dr Anne Julian for medical support of the PET study. The authors are very thankful to Jessica Foxton for correction and critical review of the article.

## Funding

This work was supported by an ANRT (Association Nationale de la Recherche et de la Technologie)—Cochlear CIFRE (Conventions industrielles de formation par la recherche) PhD funding (No 2016/138447) to CK, a grant Agir pour l’audition (APA-RD2015-6B), ANR (Agence Nationale de la Recherche) AgeHear (ANR-20-CE28-0016), ANR Hearing 3D (ANR 16-CE17-0016) to MM, OD, and BP and the recurrent funding of the Centre national de la recherche scientifique, France.

*Conflicts of interest statement.* CK and CJ are Cochlear employees.

## References

Anderson CA, Lazard DS, Hartley DEH. Plasticity in bilateral superior temporal cortex: effects of deafness and cochlear implantation on auditory and visual speech processing. *Hear Res.* 2017;343: 138–149.

Andreasen NC, Arndt S, Cizadlo T, O'Leary DS, Watkins GL, Ponto LL, Hichwa RD. Sample size and statistical power in [$^{15}$O]H$_2$O studies of human cognition. *J Cereb Blood Flow Metab.* 1996;16: 804–816.

Arndt S, Laszig R, Aschendorff A, Beck R, Schild C, Hassepass F, Ihorst G, Kroeger S, Kirchem P, Wesarg T. Unilateral deafness and cochlear implantation: audiological diagnostic evaluation and outcomes. *HNO.* 2011;59:437–446.

Arndt S, Wesarg T, Stelzig Y, Jacob R, Illg A, Lesinski-Schiedat A, Ketterer MC, Aschendorff A, Speck I. Influence of single-sided deafness on the auditory capacity of the better ear. *HNO.* 2020;68: 17–24.

Aronoff JM, Freed DJ, Fisher LM, Pal I, Soli SD. Cochlear implant patients' localization using interaural level differences exceeds that of untrained normal hearing listeners. *J Acoust Soc Am.* 2012;131:EL382–EL387.

Avan P, Giraudet F, Büki B. Importance of binaural hearing. *Audiology.* 2015;20:3–6.

Barone P, Clarey JC, Irons WA, Imig TJ. Cortical synthesis of azimuth-sensitive single-unit responses with nonmonotonic level tuning: a thalamocortical comparison in the cat. *J Neurophysiol.* 1996;75: 1206–1220.

Belin P, Zatorre RJ, Lafaille P, Ahad P, Pike B. Voice-selective areas in human auditory cortex. *Nature.* 2000;403:309–312.
Berman KF, Weinberger DR. Lateralisation of cortical function during cognitive tasks: regional cerebral blood flow studies of normal individuals and patients with schizophrenia. *J Neurol Neurosurg Psychiatry*. 1990;53:150–160.

Brugge JF, Merzenich MM. Responses of neurons in auditory cortex of the macaque monkey to monaural and binaural stimulation. *J Neurophysiol*. 1973;36:1138–1158.

Burton H, Firszt JB, Holden T, Agato A, Uchanski RM. Activation lateralization in human core, belt, and parabelt auditory fields with unilateral deafness compared to normal hearing. *Brain Res*. 2012;1454:33–47.

Buss E, Dillon MT, Rooth MA, King ER, Deres EJ, Buchman CA, Pillsbury HC, Brown KD. Effects of cochlear implantation on binaural hearing in adults with unilateral hearing loss. *Trends Hear*. 2018;22:2331216518771173.

Chan JCY, Freed DJ, Vermiglio AJ, Soli SD. Evaluation of binaural functions in bilateral cochlear implant users. *Int J Audiol*. 2008;47: 296–310.

Clarey JC, Barone P, Imig TJ. Physiology of thalamus and cortex. In: Popper AN, Fay RR, editors. *The mammalian auditory pathway: neurophysiology*. Springer handbook of auditory research. New York, NY: Springer New York; 1992. pp. 232–334

Dillon MT, Buss E, Rooth MA, King ER, Deres EJ, Buchman CA, Pillsbury HC, Brown KD. Effect of cochlear implantation on quality of life in adults with unilateral hearing loss. *Audiol Neurootol*. 2017;22:259–271.

Dorbeau C, Galvin J, Fu Q, Legris E, Marx M, Bakhos D. Binaural perception in single-sided deaf cochlear implant users with unrestricted or restricted acoustic hearing in the non-implanted ear [WWW document]. *Audiol Neurootol*. 2018;23(3):187–197. https://pubmed.ncbi.nlm.nih.gov/30352440/.

Dorman MF, Loiselle LH, Cook SJ, Yost WA, Gifford RH. Sound source localization by normal-hearing listeners, hearing-impaired listeners and cochlear implant listeners. *Audiol Neurootol*. 2016;21: 127–131.

Eggermont JJ. Acquired hearing loss and brain plasticity. *Hear Res*. 2017;343:176–190.

Eickhoff SB, Heim S, Zilles K, Amunts K. Testing anatomically specified hypotheses in functional imaging using cytoarchitectonic maps. *Neuroimage*. 2006;32:570–582.

Eisenman LM. Neural encoding of sound location: an electrophysiological study in auditory cortex (AI) of the cat using free field stimuli. *Brain Res*. 1974;75:203–214.

Firszt JB, Reeder RM, Holden TA, Burton H, Chole RA. Changes in auditory perceptions and cortex resulting from hearing recovery after extended congenital unilateral hearing loss. *Front Syst Neurosci*. 2013;7:10.3389/fnsys.2013.00108.

Firszt JB, Reeder RM, Dwyer NY, Burton H, Holden LK. Localization training results in individuals with unilateral severe to profound hearing loss. *Hear Res*. 2015;319:48–55.

Galvin JJJ, Fu Q-J, Wilkinson EP, Mills D, Hagan SC, Lupo JE, Padilla M, Shannon RV. Benefits of cochlear implantation for single-sided deafness: data from the house clinic-University of Southern California-University of California, Los Angeles clinical trial. *Ear Hear*. 2019;40:766–781.

Giraud AL, Price CJ, Graham JM, Frackowiak RS. Functional plasticity of language-related brain areas after cochlear implantation. *Brain*. 2001;124:1307–1316.

Gitlez TC, Niquette PT. Fig6 in ten. *Hear Rev*. 1995;2:28–30.

Gordon K, Henkin Y, Kral A. Asymmetric hearing during development: the aural preference syndrome and treatment options. *Pediatrics*. 2015;136:141–153.

Green KM, Julyan PJ, Hastings DL, Ramsden RT. Auditory cortical activation and speech perception in cochlear implant users: effects of implant experience and duration of deafness. *Hear Res*. 2005;205: 184–192.

Gutschalk A, Steinmann I. Stimulus dependence of contralateral dominance in human auditory cortex. *Hum Brain Mapp*. 2015;36: 883–896.

Hall JL, Goldstein MH. Representation of binaural stimuli by single units in primary auditory cortex of unanesthetized cats. *J Acoust Soc Am*. 1968;43:456–461.

Heffner RS, Heffner HE. Visual factors in sound localization in mammals. *J Comp Neurol*. 1992;317:219–232.

Ilg A, Sandner C, Büchner A, Lenarz T, Kral A, Lesinski-Schiedat A. The optimal inter-implant interval in pediatric sequential bilateral implantation. *Hear Res*. 2019;372:80–87.

Imig TJ, Irons WA, Samson FR. Single-unit selectivity to azimuthal direction and sound pressure level of noise bursts in cat high-frequency primary auditory cortex. *J Neurophysiol*. 1990;63: 1448–1466.

Jamison HL, Watkins KE, Bishop DVM, Matthews PM. Hemispheric specialization for processing auditory nonspeech stimuli. *Cereb Cortex*. 2006;16:1266–1275.

Karoui C. *Neuroplasticity behind the rehabilitation of asymmetrical hearing loss and tinnitus through cochlear implantation: from psychoacoustic evaluations to neuroimaging studies*. PhD thesis. 2019 http://www.theses.fr/2019TOU30151.

Keating P, King AJ. Developmental plasticity of spatial hearing following asymmetric hearing loss: context-dependent cue integration and its clinical implications. *Front Syst Neurosci*. 2013;7:123.

King AJ, Parsons CH, Moore DR. Plasticity in the neural coding of auditory space in the mammalian brain. *Proc Natl Acad Sci U S A*. 2000;97:11821–11828.

Kral A, Tillein J, Heid S, Klinke R, Hartmann R. Cochlear implants: cortical plasticity in congenital deprivation. *Prog Brain Res*. 2006;157: 283–313.

Kral A, Hubka P, Heid S, Tillein J. Single-sided deafness leads to unilateral aural preference within an early sensitive period. *Brain*. 2013;136:180–193.

Kral A, Dorman MF, Wilson BS. Neuronal development of hearing and language: cochlear implants and critical periods. *Annu Rev Neurosci*. 2019;42:47–65.

Kumpik DP, King AJ. A review of the effects of unilateral hearing loss on spatial hearing. *Hear Res*. 2019;372:17–28.

Langers DRM, van Dijk P, Backes WH. Lateralization, connectivity and plasticity in the human central auditory system. *Neuroimage*. 2005;28:490–499.

Lee H-J, Smieja D, Polonenko MJ, Cushing SL, Papsin BC, Gordon KA. Consistent and chronic cochlear implant use partially reverses cortical effects of single sided deafness in children. *Sci Rep*. 2020;10:21526.

Legris E, Gomot M, Charpentier J, Aoustin JM, Aussedat C, Bakhos D. Assessment of auditory discrimination in hearing-impaired patients. *Eur Ann Otorhinolaryngol Head Neck Dis*. 2018;135:335–339.

Legris E, Galvin J, Roux S, Aoustin J-M, Bakhos D. Development of cortical auditory responses to speech in noise in unilaterally deaf adults following cochlear implantation. *PLoS One*. 2020;15:e0239487.

Litovsky RY, Moua K, Godar S, Kan A, Misurelli SM, Lee DJ. Restoration of spatial hearing in adult cochlear implant users with single-sided deafness. *Hear Res*. 2019;372:69–79.

Massida Z, Belin P, James C, Rouger J, Fraysse B, Barone P, Deguine O. Voice discrimination in cochlear-implanted deaf subjects. *Hear Res*. 2011;275:120–129.
McAlpine D, Martin RL, Mossop JE, Moore DR. Response properties of neurons in the inferior colliculus of the monaurally deafened ferret to acoustic stimulation of the intact ear. *J Neurophysiol.* 1997;78:767-779.

Mertens G, Hofkens A, Punte A, De Bodt M, Van de Heyning P. Hearing performance in single-sided deaf cochlear implant users after upgrade to a single-unit speech processor [WWW document]. Otol Neurotol. 2015;36(1):51-60.

Middlebrooks J, Pettigrew J. Functional classes of neurons in primary auditory cortex of the cat distinguished by sensitivity to sound location. *J Neurosci.* 1981;1:107-120.

Moore JK, Niparko JK, Miller MR, Linthicum FH. Effect of profound hearing loss on a central auditory nucleus. *Am J Otol.* 1994;15: 588-595.

Mortensen MV, Mirz F, Gjedde A. Restored speech comprehension linked to activity in left inferior prefrontal and right temporal cortices in postlingual deafness. *Neuroimage*. 2006;31: 842-852.

Naito Y, Okazawa H, Honjo I, Hirano S, Takahashi H, Shiomi Y, Hoji W, Kawano M, Ishizu K, Yonekura Y. Cortical activation with sound stimulation in cochlear implant users demonstrated by positron emission tomography. *Cogn Brain Res.* 1995;2: 207-214.

Nelson E, Reeder RM, Holden LK, Firszt JB. Front- and rear-facing horizontal sound localization results in adults with unilateral hearing loss and normal hearing. *Hear Res.* 2019;372:3-9.

Peirce J, Gray JR, Simpson S, MacAskill M, Höchenberger R, Sogo H, Kastman E, Lindelöv JK. PsychoPy2: experiments in behavior made easy. *Behav Res Ther.* 2019;51:195-203.

Phillips DP, Gates GR. Representation of the two ears in the auditory cortex: a re-examination. *Int J Neurosci.* 1982;16:41-46.

Phillips DP, Irvine DR. Methodological considerations in mapping auditory cortex: binaural columns in AI of cat. *Brain Res.* 1979;161: 342-346.

Phillips DP, Irvine DR. Responses of single neurons in physiologically defined primary auditory cortex (AI) of the cat: frequency tuning and responses to intensity. *J Neurophysiol.* 1981;45: 48-58.

Polonenko MJ, Papsin BC, Gordon KA. Limiting asymmetric hearing improves benefits of bilateral hearing in children using cochlear implants. *Sci Rep.* 2018;8:13201.

Ponton CW, Vasama J-P, Tremblay K, Khosla D, Kwong B, Don M. Plasticity in the adult human central auditory system: evidence from late-onset profound unilateral deafness. *Hear Res.* 2001;154: 32-44.

Popelár J, Erre JP, Aran JM, Cazals Y. Plastic changes in ipsilateral contralateral differences of auditory cortex and inferior colliculus evoked potentials after injury to one ear in the adult Guinea pig. *Hear Res.* 1994;72:125-134.

Rouger J, Lagleyre S, Démonet J-F, Fraysse B, Deguine O, Barone P. Evolution of crossmodal reorganization of the voice area in cochlear-implanted deaf patients. *Hum Brain Mapp.* 2011;33: 1929-1940.

Samson FK, Barone P, Irons WA, Clarey JC, Poirier P, Imig TJ. Directionality derived from differential sensitivity to monaural and binaural cues in the cat's medial geniculate body. *J Neurophysiol.* 2000;84:1330-1345.

Sanchez-Longo LP, Forster FM. Clinical significance of impairment of sound localization. *Neurology.* 1958;8:119-125.

Sato M, Baumhoff P, Tillein J, Kral A. Physiological mechanisms in combined electric-acoustic stimulation. *Otol Neurotol.* 2017;38:e215-e223.

Scheffler K. Auditory cortical responses in hearing subjects and unilateral deaf patients as detected by functional magnetic resonance imaging. *Cereb Cortex*. 1998;8:156-163.

Schönwiesner M, Krumbholz K, Rübsamen R, Fink GR, von Craxmon DY. Hemispheric asymmetry for auditory processing in the human auditory brain stem, thalamus, and cortex. *Cereb Cortex*. 2007;17:492-499.

Seeber BU, Baumann U, Fastl H. Localization ability with bimodal hearing aids and bilateral cochlear implants. *J Acoust Soc Am.* 2004;116:1698-1709.

Sharma A, Glick H. Cross-modal re-organization in clinical populations with hearing loss. *Brain Sci.* 2016;6.

Sharma A, Dorman MF, Kral A. The influence of a sensitive period on central auditory development in children with unilateral and bilateral cochlear implants. *Hear Res.* 2005;203:134-143.

Slattery WH, Middlebrooks JC. Monaural sound localization: acute versus chronic unilateral impairment. *Hear Res.* 1994;75:38-46.

Stefanatos GA, Joe WQ, Aguirre GK, Detre JA, Wetmore G. Activation of human auditory cortex during speech perception: effects of monaural, binaural, and dichotic presentation. *Neuropsychologia.* 2008;46:301-315.

Strelnikov K, Rouger J, Demonet J-F, Lagleyre S, Fraysse B, Deguine O, Barone P. Visual activity predicts auditory recovery from deafness after adult cochlear implantation. *Brain*. 2013;136:3682-3695.

Strelnikov K, Rouger J, Lagleyre S, Fraysse B, Demonet JF, Deguine O, Barone P. Increased audiovisual integration in cochlear-implanted deaf patients: independent components analysis of longitudinal positron emission tomography data. *Eur J Neurosci.* 2015;41:677-685.

Stropahl M, Debener S. Auditory cross-modal reorganization in cochlear implant users indicates audio-visual integration. *NeuroImage Clin.* 2017;16:514-523.

Syka J. Plastic changes in the central auditory system after hearing loss, restoration of function, and during learning. *Physiol Rev.* 2002;82:601-636.

Távora-Vieira D, De Ceulaer G, Govaerts PJ, Rajan GP. Cochlear implantation improves localization ability in patients with unilateral deafness. *Ear Hear.* 2015;36:e93-e98.

Thompson GC, Masterton RB. Brain stem auditory pathways involved in reflexive head orientation to sound. *J Neurophysiol.* 1978;41: 1183-1202.

Tillein J, Hubka P, Kral A. Monaural congenital deafness affects aural dominance and degrades binaural processing. *Cereb Cortex*. 2016;26:1762-1777.

Vanderauwera J, Hellemans E, Verhaert N. Research insights on neural effects of auditory deprivation and restoration in unilateral hearing loss: a systematic review. *J Clin Med.* 2020;9.

Vannson N, James C, Fraysse B, Strelnikov K, Barone P, Deguine O, Marx M. Quality of life and auditory performance in adults with asymmetric hearing loss. *Audiol Neurootol.* 2015;20(Suppl 1):38-43.

Vannson N, Strelnikov K, James CJ, Deguine O, Barone P, Marx M. Evidence of a functional reorganization in the auditory dorsal stream following unilateral hearing loss. *Neuropsychologia.* 2020;149:107683.

Vermeire K, Van de Heyning P. Binaural hearing after cochlear implantation in subjects with unilateral sensorineural deafness and tinnitus. *Audiol Neurootol.* 2009;14:163-171.

Wanrooij MMV, Opstal AJV. Contribution of head shadow and pinna cues to chronic monaural sound localization. *J Neurosci.* 2004;24: 4163-4171.

Wedekind A, Rajan G, Van Dun B, Távora-Vieira D. Restoration of cortical symmetry and binaural function: cortical auditory
evoked responses in adult cochlear implant users with single
sided deafness. *PLoS One*. 2020;15:e0227371.

Zeitler DM, Dorman MF, Natale SJ, Loiselle L, Yost WA, Gif-
ford RH. Sound source localization and speech understand-
ing in complex listening environments by single-sided deaf

listeners after cochlear implantation. *Otol Neurotol*. 2015;36:
1467-1471.

Zirn S, Arndt S, Aschendorff A, Wesarg T. Interaural stimulation timing in single sided deaf cochlear implant users. *Hear Res*. 2015;328:148-156.