Magnetic stimulation allows focal activation of the mouse cochlea

  1. Jae-Ik Lee
  2. Richard Seist
  3. Stephen McInturff
  4. Daniel J Lee
  5. M Christian Brown
  6. Konstantina M Stankovic
  7. Shelley Fried

  • Curated by eLife

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    Evaluation Summary:

    This study provides a demonstration that magnetic stimulation of the cochlea is feasible and suggests it could be more precise than electrical stimulation for cochlear implants. The conclusions of the paper are mostly well supported by data, but some aspects of the experimental procedure, the neuronal response acquisition, and the data analysis need to be clarified and extended.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

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Abstract

Cochlear implants (CIs) provide sound and speech sensations for patients with severe to profound hearing loss by electrically stimulating the auditory nerve. While most CI users achieve some degree of open set word recognition under quiet conditions, hearing that utilizes complex neural coding (e.g., appreciating music) has proved elusive, probably because of the inability of CIs to create narrow regions of spectral activation. Several novel approaches have recently shown promise for improving spatial selectivity, but substantial design differences from conventional CIs will necessitate much additional safety and efficacy testing before clinical viability is established. Outside the cochlea, magnetic stimulation from small coils (micro-coils) has been shown to confine activation more narrowly than that from conventional microelectrodes, raising the possibility that coil-based stimulation of the cochlea could improve the spectral resolution of CIs. To explore this, we delivered magnetic stimulation from micro-coils to multiple locations of the cochlea and measured the spread of activation utilizing a multielectrode array inserted into the inferior colliculus; responses to magnetic stimulation were compared to analogous experiments with conventional microelectrodes as well as to responses when presenting auditory monotones. Encouragingly, the extent of activation with micro-coils was ~60% narrower compared to electric stimulation and largely similar to the spread arising from acoustic stimulation. The dynamic range of coils was more than three times larger than that of electrodes, further supporting a smaller spread of activation. While much additional testing is required, these results support the notion that magnetic micro-coil CIs can produce a larger number of independent spectral channels and may therefore improve auditory outcomes. Further, because coil-based devices are structurally similar to existing CIs, fewer impediments to clinical translational are likely to arise.

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  1. Version published to 10.7554/elife.76682 on eLife
  2. eLife

    Author Response

    Reviewer #1 (Public Review):

    The authors have developed cochlear implant prototypes with microcoils that allow magnetic stimulation of spiral ganglion neurons instead of conventional electrical stimulation. The neuronal response at the cortical level was evaluated in a mouse model. Magnetic stimulation was compared to acoustic stimulation and conventional electrical stimulation. The results obtained by the authors demonstrated a better spatial selectivity with a better dynamic.

    The article is well written with an introduction and a problematic allowing to understand the goal of the work by readers not expert of the domain. The scientific approach is logical and progressive allowing to explain the work in a very educational way. The figures are clear and illustrate the quality of the work.

    Here are my comments:

    Concerning the methodology and in particular the electrical stimulation, it would be necessary that the authors specify that the stimulation was monopolar. this choice of stimulation involves a more important diffusion of the current. This makes the comparison with magnetic stimulation more flattering.

    In the discussion, several points should be addressed to better explain to the reader the interest and the limits of the chosen technology. I think that you should start by reminding the reader that there are other modes of electrical stimulation than monopolar stimulation. bipolar or tripolar stimulation can reduce the diffusion of the current to improve selectivity. this stimulation strategy is already used by some manufacturers in the clinic.

    We agree with the comment and have added language to the Discussion section to remind the reader that the electric stimulation was delivered in a monopolar configuration and that bipolar, tripolar and focused multipolar stimulation strategies would all provide narrower spreads of activation. Comparisons to micro-coil stimulation will be conducted in a future project.

    [Line 336] “In this study, electric stimulation was delivered in a monopolar configuration. Other configurations, e.g., bipolar, tripolar, and focused multipolar result in improved spatial selectivity in both animal models (Snyder et al., 2008, Bierer et al., 2010, George et al., 2015) and human trials (van den Honert and Kelsall, 2007) although at the expense of increased thresholds (Bierer and Faulkner, 2010, Zhu et al., 2012, George et al., 2015). Due to the small size of the mouse cochlea, it was not feasible to test configurations that required the insertion of two or more electrodes into the cochlea. In addition, the advantage of multipolar stimulation is less obvious in species with smaller cochleae, e.g., even in the gerbil cochlea difference in spatial spread between monopolar and bipolar stimulation was not significant (Dieter et al., 2019). Nevertheless, it will be still interesting to compare spreads from micro-coils to the diverse configurations of electric stimulation in future studies.”

    In the animal model used, it is likely that even in spite of recent hearing loss, the trophicity of the spiral ganglion is preserved. This does not reflect the pathological conditions of the implanted patients. Thus, it is not at all certain that the better selectivity is the better dynamics observed with magnetic stimulation can be observed in case of damaged spiral ganglion.

    This is a good point – it is a limitation of our work and we have modified the text to remind the reader of this possibility. Because one of the main goals of our study was to compare the spread of activation across different stimulation modalities, all SGNs needed to be viable so as to not introduce any bias e.g., tonotopic sections without SGN innervation might obscure the measurement of spectral spread. In future studies, it will be essential to test magnetic stimulation in a model of neonatally deafened animals to further evaluate the translational potential of magnetic stimulation to human subjects.

    [Line 388] “In the present study, it is likely that most SGNs were intact since our deafening procedure mainly targeted hair cells. Maintaining uniform survival of SGNs was essential to ensure accurate comparison of the spread of activation across modalities, however, this situation does not uniformly reflect the pathological conditions of all implanted patients. Patients typically receive CIs months or years after the onset of deafness and often have considerable SGN loss (Khan et al., 2005; Nadol and Eddington, 2006). Thus, in future studies, it will be necessary to test coil effectiveness in neonatally deafened animals so as to more closely mimic pathological conditions of implanted patients.”

    If the passage of current in the microcoils generates a magnetic field, it is possible that an inverse effect, or even a heating effect, could be observed if this type of implant is subjected to an external magnetic field, as in an MRI. Have the authors considered this potential disadvantage in view of a clinical transfer of this technology?

    This is an important concern. Bonmassar and Serano (2020) conducted a study addressing this question in micro-coils for deep brain stem stimulation and compared micro-coils to a typical wire implant in a 1.5T MRI. Their results showed warming of the implant in both groups, however, the degree was far less in the microcoils (<1° C), than in the wire (~10° C). Conventional electrode-based cochlear implants have been also evaluated in 1.5T MRI, where a slight degree of warming was observed, however, less than seen in lead wires (Bonmassar and Serano 2020, Zeng et al., 2018). Nevertheless, we agree that it is important to point out this potential limitation and have added the following paragraph.

    [Line 381] “Another potential concern would be the compatibility of implanted micro-coils with strong exogenous magnetic fields. A previous study has tested the effect of 1.5T exogenous magnetic field on micro-coils and electric wire-based implants designed for deep brain stem stimulation (Bonmassar and Serano, 2020). Their results showed warming of the implants in both groups, however, the degree was far less in the micro-coils (<1° C) than in the electric wires (~10° C). Nevertheless, testing the effect of exogenous magnetic fields on coil-based CIs will be crucial for the translation of this technique to humans.”

    Reviewer #2 (Public Review):

    Lee, Seist et al. investigated whether magnetic stimulation of the cochlear would lead to less spread of activity - a major limitation of classical cochlear implants used nowadays - than electrical stimulation. To do so, they measured neuronal responses in the inferior colliculus of mice to acoustic, electric, and magnetic stimulation of the cochlea. The acoustic stimulation consisted of 5 ms long pure frequency tones covering the range from 8 to 48 kHz, whereas the magnetic and electrical stimulations were pulses of 25 um duration presented at a rate of 25 pulses/s delivered at 2 locations along the cochlear (one basal, one apical). The neuronal responses were measured along a 16-channel recording array inserted along the tonotopic axis of the inferior colliculus. The results demonstrate that magnetic stimulation elicited responses that were more spatially constrained and had a larger dynamic range than electrical stimulation. As one of the main limitations of the cochlear implants used nowadays is the large spatial spread of stimulation, these data bring a lot of hope for improving this neuroprosthetic technology and put magnetic stimulation as one of the most promising approaches to improve cochlear implant technologies.

    The conclusions of the paper are mostly well supported by data, but some aspects of the experimental procedure, the neuronal response acquisition, and the data analysis need to be clarified and extended.

    1. From the current description, it is not clear whether the recording electrode stays at the same location for the acoustic, magnetic, and electrical stimulation, or whether it is removed and reinserted. If it is removed and reinserted, it might be that slightly different regions of the IC are recorded from, or that the brain gets slightly damaged on every new insertion. A more detailed quantification of the brain state or neuronal responses would then be a welcome addition. This could be done in several ways. For example, the spontaneous activity or general excitability of IC neurons could be compared across the three different stimulation paradigms in the few experiments they were performed in the same mice (l. 407). Another possibility would be to compare electrical stimulation responses when performed before vs. after the magnetic stimulation (l. 403). More generally, any possible paired-statistical analysis (i.e., when the same recording sites were used to compare the different stimulating methods) would be welcome. Related to my previous comment, it is written that “experiments were terminated when responses to magnetic stimulation were no longer robust” (l. 406). Why would responses lose robustness? If this is due to damage of the recorded neurons or to cochlea damage, it will most probably also affect the results overall and hence the conclusions of the manuscript.

    The positioning of the recording electrode remained at the same location; we have added the following statement to clarify our methods:

    [Line 421] “After the original insertion into the inferior colliculus, the position of the multielectrode recording array was not repositioned while switching from one stimulus modality to the next (acoustic, electric, magnetic). Due to the fragility of the recording electrode array, we took extra care to avoid disturbing the skull, as dislodgement of the array would have altered tonotopicity and thus weakened the ability to accurately compare spectral spread between trials.”

    To minimize the potential for pain or discomfort to the animal, experiments were terminated when vital signs, such as heart rate and respiration rate, declined; this typically occurred at about 5 – 7 hours after onset of the experiment. Such declines were typically preceded by a decline in inferior colliculus responses. We have modified the language in the manuscript to make this clearer.

    [Line 474] “Experiments were terminated whenever the animal’s vital parameters, as measured by heart and respiratory rate, declined. The decline was typically observed at around 5 – 7 hours and preceded by a decline in inferior colliculus responses.”

    1. In a number of figures, only example data are presented (Figures 2, 3, 6). To give the reader the possibility to judge the variability of the results across different experiments (and hence the robustness of the results), it would be important to show also average values, or - in cases this is not relevant - at least 3 example mice.

    We agree with this concern and have added more data for ABR and IC responses in the supplement figure section (Figure 3 – figure supplement 1; Figure 4 – figure supplements 1 and 2). We also present data points for individual samples in each plot. All source data used to make figures have been uploaded to the repository following the guideline of the eLife journal. We believe this will help interested readers assess our results quantitatively.

    The advantages and limitations of magnetic stimulations are well described in the introduction and discussion sections and leave the reader with the information that is needed to evaluate the potential strengths and weaknesses of the technique. These sections also nicely emphasize that future experiments have to be performed to further characterize this stimulation strategy.

    Reviewer #3 (Public Review):

    This article describes a new way to activate auditory nerve fibers (ANFs) by magnetic stimuli (generated by micro-coils) instead of electrical currents (generated by conventional electrodes). The activation of ANFs triggered by the micro-coils seems clear but several physiological quantifications are inappropriate and the major claims are based on a very small number of experiments. I sincerely encourage the authors to continue their experiments and use more straightforward ways to quantify their results (closer to the raw data) to progress toward clarifying their effects.

    In the case of severe and profound deafness, cochlear implant is the solution to recover partial hearing and speech understanding. Cochlear implant is probably the most successful neuroprothesis but it still has limitations, especially as it is difficult to focus the currents inside the cochlea, the electrodes being in contact with a conductive liquid named perilymphe.

    In this study, the authors aim at describing a new way to activate the auditory nerve fibers (ANFs) by the use of small coils (micro-coils) which are supposed to confine ANF activation more narrowly than can be achieved with conventional electrodes used in cochlear implants. The authors recorded neuronal activity from the inferior colliculus (a subcortical auditory structure) and claim that the spread of activation is narrower with magnetic stimulation compared to electric stimulation. They also point out that the dynamic range is wider with the magnetic stimulation than with electric stimulation. Finally, they show that the evoked responses in the inferior colliculus also occurred in mice chronically deafened indicating that the micro-coils directly activate the ANFs. Activation of the ANFs triggered by the micro-coils seems clear, however, to what extent this activation differs between electric and magnetic stimulation; and differs with acoustic stimulation is unclear. Several basic quantifications are missing and the quantifications performed here are not appropriate. In addition, all the claims are based on very small samples.

    For most of the study, our conclusions are based on a sample size (N = 6-12) that is in line with similar types of studies. Our statistical calculations provided enough power for significant results. We agree with the reviewer that it would be desirable to have performed more than N=2 experiments with chronically deafened animals. However, constraints arising from the COVID-19 pandemic as well as the relocation of Dr. Stankovic’s laboratory, made it impossible to perform these additional experiments. We acknowledge that only limited conclusions can be drawn from the experiment with 2 animals (i.e., the result from chronically deafened animals; Figure 7), but nevertheless, feel the result is worth presenting.

    Quantification of the frequency response area FRA using the d’ index is very puzzling. If the authors want to quantify the breadth of the tuning curves they can use the Q10dB, the Q40dB or the Octave distance which are classically used in auditory neuroscience. Comparing the different levels of stimulus intensity to determine the breadth of tuning to sounds and to electric/magnetic stimuli does not make any sense.

    In general, we tried to use conventional methods so that readers can readily understand and interpret our results. We acknowledge that measuring the spread of activation at certain dB levels above threshold is commonly used to evaluate responses to acoustic stimulation. However, we felt that the use of the classic Q10dB or Q40dB measures to compare the spread of activation across different modalities was less suitable since each modality has a different dynamic range. For example, the dynamic range of electric stimulation was only ~ 3 dB, while that of acoustic stimulation was more than 20 dB. Therefore, we adopted an approach based on fixed significance of response strengths, i.e., measuring at an identical discrimination index. In this way, the estimation of the spread of excitation becomes independent of the stimulus’s nature and makes neural activation by different modalities more comparable. This approach is similar to that used in many previous studies in which new stimulation paradigms were evaluated (Middlebrooks et al., 2007; Bierer et al., 2010; Moreno et al., 2011; Richter et al., 2011; George et al., 2015; Xu et al., 2019; Dieter et al., 2019; Keppeler et al., 2020) and thus allows the performance of micro-coils to be more easily compared. Nevertheless, we agree that providing more detailed explanations would be helpful to many readers and have added additional language in the Method section of the revised manuscript.

    The italicized text indicates passages from the revised manuscript: [Line 528] “The value of d’ represents the distance between the means in units of a standard deviation – the larger the d’ value, the more separated the distributions are.”

    [Line 532] “To estimate the spread of activation from acoustic stimulation, previous studies measured the width of IC activation at a sound pressure level of 10 - 40 dB above threshold. However, given that dynamic ranges are significantly different across modalities (e.g., the dynamic ranges of acoustic and electric stimulations are 25.96 ± 9.17 dB SPL and 3.24 ± 0.99 dB mA, respectively.), comparing spatial spreads at a fixed dB level above threshold was not feasible. Alternatively, some studies measured spatial spreads at different dB levels above threshold for different modalities., e.g., 20 dB and 6 dB above threshold for acoustic and electric stimulation, respectively (Snyder et al., 2004). More recent studies that have evaluated novel stimulation modalities and compared them to acoustic and/or electric responses compared spatial spreads at a given response strength, typically at cumulative d’ values of 2-4 (Middlebrooks and Snyder, 2007, Bierer et al., 2010, Moreno et al., 2011, Richter et al., 2011, George et al., 2015, Xu et al., 2019, Dieter et al., 2019, Keppeler et al., 2020). Thus, to remain consistent with these previous studies, we also compared spectral spreads from acoustic, magnetic, and electric stimulation at cumulative discrimination indexes of 2 and 4.”

    We have also plotted the cumulative d’ index with respect to dB levels above threshold for each modality (Figure 2 – figure supplement 2) and added relevant descriptions in the Materials and Methods section. We believe these will facilitate understanding of our results by readers, especially those who are accustomed to the analysis based on fixed dB levels.

    [Line 550] “On average, the cumulative d′ levels of 2 and 4 correspond to 7.23 ± 5.34 and 18.53 ± 9.94 dB SPL above threshold for acoustic stimulation, 0.47 ± 0.30 and 1.41 ± 0.53 dB 1 mA above threshold for electric stimulation, and 2.57 ± 1.33 and 7.98 ± 5.41 dB 1 V above threshold for magnetic stimulation (Figure 2 – figure supplement 2).”

    Quantification of the spectral spread of activation used in figure 4A-B is not correct. Based on the 11 animals tested with ipsilateral tones (and not contralateral tones), the authors estimated that each electrode corresponds to a particular frequency, then the between-electrode distance is converted in an octave distance. First, what is the purpose of converting distances into octave? In fact, there is no possibility to calibrate the acoustic stimuli and the electric/magnetic stimuli the same way: we cannot know if a particular sound intensity (e.g. 80dB) corresponds a particular voltage (for magnetic stimulation) or intensity (for electric stimulation). By using ipsilateral sounds instead of contralateral sounds, the authors largely underestimated the acoustic inputs reaching the recording sites (because the main ascending pathways cross the midline between the cochlear nucleus and the superior olivary complex). Therefore, the comparisons between acoustic and electric/magnetic activation cannot be properly assessed, which is the crucial part of this paper.

    As the reviewer mentioned, we converted the distance of activated electrodes to octave distance based on the characteristic frequency of each electrode derived from Figure 2D. This translation provides an estimate of the activated frequency band across the tonotopic organization of the cochlea by stimulation and previous studies evaluating novel methods of artificial stimulation presented the spread of activation by artificial stimulation in a similar way (Dieter et al., 2019; Keppeler et al., 2020). Therefore, we felt the use of this approach would provide the most direct comparison to previous work. Nevertheless, we agree that quantifying the activation spread by electrode distance would be more intuitive to some readers and have added the corresponding plots in Figure 5.

    We thank the reviewers for highlighting the anatomy of the auditory pathway and, specifically, its crossing over the midline. The wording in the original manuscript was confusing as all modes of stimulation (acoustic, electric, magnetic) were delivered to the left cochlea and responses measured from the right inferior colliculus (IC); the side to which stimulation was delivered was referred to as ipsilateral and the opposite side was referred to as contralateral. We revised the wording as shown below and believe it will greatly reduce the potential for confusion.

    [Line 100] “We stimulated the left cochlea with acoustic, electric, and magnetic stimuli and measured responses from a 16-channel recording array implanted along the tonotopic axis of the right (contralateral) inferior colliculus (IC) in anesthetized mice (Figure 1C; MATERIALS AND METHODS).”

  3. eLife

    Evaluation Summary:

    This study provides a demonstration that magnetic stimulation of the cochlea is feasible and suggests it could be more precise than electrical stimulation for cochlear implants. The conclusions of the paper are mostly well supported by data, but some aspects of the experimental procedure, the neuronal response acquisition, and the data analysis need to be clarified and extended.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

  4. eLife

    Reviewer #1 (Public Review):

    The authors have developed cochlear implant prototypes with microcoils that allow magnetic stimulation of spiral ganglion neurons instead of conventional electrical stimulation. The neuronal response at the cortical level was evaluated in a mouse model. Magnetic stimulation was compared to acoustic stimulation and conventional electrical stimulation. The results obtained by the authors demonstrated a better spatial selectivity with a better dynamic.

    The article is well written with an introduction and a problematic allowing to understand the goal of the work by readers not expert of the domain. The scientific approach is logical and progressive allowing to explain the work in a very educational way. The figures are clear and illustrate the quality of the work.

    Here are my comments:

    Concerning the methodology and in particular the electrical stimulation, it would be necessary that the authors specify that the stimulation was monopolar. this choice of stimulation involves a more important diffusion of the current. This makes the comparison with magnetic stimulation more flattering.

    In the discussion, several points should be addressed to better explain to the reader the interest and the limits of the chosen technology :

    I think that you should start by reminding the reader that there are other modes of electrical stimulation than monopolar stimulation. bipolar or tripolar stimulation can reduce the diffusion of the current to improve selectivity. this stimulation strategy is already used by some manufacturers in the clinic.

    In the animal model used, it is likely that even in spite of recent hearing loss, the trophicity of the spiral ganglion is preserved. This does not reflect the pathological conditions of the implanted patients. Thus, it is not at all certain that the better selectivity is the better dynamics observed with magnetic stimulation can be observed in case of damaged spiral ganglion.

    If the passage of current in the microcoils generates a magnetic field, it is possible that an inverse effect, or even a heating effect, could be observed if this type of implant is subjected to an external magnetic field, as in an MRI. Have the authors considered this potential disadvantage in view of a clinical transfer of this technology?

  5. eLife

    Reviewer #2 (Public Review):

    Lee, Seist et al. investigated whether magnetic stimulation of the cochlear would lead to less spread of activity - a major limitation of classical cochlear implants used nowadays - than electrical stimulation. To do so, they measured neuronal responses in the inferior colliculus of mice to acoustic, electric, and magnetic stimulation of the cochlea. The acoustic stimulation consisted of 5 ms long pure frequency tones covering the range from 8 to 48 kHz, whereas the magnetic and electrical stimulations were pulses of 25 um duration presented at a rate of 25 pulses/s delivered at 2 locations along the cochlear (one basal, one apical). The neuronal responses were measured along a 16-channel recording array inserted along the tonotopic axis of the inferior colliculus. The results demonstrate that magnetic stimulation elicited responses that were more spatially constrained and had a larger dynamic range than electrical stimulation. As one of the main limitations of the cochlear implants used nowadays is the large spatial spread of stimulation, these data bring a lot of hope for improving this neuroprosthetic technology and put magnetic stimulation as one of the most promising approaches to improve cochlear implant technologies.

    The conclusions of the paper are mostly well supported by data, but some aspects of the experimental procedure, the neuronal response acquisition, and the data analysis need to be clarified and extended.

    1. From the current description, it is not clear whether the recording electrode stays at the same location for the acoustic, magnetic, and electrical stimulation, or whether it is removed and reinserted. If it is removed and reinserted, it might be that slightly different regions of the IC are recorded from, or that the brain gets slightly damaged on every new insertion. A more detailed quantification of the brain state or neuronal responses would then be a welcome addition. This could be done in several ways. For example, the spontaneous activity or general excitability of IC neurons could be compared across the three different stimulation paradigms in the few experiments they were performed in the same mice (l. 407). Another possibility would be to compare electrical stimulation responses when performed before vs. after the magnetic stimulation (l. 403). More generally, any possible paired-statistical analysis (i.e., when the same recording sites were used to compare the different stimulating methods) would be welcome.
    2. Related to my previous comment, it is written that "experiments were terminated when responses to magnetic stimulation were no longer robust" (l. 406). Why would responses lose robustness? If this is due to damage of the recorded neurons or to cochlea damage, it will most probably also affect the results overall and hence the conclusions of the manuscript.
    3. In a number of figures, only example data are presented (Figures 2, 3, 6). To give the reader the possibility to judge the variability of the results across different experiments (and hence the robustness of the results), it would be important to show also average values, or - in cases this is not relevant - at least 3 example mice.

    The advantages and limitations of magnetic stimulations are well described in the introduction and discussion sections and leave the reader with the information that is needed to evaluate the potential strengths and weaknesses of the technique. These sections also nicely emphasize that future experiments have to be performed to further characterize this stimulation strategy.

  6. eLife

    Reviewer #3 (Public Review):

    This article describes a new way to activate auditory nerve fibers (ANFs) by magnetic stimuli (generated by micro-coils) instead of electrical currents (generated by conventional electrodes). The activation of ANFs triggered by the micro-coils seems clear but several physiological quantifications are inappropriate and the major claims are based on a very small number of experiments. I sincerely encourage the authors to continue their experiments and use more straightforward ways to quantify their results (closer to the raw data) to progress toward clarifying their effects.

    In the case of severe and profound deafness, cochlear implant is the solution to recover partial hearing and speech understanding. Cochlear implant is probably the most successful neuroprothesis but it still has limitations, especially as it is difficult to focus the currents inside the cochlea, the electrodes being in contact with a conductive liquid named perilymphe.
    In this study, the authors aim at describing a new way to activate the auditory nerve fibers (ANFs) by the use of small coils (micro-coils) which are supposed to confine ANF activation more narrowly than can be achieved with conventional electrodes used in cochlear implants. The authors recorded neuronal activity from the inferior colliculus (a subcortical auditory structure) and claim that the spread of activation is narrower with magnetic stimulation compared to electric stimulation. They also point out that the dynamic range is wider with the magnetic stimulation than with electric stimulation. Finally, they show that the evoked responses in the inferior colliculus also occurred in mice chronically deafened indicating that the micro-coils directly activate the ANFs. Activation of the ANFs triggered by the micro-coils seems clear, however, to what extent this activation differs between electric and magnetic stimulation; and differs with acoustic stimulation is unclear. Several basic quantifications are missing and the quantifications performed here are not appropriate. In addition, all the claims are based on very small samples.

    Quantification of the frequency response area FRA using the d' index is very puzzling. If the authors want to quantify the breadth of the tuning curves they can use the Q10dB, the Q40dB or the Octave distance which are classically used in auditory neuroscience. Comparing the different levels of stimulus intensity to determine the breadth of tuning to sounds and to electric/magnetic stimuli does not make any sense.

    Quantification of the spectral spread of activation used in figure 4A-B is not correct. Based on the 11 animals tested with ipsilateral tones (and not contralateral tones), the authors estimated that each electrode corresponds to a particular frequency, then the between-electrode distance is converted in an octave distance. First, what is the purpose of converting distances into octave? In fact, there is no possibility to calibrate the acoustic stimuli and the electric/magnetic stimuli the same way: we cannot know if a particular sound intensity (e.g. 80dB) corresponds a particular voltage (for magnetic stimulation) or intensity (for electric stimulation). By using ipsilateral sounds instead of contralateral sounds, the authors largely underestimated the acoustic inputs reaching the recording sites (because the main ascending pathways cross the midline between the cochlear nucleus and the superior olivary complex). Therefore, the comparisons between acoustic and electric/magnetic activation cannot be properly assessed, which is the crucial part of this paper.

  7. Version published to 10.1101/2022.01.11.475825v1 on bioRxiv