Profound congenital sensorineural hearing loss (SNHL) prevents children from developing spoken language. Cochlear implantation and auditory brainstem implantation can provide partial hearing sensation, but language development outcomes can vary, particularly for patients with inner ear malformations and/or cochlear nerve deficiency (IEM&CND). Currently, the peripheral auditory structure is evaluated through visual inspection of clinical imaging, but this method is insufficient for surgical planning and prognosis. The central auditory pathway is also challenging to examine in vivo due to its delicate subcortical structures. Previous attempts to locate subcortical auditory nuclei using fMRI responses to sounds are not applicable to patients with profound hearing loss as no auditory brainstem responses can be detected in these individuals, making it impossible to capture corresponding blood oxygen signals in fMRI. In this study, we developed a new pipeline for mapping the auditory pathway using structural and diffusional MRI. We used a fixel-based approach to investigate the structural development of the auditory-language network for profound SNHL children with normal peripheral structure and those with IEM&CND under 6 years old. Our findings indicate that the language pathway is more sensitive to peripheral auditory condition than the central auditory pathway, highlighting the importance of early intervention for profound SNHL children to provide timely speech inputs. We also propose a comprehensive pre-surgical evaluation extending from the cochlea to the auditory-language network, showing significant correlations between age, gender, Cn.VIII median contrast value, and the language network with post-implant qualitative outcomes. Congenital profound hearing loss (hearing level >90 dB diagnosed at birth or in early childhood) deprives children of spoken language development and has lifelong negative consequences for education, employment, and psychosocial status . The preInner ear malformations and cochlear nerve deficiencies (IEM&CND), identifiable with CT and MRI, contribute to 15–39% of paediatric SNHL cases . The resSpeech is transmitted through the auditory pathway and understood at the language network . For chiHowever, there are several challenges in this field. Firstly, the human auditory pathway is difficult to inspect non-invasively due to its delicate nodes connected by curving and crossing fibres, especially the parts that are buried deep in the brainstem . FunctioFurthermore, previous neuroimaging studies of profound congenital SNHL excluded children with IEM&CND. However, as mentioned earlier, these subjects comprise a significant proportion of patients with congenital hearing loss and are more inclined to be faced with difficult surgical decisions and unsatisfactory post-implantation outcomes. Therefore, it is important to include and focus on children with IEM&CND when studying central adaptations associated with profound hearing loss.In the present study, we introduced a new pipeline for reconstructing the human auditory pathway and examined the brain structural development of children with profound congenital SNHL at both the acoustic processing level and the speech perception level. Specifically, we included children under the age of six with profound hearing loss, with and without IEM&CND, as well as normal hearing controls. We segmented the subcortical auditory nuclei using super-resolution track density imaging (TDI) maps and T1-weighted images, and tracked the auditory pathway and the language pathway using probabilistic tractography. Then, we used FBA to investigate the fibre properties of these two pathways. We aimed to investigate (1) the alteration of fibre metrics in the auditory-language network of children with profound SNHL; (2) the potential impact of IEM&CND on the pre-implant structural development of this network; and (3) the relationship between the pre-implant structural development of this network and the auditory-language outcomes following CI or ABI implantation. By doing so, we hope to provide new insights into the surgical strategies and rehabilitation of children with profound congenital SNHL.U test: p-value for age = 0.077, 95% confidence interval for the difference in age =  mo; p-value for gender = 0.446, 95% confidence interval for the difference in male counts = ).Twenty-three children aged under 6 years old including 13 patients with bilateral profound congenital SNHL  and 10 normal hearing volunteers  matched on age and gender were included  MRI. The presence of IEM&CND was determined based on Sennaroğlu classification criteria ; descripAll subcortical auditory nuclei, including the bilateral CN, superior olivary complex (SOC), IC, and MGB, were segmented in both group-average space and individual space with good inter-rater reliability see .We reconstructed the auditory pathway in vivo using probabilistic tractography in four subdivisions: the trapezoid body (TB), lateral lemniscus (LL), brachium of inferior colliculus (BIC), and acoustic radiation (AR) see . The audThe language pathway was also reconstructed bilaterally, each comprising two dorsal streams and two ventral streams see . Dorsal In the central auditory pathway, FBA results demonstrated reduced fibre density (FD), fibre cross-section (FC), and fibre density and cross-section (FDC) in TB and decreased FC in LL in patients with profound SNHL (pFWE < 0.05) see . There wNext, we performed a tract-of-interest analysis to examine specific subdivisions in these pathways see . Fibre mIn the present study, all seven children who underwent CI surgery had normal inner ear and cochlear nerve structure see . All sixWe divided patients with profound SNHL into a normal peripheral structure subgroup and an IEM&CND subgroup, and compared their peripheral nerve and central pathway structure. The IEM&CND subgroup had significantly lower cn.VIII median contrast values than the normal peripheral structure subgroup . Evaluations included pure tone audiometry 6 mo post-device activation, and four auditory and language scales at both the onset and 6 mo post-activation, along with changes in these scores over the intervening period. The scales we employed were the Categories of Auditory Performance (CAP), Speech Intelligibility of Rating (SIR), Infant-toddler Meaningful Auditory Integration Scale (IT-MAIS), and Meaningful Use of Speech Scale (MUSS). These scales predominantly offer a qualitative and observational measure of auditory performance, speech use, and speech intelligibility in various real-life scenarios and are rooted in subjective interpretations. A notable trend was that subjective assessments of auditory and language development, as measured by various scales, appeared to be more responsive to preoperative metrics such as age, gender, choice of surgery, peripheral nerve tissue density, and fibre densities in the central auditory and language pathways. Conversely, the objective indicator of postoperative auditory condition (PTA) exhibited a more focused correlation pattern see .Significantly, age showed a positive correlation with numerous auditory and language scales at both the initial and six-month post-activation, and with changes in these scores over this period. Gender demonstrated a correlation with IT-MAIS and MUSS at startup and with SIR 6 mo post-activation. This positive correlation implies that female patients (coded as '2') typically achieve higher scores on these scales than their male counterparts (coded as '1'). Contrasting with age and gender, the choice of surgery (CI versus ABI) manifested a unique positive correlation with PTA 6 mo post-activation, but not with auditory and language scales. This suggests a more immediate effect on the objective auditory condition. A positive correlation signifies that the patients who opted for ABI surgeries (coded as '2') typically exhibited higher PTA values (indicating poorer hearing) compared to those who underwent CI surgeries (coded as '1'), at least at the 6-month post-activation.In terms of the preoperative variables related to the auditory system, the cn.VIII median contrast value was positively correlated with CAP, IT-MAIS at 6 mo post-activation, and change in SIR. Interestingly, the FD of the central auditory pathway did not present significant correlations with the scales at any point.However, a notable trend emerged when assessing the language pathways. CAP at the onset positively correlated with all language pathways, whereas PTA at 6 mo showed no correlation with these pathways. Generally, the FD of most language pathways, particularly most dorsal streams, demonstrated positive correlations with various scales at startup and 6 mo post-activation, and also with MUSS change. These observations highlight the language pathway’s significant role in auditory development beyond the primary hearing level. When comparing the correlations between auditory and language pathways, it becomes apparent that the latter might exert a superior influence on auditory-speech outcomes. This could be attributed to the intricate and compensatory neural mechanisms involved in speech comprehension, especially in patients with auditory implants. Further exploration of these findings is elaborated upon in the ‘Discussion section.r > 0.5, many > 0.75), most did not pass the stringent FWE correction, and only managed to exceed uncorrected p-value thresholds. The only correlations that survived the rigorous FWE correction were those between age and IT-MAIS at startup, age and MUSS at 6 mo post-activation, and surgery choice and PTA at 6 mo. These findings warrant careful interpretation.Despite the uniformly positive and frequently robust correlations  and CSF, with a small width of up to around 2 mm . The SOCOur results showed that the best way to capture fibre features of different tracts in the auditory pathway is to track them separately and optimize tracking strategies for each part. We implemented probabilistic tractography and deliberately chose seeds and termination ROIs for each tract based on anatomical prior knowledge. MCP fibres were excluded when tracking the TB, which accounted for a large proportion of contralateral streamlines if not controlled and have yet been neglected in earlier studies. Exclusion ROIs are also essential when tracking the AR, because the AR crosses with several major fibre bundles that own greater FOD amplitudes in the corresponding directions. Mafei et al. found that optimal tracking parameters for the ARs were probabilistic tractography with default settings ; however, the FOD amplitude threshold was not mentioned . We examNormally, the axonal myelination of the auditory pathway starts at the 26th foetal week, becomes definitive by the 29th week of gestation, and continuously increases in density until at least 1 y postnatal age . With th2 square box in T2w and FA maps of children with profound hearing loss. They measured DTI-based metrics in the TB, SOC, IC, MGB, AR, and white matter of Heschl’s gyrus (LL and BIC not included) and found decreased FA values in all of these six ROIs , OTOF (one patient), and MYO15A (one patient). These mutations are largely associated with peripheral auditory deficits, given these genes' critical roles in inner ear development and function . ConsequOn the other hand, the significant association between FD/FC of profound hearing loss-associated impaired language fixels and cn.VIII tissue density suggests that the language pathway is more sensitive to peripheral auditory condition compared to the central auditory pathway. The language pathway, as the substrate for higher cognitive functions, develops in a way that is highly dependent on external inputs and interaction with the environment . More spTo understand the specific impact of peripheral nerve structure on the developmental trajectory of central pathways, we conducted a moderation analysis. Cn.VIII tissue density had a significant negative moderation effect on the relationship between auditory pathway FD and age, and that between language pathway FD and age. In other words, the lower the cn.VIII tissue density, the closer the relationship between FD of central pathways and age. It is worth noting that cn.VIII tissue density only moderated FD maturation; there was no significant moderation effect on FC maturation. These results may imply that the macroscopic developmental trajectory of central pathways is similar among patients with various peripheral conditions, while at the microscopic level, peripheral nerve deficiency may lead to a delayed and slowed axon generation or myelination in central pathways, which may reflect as an increased association of central FD with age in the participants ranging from 6 months to 6 years old. However, when controlling gender, gestational weeks, and birth weights, the moderation effect was not significant, necessitating a cautious interpretation of the findings. Taken together, to prevent aberrant structural development in the auditory-language network in the absence of hearing, auditory interventions should be implemented as early as possible. Special attention should be paid to patients with CND. Early interventions would provide children with timely auditory inputs during the critical period of language development and lead to better long-term outcomes.Indeed, the quantitative differences observed between the effects on the central auditory and language structures may be influenced by the varying ability to accurately image each pathway with current neuroimaging technologies. The central auditory pathway, largely situated in the brainstem, faces severe distortion in diffusion images due to the inherent properties of the echo-planar imaging (EPI) sequence used. Despite distortion correction methods, it is challenging to entirely eliminate these effects. In contrast, the language pathways, primarily located in the cerebrum, have less distortion, allowing for more accurate imaging. Additionally, the auditory pathways in the brain (e.g. the auditory radiations) intersect with numerous cerebral fibre tracts, complicating accurate tractography. While the Constrained Spherical Deconvolution (CSD) modelling approach we employed is currently the most advanced method for addressing crossing fibres, it is not entirely exempt from these issues. The language pathways, on the other hand, intersect with fewer fibre tracts, facilitating more precise reconstruction. Lastly, the language pathways are more extensive and possess more fibres than the auditory pathways. From a statistical perspective, this enables more ‘sampling’ when extracting average metrics such as FD, resulting in more stable outcomes. Therefore, the differences in our ability to visualize and quantify these pathways might have influenced the comparative effects observed. As neuroimaging technologies and methodologies continue to advance, we anticipate that our understanding of the differential effects of hearing loss on the central auditory and language structures will continue to evolve and improve. Another limitation is that the normal hearing control group did not undergo scanning with the CISS sequence, precluding the establishment of a baseline for comparing the development of auditory and language pathways in SNHL to normal development, which requires future research to include a baseline assessment.Our study delivers novel insight into the quantification of central auditory structural development and advocates an individualized, comprehensive pre-surgical evaluation of the auditory-language network to inform surgical decisions and predict prognosis see . From thBy refining the CISS-based estimation of cn.VIII tissue density, we enable more accurate quantitative assessment of peripheral nerve structure, which is essential for characterizing CND. The positive correlation of cn.VIII median contrast value with CAP and IT-MAIS at 6 mo post-activation, and with change in SIR, underscores its clinical value in predicting postoperative auditory performance.Furthermore, by reconstructing the entire central auditory pathway, we enable measurements of FD and FCs to assess the structural maturity and integrity of the central auditory pathway. Although correlations with auditory-language scales were not significant in the all-patient analysis, among CI recipients, correlations were observed in specific regions of the auditory pathway. This suggests that this approach might be indicative of postoperative auditory information transmission efficiency and highlight the need for further investigations.Moreover, by integrating the findings from HRCT, CISS MRI, and reconstruction of the central auditory pathway, we offer a holistic view from the cochlea to the auditory cortex, which may guide critical surgical decisions such as the choice between CI and ABI, and the side of implantation. Our study primarily includes patients with normal peripheral structures undergoing CI, but patients with varying malformations may also be CI candidates. Thus, while our findings provide initial insights, further investigations encompassing a more diverse patient population with different types of IEM&CND are warranted. It is also worth noting that the timepoint of outcomes post-implantation is important when comparing ABI and CI. Although our study found that ABI generally resulted in poorer PTA 6 mo post-activation compared to CI, clinical experience suggests that ABI patients may show considerable improvements over a longer term (within a year or two post-activation). Therefore, longer-term follow-up is essential to fully understand the outcomes of different surgeries. Our study’s 6-month follow-up lays the groundwork for future, more comprehensive studies.We found that FD of most language pathways positively correlates with auditory and language scales. Our findings indicate the potentially central role of the structural development of the language pathway in predicting auditory and language outcomes following implantation.Language has a recursive hierarchical structure, and the brain’s mechanism of language processing reflects this through its hierarchical representations that unfold across time and space in the brain . Speech Our findings revealed that subjective auditory-speech performance was predominantly correlated with the preoperative FD of the language pathway, rather than the structural status of the auditory system. This observation underscores the potential necessity of employing language-specific metrics to evaluate speech prognosis. It is noteworthy that sound information contains a significant redundancy for speech processing, as evidenced by the fact that people can understand degraded speech. In the context of patients with auditory implants, the received auditory signals tend to be unnatural and degraded. It is possible that the restoration of precise tonotopic mapping in these patients may not substantially influence their speech perception; instead, the dynamic interplay between STG and higher-order brain regions is instrumental in their speech comprehension capabilities. Predictions provided by higher-level centres aid patients in understanding and learning language. Peelle et al. found that listeners with cochlear implants showed greater activity in the left prefrontal cortex than listeners with normal hearing when listening to spoken words, indicating a compensatory role of the frontal lobe in language processing for implant recipients . As suchAdditionally, our results also indicate a significant positive correlation between age at the time of preoperative MRI scanning and postoperative performance. At first glance, this appears to be contradictory to the widely held view that there are advantages to performing surgery at an early age. However, it is important to note that the postoperative performance data in this study was gathered at 6 mo following surgery. Older children typically possess a more extensive repository of abstract concepts and might have a more developed top-down predictive function in higher-level brain areas. Consequently, in this short-term postoperative timeframe, older children may exhibit superior performance due to their advanced cognitive development. However, once the timeframe is extended, a wealth of behavioural evidence suggests that undergoing surgery earlier offers advantages in various areas, including auditory, linguistic, and cognitive development . TherefoOverall, while the study’s findings emphasize the value of these preoperative metrics in determining postoperative outcomes, we acknowledge the need for additional research to corroborate these findings and unlock the full potential of these evaluations. By pushing forward in these investigations, we can continue to refine and enhance auditory rehabilitation, delivering patient-specific care and ultimately improving postoperative auditory and language outcomes.The strengths of the present study include (1) the first comprehensive in vivo reconstruction of the central auditory pathway independent of using auditory stimuli; (2) the inclusion of children with IEM&CND in addition to those with normal inner ear structures to provide a more complete picture of children with congenital profound hearing loss; and (3) a precise inspection of fibre structures of the auditory pathway, the language pathway, and their subdivisions using a fixel-based approach that address crossing fibre issues.We also acknowledge some limitations of this study: (1) the genetic dataset in our study is incomplete and heterogeneous. While two patients underwent extensive testing of over 200 genes, five were tested for select common genes. For a thorough understanding of the genetic factors in auditory deficits, future studies should employ uniform and comprehensive genetic testing across participants. (2) Our cohort is of a limited size, which may limit the generalizability of these findings to a larger population. (3) The potential discrepancies in the ability to image auditory and language pathways could have influenced the observed effects. Specifically, the more pronounced distortion of the auditory pathway in diffusion images, the complex fibre-crossing issue within the auditory pathway, and the fewer fibres present compared to the language pathway may have contributed to the observed differences. (4) A ‘floor effect’ was observed in the PTA of ABI recipients and in some auditory and language scale scores. This may have masked the full extent of the relationships between the structural parameters and postoperative progress, as significant improvements could potentially be observed in some patients over a more extended period. (5) The scales employed  primarily provide subjective and observational measures. While they offer valuable qualitative insights into auditory performance and speech use in real-life contexts, they have limited quantitative precision. Their usefulness should be appreciated within this context.In conclusion, this study introduced a new pipeline for in vivo reconstruction of the central auditory pathway, found both microscopic and macroscopic fibre impairment in specific auditory and language tracts, and discovered a negative moderation effect of peripheral auditory structure on central pathway maturation. Additionally, our investigation uncovered significant correlations between fibre densities of auditory and language pathway subdivisions and various auditory and language outcomes, underscoring the potential predictive value of these structural parameters. This provides structural evidence supporting the necessity of early auditory intervention and establishes a promising comprehensive pre-surgical evaluation of the auditory-language network for children with severe-to-profound SNHL to assist with surgical planning and prognosis.Twenty-three children aged under 6 years old, including 13 patients with bilateral profound congenital SNHL and 10 controls matched on age and gender, were included.The patients met the following criteria: (1) diagnosis of bilateral profound SNHL: click ABR threshold >95 dB nHL, or pure tone average  threshold >95 dB HL ; and (2)The study protocol was approved (SH9H-2021-T449-1) by the Ethics Committee of Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital , and all enrolled subjects had informed consent provided by parent/guardian.Age, gender, gestational weeks, birth weight, and a thorough medical history of pregnancy and hearing condition were recorded.Pure tone audiometry was conducted at frequencies of 0.5k, 1k, 2k, 4k, and 8k Hz for children who were able to cooperate, serving to evaluate their hearing levels. Additionally, click ABRs were assessed. The click stimuli used in ABR tests had a duration of 100 µs and covered a broad frequency range from 100 Hz to 10,000 Hz. Examinations were performed using AC40 and Eclipse devices . Distortion product otoacoustic emissions (DPOAE) and tympanometry tests were also conducted to provide a comprehensive auditory assessment.Genetic data were obtained from the patients' records, coming from various sources, which led to variations in the testing panels among patients. Specifically, two patients underwent comprehensive hereditary deafness gene testing, which analysed over 200 genes linked to hearing loss. In contrast, five patients were tested for a limited set of common genes, such as GJB2 and MTR. Genetic data for the remaining six patients could not be obtained due to practical constraints.A temporal bone high-resolution CT (sections of 0.5 mm in thickness) and a three-dimensional (3D) CISS MRI scan  were acquired to inspect the structure of the inner ear and the cochlear nerve of patients. Two experienced neuroradiologists assessed the presence and type of IEM&CND based on Sennaroğlu classification criteria (inter-rater agreement = 0.923) .Whole-brain MRI was carried out on a 3-Tesla Siemens MAGNETOM Vida scanner  using a 64-channel head coil. To reduce motion artefacts, patients received sedation by oral intake of chloral hydrate for the MRI scan under supervision. Earplugs and sound-attenuating foam were used to decrease the noise of the scanner. Sandbags were placed on the scanner table to help attenuate vibrations during scanning. The lights in the scanner room were turned off, and blankets were wrapped around the children to create a suitable sleeping environment. Monitoring throughout the scanning session included pulse oximetry, respiration, and close observation by medical staff.2, and TR/TE  = 2400/2.38 ms) and whole-brain diffusion imaging (dMRI). The scanning protocol consisted of 3 diffusion shells  with 32, 44, and 64 diffusion-weighted directions each and 10 b0 volumes using PA phase encoding. Additionally, two b0 images in AP phase encoding were scanned for TOPUP distortion correction. The EPI readout used SMS factor of 4, Grappa acceleration factor of 2, partial Fourier factor of 6/8, isotropic resolution of 2.0 mm, axial slices of 72, matrix of 105 × 105, FOV of 210 × 210  mm2, and TR/TE of 2900/95ms.The acquisition protocol was adapted from the Developing Human Connectome Project (DHCP) that was optimized for the properties of the developing brain . All chiEach patient’s MRI was transferred to a DICOM workstation during acquisition to review any clinical or research-relevant incidental findings. Then, insufficient coverage, excessive motion, and/or ghosting were visually assessed. If any image failed the visual quality assessment, the MR technicians would decide whether to re-scan the sequence according to the child’s condition.Of 13 patients, 9 underwent auditory implantation (two ABI recipients and seven CI recipients). Postoperative data were collected during follow-up appointments.This was conducted at 6 mo after device activation.Four auditory and language scales were assessed both at activation and at 6 mo after activation. The scales included:r = 0.981, p<0.01), inter-rater reliability , and criterion validity with LittlEARS  and Griffiths   .r = 0.983, p<0.01), inter-rater reliability , and criterion validity with LittlEARS  and Griffiths   .r = 0.929, p<0.01) and inter-rater reliability . Content and construct validity were established with expert judgement and domain consistency  and inter-rater reliability . Its validity characteristics are in line with those of IT-MAIS  maps from whole-brain tractography to obtain high spatial resolution images of the white matter. These DEC-TDI maps and T1-weighted images provided complementary information and enhanced anatomical contrast for subsequent manual segmentation of subcortical auditory nuclei. The primary auditory cortex was extracted from the Human Brainnetome Atlas  and co-rThe DEC short‐tracks TDI (stTDI) map method  was usedAt the group level, a study-specific T1-weighted brain template was created using the T1-weighted images from all 10 controls using antsMultivariateTemplateConstruction2.sh in ANTs  and tranSubcortical auditory regions were segmented based on anatomical observations in histology studies  as well The CN is located on the brainstem surface at the pontomedullary junction, where auditory nerve axons enter and terminate. The CN is elongated and curved from ventrolateral to dorsomedial. The ventral and dorsal portions of the CN can be distinguished by histological cytoarchitectonic properties, although approximately 10% of their shared borders remain a grey zone . In a hoOn T1-weighted images, the CN can be located at the pontomedullary junction where cranial nerve VIII enters the brainstem and is roughly delineated along the brainstem surface from ventrolateral to dorsomedial. In DEC-TDI maps, the CN is distinguished from its medial neighbour, the ICP, by its clear blue border, as the ICP travels mainly in the rostrocaudal direction . The CN,The SOC is a group of cells located in the pons, a short distance medial and rostral to the CN. The SOC is composed of a laminar medial nucleus  and a small lateral nucleus; the entire complex is enclosed by a capsule of rostrally directed axons of the ascending auditory pathway .The SOC is not distinguishable on T1-weighted images. In DEC-TDI maps, the SOC appears as a hypointense area surrounded by hyperintense fibres in the horizontal view: medially, the medial lemnisci; ventrally, the TB; and laterally, the MCP. The SOC was delineated from the same axial plane as the rostral-most extent of the ventral CN, extending about 4 mm rostrally .The IC is easy to locate as the two inferior spherical structures of the corpora quadrigemina in the dorsal midbrain . On T1-wThe MGB is located in the ventromedial thalamus. On T1-weighted images, the MGB is identified as an oval-shaped hypointense eminence that is medial to the lateral geniculate body and lateral to the superior colliculus . In the Subcortical auditory regions were segmented manually as described above. The primary auditory cortex  was extracted from the Human Brainnetome Atlas  in the MThe neurons in the CN receive nerve innervation from the cochlea and project to the IC both directly and indirectly. The SOC is the major relay station and receives axons from mostly the contralateral, partly the ipsilateral CN; the contralateral dominance remains in the following ascending pathway . The ascTracking of the TB and LL was carried out by seeding from each CN to the SOC and the IC in both sides, using MCP as an exclusion ROI for anatomical constraints, and seeding from each SOC to the IC in both sides.All ascending projections from the auditory brainstem to the thalamus are carried in the BIC . TrackinThe AR is the final stream that links the subcortical auditory pathway to the auditory cortex . The AR https://nipy.org/nibabel/) and visualized in DSI Studio (https://dsi-studio.labsolver.org/).Streamlines were transformed into the trk format in Python via the Nibabel package  feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Our editorial process produces two outputs: (i) Decision letter after peer review:eLife. Your article has been reviewed by 3 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Barbara Shinn-Cunningham as the Senior Editor.Thank you for submitting your article "Impact of Peripheral Auditory Structure on the Development of Auditory-Language Network in Children with Profound Sensorineural Hearing Loss" for consideration by The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.Essential revisions:1) Behavioral data on the speech and language abilities of the children are available and should be reported.2) The clinical evaluation and presentation of the children, both genetically and auditorily, is inadequate. Please provide any further details that would be useful for interpreting the other results.3) The distinction between the groups isn't adequately considered. Please provide further details.4) The practical relevance of the auditory-language pathways is unclear. Aside from behavioral data , a broader consideration of the studied pathways in the overall processing of hearing and language by the brain is needed.5) Add discussion of the possibility that the quantitative difference between effects on central auditory and language structures is due to the different ability to image each pathway.Reviewer #1 (Recommendations for the authors):Overall, the authors have done a beautiful job creating high-resolution maps of the auditory pathway in these children. This type of imaging is not my speciality and so I cannot comment on the methodology or analysis behind the imaging. However, I am an expert on pediatric hearing loss and so I evaluated this manuscript from that perspective.Detailed recommendations are below:1) There are some major deficiencies with respect to the clinical evaluation/presentation of the children in this study which makes interpretation of the results difficult. First of all, there is no diagnosis provided. The causes of pediatric hearing loss is extraordinarily complex with hundreds of genetic forms and environmental causes as well. Hearing loss is not a diagnosis but is instead a symptom of an underlying pathologic change to the peripheral and/or central auditory system. The authors do not provide a diagnosis for the 13 children with hearing loss and as such any conclusions are limited. For example, if some of the children have GJB2 hearing loss, I would expect differences compared to children with CDH23 hearing loss . Similarly, variants in CHD7, are associated with CHARGE syndrome and are a common cause of cochlear nerve deficiency, with some presumed central effect. The authors should provide more clinical history on individual patients, including hearing testing, and should at the least have performed genetic testing for a full evaluation of hearing loss. Ideally, the authors would then separate their subjects into groups . This would make their study more powerful.2) This study does not include cochlear implant and/or auditory brainstem implant outcomes. Therefore, the authors cannot have any claims to determining or predicting outcomes with these devices until their correlate this finding with those results. This would be an excellent follow-up study and the authors should temper their statements on clinical applicability until this is completed.3) I assume that the CIs and ABIs were implanted after imaging? This is not specified anywhere that I could find.4) The figure legends are confusing. Please indicate whether each image is an individual patient or an average and which group each image belongs to.5) The graphs in Figure 3 are very very difficult to read. The authors should reformat these so that there is a white background and the bars are filled (or at least not use the current color scheme).6) The authors should be careful about how they use the word 'deaf'. 'Deaf or hard of hearing' is an appropriate way to describe individuals with hearing loss. Severe-to-profound or profound are accurate ways to describe the severity of a hearing loss. The use of the word 'deaf' to describe profound hearing loss is generally discouraged as it is not scientific and may be confused by 'Deaf'  which describes members of the Deaf community.Please see above.Reviewer #2 (Recommendations for the authors):General comments– Although the paper tried to justify why focusing on IEM and CND is important, such decision seems still arbitrary to this reviewer. More discussion on what makes these hearing loss etiologies distinct from other etiologies would help.– The paper does not discuss how these results help with a better understanding of speech sound encoding and decoding in listeners with normal and impaired hearing. It is particularly important to discuss these findings in the context of mapping sound patterns to phonological units.– Also, there is a rich literature on hearing, language comprehension, and speech perception network from Gregory Hickok, David Poeppel, and Jonathan Peelle which are not discussed in this paper.Title– The title needs to be more specific to the questions of this study. Using the general term "Peripheral Auditory Structure" could be misleading. Please revise to reflect both the specific types of hearing loss in this study and also the population that is children with profound hearing loss, but receive CI or ABI as interventions.Abstract:– Cochlear implantation and auditory brainstem implantation can provide hearing sensation… it is more accurate to say … provide "partial" hearing sensation …– "Previous attempts to locate subcortical auditory nuclei using fMRI responses to sounds are not applicable to deaf patients." Please add a reason(s) for why these previous attempts are not applicable.– Line 3: lifelong "negative" consequences …– Line 39: please check the in-text citations format– Line 52: "Secondly, although earlier studies reported several altered fibre tracts related to language function, …" Please add references to support this statement.– Line 83: mean [SD], age, 30.92 [6.115] months; 9 males, 4 females– Mean [SD] of age– You can remove 4 females as it is redundant– Please consider the same edit for NH– Line 85: Please indicate the confidence interval in your stats reportTable 1– I recommend using the term gender instead of sexLine 137– FC, FD, and FDC are presented here for the first time in the manuscript. So, their extended version should be used here to avoid possible confusion.Caption of Figure 3: please report the actual p-values– Line 139: ie. -->◊ i.e.Figure 3– I wonder how the data and results would look if ABI and CI groups were represented separately.– Line 167-168: please elaborate on why such surgical decisions have limited value.– Line 193: Report the actual p–values– Line 451: Provide more details on the nature of click stimuli including frequency.– Line 453: Clarify the dB HL used for NH decision (20 dB HL?).– Line 468: If these measurements were not used in this study, it is not clear to this reviewer why they are reported. Please clarify.– Line 479–481: please add inter–rater reliability to provide evidence on the acceptable agreement between raters.– Line 503–504: please report how many images were excluded in this process if any.– Line 511: Does {plus minus}0.010 refer to standard deviation? If so, please indicate that in the paper.– Table 1 and 2 in appendices: round correlation coefficients to two decimal places. More than two decimal places seem redundant.Reviewer #3 (Recommendations for the authors):Recommendations:1. Enhance the reliability and replicability of research findings by increasing the sample size for both SNHL and NH children. The current sample size is insufficient for between-group comparisons and correlational analyses, particularly when examining sub-groups of SNHL children with only 6 or 7 subjects per group.2. Incorporate post-surgical behavioral outcome measures into the analysis to assess the value of pre-surgical neuroimaging and neural analyses. This will help elucidate the relationship between pre-surgical neuroimaging and post-surgical behavioral benefits, informing clinical decision-making.3. Reevaluate data analyses for potential double dipping issues, specifically in lines 153-155 and Figure 3 C&D. The impaired pixels identified by comparing SNHL and NH groups are re-analyzed for the same comparison, potentially inflating effect size by only examining the ROI/pixels derived from the same comparison.4. To better understand age effects, conduct the analyses presented in Figure 4 for NH children, which will serve as a baseline to demonstrate how different types of SNHL modulate the development of auditory and language pathways in comparison to normal development.5. Ensure that modulation effects displayed in Figure 4 are controlled for confounding variables, such as residual hearing, sex, gestational weeks, birth weight, etc. to improve the validity of the results. Essential revisions:1) Behavioral data on the speech and language abilities of the children are available and should be reported.Thank you for the insightful comment. We agree that the inclusion of post-implantation behavioral data on speech and language abilities is crucial to further support the value of our findings. We have now incorporated this data into our analysis, which can be found in the ‘Results’ section (see Page 15-17) and ‘Discussion’ section (see Page 23-25). Our analysis shows a promising correlation between the pre-operative MRI metrics and post-implant speech and language outcomes, suggesting the potential of these imaging markers in predicting outcomes.2) The clinical evaluation and presentation of the children, both genetically and auditorily, is inadequate. Please provide any further details that would be useful for interpreting the other results.Thank you for your comment. We agree that a more comprehensive clinical and genetic characterization of the children could add valuable context to our study. Accordingly, we have included more comprehensive clinical data, available genetic testing results, and auditory evaluation results for all children in the revised manuscript. Please see Supplementary file 1 and Supplementary file 2 for these updates. For more detailed information, especially about the genetic characterization and limitations of our study, please refer to our response to Reviewer 1's Comment 1 below.3) The distinction between the groups isn't adequately considered. Please provide further details.Thank you for your comment. We acknowledge the significance of clearly defining and justifying our choice of groups, particularly emphasizing Inner Ear Malformation (IEM) and Cochlear Nerve Deficiency (CND) to enhance the contextual understanding of our research. We have carefully reviewed reviewer 2's comment 1 and incorporated it into our revision process. We have added a comprehensive discussion on the significance of focusing on IEM&CND, the challenges it poses in clinical management, and the complexities associated with its etiology in the ‘Introduction’ section . These additions aim to provide a clearer understanding of the differentiation between the groups under study.4) The practical relevance of the auditory-language pathways is unclear. Aside from behavioral data , a broader consideration of the studied pathways in the overall processing of hearing and language by the brain is needed.Thank you for your feedback. We have expanded our discussion to encompass a broader consideration of the auditory and language pathways in speech processing. This includes an exploration of both hierarchical and parallel theories of acoustic-phonological mapping involving HG and STG, as well as the dynamic interactions between STG and higher-order brain regions during speech perception. We have also addressed the implications of our findings within this context . For more details, please refer to our response to Reviewer 2's Comment 2 below.5) Add discussion of the possibility that the quantitative difference between effects on central auditory and language structures is due to the different ability to image each pathway.Thank you for your valuable comment. We agree that the inherent challenges in imaging each pathway might indeed contribute to the observed differences in their structural effects. To address this concern, we have added an in-depth discussion on this point in the sections where we discuss the respective results of the auditory and language pathways . Specifically, we have included considerations on factors such as the severe distortion in diffusion images of the auditory pathway, particularly within the brainstem, the complex fiber crossing issue that is more pronounced within the auditory pathway, and the inherent differences in fiber numbers between the auditory and language pathways.“Indeed, the quantitative differences observed between the effects on the central auditory and language structures may be influenced by the varying ability to accurately image each pathway with current neuroimaging technologies. The central auditory pathway, largely situated in the brainstem, faces severe distortion in diffusion images due to the inherent properties of the echo-planar imaging (EPI) sequence used. Despite distortion correction methods, it is challenging to entirely eliminate these effects. In contrast, the language pathways, primarily located in the cerebrum, have less distortion, allowing for more accurate imaging. Additionally, the auditory pathways in the brain  intersect with numerous cerebral fibre tracts, complicating accurate tractography. While the Constrained Spherical Deconvolution (CSD) modelling approach we employed is currently the most advanced method for addressing crossing fibres, it is not entirely exempt from these issues. The language pathways, on the other hand, intersect with fewer fibre tracts, facilitating more precise reconstruction. Lastly, the language pathways are more extensive and possess more fibres than the auditory pathways. From a statistical perspective, this enables more "sampling" when extracting average metrics such as fibre density, resulting in more stable outcomes. Therefore, the differences in our ability to visualize and quantify these pathways might have influenced the comparative effects observed. As neuroimaging technologies and methodologies continue to advance, we anticipate that our understanding of the differential effects of hearing loss on the central auditory and language structures will continue to evolve and improve.”Additionally, we have included a summary of this discussion in the 'Limitations' section of our paper  to underscore its potential impact on our results. We hope that these additions sufficiently address your comment.Reviewer #1 (Recommendations for the authors):Overall, the authors have done a beautiful job creating high-resolution maps of the auditory pathway in these children. This type of imaging is not my speciality and so I cannot comment on the methodology or analysis behind the imaging. However, I am an expert on pediatric hearing loss and so I evaluated this manuscript from that perspective.Detailed recommendations are below:1) There are some major deficiencies with respect to the clinical evaluation/presentation of the children in this study which makes interpretation of the results difficult. First of all, there is no diagnosis provided. The causes of pediatric hearing loss is extraordinarily complex with hundreds of genetic forms and environmental causes as well. Hearing loss is not a diagnosis but is instead a symptom of an underlying pathologic change to the peripheral and/or central auditory system. The authors do not provide a diagnosis for the 13 children with hearing loss and as such any conclusions are limited. For example, if some of the children have GJB2 hearing loss, I would expect differences compared to children with CDH23 hearing loss . Similarly, variants in CHD7, are associated with CHARGE syndrome and are a common cause of cochlear nerve deficiency, with some presumed central effect. The authors should provide more clinical history on individual patients, including hearing testing, and should at the least have performed genetic testing for a full evaluation of hearing loss. Ideally, the authors would then separate their subjects into groups . This would make their study more powerful.We appreciate the reviewer's insightful comment regarding the complex etiologies of pediatric hearing loss, and the importance of understanding the specific diagnoses, including potential genetic causes, to fully interpret our results. We agree that the genetic basis of hearing loss could potentially influence the outcomes we have studied, and that this is a limitation of our current study. As stated in our response to the Essential Revision, we have now included more detailed clinical, auditory, and available genetic data for all patients in our study.To further elucidate our study participants' audiological profiles, we have included a detailed table in the supplements. This comprehensive table delineates each patient's audiological history and current status, including newborn hearing screening results, initial diagnosis parameters, intervention details, and recent preoperative audiometric evaluations. We believe this enriched data set will provide valuable context for interpreting our study's results (see Supplementary file 1).Notably, all children included in our study have been clinically characterized as having non-syndromic hearing loss (see Supplementary file 2). Comprehensive family histories have been obtained, with no reported congenital hearing loss or known genetic disorders within their immediate families. In addition, full-body examinations have been performed to exclude any syndromic forms of hearing loss. Therefore, while we appreciate the importance of genetic factors as pointed out by the reviewer, it is important to note that our cohort is composed of children clinically diagnosed with non-syndromic hearing loss. To enhance clarity, we have included this information in the first paragraph of the ‘Introduction’ .“The etiology of these impairments is multifaceted, with genetic factors playing a significant role, alongside external contributors such as congenital infections . Hearing loss is categorized as syndromic, with accompanying physical or laboratory findings, or non-syndromic, where hearing loss is the sole symptom and has a highly heterogeneous genetic basis . This article primarily focuses on non-syndromic sensorineural hearing loss.”We have added the available genetic testing results for half of our patients  and have included a discussion on the possible implications of these results for our study's findings . However, it is not feasible for us to recall the remaining patients for this testing due to practical constraints. We acknowledge in the manuscript that the absence of genetic testing results for all patients limits our ability to draw definitive conclusions regarding the impact of specific genetic variants on our findings . “Our findings revealed a stronger and more significant correlation between language pathway fibre metrics and peripheral nerve tissue density than with central auditory metrics. This might seem counterintuitive given the structural and functional connections between the central auditory pathway and the peripheral cochlear nerve. For patients with profound SNHL, who present normal cochlear nerves and inner ear structures, the primary pathology is often located at the cellular level within the cochlea. However, in non-syndromic profound SNHL patients exhibiting IEM&CND, more severe genetic abnormalities are typically suspected. In our study cohort, genetic testing results were acquired for seven participants, revealing mutations in GJB2 (two patients), OTOF (one patient), and MYO15A (one patient). These mutations are largely associated with peripheral auditory deficits, given these genes' critical roles in inner ear development and function . Consequently, we hypothesized that observed central auditory pathway alterations could be adaptive changes due to these peripheral deficits. Nevertheless, it remains uncertain whether the detected central auditory anomalies stem from genetic factors directly or whether they are the result of underdevelopment due to auditory deprivation following peripheral dysfunction. Our findings suggest a weak association between profound hearing loss-related impaired fixels in the central auditory pathway and cn.VIII tissue density, casting doubt on the former hypothesis. It is important to consider, however, the potential of certain gene mutations such as CDH23 or CHD7 – typically linked with syndromic forms of hearing loss – to directly affect central auditory pathways . Although our study primarily included non-syndromic hearing loss patients, these potential genetic influences highlight the complexities inherent in interpreting auditory function and call for further in-depth investigation.” “We also acknowledge some limitations to this study: (1) The genetic dataset in our study is incomplete and heterogeneous. While two patients underwent extensive testing of over 200 genes, five were tested for select common genes. For a thorough understanding of the genetic factors in auditory deficits, future studies should employ uniform and comprehensive genetic testing across participants;”Subsequent adjustments to the methodological and Results sections have been made accordingly, which can be found in Page 28, Line 701-705 (Methods) and Page 5, Line 117-119 (Results).We hope that these additions address the reviewer's concerns, and we thank them for prompting us to more thoroughly discuss these important issues.2) This study does not include cochlear implant and/or auditory brainstem implant outcomes. Therefore, the authors cannot have any claims to determining or predicting outcomes with these devices until their correlate this finding with those results. This would be an excellent follow-up study and the authors should temper their statements on clinical applicability until this is completed.We appreciate your suggestion to include post-implantation outcomes to strengthen our findings and their clinical applicability. As addressed in our response to the essential revisions, we have now incorporated these outcomes into our analysis (see Page 15-17). Additionally, we have introduced a section titled “Integrating pre-surgical evaluations for optimized auditory-language rehabilitation” in the ‘Discussion’ to elaborate on the implications and limitations of these results (see Page 23-25). This inclusion lends more substantiation to our assertions regarding the predictive value of the pre-operative MRI metrics for CI/ABI outcomes.3) I assume that the CIs and ABIs were implanted after imaging? This is not specified anywhere that I could find.Yes, both CT and MRI scans were conducted preoperatively during the evaluation phase for CI or ABI implantation. To enhance clarity, we have now restructured our 'Methods' section into five major subsections, namely: 'Study sample,' 'Pre-operative clinical and imaging evaluation', 'Post-operative outcomes assessment,' 'MRI data analysis,' and 'Statistical analysis.' The 'Clinical data' and 'CT, MRI acquisition, and quality assessment' aspects have been incorporated under the 'Pre-operative clinical and imaging evaluation' subsection.4) The figure legends are confusing. Please indicate whether each image is an individual patient or an average and which group each image belongs to.Thank you for your comment. We have made revisions to the legends in Figure 1 and Figure 2 to provide clearer information. We apologize for any confusion caused. If there are any other specific points that require clarification or if you have further suggestions, please let us know, and we will address them accordingly. Your feedback is greatly appreciated.5) The graphs in Figure 3 are very very difficult to read. The authors should reformat these so that there is a white background and the bars are filled (or at least not use the current color scheme).Thank you for your comment. We apologize for any difficulties in interpretation caused by the current color scheme and formatting. We have made the necessary adjustments. If you have any other specific recommendations or concerns, please let us know, and we will address them accordingly.6) The authors should be careful about how they use the word 'deaf'. 'Deaf or hard of hearing' is an appropriate way to describe individuals with hearing loss. Severe-to-profound or profound are accurate ways to describe the severity of a hearing loss. The use of the word 'deaf' to describe profound hearing loss is generally discouraged as it is not scientific and may be confused by 'Deaf'  which describes members of the Deaf community.Please see above.We appreciate this comment. The revised terms are now highlighted in green color throughout the manuscript. We consistently use 'profound hearing loss' to describe the patients in this study (hearing level over 95 dB at both sides before operation) and choose accurate descriptions when referencing the work of other authors.Reviewer #2 (Recommendations for the authors):General comments– Although the paper tried to justify why focusing on IEM and CND is important, such decision seems still arbitrary to this reviewer. More discussion on what makes these hearing loss etiologies distinct from other etiologies would help.Thank you for your valuable feedback. We understand the reviewer's concern regarding the justification for focusing on IEM&CND and the need to address it more comprehensively.Emphasizing IEM & CND is crucial because it poses increased challenges in clinical decision-making compared to cases with normal inner ear structures, particularly in determining the suitable surgical intervention.It is worth noting that the etiology of IEM&CND involves both genetic and environmental factors, similar to patients with normal inner ears. However, the genetic basis of non-syndromic IEM&CND is not extensively studied, which makes establishing clear genetic correlations challenging. Nonetheless, it is generally understood that the developmental arrest associated with IEM&CND occurs earlier compared to cases with normal inner ears.To address these concerns, we have revised the second paragraph of the ‘Introduction’ . This revised section elaborates on the challenges in clinical management posed by IEM&CND, provides an explanation for its complex etiology, and highlights the limitations of contemporary clinical imaging in diagnosing, evaluating prognosis, and guiding surgical strategies for profound SNHL patients, particularly those with IEM&CND.“Inner ear malformations and cochlear nerve deficiencies (IEM&CND), identifiable with CT and MRI, contribute to 15-39% of pediatric sensorineural hearing loss (SNHL) cases . The rest is primarily due to cellular-level abnormalities. The etiology of IEM&CND is complex and largely unknown, yet these abnormalities suggest an earlier developmental arrest compared to cases with normal inner ear structures . Addressing IEM&CND is vital as it presents specific challenges in clinical management. Cochlear implantation (CI) and auditory brainstem implantation (ABI) are currently the only solutions for profound SNHL, but the choice between CI and ABI presents a dilemma for many IEM&CND patients. CI directly stimulates the spiral ganglion cells, the first-order neurons of the auditory pathway, while ABI bypasses the cochlear nerve and stimulates the second-order auditory neurons in the cochlear nucleus when complex inner ear malformation or cochlear nerve aplasia makes CI inapplicable . Both CI and ABI are capable of providing hearing sensation and language development for children with severe-to-profound prelingual hearing loss, but postoperative outcomes vary among individuals. ABI recipients generally have poorer speech recognition performance and delayed and incomplete language development compared to CI recipients . However, the prognosis of CI may not necessarily be better than that of ABI for certain IEMs, including common cavity, cochlear hypoplasia, incomplete partition-type I, and cochlear aperture abnormalities, as the presence of sufficient cochlear fibres required for CI success is uncertain . This uncertainty is hard to address for two reasons: (1) assessing the cochlear nerve through visual inspection of MRI poses challenges, including subjective limitations, image quality, and difficulty distinguishing the cochlear nerve from the cranial nerve VIII (the cochleovestibular nerve) in cases of common cavity; and (2) the absence of the cochlear nerve structurally does not always indicate a lack of functional hearing . Furthermore, distinguishing certain types of IEMs can be problematic and may impact surgical decision-making. For example, differentiating cochlear aplasia with a dilated vestibule (CADV) from a common cavity is challenging; CADV is a definitive indication for ABI, while a common cavity allows for either CI or ABI. These observations underscore the importance of a deep dive into IEM&CND, and highlight the limitations of contemporary clinical imaging in diagnosis, prognosis evaluation, and surgical guidance.”Additionally, the penultimate paragraph of the introduction reinforces the inclusion of IEM&CND in our study .“Furthermore, previous neuroimaging studies of profound congenital SNHL excluded children with IEM&CND. However, as mentioned earlier, these subjects comprise a significant proportion of patients with congenital hearing loss, and are more inclined to be faced with difficult surgical decisions and unsatisfactory post-implantation outcomes. Therefore, it is important to include and focus on children with IEM&CND when studying central adaptations associated with profound hearing loss.”We hope that these modifications effectively justify the significance of focusing on IEM&CND and adequately address the concerns raised by the reviewer.– The paper does not discuss how these results help with a better understanding of speech sound encoding and decoding in listeners with normal and impaired hearing. It is particularly important to discuss these findings in the context of mapping sound patterns to phonological units.– Also, there is a rich literature on hearing, language comprehension, and speech perception network from Gregory Hickok, David Poeppel, and Jonathan Peelle which are not discussed in this paper.We appreciate your feedback regarding the need to contextualize our findings in the understanding of speech processing in listeners with normal and impaired hearing.We opted to employ Angela D. Friederici's language model, given its explicit elucidation of the neuroanatomical fiber bundles associated with specific language functions. This aspect is particularly aligned with our study's emphasis on white matter structure. While Hickok and Poeppel's dual-stream model offers valuable insights, it does not directly associate the processing streams with specific neuroanatomical fiber bundles. However, it is noteworthy that there are considerable similarities between the two models, as both recognize the role of ventral streams in semantic processing and dorsal streams in sensorimotor integration. Additionally, Friederici's model includes a dorsal stream dedicated to syntactic processing. Our reason for basing our language pathway tracking on Friederici's model has been added in the Discussion section .Further, we have expanded our discussion to elaborate on how our findings contribute to a better understanding of speech processing. We have included a discussion on both the hierarchical and parallel theories of acoustic-phonological mapping in HG and STG. Additionally, we have highlighted the significance of the dynamic interplay between STG and higher-level brain areas in speech perception, particularly under challenging conditions such as the use of auditory implants. We have discussed the implications of our findings in relation to these aspects. Please refer to Page 23-24, Line 584-619 for the revised content.Title– The title needs to be more specific to the questions of this study. Using the general term "Peripheral Auditory Structure" could be misleading. Please revise to reflect both the specific types of hearing loss in this study and also the population that is children with profound hearing loss, but receive CI or ABI as interventions.Thank you for your feedback. We agree that the term "Peripheral Auditory Structure" may not accurately convey the focus of our study. As a result, we have revised the title to "Impact of Inner Ear Malformations and Cochlear Nerve Deficiencies on the Development of Auditory-Language Network in Children with Profound Sensorineural Hearing Loss" to address this concern.Regarding the decision not to include "receive CI or ABI" in the title, our intention was to avoid any potential ambiguity that could lead readers to assume that our study primarily focuses on post-implantation developmental changes in the auditory-language network. However, what we analyzed are the pre-implant MRI structures. We sincerely appreciate your valuable feedback, and we have taken your comments into account to enhance the clarity and accuracy of our study.Additionally, we have updated the title of the fifth subsection in 'Results,' changing it from 'Peripheral auditory structure moderated the structural development of central pathways' to 'Peripheral nerve structure…' for enhanced clarity .Abstract:– Cochlear implantation and auditory brainstem implantation can provide hearing sensation… it is more accurate to say … provide "partial" hearing sensation …We agree with this comment and have added the word “partial”.– "Previous attempts to locate subcortical auditory nuclei using fMRI responses to sounds are not applicable to deaf patients." Please add a reason(s) for why these previous attempts are not applicable.We appreciate this comment and have added the reason as follows.“Previous attempts to locate subcortical auditory nuclei using fMRI responses to sounds are not applicable to patients with profound hearing loss as no auditory brainstem responses can be detected in these individuals, making it impossible to capture corresponding blood oxygen signals in fMRI.”– Line 3: lifelong "negative" consequences …We agree with this comment and have added the word “negative”.– Line 39: please check the in-text citations formateLife. In regard to the two references published in 2019 with different authors named "Wang," we used their initials to differentiate them. However, we have now updated the references to use the first and second authors for proper distinction . If you have any specific requirements or further recommendations regarding this scenario, please let us know.Thank you for your comment. We have followed the APA style, as suggested by “” >> “”– Line 52: "Secondly, although earlier studies reported several altered fibre tracts related to language function, …" Please add references to support this statement.Thank you for your comment. To address any potential misunderstanding, we have included the references again in Line 72-73, even though they were previously mentioned in the paragraph from Line 54-59.– Line 83: mean [SD], age, 30.92 [6.115] months; 9 males, 4 females– Mean [SD] of age– You can remove 4 females as it is redundant– Please consider the same edit for NH– Line 85: Please indicate the confidence interval in your stats reportWe agree with these two comments and have revised them in Page 5, Line 105-110.“Twenty-three children aged under six years old including thirteen patients with bilateral profound congenital sensorineural hearing loss  and ten normal hearing volunteers  matched on age and gender were included .”Table 1– I recommend using the term gender instead of sexWe appreciate this comment and have revised “sex” to “gender” through the manuscript.Line 137– FC, FD, and FDC are presented here for the first time in the manuscript. So, their extended version should be used here to avoid possible confusion.We agree with this comment and have provided the extended version in Page 10, Line 167-168.“In the central auditory pathway, FBA results demonstrated reduced fibre density (FD), fibre cross-section (FC), and fibre density and cross-section (FDC) in TB and decreased FC in LL in patients with profound SNHL.”Caption of Figure 3: please report the actual p-valuesThank you. We have revised it in Figure 3 as well as in Figure 4.– Line 139: ie. -->◊ i.e.Thank you. We have corrected this .Figure 3– I wonder how the data and results would look if ABI and CI groups were represented separately.Thank you for your comment. We recognize the merit in examining the differences between the ABI and CI groups in Figure 3. Although the primary objective of Figure 3 was to compare the hearing-impaired patients as a collective group against the normal control group, we have addressed your request by incorporating an additional figure , which compares the ABI, CI, and NH groups. Initially, we employed a one-way ANOVA to assess FD, FC, and FDC at the fixel-level with FWE correction, but no significant fixels were observed, possibly due to the small sample size. Subsequently, tract-level measures were used to illustrate the trend of differences among these three groups in Figure 3—figure supplement 1. We did not perform an ANOVA or post hoc tests at the tract-level to avoid the double dipping issue, especially since the fixel-level ANOVA did not yield significant results.– Line 167-168: please elaborate on why such surgical decisions have limited value.Thank you for the comment. We have elaborated on the challenges faced in making surgical decisions for patients with IEM&CND in a new paragraph in the ‘Introduction’ section, where we discuss the limitations of relying solely on visual inspection through CT and MRI (please refer to our response to your first comment). In light of this addition, we have decided to remove this sentence in the ‘Results’ section as the issue is now addressed in the ‘Introduction’.– Line 193: Report the actual p–valuesThank you. We have reported the actual p-values through the section ‘Peripheral nerve structure moderated the structural development of central pathways’ to improve clarity (Page 12).– Line 451: Provide more details on the nature of click stimuli including frequency.Thank you for pointing out this omission. We used standard brief acoustic signals, also known as "clicks," for our study. These click stimuli have a duration of 100 microseconds and cover a broad frequency range from 100 Hz to 10,000 Hz. We have included these details in the ‘Methods’ section in Page 28, Line 695-698.– Line 453: Clarify the dB HL used for NH decision (20 dB HL?).Yes, we have added the standard .“The controls had normal hearing in both ears (click ABR threshold/PTA < 20 dB HL).”– Line 468: If these measurements were not used in this study, it is not clear to this reviewer why they are reported. Please clarify.Thank you for your observation. We acknowledge the lack of clarity in our initial manuscript. As indicated in our responses to the essential revisions and Reviewer 1's comment, we have now included post-implant behavioral outcome measures into our analysis (see Page 15-17 and Page 23-25). This update serves to validate the utility of our pre-operative MRI metrics for predicting post-implant behavioral outcomes.– Line 479–481: please add inter–rater reliability to provide evidence on the acceptable agreement between raters.Thank you for your suggestion. We have added the inter-rater reliability information to the relevant section  of our manuscript to provide additional evidence for the reliability of our findings.– Line 503–504: please report how many images were excluded in this process if any.Thank you for your comment. It's important to clarify that no images were excluded during the quality control process. In one instance, an inappropriate head position was observed at the beginning of the scanning session, but it was promptly identified and corrected to ensure reliable data collection. As this issue was promptly resolved and did not impact the final dataset, it was not mentioned in the manuscript.– Line 511: Does {plus minus}0.010 refer to standard deviation? If so, please indicate that in the paper.Yes, we have clarified it .“The Cn.VIII was segmented on each axial section using ITK-SNAP  by two independent raters. The inter-rater agreement was assessed using the DICE coefficient, yielding a value of 0.977±0.010 (mean± SD).”– Table 1 and 2 in appendices: round correlation coefficients to two decimal places. More than two decimal places seem redundant.We agree with this comment and have rounded correlation coefficients to two decimal places .Reviewer #3 (Recommendations for the authors):Recommendations:1. Enhance the reliability and replicability of research findings by increasing the sample size for both SNHL and NH children. The current sample size is insufficient for between-group comparisons and correlational analyses, particularly when examining sub-groups of SNHL children with only 6 or 7 subjects per group.Thank you for your valuable comments. We wholeheartedly agree that a larger sample size can provide more robust and generalizable results. However, in the context of our current study, we are confronted with practical constraints, including the unique characteristics of our target population and limited available resources. Expanding the participant pool requires specific procedures such as patient recruitment, informed consent, data collection, and data processing. Given the scope of our current study and resources, it is challenging to significantly expand our sample size at this stage. Despite this limitation, we believe our findings are valuable, shedding light on an area with limited prior research. We have exercised rigorous statistical controls and analyses to maximize the validity and reliability of our findings within the confines of our sample size. We recognize the necessity for further research with larger, more diverse cohorts, and have acknowledged this need in the limitations section of our paper. Thank you once again for your constructive suggestions.2. Incorporate post-surgical behavioral outcome measures into the analysis to assess the value of pre-surgical neuroimaging and neural analyses. This will help elucidate the relationship between pre-surgical neuroimaging and post-surgical behavioral benefits, informing clinical decision-making.We appreciate your suggestion to incorporate post-surgical behavioral outcome measures into our analysis. As we mentioned in our responses to previous comments, we have incorporated these measures into our analysis (see Page 15-17 and Page 23-25). The correlation between pre-operative MRI metrics and post-implant behavioral outcomes further supports the potential utility of our imaging markers in informing clinical decision-making.3. Reevaluate data analyses for potential double dipping issues, specifically in lines 153-155 and Figure 3 C&D. The impaired pixels identified by comparing SNHL and NH groups are re-analyzed for the same comparison, potentially inflating effect size by only examining the ROI/pixels derived from the same comparison.Thank you for your comment. We recognize that there is indeed a risk of inflating the effect size by re-analyzing the impaired pixels identified from the same comparison.In our study, we opted for ROI-based analysis to visually demonstrate the fiber structure of each segment in the auditory pathway, as it offers a clear and intuitive representation. We used FWE correction as a statistical control to mitigate the likelihood of false positives in the ROI analysis. However, we acknowledge that FWE correction does not directly address the potential double dipping issue.We have acknowledged this limitation and included a note in the Results section of our paper . Your feedback has prompted us to provide a more explicit explanation of the limitations and considerations associated with our analysis methods. We sincerely appreciate your valuable input.“It is worth noting, however, that in our tract-of-interest analysis, there is the potential for double dipping as we re-analysed the impaired pixels identified from the same comparison, which could have impacted the reported effect size.”4. To better understand age effects, conduct the analyses presented in Figure 4 for NH children, which will serve as a baseline to demonstrate how different types of SNHL modulate the development of auditory and language pathways in comparison to normal development.Thank you for your comment and suggestion. We appreciate your suggestion about studying the relationship between peripheral nerve development and central auditory and language pathways in normal condition.However, we would like to mention that in our study, the normal hearing control group did not undergo scanning with the CISS sequence, which is necessary for measuring peripheral nerve indicators. Consequently, we currently lack the data required for a direct comparison of the development of auditory and language pathways between NH children and those with different types of sensorineural hearing loss.We have acknowledged this limitation in our study and have discussed it in the relevant section of discussion . We sincerely appreciate your feedback, and it will undoubtedly guide our future research efforts.“Another limitation is that the normal hearing control group did not undergo scanning with the CISS sequence, precluding the establishment of a baseline for comparing the development of auditory and language pathways in SNHL to normal development, which requires future research to include a baseline assessment.”5. Ensure that modulation effects displayed in Figure 4 are controlled for confounding variables, such as residual hearing, sex, gestational weeks, birth weight, etc. to improve the validity of the results.Thank you for your valuable comment. We acknowledge that these variables could potentially impact the validity of the results. We acknowledge the importance of considering residual hearing as a potential factor; however, it is worth noting that all patients in our study exhibited click ABR and/or pure tone thresholds  that were over 95 dB HL bilaterally, indicating a profound degree of hearing loss. In fact, the pure tone audiometry results showed thresholds over 95 dB HL at each frequency of 0.5k, 1k, 2k, and 4k Hz for all patients who took the exam. Given this, we did not include residual hearing as a covariate in our analysis. However, we have re-calculated the moderation analyses while controlling for other variables including gender, gestational weeks, and birth weights. The results of these analyses can be found in Figure 4-source data 2, and are described in the relevant sections under ‘Results’  and ‘Discussion’ . The moderation effect became non-significant after controlling these variables, potentially due to a relatively small sample size in comparison to the number of control variables. We appreciate your insightful suggestion, as it has urged us to interpret the results with greater caution.eLife. We are open to further suggestions and look forward to your response.We hope that the revisions and our responses adequately address the reviewers' comments and meet the standards of


Varicose veins of the lower extremities are a very common condition in vascular surgery. With advances in technology and medicine, minimally invasive endovenous thermal ablation has become the primary approach used to treat patients with moderate or severe varicose veins. Electrocoagulation for thermal ablation is a relatively simple and economical procedure, but standards vary according to location and some limitations exist. We report a case of a 58-year-old female patient with small saphenous varicose veins in the right lower extremity in which an electrocoagulation rod commonly used in laparoscopic surgery was innovatively used instead of a standard variable electrocoagulation device. The venous clinical severity score was used to assess changes in clinical symptoms before and 3 months after the procedure. The procedure was shown to have eliminated venous reflux, improved the patient's clinical symptoms, and venous function. This procedure may be a reliable option for future endovenous electrocoagulation thermal ablation procedures for varicose veins that are simple and convenient to perform. Varicose veins of the lower extremities are a common condition in vascular surgery. Successful surgical treatment of patients with moderate or severe varicose veins with swelling and ulceration of the lower extremities involves eliminating all sources of venous return. Historically, standard treatment involved high ligation and stripping of the great saphenous vein (GSV). However, many surgeons have used endovascular techniques in recent years and achieved good results . ConsequA 58-year-old woman, who had varicose veins in the right lower extremity for 9 years , was adm3 + 20 ml 0.2% lidocaine) was injected along the saphenous fascia chamber  under ultrasound guidance. An EC rod (3 mm diameter for laparoscopy) was inserted from the end of the sheath toward the heart, with a single-electrode electrocoagulation device attached to the end, and the head of the EC rod was positioned in the proximal small saphenous vein, with the beginning of the fascial compartment about 4 cm from the saphenopopliteal junction . Under u chamber . Single- chamber . Superfi chamber . At the  chamber . Oral ciIn current treatment protocols, endovenous thermal ablation is preferred for patients with saphenous varicose veins in the lower extremities who meet the indications for surgical treatment . The useEC rods are usually available in diameters of 3 mm, 5 mm, and 10 mm and can be used to stop bleeding in wounds of different diameters. The principle of EC is that when the EC head comes into contact with tissue, the change in electrical resistance generates heat energy, which then destroys the tissue and stops bleeding. Therefore, we developed the novel idea of using currently available 3-mm and 5-mm EC rods for endovenous electrothermal ablation via puncture sheaths of corresponding diameters, thus optimising therapeutic efficacy. In the present case, the patient opted not to pay for the catheter consumables required for laser or radiofrequency ablation, and after comprehensive consideration, we used a common laparoscopic EC technique for endovenous ablation, achieving the desired clinical results. EC ablation, using radiofrequency and laser ablation techniques, is contraindicated for treating certain cases of saphenous varicose veins that require surgical treatment. For example, a varicose vein with a severely dilated diameter and a thick wall is very susceptible to incomplete vessel closure after EC, and the risk of recurrence is high. The basic principles of vein stripping surgery must be strictly followed to achieve treatment efficacy, and it may be insufficient to pursue the most minimally invasive procedure alone. On the other hand, the reliability and stability of this innovative method must be further studied and observed objectively.The use of a laparoscopic EC rod as the conductive electrode of the thermal ablation electric knife in the present case may provide a reference for future improvements and developments in EC for varicose veins.


Cathepsins are a type of lysosomal globulin hydrolase and are crucial for many physiological processes, including the resorption of bone matrix, innate immunity, apoptosis, proliferation, metastasis, autophagy, and angiogenesis. Findings regarding their functions in human physiological processes and disorders have drawn extensive attention. In this review, we will focus on the relationship between cathepsins and oral diseases. We highlight the structural and functional properties of cathepsins related to oral diseases, as well as the regulatory mechanisms in tissue and cells and their therapeutic uses. Elucidating the associated mechanism between cathepsins and oral diseases is thought to be a promising strategy for the treatment of oral diseases and may be a starting point for further studies at the molecular level. Oral diseases are undoubtedly a more serious and widespread public health issue among socially marginalized and disadvantaged communities, but they have received less attention than other chronic diseases. Chronic progressive processes are frequently accompanied by pain and intense discomfort, which may impair one’s ability to work and learn and lower one’s quality of life . SimultaThe word cathepsin, which means “to digest”, initially originated from the Greek kathepsein. It was first used to refer to the idea of proteases that are found in the endosomal/lysosomal proteolytic system and are active in a mildly acidic environment . CathepsIn this review, we will select dental caries, periodontitis, oral cancer, periapical lesions, and oral lichen planus among the common oral diseases to illustrate the relationship between cathepsins and oral diseases. Starting with the pathophysiology, we’ll go over cathepsins’ structure-function characteristics and regulatory processes in tissue and cells before moving on to potential future therapeutic strategies. By outlining the connection between cathepsins and the development of oral diseases, it is believed that we can more effectively look for treatments, lessening the burden and suffering which oral diseases place on patients.2Cathepsins in the human body are divided into three categories: cysteine proteases, serine proteases, and aspartic proteases. The cathepsins B, C, F, H, K, L, O, S, V, X, and W are the eleven cysteine proteases. Two serine proteases include cathepsins A and G while aspartic proteases contain cathepsins E and D Table 1 33.1Dental caries is the most common oral disease in the world, characterized by demineralization of tooth hard tissue and an imbalance in the equilibrium between tooth minerals and biofilms. Microbial, behavioral, genetic, and environmental factors may all have some bearing on the occurrence and progression of caries, which is defined as a multifactorial disease , 57. TheThe mineral  and organic matrix make up about 70% and 20% of the dentin respectively, and the rest of the dentin is water. Collagen makes up the majority of the organic matrix in dentin (around 90% type I collagen and 10% noncollagenous proteins) . The orgAlong with MMPs, cysteine cathepsin also plays a significant role in the etiology of dental caries. Cathepsins are involved in the degradation process of collagen: Cathepsin B and L can cleave in the non-helical telopeptide extensions of collagens , while c3.2+ in silver diamine fluoride (SDF), which may prevent the advancement of caries by either blocking the active site of collagen to protect it from enzymatic attack or by inactivating enzyme-mediated collagen degradation  had a high binding capacity to dental enamel and is highly inhibitory to cathepsin B, K, and L, implicating the ability of this protein to prevent tooth decay by modifying AEP, an acellular film that functions as a diffusion barrier or selective permeation membrane formed on the tooth surface by selective adsorption of salivary proteins and glycoproteins. The new cystatin forms a strong bond with the dental enamel, consequently shielding it from acid erosion . Accordiradation . Besidesradation . An incrradation . It is rradation . In addiradation .44.1P. gingivalis (LPS), peptidoglycan, protease, lipoteichoic acid, and toxins. After being released by bacteria, these virulence factors can be recognized by Toll-like receptors (TLRs) on the surface of host cells, which in turn trigger host cell signaling, activate the host immune system, produce inflammatory mediators such as cytokines and proteolytic enzymes, and induce tissue destruction and bone resorption  family, are essential pattern recognition receptors in the innate immune response and are composed of a leucine-rich repeat (LRR) domain that recognizes ligands, a transmembrane domain, and a Toll/interleukin-1 receptor (TIR) , 81. As via the TLR9 signaling pathway. TLR9 activation attracts a particular class of adaptors, particularly those dependent on the MyD88 pathway. Nuclear factor-κB kinase (IKK) complex inhibition by TLR9 signaling pathways results in activation of the transcription factor NF-κB and NF-κB signaling cascade. When NF-κB is activated, cytokines are produced, which stimulates the inflammatory response , a direct inducer of osteoclasts. IL-6 could mediate helper T cell 17 (Th17) induction to boost the synthesis of IL-17, which is also an important inducer of RANKL . The synin vitro . Therefoin vitro detection of cathepsin K RNA expression in RAW264.7 macrophages , chemokines CXCl2, and bone resorption. Besides, the mRNA and protein levels of cathepsin C were significantly increased in acute periapical periodontitis. In addition, macrophages, mast cells, plasma cells, and other inflammatory cells all have high levels of cathepsin C expression in their cytoplasms. Furthermore, the expression of RANKL and the volume of periapical absorption changed more drastically when cathepsin C was activated Figure 66.2in vivo, which could in turn inhibit osteoclast function thus significantly reducing pulp disease development, bone destruction, and the severity of inflammatory pulp disease in periapical lesions  is characterized by the accumulation of inflammatory cells in the lamina propria and the degeneration of the epithelial basal cell layer. Although the exact cause of OLP is unknown, some evidence suggests that antigen-triggered T cells play a role in the disease’s immunological process . Both spSiponen M reported that the expression of cathepsin K in OLP was significantly higher than that in normal oral mucosa, indicating that this enzyme may play a role in the pathogenesis of OLP. The cathepsin K-positive cells were found in the superficial lamina propria and the lower epithelia, which may be the most active sites in the pathogenesis of OLP. Additionally, melanocytes in OLP express cathepsin K, which might be a sign of a connected inflammatory condition. Besides, cathepsin K may be involved in the up-regulation of cytokine activity by DC. Interestingly, cathepsin K could coexist with TLR4 and TLR9 in some oral mucosal cells, which reveals that the TLR pathway and cathepsin K may interact in oral lichen planus. Moreover, hyaluronic acid and cathepsin K may involve in the pathological process of OLP, however, further research is needed in this area. Type 1 collagen and other extracellular matrix (ECM) proteins have altered expression in OLP, as well. But whether cathepsin K is involved in the degradation of extracellular collagen and elastin degradation in oral lichen planus remains unclear. Based on the present study, it cannot be confirmed that cathepsin K is active and functional in OLP, in that case, further investigation is required .Georgakopoulou E A et al. suggested that OLP is a tumor-like matrix microenvironment, which is associated with hypoxia, inflammation-related cytokines, transcription factor signals, and decreased blood vessels. The tumor-like microenvironment is also dominated by the protease represented by cathepsin B. Epithelial cells may adopt a state of cell stasis and increase sensitivity to cellular injury as a result of cathepsin B. Additionally, cathepsin B could facilitate cell migration, break down the epithelial integrity, and digest the extracellular matrix . In line7.2According to the above, the pathogenesis of OLP is yet unknown. We hypothesize that the regulation of cathepsin K and B may be beneficial in the treatment of lichen planus, while further research is still needed to determine the exact therapy strategy.8In this review, we explored the relationship between cathepsins and the pathogenesis of dental caries, periodontitis, oral cancer, periapical lesions, and oral lichen planus respectively. Cathepsins are affirmed to be promising as a potential therapeutic target for oral diseases. The specific pathways linking cathepsins to oral diseases, however, has not yet been entirely analyzed, thus further research in this area is required. When it comes to treating oral disorders, cathepsins are still at the hypothetical stage. It is envisaged that in the future, this type of treatment will be made possible in order to avert and lessen the occurrence of oral diseases.XL conceptualized, led and funded the project. HJ, XX and ZD conceived the structure of the article and wrote the manuscript. All authors contributed to the article and approved the submitted version.