JARO Research News

spARO volunteers are submitting Research News highlights about recent articles published in JARO, our society's journal. If you are interested in joining this effort, please contact the Publication's Committee representative from spARO (Mary O’Sullivan, mary29(at)stanford.edu). Members can find guidelines for submitting a JARO Research News report here.

March 2010          Predicting success of a cochlear implant

January 2020        Keeping neurons alive in the deaf ear
December 2019     Protecting the cochlea from noise damage
November 2019     Animal model of early-onset hearing loss
October 2019        Cochlear implants and nerve health
August 2019          Animal model for vestibular disorders
June 2019             Cochlear implants and music appreciation


March 2020

Pre-operative Brain Imaging Using Functional Near-Infrared Spectroscopy Helps Predict Cochlear Implant Outcome in Deaf Adults

Carly A. Anderson, Ian M. Wiggins, Padraig T. Kitterick, and Douglas E. H. Hartley

Anderson, C.A., Wiggins, I.M., Kitterick, P.T., & Hartley, D.E. JARO (2019) 20: 511- 528 doi.org/10.1007/s10162-019-00729-z

Reported by:  Jacquelyn DeVries, B.S. & Christine Boone, M.D., Ph.D., University of California, San Diego School of Medicine 

Cochlear implant (CI) offers the hope of hearing restoration to deaf patients, but outcomes of the procedure are highly variable, and difficult to predict. This report shows that brain activity during a speechreading task may serve as a biomarker that is predictive of cochlear implant success.  

Currently, the best practice for prognostication is to consider hearing loss age-at-onset, duration of auditory deprivation, residual hearing, and hearing-aid use. However, these indicators account for only 22% of variability in CI outcome1. This study revealed superior temporal cortex activation (STC) as a promising potential biomarker to facilitate prediction of future speech comprehension in CI users. Deaf patients may experience cortical reorganization of sensory and speech processing associated with differences in speech comprehension. Deafness-induced cross-modal plasticity has been observed bilaterally within the posterior superior temporal cortex (bSTC), which is activated by auditory input in normal hearing individuals.  Heightened visual speechreading skills have been associated with enhanced bSTC activation and faster neural processing of speech2.

In this study, speechreading ability and cortical activation were measured in 17 adults with bilateral profound deafness (CI group) preoperatively and 17 normal hearing (NH) adults. Six months after CI implantation, auditory speech recognition was tested. Functional near-infrared spectroscopy (fNIRS), a neuroimaging modality based on hemodynamic responses, was used to assess neural activity. Preoperative bSTC activation in response to visual speech stimuli did not differ between CI and NH groups (Figure A). In the CI group, however, pre-implantation speechreading ability was positively associated with visual speech-related activation of bSTC and left STC. Cortical reorganization in this region may be associated with superior speechreading abilities observed in deaf individuals.

Figure A. (Image at Right) Map of pre-implant cortical activation for visual speech. As a group, the level of cross-modal activation was not significantly enhanced in deaf participants compared to normal hearing control participants.

Pre-implantation bSTC activation to visual speech was predictive of worse auditory speech recognition 6 months after implantation (Figure B). This negative relationship was driven by pre- and peri-lingually deaf patients, but not post-lingually deaf patients. Regression analysis revealed bSTC activation from fNIRS data added significant incremental predictive value, independent of age-at-onset of deafness, duration of deafness, and speechreading ability covariates. Greater bSTC activation to visual speech before CI was not associated with reduced bSTC activation in response to auditory speech at 6 months after CI, suggesting that cross-modal activation and cortical reorganization in deafness did not hinder subsequent recruitment of activity in this region with auditory speech after CI.

Figure B.  (Image at Left). CI outcome at 6 months postoperatively is predicted by pre-implant cross-modal STC activation. Open markers represent data obtained from pre- and peri-lingually deaf CI users.

 Overall, this paper is a promising development towards a tool to help inform patients’ expectations and assist with decision-making in considering CI treatment. Further investigation could help determine the clinic utility of this potential biomarker and the nature of its relationship with pre- and post-lingual deafness.

 

1.    Lazard DS, Vincent C, Venail F, et al. Pre-, per- and postoperative factors affecting performance of postlinguistically deaf adults using cochlear implants: a new conceptual model over time. PLoS One. 2012;7(11):e48739.
2.    Suh MW, Lee HJ, Kim JS, Chung CK, Oh SH. Speech experience shapes the speechreading network and subsequent deafness facilitates it. Brain. 2009;132(Pt 10):2761-2771.


 

January 2020

AAV-Mediated Neurotrophin Gene Therapy Promotes Improved Survival of Cochlear Spiral Ganglion Neurons in Neonatally Deafened Cats: Comparison of AAV2-hBDNF and AAV5-hGDNF

Patricia A. Leake, Stephen J. Rebscher, Chantale Dore‘ & Omar Akil

Leake PA, Rebscher SJ, Dore', Akil O. JARO (2019) volume 20: 341. DOI: 10.1007/s10162-019-00723-5

Reported by: Sumana Ghosh, Ph.D., University of Mississippi Medical Center, Department of Neurobiology and Anatomical Sciences

Cochlear implant (CI) technology has revolutionized the treatment of sensorineural hearing loss (SNHL), but it depends on the health and survival of spiral ganglion neurons (SGNs) to ensure a maximal benefit for speech and language perception. To address this need, a new study by Leake and collaborators has focused on virus-based delivery of growth factors directly into the deafened cochlea in an animal model.

Various neurotrophic factors (NFs) including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and glial cell-line derived neurotrophic factor (GDNF) are known to regulate the survival and maturation of neurons during development. A previous study by the same group showed that the administration of BDNF by osmotic pump accompanied by electrical stimulation improved neural survival in deafened cats, although it also induced ectopic sprouting of radial nerve fibers as a side-effect.  These aberrant trajectories can muddle the transmission of tonotopic information and, in principle, affect speech-in-noise perception. Moreover, the osmotic pump suffers as a mode of drug delivery, since it presents a pathogen infection risk to the inner ear.

In this study, the authors investigated the efficacy of adeno-associated virus (AAV) - mediated NF gene delivery approach in mitigating SGN degeneration in juvenile cats who were first deafened before hearing onset by an ototoxic antibiotic. Two different serotypes of AAV vectors containing either hGDNF (serotype 5) or hBDNF (serotype 2), provided by uniQure Biopharma, Amsterdam, the Netherlands, were injected into the cochlea unilaterally while the contralateral ear served as control. Gene transduction  efficacy was confirmed by transducing green fluorescent protein in a different group of “control” animals (Figure A).

 

Figure A. GFP immunofluorescence in the SG 4 weeks after AAV-GFP transfection in the neonatally deafened cat.

After three months, both the NFs significantly improved SGN survival. However, the two NFs varied in their effects on radial fiber behavior.  AAV5-hGDNF showed ectopic radial fiber sprouting, while AAV2-hBDNF did not. Moreover, the protective effects of hBDNF were persistent over a long period (six months after transfection) compared to the progressive degeneration of SGNs on the control side (Figure B). hBDNF augmented the survival of radial fibers by two-fold compared to the untreated contralateral ears in which  SGNs progressively degenerated. Maintenance of the auditory nerve is critical for successful outcome of both pediatric and elderly populations with auditory neuropathies. This study demonstrates that although AAV2 transfects only 5-10% of SGNs, this produces a physiological concentration of NF without undesired side effects. Importantly, the resulting neuro-protective effect can be achieved by only a single injection of virus, which is advantageous over osmotic pumps in a clinical setting.


Figure B. Staining of cochlear sections with toluidine blue and subsequent visualization by light microscopy demonstrated improved survival of the neural cells and the radial fibers (indicated by black arrow) in AAV2-hBDNF transfected ear (a) compared the contralateral ear (b) 26weeks post-injection.


December 2019

Inhibition of Histone Methyltransferase G9a Attenuates Noise-Induced Cochlear Synaptopathy And Hearing Loss

Hao Xiong, Haishan Long, Song Pan, Ruosha Lai, Xianren Wang, Yuanping Zhu, Kayla Hill, Qiaojun Fang, Yiqing Zheng and Su-Hua Sha

Xiong, H., Long, H., Pan, S., Lai, R., Wang, X., Zhu, Y., Hill, K., Fang, Q., Zheng, Y., Sha,SH.  JARO (2019) 20: 217–232 DOI: 10.1007/s10162-019-00714-6

Reported by: Niliksha Gunewardene, Ph.D., Bionics Institute, Australia

Noise-induced hearing loss is one of the most common forms of sensorineural hearing loss in humans, and it has been on the rise for the last decade. This new study manipulates a biochemical pathway in noise-exposed mice that appears to protect the inner ear from some of this damage.

In the recent publication, Xiong et al. propose a novel epigenetic mechanism for noise-induced hearing loss in mice. Epigenetic changes contribute to chromatin structural changes, whereby open versus closed chromatin states are associated with gene activation and repression, respectively. This study reports a role for the epigenetic enzyme G9a in mediating susceptibility of cochlear hair cells to noise damage. G9a is a histone lysine methyltransferase enzyme, that specifically methylates histone 3 of lysine 9 (H3K9me2), causing gene silencing.

Here, the authors utilise a published moderate noise damage model in mice that causes permanent auditory threshold shifts, loss of ribbon synapses and outer hair cell loss particularly in the basal (high-frequency) region1. This manipulation activates G9a, causing an increase in H3K9me2 in cochlear cells, as evidenced by immunolabelling.

Notably, treatment of mice prior to noise exposure using inhibitors of G9a (either a pharmaceutical or a small-interfering RNA) resulted in significant attenuation of noise-induced threshold shifts and protection of the outer hair cells and ribbon synapses, particularly in the basal regions (Figure A). To explore one mechanism underlying the protective effect of G9a, the authors focused on potassium voltage-gated channel subfamily Q member 4 (KCNQ4), expressed in sensory hair cells. They show that G9a inhibition in noise-damaged cochleae maintains the levels of KCNQ4 (which would otherwise be downregulated) and reduces the susceptibility of outer hair cells to noise-induced damage.

 

Figure A: Inhibition of G9a prevents loss of synapses in the basal turn of the cochlea. Differences in the number of synaptic puncta (Ctpb2+) between normal (top), noise-exposed (middle), and noise-exposed treated with a pharmacological inhibitor of G9a (bottom).  Scale bar = 10 μm. From Xiong et al., (2019).

Treatments to protect or reverse hearing loss will benefit from a better understanding of the molecular mechanisms underlying cochlear damage. This study has effectively identified a potential mechanism that can be manipulated to protect cochlear hair cells and synapses from noise damage in mice. While it will be interesting to determine if G9a inhibition has an effect post-noise exposure, these findings indicate a role for epigenetic modifications in altering the susceptibility of cochlear cells to noise-induced damage.

 

1.    Hill, K., Yuan, H., Wang, X., and Sha, S.H. (2016). Noise-Induced Loss of Hair Cells and Cochlear Synaptopathy Are Mediated by the Activation of AMPK. J Neurosci 36, 7497-7510.

 


November 2019

Early Hearing Loss upon Disruption of Slc4a10 in C57BL/6 Mice

Antje K. Huebner, Hannes Maier, Alena Maul, Sandor Nietzsche, Tanja Herrmann,
Jeppe Praetorius, and Christian A. Hübner

Huebner, A.K., Maler, H., Maul, A., Nietzsche, S., Herrmann, T., Praetorius, J., Hübner, C.A. JARO (2019) 20: 233-245. https://doi.org/10.1007/s10162-019-00719-1

Reported by: Arielle Hogan, B.S., University of Virginia School of Medicine, Department of Cell and Developmental Biology

Progressive hearing loss is a common symptom that comes with age. In this publication, Huebner et al. investigate a possible key component to the mechanism of degenerative hearing loss—a sodium-coupled bicarbonate transporter found in gap junctions known as Scl4a10. They show that Slc4a10 plays a major role in maintenance of auditory sensory function through its regulation of endocochlear potential and hair cell morphology in the inner ear.   

The sensory phenomenon of hearing is a complex biological function. Key to its smooth operation is maintenance of concentration gradients and their resulting current potentials in the cochlea. The endocochlear potential (EP) is the current potential generated from the differential concentrations of potassium (K+) between the endolymph and perilymph, two fluids of the cochlear canal separated by the basilar membrane. The K+ gradient and EP are maintained by the cells of the stria vascularis that are connected to fibrocytes of the spiral ligament (SL) through gap junctions.  

After verifying Slc4a10’s expression in the SL fibrocytes, experiments measuring acid extrusion efficiency were conducted to see if Slc4a10 had a conserved function of acid extrusion in the inner ear as in other cell types. The findings, however, were normal in Slc4a10 knockout (KO) mice showing that there may be redundancy with other transporters to facilitate acid extrusion in the inner ear.

Researchers then decided to test hearing ability by recording auditory-evoked brainstem responses. In Slc4a10 KO mice hearing threshold was increased and continued to increase with age providing evidence for Slc4a10’s implication in early-onset hearing loss.  

In order to determine the cause of the early-onset hearing loss in the Slc4a10 KO mice, given that acid extrusion in the mutant mice was normal, researchers decided to test for electrochemical and morphological disruptions in the cochlea. To do this, they measured the EP and stained tissue to visualize the morphology of cochlear hair cells. Heubner et al found the EP to be lowered and they found progressive loss of outer hair cells in Slc4a10 knockout mice showing that Scl4a10 plays a crucial role in maintenance of cochlear electrochemical and morphological integrity (Figure A).

Figure A: Immunofluorescent staining of hair cells of Organ of Corti show progressive degeneration of hair cells in Slc4a10 knockout mice compared to normal hair cell morphology in wild type mice

Together, these experiments showed that knockout of Slc4a10 in mice results in early-onset hearing loss due to a lowered EP and progressive loss of outer hair cells. These findings are significant because they elucidate another potential therapeutic target for regulation of EP and hair cell morphogenesis in deafness related diseases.


October 2019

Evaluating Psychophysical Polarity Sensitivity as an Indirect
Estimate of Neural Status in Cochlear Implant Listeners

Kelly N. Jahn, and Julie G. Arenberg

Jahn, K.N. & Arenberg, J.G. JARO (2019) 20: 415-430. https://doi.org/10.1007/s10162-019-00718-2

Reported by: Agudemu Borjigin, M.E., Purdue University, Department of Biomedical Engineering

This paper has important implications for evaluating the functional status of spiral ganglion neurons in cochlear implant (CI) listeners. Measuring and monitoring neural health in CI listeners is crucial not only for optimizing hearing status shortly after implantation, but also for evaluating the implant over time.  While it has been difficult to assess the auditory nerve due to the lack of direct accessibility, modeling studies have suggested that differential responses to the mode of CI electrode stimulation (positive vs. negative discharge of ions) may provide a means to assess neural health.  The current study tests this prediction.

Biophysical modeling suggested that anodic stimulation, i.e. discharging positive ions into peripheral nerve, becomes more effective in poor neural health conditions, as compared to cathodic stimulation. The authors tested this so-called “polarity effect” and, more importantly, asked if this evaluation approach was independent of two factors known to be associated with electrode-neuron interface: electrode location and cochlear tissue resistance (CTR). Electrode location was estimated through composite tomography (CT) imaging for each subject (Figure A). The CTR was estimated using electrical field imaging to measure the voltage response to low-level current stimulations.

Figure A.  CT imaging reveals electrode location within the cochlea. The image from a patient CT scan (a) is mapped onto an imaging atlas (b) and eventually combined with scans from other levels to create a 3D reconstruction, where red dots represent CI electrodes (c). From:  Jahn & Arenberg, JARO 20: 415-430.

Results showed that the polarity effect was not related to electrode location or the CTR. Furthermore, the polarity effect explained a significant portion of the variations observed in a focused threshold measurement, which has been shown to reflect general cochlear status including local electrode position, the CTR, and neural integrity. Combined, the data support the hypothesis that the polarity effect can be used as an indicator of neural integrity in CI listeners, independent of electrode location and the CTR. The hypothesis was further supported by the correlation between the polarity effect and the duration of deafness, which is a common implicit assessment of neural integrity. This piece of evidence provides a way to evaluate neural contributions to the significant variations observed across CI listeners. This study has important clinical implications for individualizing CI programing for the best possible hearing outcome in patients. This study also paves a new way forward for clinical applications of new emerging research technologies, such as gene therapy for neural regeneration, where neural assessment is usually the first step.


August 2019

A New Model for Congenital Vestibular Disorders

Sigmund J. Lilian, Hayley E. Seal, Anastas Popratiloff, June C. Hirsch, and Kenna D. Peusner

Lilian, S.J., Seal, H.E., Popratiloff, A., Hirsch, J.C. & Peusner, K.D. JARO (2019) 20: 133. https://doi.org/10.1007/s10162-018-00705-z

Reported by:  Lukas D. Landegger, M.D., Ph.D. Medical University of Vienna, Department of Otorhinolaryngology-Head and Neck Surgery

 

Figure A:  Paint fills of inner ears on embryonic day 13 show differences between normal (a) and sac-like ARO chicks (b,c).  From Lilian et al., 2019, JARO 20: 133-149.

 

 Congenital vestibular disorders comprise a range of inner ear pathologies, hampered motor development, and balance and posture problems. Apart from mouse models of congenital vestibular disorders, until recently, no appropriate animal model had been established, which limited the study of central vestibular circuits. The rewiring of these neural connections has important ramifications for the understanding and potential subsequent therapy of these debilitating conditions.

In their recent publication, Lilian et al. describe a chick embryo model allowing them to analyze the developing vestibular system in the above-mentioned disorders. By surgically rotating the otocyst (a structure that gives rise to the inner ear) of 2-day-old chick embryos (180° in the anterior-posterior axis), they form the “anterior-posterior axis rotated otocyst” or ARO chick (a tip of the hat to our scientific society, perhaps?). In this model, a reproducible pathology of a sac with truncated/missing semicircular canals can be induced (Figure A), which represents the most prevalent inner ear defect in pediatric patients with congenital vestibular disorders.

Meticulous analysis of the resulting anatomy in embryonic day 13 ARO chicks led the researchers to discover that the sac contains all five vestibular organs (maculae utriculi and sacculi as well as three cristae), but the macula utriculi and superior crista are shortened along the anterior-posterior axis. Additional changes are not just restricted to the inner ear but also include a synaptic station in the brainstem that receives vestibular input from inner ear: the tangential nucleus demonstrates a 66% reduction in the number of principal cells on the rotated side.

These anatomical changes are accompanied by a subset of behavioral deficits: the ARO chicks have a constant right head tilt and gait problems (stumbling and walking with a widened base; Figure B), mimicking some human forms of congenital vestibular disorders. In contrast, the righting reflex times after hatching are unaffected, with no difference observed between control and ARO chicks.

This novel technique appears to be relatively straightforward and gives researchers an important tool to assess the resulting changes in the central nervous system, which should hopefully help to develop new treatments for people affected by congenital vestibular disorders.

 

Figure B.  5-day hatchling chicks show differences between a normal animal (a) and an ARO chick with a head tilt at rest (b) and a widened stance after performing a righting reflex (c). From Lilian et al., 2019, JARO 20: 133-149.

 

 


June 2019

Interaction Between Pitch and Timbre Perception in Normal-Hearing Listeners and Cochlear Implant Users

Xin Luo, Samara Soslowsky, and Kathryn R.Pulling

Luo, X., Soslowsky, S. & Pulling, K.R. JARO (2019) 20: 57.  https://doi.org/10.1007/s10162-018-00701-3

Reported by:
Karen Chan Barrett, Ph.D. & Nicole Jiam, M.D.
University of California, San Francisco, Department of Otolaryngology-Head and Neck Surgery

Cochlear implant (CI) users find it difficult to enjoy music, and a new paper by Luo et al. explores their struggles with perception of certain acoustic dimensions. Using an innovative approach, the authors studied the interaction between pitch and timbre perception, rather than treating these two features independently.  Pitch is the perceptual correlate of fundamental frequency (or F0); timbre refers to the quality of a sound as distinct from pitch or intensity that helps to differentiate instruments or speakers from one another. In normal hearing (NH) adults, musical chords are perceived differently when played on different instruments1 and non-musician adults have a difficult time rapidly categorizing stimuli based on pitch or timbre, often confusing the two.2  In the current study, the authors designed two experiments to evaluate the relationship between pitch and timbre perception in non-musical NH listeners and CI users.  Both designs revealed better performance when the two acoustic dimensions were varied congruently (as expected for human musical predilections) rather than incongruently, despite an overall worse performance by CI users.

In experiment 1, participants completed tasks to determine fundamental frequency (F0) and spectral slope (timbre correlate) difference limens (DLs) without variations in the non-target dimension. Pitch and sharpness rankings were then separately tested when the F0 and the spectral slope of harmonic complex tones varied by the same multiple of individual DLs either congruently (e.g. higher pitch accompanied with a sharper timbre or a lower pitch with a duller timbre) or incongruently (e.g. higher pitch with a duller timbre). In general, CI users had poorer timbre and pitch perception compared to NH adults. Additionally, a symmetric and bidirectional interaction between pitch and timbre perception was found in that better performance was seen for congruent F0 and spectral slope variations. In experiment 2, CI users performed melodic contour identification (MCI) of harmonic complex tones with or without spectral slope variations.  All participants repeated pitch and timbre discrimination tasks to obtain F0 and spectral slope limens, and then completed the MCI task where the contours either had no spectral slope variations, congruent variations (i.e. spectral slope and F0 increased together or decreased together), or incongruent variations (i.e. spectral slope and F0 moved in opposite directions).  Results again demonstrated an interaction between pitch and timbre; better performance was found for congruent stimuli.  Additionally, MCI performance was significantly degraded with amplitude roving, suggesting that there may also be a perceptual interaction between loudness and pitch cues. 

In summary, this study is notable in that it explores how acoustic dimensions interact and are perceived by CI users, a crucial step towards a deeper understanding of complex sound perception in implantees. These findings are significant because they may have implications for future methods to improve music enjoyment in CI users.

1.     Beal AL. The skill of recognizing musical structures. Mem Cognit. 1985 Sep;13(5):405–12.
2.     Pitt MA. Perception of pitch and timbre by musically trained and untrained listeners. J Exp Psychol Hum Percept Perform. 1994 Oct; 20(5):976–86.