Evaluating and Comparing Behavioural and Electrophysiological Estimates of Neural Health in Cochlear Implant Users

Abstract Variations in neural health along the cochlea can degrade the spectral and temporal representation of sounds conveyed by cochlear implants (CIs). We evaluated and compared one electrophysiological measure and two behavioural measures that have been proposed as estimates of neural health patterns, in order to explore the extent to which the different measures provide converging and consistent neural health estimates. All measures were obtained from the same 11 users of the Cochlear Corporation CI. The two behavioural measures were multipulse integration (MPI) and the polarity effect (PE), both measured on each of seven electrodes per subject. MPI was measured as the difference between thresholds at 80 pps and 1000 pps, and PE as the difference in thresholds between cathodic- and anodic-centred quadraphasic (QP) 80-pps pulse trains. It has been proposed that good neural health corresponds to a large MPI and to a large negative PE (lower thresholds for cathodic than anodic pulses). The electrophysiological measure was the effect of interphase gap (IPG) on the offset of the ECAP amplitude growth function (AGF), which has been correlated with spiral ganglion neuron density in guinea pigs. This ‘IPG offset’ was obtained on the same subset of electrodes used for the behavioural measures. Despite high test–retest reliability, there were no significant correlations between the neural health estimates for either within-subject comparisons across the electrode array, or between-subject comparisons of the means. A phenomenological model of a population of spiral ganglion neurons was then used to investigate physiological mechanisms that might underlie the different neural health estimates. The combined experimental and modelling results provide evidence that PE, MPI and IPG offset may reflect different characteristics of the electrode-neural interface.

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Evaluating and comparing behavioural and electrophysiological estimates of neural health in cochlear implant users

10.31234/osf.io/2kp7x ◽

2020 ◽

Cited By ~ 3

Author(s):

Tim Brochier ◽

Francois Guerit ◽

Charlotte Garcia ◽

John M. Deeks ◽

Manohar L. Bance ◽

...

Keyword(s):

Spiral Ganglion ◽

Electrode Array ◽

Growth Function ◽

Physiological Mechanisms ◽

Temporal Representation ◽

Health Patterns ◽

The Difference ◽

Ganglion Neurons ◽

Test Retest Reliability ◽

Different Characteristics

Variations in neural health along the cochlea can degrade the spectral and temporal representation of sounds conveyed by cochlear implants (CIs) . We evaluated and compared several methods that have been proposed as estimates of neural health patterns, in order to explore the extent to which the different measures provide converging and consistent neural health estimates. All measures were obtained from the same 11 users of the Cochlear Corporation CI. The two behavioural measures were multipulse integration (MPI) and the polarity effect (PE), both measured on each of seven electrodes per subject. MPI was measured as the difference between thresholds at 80-pps and 1000-pps, and PE as the difference in thresholds between cathodic- and anodic-centred quadraphasic (QP) 80-pps pulse trains. It has been proposed that good neural health corresponds to a large MPI and to a large negative PE (lower thresholds for cathodic than anodic pulses). The electrophysiological measure was the effect of interphase gap (IPG) on the offset of the ECAP amplitude growth function (AGF), which has been correlated with spiral ganglion nerve density in guinea pigs. This “IPG offset” was obtained on the same subset of electrodes as for the behavioural measures. Despite high test-retest reliability, there were no significant correlations between the neural health estimates for either within-subject comparisons across the electrode array, or between-subjects comparisons of the means. A phenomenological model of a population of spiral ganglion neurons was then used to investigate physiological mechanisms that might underlie the different neural health estimates. The combined experimental and modelling results provide evidence that PE, MPI, and IPG offset reflect different characteristics of the electrode-neural interface.

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Mechanism and Prevention of Spiral Ganglion Neuron Degeneration in the Cochlea

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.814891 ◽

2022 ◽

Vol 15 ◽

Author(s):

Li Zhang ◽

Sen Chen ◽

Yu Sun

Keyword(s):

Gene Therapy ◽

Hearing Loss ◽

Stem Cell ◽

Cell Therapy ◽

Sensory Neurons ◽

Stem Cell Therapy ◽

Spiral Ganglion ◽

Spiral Ganglion Neuron ◽

Regeneration Ability ◽

Ganglion Neurons

Sensorineural hearing loss (SNHL) is one of the most prevalent sensory deficits in humans, and approximately 360 million people worldwide are affected. The current treatment option for severe to profound hearing loss is cochlear implantation (CI), but its treatment efficacy is related to the survival of spiral ganglion neurons (SGNs). SGNs are the primary sensory neurons, transmitting complex acoustic information from hair cells to second-order sensory neurons in the cochlear nucleus. In mammals, SGNs have very limited regeneration ability, and SGN loss causes irreversible hearing loss. In most cases of SNHL, SGN damage is the dominant pathogenesis, and it could be caused by noise exposure, ototoxic drugs, hereditary defects, presbycusis, etc. Tremendous efforts have been made to identify novel treatments to prevent or reverse the damage to SGNs, including gene therapy and stem cell therapy. This review summarizes the major causes and the corresponding mechanisms of SGN loss and the current protection strategies, especially gene therapy and stem cell therapy, to promote the development of new therapeutic methods.

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Wnt Signaling Protects against Paclitaxel-Induced Spiral Ganglion Neuron Damage in the Mouse Cochlea In Vitro

BioMed Research International ◽

10.1155/2019/7878906 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12

Author(s):

Xue Wang ◽

Yuechen Han ◽

Man Wang ◽

Chuan Bo ◽

Zhenbiao Zhang ◽

...

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Degenerative Change ◽

Wnt Signaling Pathway ◽

Spiral Ganglion ◽

Spiral Ganglion Neuron ◽

Cell Protection ◽

Ganglion Neurons ◽

Paclitaxel Treatment

It has been reported that paclitaxel administration could cause sensorineural hearing loss, and Wnt activation is important for the development and cell protection of mouse cochlea. However, the effect of Wnt signaling in spiral ganglion neurons (SGNs) damage induced by paclitaxel has not yet been elucidated. In this study, we explored the effect of paclitaxel on SGNs in the mouse cochlea and the neuroprotective effects of Wnt signaling pathway against paclitaxel-induced SGN damage by using Wnt agonist/antagonists in vitro. We first found that paclitaxel treatment resulted in a degenerative change and reduction of cell numbers in SGNs and induced caspase-mediated apoptosis in SGNs. The expression levels of β-catenin and C-myc were increased, thus indicating Wnt signaling was activated in SGNs after paclitaxel treatment. The activation of Wnt signaling pathway protected against SGN loss after exposure to paclitaxel, whereas the suppression of Wnt signaling in SGNs made them more vulnerable to paclitaxel treatment. We also showed that activation of Wnt signaling in SGNs inhibited caspase-mediated apoptosis. Our findings demonstrated that Wnt signaling had an important role in protecting SGNs against paclitaxel-induced damage and thus might be an effective therapeutic target for the prevention of paclitaxel-induced SGN death.

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Regional Specification of Threshold Sensitivity and Response Time in CBA/CaJ Mouse Spiral Ganglion Neurons

Journal of Neurophysiology ◽

10.1152/jn.00284.2007 ◽

2007 ◽

Vol 98 (4) ◽

pp. 2215-2222 ◽

Cited By ~ 27

Author(s):

Qing Liu ◽

Robin L. Davis

Keyword(s):

Spiral Ganglion ◽

Positional Information ◽

Spike Timing ◽

Spiral Ganglion Neuron ◽

Spiral Ganglion Neurons ◽

Threshold Levels ◽

Wide Range ◽

Acoustic Processing ◽

Neuron Electrophysiology ◽

Ganglion Neurons

Previous studies of spiral ganglion neuron electrophysiology have shown that specific parameters differ according to cochlear location, with apical neurons being distinctly different from basal neurons. To align these features more precisely along the tonotopic axis of the cochlea, we developed a novel spiral ganglion culture system in which positional information is retained. Patch-clamp recordings made from neurons of known gangliotopic location revealed two basic firing pattern distributions. Membrane characteristics related to spike timing, such as accommodation, latency and onset tau, were distinctly heterogeneous, yet when averaged, they were distributed in a graded manner along the length of the cochlea. Action potential threshold levels also displayed a wide range, the averages of which were distributed nonmonotonically such that neurons with the greatest sensitivity were localized to the mid-regions of the ganglion. These studies shed new light on the complexity and sophistication of the intrinsic firing features of spiral ganglion neurons. Because timing-related elements are organized in an overall tonotopic manner, it is hypothesized that they contribute to aspects of frequency-dependent acoustic processing. On the other hand, the different distribution of threshold levels, with the greatest sensitivity in the middle region of the tonotopic map, suggests that this neuronal parameter is regulated differently and thus may contribute a distinct realm of auditory sensory processing.

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Anti-inflammatory compounds improve spiral ganglion neuron survival after aminoglycoside-induced hair cell loss in rats

10.1101/2021.12.03.470945 ◽

2021 ◽

Author(s):

Muhammad T. Rahman ◽

Erin M. Bailey ◽

Benjamin M. Gansemer ◽

Andrew Pieper ◽

J. Robert Manak ◽

...

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Spiral Ganglion ◽

Cell Loss ◽

Spiral Ganglion Neuron ◽

Auditory Information ◽

Activated Macrophages ◽

Hair Cell Loss ◽

Cochlear Hair Cells ◽

Ganglion Neurons

AbstractSpiral ganglion neurons (SGNs) relay auditory information from cochlear hair cells to the central nervous system. After hair cells are destroyed by aminoglycoside antibiotics, SGNs gradually die. However, the reasons for this cochlear neurodegeneration are unclear. We used microarray gene expression profiling to assess transcriptomic changes in the spiral ganglia of kanamycin-deafened and age-matched control rats and found that many of the genes upregulated after deafening are associated with immune/inflammatory responses. In support of this, we observed increased numbers of macrophages in the spiral ganglion of deafened rats. We also found, via CD68 immunoreactivity, an increase in activated macrophages after deafening. An increase in CD68-associated nuclei was observed by postnatal day 23, a time before significant SGN degeneration is observed. Finally, we show that the immunosuppressive drugs dexamethasone and ibuprofen, as well as the NAD salvage pathway activator P7C3, provide at least some neuroprotection post-deafening. Ibuprofen and dexamethasone also decreased the degree of macrophage activation. These results suggest that activated macrophages specifically, and perhaps a more general neuroinflammatory response, are actively contributing to SGN degeneration after hair cell loss.

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Generation of a Spiral Ganglion Neuron Degeneration Mouse Model

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761847 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zhengqing Hu ◽

Fnu Komal ◽

Aditi Singh ◽

Meng Deng

Keyword(s):

Inner Ear ◽

Mouse Strain ◽

Diphtheria Toxin ◽

Damage Model ◽

Spiral Ganglion ◽

Functional Study ◽

Spiral Ganglion Neuron ◽

Mouse Strains ◽

Brainstem Response ◽

Ganglion Neurons

Spiral ganglion neurons (SGNs) can be injured by a wide variety of insults. However, there still is a lack of degeneration models to specifically damage the SGNs without disturbing other types of cells in the inner ear. This study aims to generate an SGN-specific damage model using the Cre-LoxP transgenic mouse strains. The Cre-inducible diphtheria toxin receptor (iDTR+/+) knock-in mouse strain was crossed with a mouse strain with Cre activity specific to neurons (NeflCreER/CreER). Expression of the Cre-recombinase activity was evaluated using the reporter mouse strain Ai9 at pre-hearing, hearing onset, and post-hearing stages. Accordingly, heterozygous NeflCreER/+;iDTR+/– mice were treated with tamoxifen on postnatal days 1–5 (P1–5), followed by diphtheria toxin (DT) or vehicle injection on P7, P14, and P21 to evaluate the SGN loss. Robust tamoxifen-induced Cre-mediated Ai9 tdTomato fluorescence was observed in the SGN area of heterozygous NeflCreER/+;Ai9+/– mice treated with tamoxifen, whereas vehicle-treated heterozygote mice did not show tdTomato fluorescence. Compared to vehicle-treated NeflCreER/+;iDTR+/– mice, DT-treated NeflCreER/+;iDTR+/– mice showed significant auditory brainstem response (ABR) threshold shifts and SGN cell loss. Hair cell count and functional study did not show significant changes. These results demonstrate that the NeflCreER/CreER mouse strain exhibits inducible SGN-specific Cre activity in the inner ear, which may serve as a valuable SGN damage model for regeneration research of the inner ear.

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Interaction of micropatterned topographical and biochemical cues to direct neurite growth from spiral ganglion neurons

10.1101/2021.03.10.434606 ◽

2021 ◽

Author(s):

Kristy Truong ◽

Braden Leigh ◽

Joseph T. Vecchi ◽

Reid Bartholomew ◽

Linjing Xu ◽

...

Keyword(s):

Cochlear Implants ◽

Microcontact Printing ◽

Spiral Ganglion ◽

Neurite Growth ◽

Spiral Ganglion Neuron ◽

Electrode Arrays ◽

Prosthetic Devices ◽

Neural Prosthetic ◽

Flat Surfaces ◽

Ganglion Neurons

AbstractFunctional outcomes with neural prosthetic devices, such as cochlear implants, are limited in part due to physical separation between the stimulating elements and the neurons they stimulate. One strategy to close this gap aims to precisely guide neurite regeneration to position the neurites in closer proximity to electrode arrays. Here, we explore the ability of micropatterned biochemical and topographic guidance cues, singly and in combination, to direct the growth of spiral ganglion neuron (SGN) neurites, the neurons targeted by cochlear implants. Photopolymerization of methacrylate monomers was used to form unidirectional topographical features of ridges and grooves in addition to multidirectional patterns with 90° angle turns. Microcontact printing was also used to create similar uni- and multi-directional patterns of peptides on polymer surfaces. Biochemical cues included peptides that facilitate (laminin, LN) or repel (EphA4-Fc) neurite growth. On flat surfaces, SGN neurites preferentially grew on LN-coated stripes and avoided EphA4-Fc-coated stripes. LN or EphA4-Fc was selectively adsorbed onto the ridges or grooves to test the neurite response to a combination of topographical and biochemical cues. Coating the ridges with EphA4-Fc and grooves with LN lead to enhanced SGN alignment to topographical patterns. Conversely, EphA4-Fc coating on the grooves or LN coating on the ridges tended to disrupt alignment to topographical patterns. SGN neurites respond to combinations of topographical and biochemical cues and surface patterning that leverages both cues enhance guided neurite growth.

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Polarity Sensitivity in Pediatric and Adult Cochlear Implant Listeners

Trends in Hearing ◽

10.1177/2331216519862987 ◽

2019 ◽

Vol 23 ◽

pp. 233121651986298 ◽

Cited By ~ 2

Author(s):

Kelly N. Jahn ◽

Julie G. Arenberg

Keyword(s):

Cochlear Implant ◽

Dynamic Range ◽

Single Channel ◽

Spiral Ganglion ◽

High Amplitude ◽

Electrical Stimulus ◽

Polarity Sensitivity ◽

The Difference ◽

Phoneme Perception ◽

Ganglion Neurons

Modeling data suggest that sensitivity to the polarity of an electrical stimulus may reflect the integrity of the peripheral processes of the spiral ganglion neurons. Specifically, better sensitivity to anodic (positive) current than to cathodic (negative) current could indicate peripheral process degeneration or demyelination. The goal of this study was to characterize polarity sensitivity in pediatric and adult cochlear implant listeners (41 ears). Relationships between polarity sensitivity at threshold and (a) polarity sensitivity at suprathreshold levels, (b) age-group, (c) preimplantation duration of deafness, and (d) phoneme perception were determined. Polarity sensitivity at threshold was defined as the difference in single-channel behavioral thresholds measured in response to each of two triphasic pulses, where the central high-amplitude phase was either cathodic or anodic. Lower thresholds in response to anodic than to cathodic pulses may suggest peripheral process degeneration. On the majority of electrodes tested, threshold and suprathreshold sensitivity was lower for anodic than for cathodic stimulation; however, dynamic range was often larger for cathodic than for anodic stimulation. Polarity sensitivity did not differ between child- and adult-implanted listeners. Adults with long preimplantation durations of deafness tended to have better sensitivity to anodic pulses on channels that were estimated to interface poorly with the auditory nerve; this was not observed in the child-implanted group. Across subjects, duration of deafness predicted phoneme perception performance. The results of this study suggest that subject- and electrode-dependent differences in polarity sensitivity may assist in developing customized cochlear implant programming interventions for child- and adult-implanted listeners.

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Ouabain-Induced Apoptosis in Cochlear Hair Cells and Spiral Ganglion NeuronsIn Vitro

BioMed Research International ◽

10.1155/2013/628064 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 14

Author(s):

Yong Fu ◽

Dalian Ding ◽

Lei Wei ◽

Haiyan Jiang ◽

Richard Salvi

Keyword(s):

Hair Cells ◽

Gene Array ◽

Spiral Ganglion ◽

Spiral Ganglion Neuron ◽

Round Window Membrane ◽

Spiral Ganglion Neurons ◽

Cochlear Hair Cells ◽

Ganglion Neurons

Ouabain is a common tool to explore the pathophysiological changes in adult mammalian cochleain vivo. In prior studies, locally administering ouabain via round window membrane demonstrated that the ototoxic effects of ouabainin vivovaried among mammalian species. Little is known about the ototoxic effectsin vitro. Thus, we prepared cochlear organotypic cultures from postnatal day-3 rats and treated these cultures with ouabain at 50, 500, and 1000 μM for different time to elucidate the ototoxic effects of ouabainin vitroand to provide insights that could explain the comparative ototoxic effects of ouabainin vivo. Degeneration of cochlear hair cells and spiral ganglion neurons was evaluated by hair-cell staining and neurofilament labeling, respectively. Annexin V staining was used to detect apoptotic cells. A quantitative RT-PCR apoptosis-focused gene array determined changes in apoptosis-related genes. The results showed that ouabain-induced damagein vitrowas dose and time dependent. 500 μM ouabain and 1000 μM ouabain were destructively traumatic to both spiral ganglion neurons and cochlear hair cells in an apoptotic signal-dependent pathway. The major apoptotic pathways in ouabain-induced spiral ganglion neuron apoptosis culminated in the stimulation of the p53 pathway and triggering of apoptosis by a network of proapoptotic signaling pathways.

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