By Linda J. Hood
The Academy Research Conference (ARC) 2021 took place virtually on April 8, 2021, focusing on the topic of auditory neuropathy (AN). This year’s ARC brought together an outstanding group of experts from basic science, translational research, and clinical practice to address current issues and new directions in the evaluation and management of patients presenting with this auditory disorder.
Several terms are used to describe this group of patients, building on the first modern description of auditory neuropathy by Starr et al in 1996. The considerable variation observed among patients has been captured by terms such as auditory dys-synchrony and auditory neuropathy spectrum disorder (AN/ANSD). Recent developments have led to the term auditory synaptopathy and the ability to distinguish patients with auditory neuropathy from those with auditory synaptopathy (Moser and Starr, 2016).
Research continues at a rapid pace as scientists and clinicians work to understand this complex hearing disorder, identify associated genetic mutations and genotype-phenotype relationships, develop methods for accurate diagnosis, and implement evidence-based, effective management. The unique challenges that these patients, ranging in age across the lifespan, present underscore continued interest in sharing new findings and clinical experience, which fits the goals of the Academy Research Conference.
The abstracts provided here summarize the presentations of the 2021 ARC speakers.
AN/ANSD: Current Status, Clinical Issues, Future Directions
Linda Hood, PhD
ARC2021 Program Chair
Professor, Department of Hearing and Speech Sciences
Vanderbilt University Medical Center
Patients with auditory neuropathy ((AN) also referred to as auditory neuropathy spectrum disorder (ANSD), auditory synaptopathy (AS), and auditory neuropathy/dys-synchrony (AN/AD)) present unique challenges to clinicians in relation to audiological evaluation and management.
Patients vary widely in speech understanding and communication ability, with difficulty understanding speech-in-noise. Test results often present a mismatch with behavioral audiometric thresholds, which is a characteristic of hearing losses affecting synaptic and neural function. Physiologic responses are key to accurate identification and monitoring of patients over time.
Various mechanisms underlie AN/AS and characteristics such as etiology, age at onset, genetics, and multiple system involvement vary among patients. Management approaches should be individualized with consideration of individual variation and the possibility of change over time.
Many patients with accurately characterized AN/AS demonstrate success with cochlear implants. Trial with amplification is recommended prior to consideration of implantation. Areas of discovery include accurate differential diagnosis, understanding of synaptic and neural mechanisms, genotype/phenotype relationships, and contributions of cochlear and cortical evoked potentials. Advances in each area will promote accurate clinical evaluation and management of infants, children, and adults with AN/AS.
Electrophysiology in Patients with Gene Mutations Related to AN/ANSD
Rosamaria Santarelli, MD, PhD
Professor, Department of Neurosciences
University of Padova
Auditory neuropathy (AN) is a disorder characterized by disruption of the temporal coding of acoustic signals in auditory fibers with consequent impairment of auditory perceptions dependent on temporal cues. The most well-known forms of AN are due to gene mutations and the mechanisms believed to be involved are functional alterations at pre- and post-synaptic sites, including neurotransmitter release from ribbon synapses, spike initiation in auditory nerve terminals, and the neural dys-synchrony accompanying demyelination and axonal loss, all resulting in impairment of auditory nerve discharge in response to acoustic stimuli.
Alterations of cochlear receptor activity and of auditory nerve discharge can be identified in patients with AN by using transtympanic electrocochleography (ECochG). ECochG findings help to define objectively the sites of auditory neural dysfunction as affecting inner hair cell receptor summating potential or compound action potential, the latter reflecting disorders of ribbon synapsis and auditory nerve fibers.
The identification of specific gene mutations combined with typical electrophysiological patterns may be the key-factor in revealing how the failure of different molecular processes underlies the varieties of AN. Moreover, elucidation of the physiopathological mechanisms and site of lesion help to predict the outcome of cochlear implantation or hearing aid use in patients with AN related to different gene mutations.
Sound Coding in the Auditory Nerve: Toward New Diagnostic Tools
Jean-Luc Puel, PhD
Professor, University Montpellier
Institute for Neurosciences of Montpellier
Auditory nerve fibers (ANFs) convey acoustic information from the sensory cells to the brainstem using an elaborated neural code based on both spike timing and rate. As the stimulus tone frequency increases, time coding fades and ceases, resulting in high-frequency tone encoding that relies mostly on the spike discharge rate.
We recapitulate our recent single unit data from gerbil’s auditory nerve to highlight the most relevant mode of coding (spike timing versus spike rate) in tone-in-noise. We report that high-spontaneous rate (SR) fibers driven by low-frequency tones in noise can phase lock ~30 dB below the level that evoked a significant elevation of the discharge rate. For high-frequency tone, the low-threshold/high-SR fibers reach their maximum discharge rate in noise and do not respond to tones, whereas medium- and low-SR fibers are still able to respond to tones making them more resistant to background noise.
Based on these findings, we first discuss the ecological function of the ANF distribution according to their spontaneous discharge rate. Based on ouabain-induced ANF loss, we furthermore point out the poor synchronization of the low-SR ANFs, accounting for the discrepancy between ANF number and the amplitude of the compound action potential of the auditory nerve after ouabain. Finally, we propose a new diagnostic tool to assess low-SR fibers, which does not rely on the onset response of the ANFs.
Cochlear Deafferentation in Noise- and Age-Related Hearing Loss: Basic Observations and Translation to Human
Sharon G. Kujawa, PhD
Associate Professor, Harvard Medical School
Director of Audiology Research and Senior Scientist, Massachusetts Eye and Ear
After decades of focus on the sensory component of noise- and age-related hearing loss, animal studies have more recently turned attention to neural status, identifying loss of hair-cell communications with cochlear neurons as an early event for both etiologies. Losses with age are gradually progressive throughout the lifespan, and widespread throughout the cochlea. After noise, losses are sudden and can be progressive, changing the way ears and hearing age, long after the exposure has stopped.
The basic result has been documented in every mammalian species in which it has been studied, including compelling observations in age-graded human temporal bones, where the degeneration appears even greater than that seen in laboratory animals. Here, we provide an update on our basic observations of these degenerative processes and progress toward human translation. Work supported by grants from the National Institutes of Health (NIH/NIDCD), Department of Defense and Office of Naval Research.
Speech-Evoked Cortical Responses in Infants and Children With and Without Hearing Loss
Kristin M. Uhler, PhD (Phillip M. Gilley, PhD, Contributor)
Chair, Audiology, Speech Pathology, and Learning Services, Children’s Hospital Colorado
Associate Professor, Physical Medicine and Rehabilitation, Otolaryngology, and Psychiatry
University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado
Our work focuses on developing a tool to assess speech discrimination shortly after infants are fit with hearing aids, and to examine how discrimination relates to later language outcomes. We have examined two different auditory evoked potentials, acoustic change complex (ACC) and mismatched response (MMR) to evaluate speech discrimination abilities in young infants. Our findings indicate that:
- mismatched response (MMR) is sensitive to measuring speech discrimination in individual sleeping infants,
- infants can and do process speech information during sleep,
- these processes include speech discrimination,
- we can observe these processes using advanced EEG analyses, and
- MMR measured at three months of age predicts performance at nine months of age.
These early results suggest informative correlations between a variety of speech and language measures at different ages throughout development. In a patient diagnosed with auditory neuropathy, speech discrimination was assessed at multiple intensity levels and MMR responses were observed at 60 dB SPL-A, but not at 70 dB SPL-A.
Both measures of speech perception abilities resulted in poorer speech perception as a function of increased intensity for /a-i/ which differs from those participants with normal hearing or other forms of hearing loss. We are optimistic that these measures will provide insights into other factors affecting hearing aid outcomes, such as those factors relating to the quality and quantity of hearing aid use.
AN/ANSD: Assessment in Infants and Toddlers
Yvonne Sininger, PhD
Professor Emeritus, University of California Los Angeles
C&Y Consulting, Santa Fe, New Mexico
Infants who have failed newborn screening and toddlers with abnormal auditory development make up the majority of audiologic patients with ANS. Assessment of these patients is based on objective measures. The ways in which ANS is manifested in audiologic test batteries is reviewed and discussed in relation to the physiology.
Appropriate use of auditory brainstem response, cochlear microphonic recordings, otoacoustic emissions, middle-ear and acoustic reflex measures are emphasized. Finally, interpretation of auditory electrophysiologic tests for assessment and differential diagnosis of ANS is discussed.
Psychophysics and Bimodal Hearing in AN/ANSD
Sterling Sheffield, AuD, PhD
Assistant Professor, Department of Speech, Language, and Hearing Sciences
University of Florida
Management of auditory neuropathy spectrum disorder (ANSD) remains challenging, and research continues to seek effective treatment with differing professional opinions on the benefits of hearing aids and cochlear implants. In this presentation, temporal processing, spectral processing, and speech recognition data collected in adults with ANSD, normal-hearing thresholds, and sensorineural hearing loss are compared to illustrate group effects and hearing aid, cochlear implant, and bimodal hearing effects.
Temporal processing was evaluated with gap detection and voice-onset time discrimination. Spectral processing was evaluated with a spectral modulation detection task and consonant discrimination. Speech recognition was evaluated with words and sentences in quiet and in noise. Results indicate better performance on all tasks with bimodal hearing for both adults with sensorineural hearing loss and with ANSD.
Gene Therapy for Genetic Hearing Loss
Lawrence Lustig, PhD
Professor and Chair, Department of Otolaryngology-Head and Neck Surgery
Columbia University Medical Center / New York Presbyterian Hospital
Gene therapy has undergone significant advances towards the treatment of genetic hearing loss. Initial studies focused on methodologies and viral constructs that would be successful for adequate delivery to the appropriate cells of the inner ear. Newer virus subtypes as well as methodologies that allow the delivery of larger genes have greatly accelerated the advances in this field the point that there are now several start-up companies focused on gene therapy for genetic hearing loss. This talk summarizes the state of the field and focuses on two forms of hearing loss in particular, a subtype of Usher Syndrome (3a) and a form of non-syndromic deafness due to loss of function of Otoferlin.
The American Academy of Audiology and the 2021 Academy Research Conference organizers wish to express their sincere gratitude to all of the speakers for sharing their expertise and time. Their outstanding presentations made the 2021 ARC a resounding success.
Over 230 individuals participated in the virtual ARC with the majority attending the live session and taking an active role in generating questions and discussion. In addition, all participants could take advantage of access to the recordings for a month following the meeting.
This article is a part of the May/June 2021 Audiology Today issue.
Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. (1996) Auditory neuropathy. Brain 119:741-753.
Moser T, Starr A. (2016) Auditory neuropathy – neural and synaptic mechanisms. Nature Rev Neurol 12:135-149.