Saul and Ida Epstein Laboratory for Auditory Physiology and Genetics

TheĀ Saul and Ida Epstein Laboratory for Auditory Physiology and Genetics was established by generous gifts from Saul and Ida Epstein in 1976. Since that time continuing gifts from the Epsteins as well as grant and contract funding from the National Institutes of Health, Hearing Research Incorporated, Deafness Research Foundation and several other donors have supported a wide range of basic hearing projects. The laboratory is approximately 1,700 square feet and was completed in November, 1992. It includes areas for electron microscopy, light microscopy, imaging and image analysis, electrophysiology, psychophysics, recovery surgery and biomedical engineering.

Current Research

The Effects of Intracochlear Electrical Stimulation on Neural Survival and Function Figure 1: Sections of two cochleas from a model of neonatal/congenital sensorineural deafness. A cochlear implant was surgically inserted into the cochlea on the left to infuse the cochlea with BDNF for 10 weeks beginning at the onset of deafness, and also to stimulate the auditory nerve. The cochlea on the right is a deaf control that was not implanted (and so not treated with BDNF or stimulated). Survival of spiral ganglion (auditory nerve) cells and their radial fibers is poor in the untreated cochlea and more nearly normal in the treated one. A fibrous encapsulation of the implant electrode can be seen in the treated cochlea It is not an exaggeration to say that the cochlear implant (CI) has revolutionized the rehabilitation of individuals with severe to profound sensorineural hearing loss. Almost all adult CI recipients enjoy significantly enhanced lip-reading capabilities, and a majority of those using the latest technology score above 80-percent correct on high-context sentences without visual cues. Further, CI electrodes are now being implanted and used in combination with hearing aids in individuals with significant residual hearing. The success of this electrical-acoustical (EAS) hearing has re-focused attention on reducing trauma during CI implantation, maintaining residual hearing, and on the importance of the condition of the cochlea and auditory nerve in CI function. In fact, exogenous delivery of the neurotrophin BDNF has been proposed for human CI subjects to promote improved auditory nerve survival, and CI electrodes modified for drug delivery have already been developed. However, animal studies examining the effects of intracochlear delivery of BDNF in promoting auditory nerve survival are extremely limited to date, and we believe several critical issues must be addressed prior to considering human application. Further, thousands of very young deaf children, including congenitally deaf infants, now are receiving CIs. It is encouraging that many of these children eventually are mainstreamed into public education settings. However, other pediatric CI recipients lag far behind in language development and some children cannot even discriminate between the most basal and most apical electrodes of their implants. Thus, beyond the bioengineering challenges in maintaining a CI over the lifetime of an implanted child, there are important developmental and neurobiological issues concerning the effects of ICES on the immature auditory system. The rationale for implanting at very young ages is based on the belief that there is a critical period for language acquisition as suggested by the profound effects of auditory deprivation in congenitally deaf children and adults and by research demonstrating that implantation before the age of 2 results in significant advantages in speech perception.Many animal studies have suggested that auditory deprivation during maturation is especially harmful in causing degeneration/reorganization in the central auditory system. With pediatric CIs, it is generally assumed that restoring input during this critical period will be more effective in preventing the degenerative consequences of deafness and that the immature auditory system will be more plastic, better able to adapt to ICES. But it is important to recognize that the increased plasticity that characterizes critical periods of nervous system development might also have negative consequences. ICES delivered in a particular format might entrain the immature auditory system into an idiosyncratic organization that could be suboptimal for effective processing of other patterns or formats of ICES introduced later in life. Studies in the visual system show that early restricted or aberrant inputs can have profound effects on central nervous system development that are irreversible due to developmental critical periods. Broadly distributed, synchronous input to the retina (e.g., electrical stimulation of the optic nerve or stroboscopic illumination) in the immature visual system causes profound changes in central processing that are not reversible if normal visual input is later restored.The overall premise in our ICES research is that with so many very young (<12 months) congenitally deaf children now receiving CIs, it is critical to better understand the effects of ICES on the developing auditory system. Our previous work focused on defining the effects of total auditory deprivation and highly controlled, unilateral ICES in neonatally deafened animals. Significant progress has been made, but many important questions remain.Previous studies conducted by our research group at UCSF have shown that chronic intracochlear electrical stimulation (ICES) delivered by a cochlear implant (CI) can promote significantly improved survival of auditory nerve neurons. However, ICES can also induce potentially negative functional changes in the central auditory system in an model of pediatric deafness. The overall objective of this proposed research is to explore the mechanisms by which ICES and/or neurotrophic agents can optimize anatomical and functional integrity of the deafened auditory system. Our long-term goal is to develop methods and protocols that can be applied in human CI recipients to help optimize the function of a multichannel auditory prosthesis.The specific aims of this research are:

  • To explore the mechanisms by which chronic ICES promotes the survival of auditory nerve neurons in profound hearing loss that has occurred early in life. In particular, to examine possible interactive effects of co-administration of ICES and neurotrophic or anti-inflammatory agents. We would also like to determine whether there is a developmental critical period for the survival-promoting effects of these neurotrophic agents.
  • To study the influence of early deafness with ICES on degradation in the selectivity of auditory nerve projections to the cochlear nucleus, specifically, whether such changes underlie and parallel the functional alterations seen in the central auditory system after chronic ICES.
  • To examine the structural and functional changes within the central auditory system elicited by deafness and various formats of chronic ICES, and to determine whether functional alterations recorded after prolonged periods of deafness are primarily related to degeneration of the auditory nerve in the cochlea or to degenerative alterations in the central auditory system.
  • To determine whether potentially negative functional changes in the central auditory system induced by chronic ICES delivered on a single broadband CI channel are reversible later in life after introducing competitive inputs delivered on 2 or more intracochlear ICES channels of asynchronous patterned stimulation.

Publications

Auditory Prosthesis Development

  • Middlebrooks JC, Snyder RL. Intraneural stimulation for auditory prosthesis: modiolar trunk and intracranial stimulation sites. Hear. Res 2008 Aug;242(1-2):52-63.
  • Rebscher SJ, Hetherington A, Bonham B, Wardrop P, Whinney D, Leake PA. Considerations for design of future cochlear implant electrode arrays: electrode array stiffness, size, and depth of insertion. J Rehabil Res Dev 2008;45(5):731-747.
  • Rebscher SJ, Hetherington AM, Snyder RL, Leake PA, Bonham BH. Design and fabrication of multichannel cochlear implants for research. J. Neurosci. Methods 2007 Oct;166(1):1-12.
  • Stakhovskaya O, Sridhar D, Bonham BH, Leake PA. Frequency map for the human cochlear spiral ganglion: implications for cochlear implants. J. Assoc. Res. Otolaryngol 2007 Jun;8(2):220-233.
  • Middlebrooks JC, Snyder RL. Auditory prosthesis with a penetrating nerve array. J. Assoc. Res. Otolaryngol 2007 Jun;8(2):258-279.
  • Sridhar D, Stakhovskaya O, Leake PA. A frequency-position function for the human cochlear spiral ganglion. Audiol. Neurootol 2006;11 Suppl 1:16-20.
  • Wardrop P, Whinney D, Rebscher SJ, Roland JT, Luxford W, Leake PA. A temporal bone study of insertion trauma and intracochlear position of cochlear implant electrodes. I: Comparison of Nucleus banded and Nucleus Contour electrodes. Hear. Res 2005 May;203(1-2):54-67.

The Role of Chemical Neurotrophic Factors along with Electrical Stimulation with a Cochlear Implant in Maintaining the Spiral Ganglion Neurons

  • Leake PA, Stakhovskaya O, Hradek GT, Hetherington AM. Factors influencing neurotrophic effects of electrical stimulation in the deafened developing auditory system. Hear. Res 2008 Aug;242(1-2):86-99.
  • Leake PA, Hradek GT, Vollmer M, Rebscher SJ. Neurotrophic effects of GM1 ganglioside and electrical stimulation on cochlear spiral ganglion neurons deafened as neonates. J. Comp. Neurol 2007 Apr;501(6):837-853.
  • Osofsky MR, Moore CM, Leake PA. Does exogenous GM1 ganglioside enhance the effects of electrical stimulation in ameliorating degeneration after neonatal deafness? Hear. Res 2001 Sep;159(1-2):23-35.

Functional Responses of the Central Auditory System to Electrical Stimulation with a Cochlear Implant

  • Snyder RL, Middlebrooks JC, Bonham BH. Cochlear implant electrode configuration effects on activation threshold and tonotopic selectivity. Hear. Res 2008 Jan;235(1-2):23-38.
  • Snyder RL, Bierer JA, Middlebrooks JC. Topographic spread of inferior colliculus activation in response to acoustic and intracochlear electric stimulation. J. Assoc. Res. Otolaryngol 2004 Sep;5(3):305-322.
  • Vollmer M, Beitel RE, Snyder RL. Auditory detection and discrimination: psychophysical and neural thresholds for intracochlear electrical signals. J. Neurophysiol 2001 Nov;86(5):2330-2343.
  • Leake PA, Snyder RL, Rebscher SJ, Moore CM, Vollmer M. Plasticity in central representations in the inferior colliculus induced by chronic single- vs. two-channel electrical stimulation by a cochlear implant after neonatal deafness. Hear. Res 2000 Sep;147(1-2):221-241.
  • Snyder RL, Vollmer M, Moore CM, Rebscher SJ, Leake PA, Beitel RE. Responses of inferior colliculus neurons to amplitude-modulated intracochlear electrical pulses. J. Neurophysiol 2000 Jul;84(1):166-183.
  • Beitel RE, Snyder RL, Schreiner CE, Raggio MW, Leake PA. Electrical cochlear stimulation: comparisons between psychophysical and central auditory neuronal thresholds. J. Neurophysiol 2000 Apr;83(4):2145-2162.
  • Beitel RE, Vollmer M, Snyder RL, Schreiner CE, Leake PA. Behavioral and neurophysiological thresholds for electrical cochlear stimulation. Audiol. Neurootol 2000 Feb;5(1):31-38.

Changes in the Central Auditory System Caused by Deafness or Electrical Stimulation with a Cochlear Implant

  • Stakhovskaya O, Hradek GT, Snyder RL, Leake PA. Effects of age at onset of deafness and electrical stimulation on the developing cochlear nucleus. Hear. Res 2008 Sep;243(1-2):69-77.
  • Leake PA, Hradek GT, Bonham BH, Snyder RL. Topography of auditory nerve projections to the cochlear nucleus after neonatal deafness and electrical stimulation by a cochlear implant. J. Assoc. Res. Otolaryngol 2008 Sep;9(3):349-372.
  • Vollmer M, Beitel RE, Snyder RL, Leake PA. Spatial selectivity to intracochlear electrical stimulation in the inferior colliculus is degraded after long-term deafness. J. Neurophysiol 2007 Nov;98(5):2588-2603.
  • Leake PA, Hradek GT, Chair L, Snyder RL. Neonatal deafness results in degraded topographic specificity of auditory nerve projections to the cochlear nucleus. J. Comp. Neurol 2006 Jul;497(1):13-31.
  • Vollmer M, Leake PA, Beitel RE, Rebscher SJ, Snyder RL. Degradation of temporal resolution in the auditory midbrain after prolonged deafness is reversed by electrical stimulation of the cochlea. J. Neurophysiol 2005 Jun;93(6):3339-3355.
  • Moore CM, Vollmer M, Leake PA, Snyder RL, Rebscher SJ. The effects of chronic intracochlear electrical stimulation on inferior colliculus spatial representation. Hear. Res 2002 Feb;164(1-2):82-96.
  • Rebscher SJ, Snyder RL, Leake PA. The effect of electrode configuration and duration of deafness on threshold and selectivity of responses to intracochlear electrical stimulation. J. Acoust. Soc. Am 2001 May;109(5 Pt 1):2035-2048.

Reviews

  • Bonham BH, Litvak LM. Current focusing and steering: modeling, physiology, and psychophysics. Hear. Res 2008 Aug;242(1-2):141-153.
  • Middlebrooks JC, Bierer JA, Snyder RL. Cochlear implants: the view from the brain. Curr. Opin. Neurobiol 2005 Aug;15(4):488-493.

Other Auditory System Research (not Involving Cochlear Implants)

Function and Plasticity of the Central Auditory System

  • Cheung SW, Bonham BH, Schreiner CE, Godey B, Copenhaver DA. Realignment of interaural cortical maps in asymmetric hearing loss. J. Neurosci 2009 May;29(21):7065-7078.
  • Sumner CJ, Scholes C, Snyder RL. Retuning of inferior colliculus neurons following spiral ganglion lesions: a single-neuron model of converging inputs. J. Assoc. Res. Otolaryngol 2009 Mar;10(1):111-130.
  • Snyder RL, Bonham BH, Sinex DG. Acute changes in frequency responses of inferior colliculus central nucleus (ICC) neurons following progressively enlarged restricted spiral ganglion lesions. Hear. Res 2008 Dec;246(1-2):59-78.
  • Strata F, deIpolyi AR, Bonham BH, Chang EF, Liu RC, Nakahara H, Merzenich MM. Perinatal anoxia degrades auditory system function in rats. Proc. Natl. Acad. Sci. U.S.A 2005 Dec;102(52):19156-19161.
  • Godey B, Atencio CA, Bonham BH, Schreiner CE, Cheung SW. Functional organization of primary auditory cortex: responses to frequency-modulation sweeps. J. Neurophysiol 2005 Aug;94(2):1299-1311.
  • Philibert B, Beitel RE, Nagarajan SS, Bonham BH, Schreiner CE, Cheung SW. Functional organization and hemispheric comparison of primary auditory cortex (Callithrix jacchus). J. Comp. Neurol 2005 Jul;487(4):391-406.
  • Snyder RL, Sinex DG. Immediate changes in tuning of inferior colliculus neurons following acute lesions of the spiral ganglion. J. Neurophysiol 2002 Jan;87(1):434-452.
  • Snyder RL, Sinex DG, McGee JD, Walsh EW. Acute spiral ganglion lesions change the tuning and tonotopic organization of inferior colliculus neurons. Hear. Res 2000 Sep;147(1-2):200-220.

Development of the Auditory System

  • Jones TA, Leake PA, Snyder RL, Stakhovskaya O, Bonham B. Spontaneous discharge patterns in cochlear spiral ganglion cells before the onset of hearing. J. Neurophysiol 2007 Oct;98(4):1898-1908.
  • Bonham BH, Cheung SW, Godey B, Schreiner CE. Spatial organization of frequency response areas and rate/level functions in the developing AI. J. Neurophysiol 2004 Feb;91(2):841-854.
  • Leake PA, Snyder RL, Hradek GT. Postnatal refinement of auditory nerve projections to the cochlear nucleus. J. Comp. Neurol 2002 Jun;448(1):6-27.

Research Team

  • Ralph E. Beitel, PhD
  • Chantale Dore
  • Marshal Fong, MSEE
  • Alexander Hetherington, MS
  • Gary Hradek, MA
  • Stephen J. Rebscher, MA
  • Marcia Raggio, PhD
  • Olga Skakhovskaya, MD, PhD

Collaborators

  • Jullie Bierer, PhD
  • Steve Bierer, PhD
  • Johan Frijns, MD, PhD
  • Steven Green
  • Tania Hanekom, PhD
  • Timothy A. Jones, PhD
  • Jennifer H. Lavail, PhD
  • Leonid Litvak, PhD
  • John C. Middlebrooks, PhD
  • Christoph Schreiner, MD, PhD
  • Robert V. Shannon, PhD
  • Donal G. Sinex, PhD