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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (1976)

    Cover page: Scanning electron microscopic observations of labyrinthine sense organs and fiber degeneration studies of secondary vestibular and auditory pathways in caiman crocodilus
    • Thesis
    • Peer Reviewed
    UC Berkeley Electronic Theses and Dissertations (2010)

    Cochlear implants (CIs) are neural prostheses that currently provide acoustic sensation to more than 120,000 profoundly hearing-impaired people throughout the world. The majority of these CI users are able to understand speech without lip reading and to converse over the telephone. The most fortunate among them can even perform and appreciate music. Unfortunately, however, many CI recipients receive much less benefit from their devices. In order to examine the neuronal bases for these disparate outcomes, a recording system was developed to overcome specific technical limitations in previous studies that recorded neuronal responses to cochlear implant stimulation in animal models. This recording system was then used in two studies comparing responses to normal acoustic stimulation and electrical cochlear implant stimulation in guinea pigs and cats.

    The design of the recording system included a 32-channel recording amplifier and a software technique for removing stimulus artifacts from recordings of neural responses to high-rate electrical stimulation. Contemporary cochlear implants often deliver current pulse trains with carrier rates of 1000 pulses/s or higher. In neurophysiology studies, this electrical stimulation produces artifacts that are typically much larger than neuronal responses. Therefore, the recording system was specifically designed to record neuronal responses and cancel these electrical stimulus artifacts. When biphasic full-scale-input pulses (1.5-V) are applied directly to the amplifier inputs, each recording channel settles to 20 micro-volts in less than 80 microseconds. This fast recovery makes it likely that the recording electrode-electrolyte interface, not the recording electronics, will limit artifact settling times. Artifacts are blanked in software, allowing flexibility in the choice of blanking period and the possibility of recovering neural data occurring simultaneously with non-saturating artifacts. The system has been used in-vivo to record central neuronal responses to intracochlear electrical stimulation at rates up to 2000 pulses/s.

    Using this recording system, systematic and quantitative comparisons of inferior-colliculus responses to acoustic stimulation and electrical stimulation in two configurations (monopolar and bipolar) were carried in guinea pigs and cats. Previous cochlear implant studies using isolated electrical stimulus pulses in animal models have reported that monopolar stimulus configurations elicit broad extents of neuronal activation within the central auditory system--much broader than the activation patterns produced by bipolar electrode pairs or acoustic tones. However, psychophysical and speech reception studies that use sustained pulse trains do not show clear performance differences between monopolar and bipolar configurations. To evaluate whether monopolar intracochlear stimulation can produce selective excitation of the inferior colliculus, activation widths were determined along the tonotopic axis of the inferior colliculus for acoustic tones and 1000-pulse/s electrical pulse trains in guinea pigs and cats. Electrical pulse trains were presented using an array of 6-12 stimulating electrodes distributed longitudinally along a space-filling silicone carrier positioned in the scala tympani of the cochlea. The data indicated that for monopolar, bipolar, and acoustic stimuli, activation widths were significantly narrower for sustained responses than for the transient response to the stimulus onset. Furthermore, monopolar and bipolar stimuli elicited similar activation widths when compared at stimulus levels that produced similar peak spike rates. Surprisingly, monopolar and bipolar stimuli produced narrower sustained activation than 60 dB SPL acoustic tones when compared at stimulus levels that produced similar peak spike rates. Therefore, the conclusion from these experiments was that intracochlear electrical stimulation using monopolar pulse trains can produce activation patterns that are at least as selective as bipolar or acoustic stimulation, if stimulus intensities are appropriately matched.

    The second study compared responses to acoustic and monopolar electrical stimuli that were sinusoidally amplitude modulated (SAM), in order to better model the complex signals delivered by CI processors. For both normal hearing listeners and cochlear implant users, SAM signals produce psychophysical interactions that can extend across large differences in carrier frequency or large intracochlear electrode separations. However, the neural correlates of these phenomena are not well understood. This study was designed to determine whether SAM stimuli elicit activation across a broader extent of the frequency axis of the inferior colliculus than unmodulated steady-state stimuli, and whether this activation is strongly phase locked to the SAM stimulus envelope. To address these questions neuronal activity in the inferior colliculus of guinea pigs, normal cats and chronically deafened cats was recorded in response to acoustic and electrical stimulation. Quantitative analysis of recordings indicated that the extent of inferior colliculus activation was up to 70% broader for SAM stimuli than for unmodulated steady-state stimuli in normal cats and guinea pigs and 160% broader in chronically deafened cats. This activity was also phase-locked to the SAM envelope across a broad extent of the frequency axis of the inferior colliculus. These results suggest that a number of cross-carrier frequency interactions for SAM stimuli could occur at the level of the inferior colliculus. They also show that direct comparisons of responses to acoustic and electrical SAM stimuli can reveal attributes of neural processing that underlie specific psychophysical findings in CI recipients--and thereby can provide a powerful basis for guiding development of new processing strategies for future cochlear implants.

      Cover page: Inferior-Colliculus Responses to Amplitude-Modulated and Unmodulated Acoustic Tones and Cochlear-Implant Pulse Trains
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2020)
      Hearing impairment is a major health and economic concern worldwide. Currently, the cochlear implant (CI) is the standard of care for remediation of severe to profound hearing loss, and in general, contemporary CIs are highly successful. But there is great variability in outcomes among individuals, especially in children, with many CI users deriving much less or even marginal benefit. Much of this variability is related to differences in auditory nerve survival, and there has been substantial interest in recent years in exploring potential therapies to improve survival of the cochlear spiral ganglion neurons (SGN) after deafness. Preclinical studies using osmotic pumps and other approaches in deafened animal models to deliver neurotrophic factors (NTs) directly to the cochlea have shown promising results, especially with Brain-Derived Neurotrophic Factor (BDNF). More recent studies have focused on the use of NT gene therapy to force expression of NTs by target cells within the cochlea. This could provide the means for a one-time treatment to promote long-term NT expression and improve neural survival after deafness. This review summarizes the evidence for the efficacy of exogenous NTs in preventing SGN degeneration after hearing loss and reviews the animal research to date suggesting that NT gene therapy can elicit long-term NT expression in the cochlea, resulting in significantly improved SGN and radial nerve fiber survival after deafness. In addition, we discuss NT gene therapy in other non-auditory applications and consider some of the remaining issues with regard to selecting optimal vectors, timing of treatment, and place/method of delivery, etc. that must be resolved prior to considering clinical application.
        Cover page: Neurotrophin gene therapy to promote survival of spiral ganglion neurons after deafness
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2016)
        Many previous studies have shown significant neurotrophic effects of intracochlear delivery of BDNF in preventing degeneration of cochlear spiral ganglion (SG) neurons after deafness in rodents and our laboratory has shown similar results in developing cats deafened prior to hearing onset. This study examined the morphology of the cochlear nucleus (CN) in a group of neonatally deafened cats from a previous study in which infusion of BDNF elicited a significant improvement in survival of the SG neurons. Five cats were deafened by systemic injections of neomycin sulfate (60 mg/kg, SQ, SID) starting one day after birth, and continuing for 16-18 days until auditory brainstem response (ABR) testing demonstrated profound bilateral hearing loss. The animals were implanted unilaterally at about 1 month of age using custom-designed electrodes with a drug-delivery cannula connected to an osmotic pump. BDNF (94 μg/ml; 0.25 μl/hr) was delivered for 10 weeks. The animals were euthanized and studied at 14-23 weeks of age. Consistent with the neurotrophic effects of BDNF on SG survival, the total CN volume in these animals was significantly larger on the BDNF-treated side than on the contralateral side. However, total CN volume, both ipsi- and contralateral to the implants in these deafened juvenile animals, was markedly smaller than the CN in normal adult animals, reflecting the severe effects of deafness on the central auditory system during development. Data from the individual major CN subdivisions (DCN, Dorsal Cochlear Nucleus; PVCN, Posteroventral Cochlear Nucleus; AVCN, Anteroventral Cochlear Nucleus) also were analyzed. A significant difference was observed between the BDNF-treated and control sides only in the AVCN. Measurements of the cross-sectional areas of spherical cells showed that cells were significantly larger in the AVCN ipsilateral to the implant than on the contralateral side. Further, the numerical density of spherical cells was significantly lower in the AVCN ipsilateral to the implant than on the contralateral side, consistent with the larger AVCN volume observed with BDNF treatment. Together, findings indicate significant neurotrophic effects of intracochlear BDNF infusion on the developing CN.
          Cover page: Effects of brain-derived neurotrophic factor (BDNF) on the cochlear nucleus in cats deafened as neonates
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2019)
          Outcomes with contemporary cochlear implants (CI) depend partly upon the survival and condition of the cochlear spiral ganglion (SG) neurons. Previous studies indicate that CI stimulation can ameliorate SG neural degeneration after deafness, and brain-derived neurotrophic factor (BDNF) delivered by an osmotic pump can further improve neural survival. However, direct infusion of BDNF elicits undesirable side effects, and osmotic pumps are impractical for clinical application. In this study, we explored the potential for two adeno-associated viral vectors (AAV) to elicit targeted neurotrophic factor expression in the cochlea and promote improved SG and radial nerve fiber survival. Juvenile cats were deafened prior to hearing onset by systemic aminoglycoside injections. Auditory brainstem responses showed profound hearing loss by 16-18 days postnatal. At ~ 4 weeks of age, AAV2-GFP (green fluorescent protein), AAV5-GFP, AAV2-hBDNF, or AAV5-hGDNF (glial-derived neurotrophic factor) was injected through the round window unilaterally. For GFP immunofluorescence, animals were studied ~ 4 weeks post-injection to assess cell types transfected and their distributions. AAV2-GFP immunofluorescence demonstrated strong expression of the GFP reporter gene in residual inner (IHCs), outer hair cells (OHCs), inner pillar cells, and in some SG neurons throughout the cochlea. AAV5-GFP elicited robust transduction of IHCs and some SG neurons, but few OHCs and supporting cells. After AAV-neurotrophic factor injections, animals were studied ~ 3 months post-injection to evaluate neural survival. AAV5-hGDNF elicited a modest neurotrophic effect, with 6 % higher SG density, but had no trophic effect on radial nerve fiber survival, and undesirable ectopic fiber sprouting occurred. AAV2-hBDNF elicited a similar 6 % increase in SG survival, but also resulted in greatly improved radial nerve fiber survival, with no ectopic fiber sprouting. A further study assessed whether AAV2-hBDNF neurotrophic effects would persist over longer post-injection periods. Animals examined 6 months after virus injection showed substantial neurotrophic effects, with 14 % higher SG density and greatly improved radial nerve fiber survival. Our results suggest that AAV-neurotrophin gene therapy can elicit expression of physiological concentrations of neurotrophins in the cochlea, supporting improved SG neuronal and radial nerve fiber survival while avoiding undesirable side effects. These studies also demonstrate the potential for application of cochlear gene therapy in a large mammalian cochlea comparable to the human cochlea and in an animal model of congenital/early acquired deafness.
            Cover page: AAV-Mediated Neurotrophin Gene Therapy Promotes Improved Survival of Cochlear Spiral Ganglion Neurons in Neonatally Deafened Cats: Comparison of AAV2-hBDNF and AAV5-hGDNF
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2019)
            Contemporary cochlear implants (CI) are generally very effective for remediation of severe to profound sensorineural hearing loss, but outcomes are still highly variable. Auditory nerve survival is likely one of the major factors underlying this variability. Neurotrophin therapy therefore has been proposed for CI recipients, with the goal of improving outcomes by promoting improved survival of cochlear spiral ganglion neurons (SGN) and/or residual hair cells. Previous studies have shown that glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor, and neurotrophin-3 can rescue SGNs following insult. The current study was designed to determine whether adeno-associated virus vector serotype 5 (AAV-5) encoding either green fluorescent protein or GDNF can transduce cells in the mouse cochlea to express useful levels of neurotrophin and to approximate the optimum therapeutic dose(s) for transducing hair cells and SGN. The findings demonstrate that AAV-5 is a potentially useful gene therapy vector for the cochlea, resulting in extremely high levels of transgene expression in the cochlear inner hair cells and SGN. However, overexpression of human GDNF in newborn mice caused severe neurological symptoms and hearing loss, likely due to Purkinje cell loss and cochlear nucleus pathology. Thus, extremely high levels of transgene protein expression should be avoided, particularly for proteins that have neurological function in neonatal subjects.
              Cover page: Virally Mediated Overexpression of Glial-Derived Neurotrophic Factor Elicits Age- and Dose-Dependent Neuronal Toxicity and Hearing Loss
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2013)
              Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545, 2011). Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (>50 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC thresholds were correlated with more selective activation widths as expected, but no such correlation was seen after BDNF + ES due to much greater variability in both measures.
                Cover page: Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2012)
                Previous cochlear implant studies using isolated electrical stimulus pulses in animal models have reported that intracochlear monopolar stimulus configurations elicit broad extents of neuronal activation within the central auditory system-much broader than the activation patterns produced by bipolar electrode pairs or acoustic tones. However, psychophysical and speech reception studies that use sustained pulse trains do not show clear performance differences for monopolar versus bipolar configurations. To test whether monopolar intracochlear stimulation can produce selective activation of the inferior colliculus, we measured activation widths along the tonotopic axis of the inferior colliculus for acoustic tones and 1,000-pulse/s electrical pulse trains in guinea pigs and cats. Electrical pulse trains were presented using an array of 6-12 stimulating electrodes distributed longitudinally on a space-filling silicone carrier positioned in the scala tympani of the cochlea. We found that for monopolar, bipolar, and acoustic stimuli, activation widths were significantly narrower for sustained responses than for the transient response to the stimulus onset. Furthermore, monopolar and bipolar stimuli elicited similar activation widths when compared at stimulus levels that produced similar peak spike rates. Surprisingly, we found that in guinea pigs, monopolar and bipolar stimuli produced narrower sustained activation than 60 dB sound pressure level acoustic tones when compared at stimulus levels that produced similar peak spike rates. Therefore, we conclude that intracochlear electrical stimulation using monopolar pulse trains can produce activation patterns that are at least as selective as bipolar or acoustic stimulation.
                  Cover page: Monopolar Intracochlear Pulse Trains Selectively Activate the Inferior Colliculus
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