Josef M Miller

• University of Michigan

Impairment of spiral ganglion neurons (SGNs) of the auditory nerve is a major cause for hearing loss occurring independently or in addition to sensory hair cell damage. Unfortunately, mammalian SGNs lack the potential for autonomous regeneration. Stem cell based therapy is a promising approach for auditory nerve regeneration, but proper integration...

Repeated noise exposure induces inflammation and cellular adaptations in the peripheral and central auditory system resulting in pathophysiology of hearing loss. In this study, we analyzed the mechanisms by which noise-induced inflammatory-related events in the cochlea activate glial-mediated cellular responses in the cochlear nucleus (CN), the fir...

Noise overstimulation can induce loss of synaptic ribbons associated with loss of Inner Hair Cell - Auditory Nerve synaptic connections. This study examined if systemic administration of Piribedil, a dopamine agonist that reduces the sound evoked auditory nerve compound action potential and/or Memantine, an NMDA receptor open channel blocker, would...

Background: The indications for a cochlear implant (CI) have been extended to include patients with some residual hearing. Shorter and thinner atraumatic electrodes have been designed to preserve the residual hearing in the implanted ear. However, the insertion of the electrode array into the cochlea, with potential mechanical trauma and the prese...

This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of β-carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose con...

Scientific Reports 6: Article number: 2269010.1038/srep22690; published online: March112016; updated: April202016 This Article contains errors in the legend of Fig. 5. “Post-weaning dietary supplement slowed or reversed hearing loss in Diap3-Tg mutant mice.” should read: “Post-weaning dietary supplement accelerated hearing loss in Diap3-Tg muta...

An appropriate conditioning noise exposure may reduce a subsequent noise-induced threshold shift. Although this “toughening” effect helps to protect the auditory system from a subsequent traumatic noise exposure, the mechanisms that regulate this protective process are not fully understood yet. Accordingly, the goal of the present study was to char...

Dietary supplements consisting of beta-carotene (precursor to vitamin A), vitamins C and E and the mineral magnesium (ACEMg) can be beneficial for reducing hearing loss due to aminoglycosides and overstimulation. This regimen also slowed progression of deafness for a boy with GJB2 (CONNEXIN 26) mutations. To assess the potential for treating GJB2 a...

Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of i...

This chapter reviews some of the major causes of hearing loss, the underlying pathology, the role of oxidative stress in that pathology, and the potential that antioxidant therapeutics can prevent the onset or progression of hearing loss. Age is one of the major risk factors for hearing loss. One of the key challenges in the identification of pure...

The science of free radical physiology has significantly advanced across most if not all fields of medicine, including ear, nose, and throat (ENT) medicine. Within otology, free radicals have been implicated in hearing loss after noise, aminoglycosides, cisplatin, stapedectomy, trauma during electrode insertion as part of a cochlear implant surgery...

Basic research of free radical biology has led to an increased understanding of the importance of these moieties (atoms, molecules, and ions) in both maintenance of normal tissue homeostasis and defining a common pathway to cell death in many tissues and following a variety of stress factors. In small number, they are essential to life; in high num...

Hearing performance with modern cochlear implants is dependent on remaining sensory and neural elements. CNS plasticity and individual capacity for outstanding performance with meager peripheral neural survival provide some exceptions; however, both human and animal studies support a direct relationship of performance with structural integrity/func...

The growing increase in age-related hearing loss (ARHL), with its dramatic reduction in quality of life and significant increase in health care costs, is a catalyst to develop new therapeutic strategies to prevent or reduce this aging-associated condition. In this regard, there is extensive evidence that excessive free radical formation along with...

This comprehensive volume examines the current state of free radical biology and its impact on otology, laryngology, and head and neck function. The chapters collectively highlight the interrelationship of basic and translational studies in each area, define the challenges to translation, and identify the existing basic issues that demand investiga...

The use of brain signals for interaction and for controlling robots and prosthetic devices is a rapidly emerging field of multidisciplinary research called brain–machine interfaces (BMI), or brain–computer interfaces (BCI), which has seen impressive achievements in recent years. A BMI monitors the user’s brain activity, extracts specific features f...

Gentamicin is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Treatment with this antibiotic carries the potential for adverse side effects, including ototoxicity and nephrotoxicity. Ototoxic effects are at least in part a consequence of oxidative stress, and various antioxidants have been used to attenuate gentamicin...

The protective effects of antioxidant vitamins on hearing loss are well established in animal studies but in few human studies. Recent animal studies suggest that magnesium intake along with antioxidants may act in synergy to prevent hearing loss. We examined associations between intake of antioxidant vitamins (daily β-carotene and vitamins C and E...

Background: Although cadmium and lead are known risk factors for hearing loss in animal models, few epidemiologic studies have been conducted on their associations with hearing ability in the general population. Objectives: We investigated the associations between blood cadmium and lead exposure and hearing loss in the U.S. general population while...

In the last decade, a paradigm shift has occurred in our vision for the prevention and treatment of hearing impairment. No longer are the solutions restricted to hearing aids, surgery, and implants to restore hearing, control of serum levels to prevent drug-induced ototoxicity, hearing protectors to prevent noise-induced hearing loss (NIHL), and fo...

The auditory sensory epithelium in non-mammalian vertebrates can replace lost hair cells by transdifferentiation of supporting cells, but this regenerative ability is lost in the mammalian cochlea. Future cell-based treatment of hearing loss may depend on stem cell transplantation or on transdifferentiation of endogenous cells in the cochlea. For b...

Noise-induced hearing loss (NIHL) is a significant clinical, social, and economic issue. The development of novel therapeutic agents to reduce NIHL will potentially benefit multiple very large noise-exposed populations. Oxidative stress has been identified as a significant contributor to noise-induced sensory cell death and NIHL, and several antiox...

Wnt/β-catenin signaling promotes neural differentiation by activation of the neuron-specific transcription factors, Neurogenin1 (Ngn1), NeuroD, and Brn3a, in the nervous system. As neurons in cranial sensory ganglia and dorsal root ganglia transiently express Ngn1, NeuroD, and Brn3a during embryonic development, we hypothesized that Wnt proteins co...

For patients with profound hearing loss, a cochlear implant is the only treatment available today. The function of a cochlear implant depends in part on the function and survival of spiral ganglion neurons. Following deafferentation, glial cell-derived neurotrophic factor (GDNF) is known to affect spiral ganglion neuron survival. The purpose of thi...

Temporary changes in hearing measured after use of a personal music player

Noise-induced hearing loss (NIHL) is a significant clinical, social, and economic issue. Although we once thought virtually all NIHL was a consequence of mechanical damage to cells in the inner ear, we now know that intense metabolic activity drives the formation of free radicals (short-lived, unstable, highly reactive clusters of atoms) in the inn...

As hybrid cochlear implant devices are increasingly used for restoring hearing in patients with residual hearing it is important to understand electrically evoked responses in cochleae having functional hair cells. To test the hypothesis that extracochlear electrical stimulation (EES) from sinusoidal current can provoke an auditory nerve response w...

The present investigation demonstrates the utility of the laser Doppler flowmeter to provide a measure of cochlear blood flow dynamics. Cochlear and cutaneous blood flow were compared with arterial blood pressure during and following exposure to Angiotensin II, 5% carbon monoxide, 100% oxygen, mannitol, and saline. The observations indicate that: 1...

To investigate the ototoxic potential of ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%, after administration to the guinea pig middle ear. Fifty guinea pigs were randomly assigned to 4 test groups of 10 animals each and 2 control groups of 5 animals each. The 4 test groups were treated twice daily for 4 weeks with 10 muL of (1) ciprof...

Electrical stimulation (ES) of spiral ganglion cells (SGC) via a cochlear implant is the standard treatment for profound sensor neural hearing loss. However, loss of hair cells as the morphological correlate of sensor neural hearing loss leads to deafferentation and death of SGC. Although immediate treatment with ES or glial cell line-derived neuro...

Cell replacement therapy in the inner ear will contribute to the functional recovery of hearing loss. Cell replacement therapy is a potentially powerful approach to replace degenerated or severely damaged spiral ganglion neurons. This study aimed at stimulating the neurite outgrowth of the implanted neurons and enhancing the potential therapeutic o...

Differentiation of the pluripotent neuroepithelium into neurons and glia is accomplished by the interaction of growth factors and cell-type restricted transcription factors. One approach to obtaining a particular neuronal phenotype is by recapitulating the expression of these factors in embryonic stem (ES) cells. Toward the eventual goal of auditor...

The successful function of cochlear prostheses depends on activation of auditory nerve. The survival of auditory nerve neurons, however, can vary widely in candidates for cochlear implants and influence implant efficacy. Stem cells offer the potential for improving the function of cochlear prostheses and increasing the candidate pool by replacing l...

Deafferentation of the auditory nerve from loss of sensory cells is associated with degeneration of nerve fibers and spiral ganglion neurons (SGN). SGN survival following deafferentation can be enhanced by application of neurotrophic factors (NTF), and NTF can induce the regrowth of SGN peripheral processes. Cochlear prostheses could provide target...

Proteins of the Bcl-2 family have been implicated in control of apoptotic pathways modulating neuronal cell death, including noise-induced hearing loss. In this study, we assessed the expressions of anti- and proapoptotic Bcl-2 genes, represented by Bcl-xL and Bak following noise exposures, which yielded temporary threshold shift (TTS) or permanent...

Cochlear implant surgery is currently the therapy of choice for profoundly deaf patients. However, the functionality of cochlear implants depends on the integrity of the auditory spiral ganglion neurons. This study assesses the combined efficacy of two classes of agents found effective in preventing degeneration of the auditory nerve following deaf...

The extent to which neurotrophic factors are able to not only rescue the auditory nerve from deafferentation-induced degeneration but also promote process regrowth is of basic and clinical interest, as regrowth may enhance the therapeutic efficacy of cochlear prostheses. The use of neurotrophic factors is also relevant to interventions to promote r...

To define the role of free radical formation and potential energy depletion in noise induced hearing loss (NIHL), we measured the effectiveness of tempol (free radical scavenger) and creatine (enhances cellular energy storage) alone and in combination to attenuate NIHL. Guinea pigs were divided into four treatment groups: controls, 3% creatine diet...

Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7-10 days after noise exposure. Reduction in...

Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7-10 days following noise exposure, and one mechanism underlying n...

Based on in vitro studies, it is hypothesized that neurotrophic factor deprivation following deafferentation elicits an oxidative state change in the deafferented neuron and the formation of free radicals that then signal cell death pathways. This pathway to cell death was tested in vivo by assessing the efficacy of antioxidants (AOs) to prevent de...

Brain derived neurotrophic factor (BDNF) and transforming growth factor-beta (TGFbeta) subtypes have demonstrated their importance in cochlear functions. The aim of this study was to determine gene and protein expression patterns of BDNF, TGFbeta1/2 and their main receptors trkB and TGFbetaR1/R2 in the auditory nerve and inferior colliculus of norm...

Nerve growth factors play key roles in spiral ganglion cells survival and excitability. Our aim was to determine gene expression patterns of glial cell line-derived neurotrophic factor family (GDNF) members and their receptors in the auditory nerve and inferior colliculus of deafened rats. The gene expression of GDNF, persephin, artemin and neurtur...

Time lapse video recordings of cultured adult human and guinea pig spiral ganglion (hSG and gpSG) show that mitogen responsive progenitor/stem cells develop in the form of spheres that proliferate and differentiate into mature neurons and glia cells. Neurospheres, cultured with EGF and bFGF showed expression of nestin and incorporation of 5'-Bromo-...

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in sensory cell and neural death in the peripheral nervous system, including damage induced by noise trauma. Antioxidant administration prior to or concomitant with noise exposure can prevent auditory deficits, but the efficacy of a delayed treatment is not known. We hav...

Apoptosis plays a critical role in neuronal cell death, including sensory cell death in noise-induced hearing loss. The purpose of this study is to investigate the role of a caspase-independent apoptotic pathway, involving apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in cell death in the inner ear after intense noise exposure (120 dB...

The protective effect of dexamethasone (DEX) against noise-induced trauma, as reflected in hair cell destruction and elevation in auditory brainstem response (ABR) sensitivity, was assessed in guinea pigs. The animals were administered DEX (1, 10, 100, and 1000 ng/ml) or artificial perilymph (AP) via a mini-osmotic pump directly into scala tympani...

Acoustic overstimulation increases Ca(2+) concentration in auditory hair cells. Because calcineurin is known to activate cell death pathways and is controlled by Ca(2+) and calmodulin, this study assessed the role of calcineurin in auditory hair cell death in guinea pigs after intense noise exposure. Immediately after noise exposure (4-kHz octave b...

Benefits of cochlear prostheses for the deaf are dependent on survival and excitability of the auditory nerve. Degeneration of deafferented auditory nerve fibers is prevented and excitability maintained by immediate replacement therapy with exogenous neurotrophic factors, in vivo. It is important to know whether such interventions are effective aft...

Reactive oxygen and reactive nitrogen species (ROS, RNS) formed in the inner ear in response to high-intensity noise are thought to play an important role in noise-induced hearing loss (NIHL). ROS appear rapidly and transiently in the inner ear during and following noise exposure, while hair cell loss progresses over time stabilizing two or more we...

Immature dorsal root ganglion (DRG) neurons have previously been shown to survive implantation to the cavity of extirpated adult native DRG, send axons via the dorsal root into the host spinal cord and make functional sypnatic connections. Regeneration or replacement of the auditory nerve would provide a major intervention in the clinical treatment...

The tissue tolerance of N-chlorotaurine (NCT), a mild endogenous antimicrobial oxidant, has been investigated by application to the guinea pig middle ear. The animals were implanted with a novel cannula system that allows chronic external drug delivery to the round window niche. In the first part of the study, 3 animals each received 100 μL of 0.1%...

Amelioration of cisplatin-induced side-effects is of great clinical importance. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. The ideal substance for local administration has yet to be identified. Thiourea (TU) ha...

There is increasing evidence that at least one function of both the medial and the lateral olivocochlear efferent systems is to provide adjustment of the set point of activity in their postsynaptic target, the outer hair cells and afferent processes, respectively. New results, summarized in this review, suggest that both efferent systems can provid...

It has previously been demonstrated that ototoxicity induced by systemic administration of cisplatin is reduced by concomitant administration of melanocortins, like alpha-melanocyte stimulating hormone (alpha-MSH). However, these experiments were hampered by large interanimal variability. Therefore, we re-investigated the effects of systemically ad...

Noise exposure induces the formation in the cochlea of 8-isoprostaglandin F2α (8-iso-PGF2α), a marker for reactive oxygen species [Ohinata et al., 2000a] and a potent vasoconstrictor, raising the possibility that 8-iso-PGF2α may be responsible for noise-induced reductions in cochlear blood flow (CBF). To test this hypothesis, CBF was assessed in th...

The influence of neonatal deafness on cochlear electrically evoked Fos expression in the auditory brainstem was examined. Newborn rats were deafened by systemic injection of kanamycin, 1 mg/g daily for 12 days. At 4, 5, 6 or 8 weeks of age, these animals received cochlear electrical stimulation with a basal monopolar electrode for 90 minutes. Age-m...

Patients undergoing temporal bone surgery or subjects working with vibrating tools may develop vibration-induced hearing loss (VHL). The aim of this study was to characterize the effects of pretreatment with N-acetylcysteine (NAC) or the neurotrophic factors, brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), on VHL in...

In order to assess the role of L-type voltage-gated calcium channels in electrical stimulation-mediated neuroprotection in vivo, we assessed survival of primary auditory afferents (spiral ganglion cells) in systemically deafened guinea pigs following chronic electrical stimulation with or without intracochlear infusion of verapamil, an L-type volta...

In order to delineate mechanisms of noise-induced hearing loss, we assessed noise trauma and its pharmacological modulation in the guinea pig. Auditory threshold shifts (measured by auditory brainstem responses), hair cell loss and lipid peroxidation (8-isoprostane formation) were determined in the absence or presence of agents known to influence t...

As with other cranial nerves and many CNS neurons, primary auditory neurons degenerate as a consequence of loss of input from their target cells, the inner hair cells (IHCs). Electrical stimulation (ES) of spiral ganglion cells (SGCs) has been shown to enhance their survival. Glial cell line-derived neurotrophic factor (GDNF) has also been shown to...

Noise exposure induces the formation in the cochlea of 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), a marker for reactive oxygen species [Ohinata et al., 2000a] and a potent vasoconstrictor, raising the possibility that 8-iso-PGF(2alpha) may be responsible for noise-induced reductions in cochlear blood flow (CBF). To test this hypothesis, CBF...

This study demonstrates the attenuation of aminoglycoside ototoxicity by cochlear infusion of dexamethasone (Dex) using a microcannulation-osmotic pump delivery system. The results indicate that treating the cochlea with Dex both before and after kanamycin administration was more effective in preventing ototoxicity than Dex treatment only after kan...

Noise overstimulation will induce or influence intracellular molecular pathways in the cochlea. One of these is the 'classical' stress response pathway involving heat shock proteins. Hsp70 is induced in the cochlea by a wide variety of stresses including noise, hyperthermia and ototoxic drugs. When a stress that induces Hsp70 is applied to the coch...

Inner ear disease due to hair cell loss is common, and no restorative treatments for the balance and hearing impairment are currently available. To develop clinical means for enhancing protection and regeneration in the inner ear, it is necessary to understand the molecular basis for hereditary and acquired deafness and vestibular disorders. One ap...

Deafness, with loss of sensory (hair) cells, results in progressive pathophysiological changes ending in the degeneration of most auditory nerve neurons. It is now possible to consider these events in the broader context of anti-apoptotic survival factors in the peripheral and central nervous system. One consequence of deafferentation of a neuron i...

The influence of noise exposure on the endothelial transport system in the cochlea was investigated using cationic polyethyleneimine (PEI), since systemically administered PEI passes through the capillary endothelial cell and attaches to basal lamina (BL) anionic sites in the cochlea. Under general anesthesia, all guinea pigs were administered an i...

A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, r...

Environmental inner ear insults often lead to hair cell injury and loss. Therapeutic measures for the prevention of hair cell loss are currently limited. Several reports have demonstrated the applicability of growth factors for hair cell protection. The goal of the experiments presented here was to assess the protective capability of the human GDNF...

Recent findings that glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and transforming growth factor a can protect the auditory hair cells from acoustic trauma or aminoglycoside ototoxicity in vivo raise the question of whether other neurotrophic factors can also protect the hair cells in vivo. Fibroblast growth factor-2 (...

We have studied the morphological and cellular changes in the cochlear nucleus (CN) after cochlear nerve degeneration and whether these changes can be prevented by rescuing the primary cochlear neurons from degeneration with local glial cell line derived neurotrophic factor (GDNF) treatment. Degeneration of spiral ganglion neurons was seen to lead...

Fos immunoreactive (IR) staining was used to examine changes in excitatory neuronal activity in the rat inferior colliculus (IC) between normal hearing and 21 day deaf rats evoked by basal or apical monopolar cochlear electrical stimulation. The location of evoked Fos IR neurons was consistent with expected tonotopic areas. The number of Fos IR cel...

This study investigates the correlation between the formation of reactive oxygen species (ROS) and auditory damage in noise-induced hearing loss. The noise exposure (4-kHz octave band, 115 dB SPL, 5 h) created permanent threshold shifts at frequencies from 2 to 20 kHz. The lipid peroxidation product, 8-isoprostane, was determined biochemically and...

The protective efficacy of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) at 1 or 10 microg/ml was assessed in guinea pigs exposed to 4 kHz octave band noise at 115 dB SPL for 5 h. BDNF, NT-3 or artificial perilymph was delivered to the scala tympani via a mini-osmotic pump, beginning 4 days prior to noise exposure and continuin...

The generation of reactive oxygen species (ROS) is thought to be part of the mechanism underlying noise-induced hearing loss (NIHL). Glutathione (GSH) is an important cellular antioxidant that limits cell damage by ROS. In this study, we investigated the effectiveness of a GSH supplement to protect GSH-deficient animals from NIHL. Pigmented guinea...

Fos-like immunoreactivity evoked by basal, second or apical turn bipolar intracochlear electrical stimulation was evaluated in the spiral ganglion and cochlear nuclei. At stimulation levels of six times the electrically evoked auditory brain stem response thresholds, immunoreactive neurons were observed at appropriate discrete cochleotopic regions...

Gentamicin administration often results in cochlear and/or vestibular hair cell loss and hearing and balance impairment. It has been demonstrated that adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor (GDNF) can protect cochlear hair cells against ototoxic injury. In this study, we evaluated the protective effects of...

We examined the effectiveness of glial cell line-derived neurotrophic factor (GDNF) to attenuate cochlear damage from intense noise stress. Subjects were exposed to 115 dB SPL one octave band noise centered at 4 kHz for 5 h. They received artificial perilymph with or without GDNF into the left scala tympani at 0.5 μl/h from 4 days before noise expo...

As a follow-up to the Brown et al., 1993 technique, we have made several improvements to the micro-cannula, osmotic pump procedure, enabling chronic intracochlear infusions while maintaining hearing. In addition, acute bolus injection techniques are briefly described in guinea pig, rat and mouse.

Trauma and loss of cochlear inner hair cells causes a series of events that result first in the retraction of the peripheral processes of the auditory nerve, scar formation in the organ of Corti, and over the course of weeks to months (depending on the species) the loss of auditory nerve cell bodies (spiral ganglion cells). Neurotrophic factors pla...