In the last part of the past century, reseach solved some of the greatest mysteries in hearing science. Determining the basis of the elegant qualities of mammalian hearing in the electromotility of the outer hair cells of the cochlea was an extraordinary discovery.
Subsequent findings that identified a specific protein as the motor molecule responsible for electromotility were just as remarkable. Other research involving the central auditory nervous system uncovered significant findings as well. The following discussion will review current research in the hearing sciences that is especially notable for its relevance to the clinical setting.
Hair Cell Research
As noted above, outer hair cell electromotility is crucial for the enhanced sensitivity and frequency selectivity of the mammalian cochlea. Great advances have been made in substantiating the notion that the basis of cochlear amplification is in the microvibrations of the outer hair cells of the cochlea. These advances recently have been complemented by determining the molecular mechanism of electromotility. The finding that prestin, a membrane protein embedded in the lateral wall of the outer hair cell, is the molecular mechanism of electromotility has allowed a more complete understanding of the beginning stages of both the normal hearing process and the development of hearing loss.
Our increased understanding of the central role that passive and active outer hair cell mechanics play in hearing is also relevant to broader research questions based on the ability of otoacoustic emissions to monitor the status of the mechanisms responsible for the fine qualities of human hearing. The clinical utility of otoacoustic emissions stems from the observation that outer hair cells represent the most vulnerable structural component of the cochlea, and damage to these sensory cells is associated with both hearing loss and loss of otoacoustic emissions.
There is no doubt that recent investigations aimed at refining otoacoustic emission testing have led to the development of rapid, low-cost methods of screening all newborns for hearing loss. Universal newborn hearing screening is becoming the standard of care because related research suggests that early intervention significantly improves language development among infants and children with hearing loss.
Some of the most common causes of hearing loss in the adult population are mediated by ototoxic drugs, loud nois es, or aging processes. For example, it has long been known that certain common classes of chemotherapeutic (e.g., cisplatin) and antibiotic (e.g., gentamicin) drugs cause hearing loss. Similarly, the permanent, damaging effects of exposure to loud noise were also recognized during the first half of the last century. Recent efforts in "training" the ear to be more resistant to intense sounds through prophylactic noise exposure have discovered that the cochlear efferent system, which comprises a major portion of the descending central auditory nervous system, may play a crucial role in protecting individuals from noise-induced hearing loss in noisy work and recreational environments. Finally, contemporary research with inbred mutant mouse strains that exhibit early age-related hearing loss has highlighted the importance of genetic factors in contributing to hearing loss associated with aging, that is, presbycusis.
One prevailing theory of the cochlear injury caused by all these disorders is that such damaging events activate an initial toxic biochemical episode that induces the formation of reactive oxygen species, which trigger lethal downstream metabolic pathways of cell death. These findings offer great hope for the eventual development of otoprotective strategies to prevent these common disorders by introducing scavengers of free oxygen radicals to provide a pharmacological rescue of sensory cells.
Many of the problems related to childhood hearing loss are hereditary. Enormous strides in identifying the large number of genes responsible for hereditary hearing loss are being made by scientists around the world. In the hunt for genes that cause deafness, one of the greatest success stories in the past few years is the identification of a gene that makes an appreciable contribution to autosomal recessive nonsyndromic hearing loss and also accounts for about 20% of all childhood deafness. A single mutation of a gene known as GJB2 leads to a disruption of the protein it encodes, connexin 26, which is a gap junction protein that maintains the high potassium concentration within the cochlea's scala media necessary for normal stimulus transduction. This discovery has made diagnostic genetic testing available to patients with prelingual, severe-to-profound sensorineural hearing loss of unknown origin and resulted in reassurance and genetic counseling for concerned families, and early habilitation of identified patients.
Most recently, genetic research is gradually moving from gene discovery and identification to understanding gene function. As the specific sequences of DNA that comprise the genes contributing to deafness are becoming known, a greater understanding of the function of such proteins encoded by these genes is also developing. Recognizing the underlying causal mutations make experimental, "space-age" treatment methods such as gene-replacement therapy more realistic. The feasibility of delivering genes encoding missing molecules directly to the cochlea depends on success of developing new therapeutic technologies. These technologies would safely express transgenes in the inner ear that surmount some of the limitations caused by the short half-life of critical enzymes administered systemically, or the lack of uptake by cells of intracochlear-injected proteins.
Deafness was considered a permanent and untreatable disorder until very recently. A major breakthrough occurred during the last decade when it was discovered that, in certain species including fish and birds, the hair cell receptors in the inner ear that are destroyed during deafness can regenerate. Over the past few years, scientists have investigated the fundamental processes that regulate the regeneration of sensory cells so that the biological signals that trigger regeneration can be identified. Once these signals are known, medical treatments can be developed to restore the hearing of individuals with severe and profound hearing loss through hair cell regeneration.
Central Auditory Nervous System
During the past decade, research has provided greater insight into the reorganization of the central auditory nervous system in response to a damaged peripheral ear. Many guiding principles of experience-dependent plasticity have been developed primarily in animal models such as the barn owl, which exhibits adaptive changes in central auditory neuronal activity in response to deliberate manipulations of the peripheral ear that cause abnormal hearing. However, not all forms of hearing loss are due to sensory processing anomalies in the peripheral ear, but to abnormal information processing in the brain.
Disturbances in the central auditory system that interfere with the processes of learning language, reading, and verbal communication are being better diagnosed and treated using advanced electrophysiological, magnetoelectroencephalographic, and other functional methods that include high-resolution functional magnetic resonance imaging and positron emission tomography. All these functional imaging strategies show great promise in providing a better understanding of the processes that support the reorganization of neural pathways and neuronal-distribution patterns associated with activity-dependent plasticity. Hopefully, increased understanding of the reactive plasticity of the abnormal auditory system will lead to the development of more efficacious hearing aids and cochlear implants for treating individuals with hearing loss.
In other applications, technological developments have led to sophisticated algorithms and automated procedures for objective assessment of lower auditory brainstem function using auditory brainstem responses as well as the advancement of other evoked response procedures. For example, initial investigations of the auditory steady-state response as a frequency-specific estimator of audiometric thresholds in infants are very promising. In addition, magnetic field recordings using magnetoencephalographic methods promise to provide insight into the abnormal auditory brain processes underlying dyslexia.
Moreover, functional magnetic resonance imaging is being used to track the cortical representation of restored hearing in patients being treated for idiopathic sudden sensorineural hearing loss. One interesting finding from this study using functional brain imaging is that the alteration of the cortical response in deafness occurs much earlier than suggested by previous reports using more classic morphological methods. Positron emission tomography remains a useful measure of activity-induced hemodynamic changes in higher-level auditory systems in patients with cochlear implants or auditory prostheses that incorporate an implanted magnet that may limit the use of magnetic resonance imaging for functional brain testing.
Beyond the continued technological development of better hardware components, a number of important advances have been made over the past few years with respect to cochlear implants for severe and profound hearing loss. Observations of the high degree of plasticity in developing brains have led to children under 2 years of age receiving implants. Bilateral implants are also being used, and an auditory brainstem implant has been developed for patients who have neurofibromatosis type 2 who have lost the integrity of their auditory nerves bilaterally following removal of vestibular schwanomas.
Finally, in the growing era of surgical audiology, several types of middle-ear implantable hearing aids are undergoing rapid development and expanding the options for selecting the optimal medical device for a particular hearing problem. These implants, which primarily offer improved cosmesis and efficient energy transfer, add another dimension to the medical device industry. Most certainly, though, due to tremendous progress in understanding the cellular and molecular workings of such biologically active substances as neurotrophic factors, the expansion of the cochlear implant into a biological prosthesis that dispenses compounds to repair and regenerate critical cochlear structures is a real possibility within the next decade.
Recent advances in the cellular and molecular biology and molecular genetics of hearing and deafness are clearly being transferred from the research laboratory to the clinical arena. One noteworthy aspect of the current research climate in the hearing sciences is its truly multidisciplinary nature. Rather than depending on one investigator to master expertise in a number of relevant disciplines such as developmental biology, biophysics, molecular genetics, and psychoacoustics, researchers from these distinct fields are interacting and growing closer together.
During the beginning years of this new century, these team efforts are bound to further research on the cellular, molecular, and genetic mechanisms of both inner ear function and dysfunction at an accelerated rate. Such endeavors by researchers with diverse but complementary expertise will enable both scientists and clinicians to develop more powerful ways to diagnose, treat, cure, and prevent hearing loss.