The inner ear, which contains both the organ of hearing, the cochlea, and the organ of balance, the vestibular system, is embedded deep within the skull near the brainstem in the petrous bone, one of the hardest bones in the body. The extreme inaccessibility of the cochlea, coupled with its very small size, creates unique though tractable problems for cochlear drug delivery. The complexity of the cochlear structures and their extreme sensitivity to the changes in fluid volume also must be considered.
The cochlea can be thought of as a long coiled tube, 31–33 mm in human, [20
] looking much like the snail shell from which it derives its name. It varies in diameter along its length from apex to base. Stretched across the middle of the tube is the organ of Corti, which is the highly organized basilar membrane that contains the mechano-sensory cells of the inner ear. The basilar membrane moves in response to sound waves that enter the inner ear. The structure of the organ of Corti is tonotopically organized so that high frequency sounds produce the greatest motion in the base of the tube and low frequency sounds move the organ most at the apex.
The mechano-sensory cells of the ear are called hair cells because early microscopists considered the stereocilia at the apical surfaces to look like tiny hairs. Hair cells are organized into rows that run the length of the coil from its base to its apex and are organized tonotopically in their response to sound. There are two types of hair cells: a single row of inner hair cells responds to sound by releasing a neurotransmitter to excite afferent auditory neurons, and three rows of outer hair cells serve to amplify the sound-evoked motion of the basilar membrane to more effectively deliver frequency-specific stimulation to the inner hair cells.
If one looks at a cross section through the cochlea, as shown in , a distinctive feature is the presence of three relatively large fluid-filled compartments. These three compartments coil up the cochlea along with the organ of Corti. The middle compartment is the scala media, which is filled with endolymph (discussed below). The scala media forms a border of the organ of Corti, and the apical surfaces of cells in the organ of Corti, including the hair cells, project into the scala media. The lower and upper fluid compartments respectively are the scala tympani and scala vestibuli, both of which are filled with perilymph. These two compartments communicate with each other at the apex of the cochlea through the helicotrema. There are two orifices in the surface of the cochlear bone, both of which are located at the base of the cochlea. The round window is a membranous opening in the bone within the scala tympani. It sits at the base of the scala tympani and is very compliant, capable of bulging into the middle ear. It separates perilymph from the middle ear space. The oval window, in the scala vestibuli, contains the footplate of the stapes, one of the middle ear bones, that transmits acoustic vibrations from eardrum to the inner ear.
Figure 1 (a) A mid-modiolar section from a human temporal bone indicates the coiled structure of the cochlea as it winds around a central modiolus, which contains the spiral (auditory) ganglion and its associated auditory nerve fibers. (b) Each segment contains (more ...)
Perilymph is the primary fluid of the cochlea. It bathes most of the cells within the cochlea including the basolateral surfaces of the sensory cells, the neurons, and most of the other specialized structures within the cochlea. Perilymph is similar to cerebrospinal fluid (CSF), with which it is in diffusional continuity, though protein concentration in perilymph is significantly (10 to 20 times) higher than in CSF [21
]. The volume of perilymph in the human cochlea is about 70 µL, with around 40 µl in the scala tympani [26
The scala media is filled with endolymph, about 8 µL in human, which has an ionic composition similar to the intracellular environment, high in potassium and low in sodium. The fluid space provides a highly unique environment for the apical surface of the hair cells. The cells that form the borders of the scala media are all connected by tight junctions. The primary function of the scala media is to provide an electrochemical environment that supports the hair cells’ ability to transduce mechanical motion into electrical potentials. It contains a relatively large (100 mV) positive electrical potential. This unique electrochemical environment is created by a structure called the stria vascularis, which is, as its name implies, highly vascularized. It runs along the outside of the scala media and extracts energy from the blood that is needed to create the electrochemical battery of the scala media.
The cochlea can be viewed as a set of membranous tubes within a coiled bony tunnel with the organ of Corti, containing the hair cells, stretched across the middle, the scala media providing the electrochemical battery for transduction forming the apical border of the organ of Corti, and tubes containing perilymph and bathing most of the cochlear structures on either side of the organ of Corti and scala media. The stria vascularis runs along the outside of the scala media. Finally, the coil of the cochlea winds around the modiolus, into which are packed the cell bodies of the auditory neurons, appropriately termed the spiral ganglion neurons (SGN). These bipolar neurons send dendrites to the inner hair cells and axons to the brain.
Airborne sound passes through the external auditory canal and moves the tympanic membrane. Motion of the membrane by the sound waves is transmitted through the ossicles (3 tiny bones: the malleus, the incus, and the stapes) to transfer the airborne sound into the movement of the footplate of the stapes, which is inserted in the oval window of the inner ear. The piston-like motion of the stapes transfers a pressure wave to the fluid-filled space of the inner ear behind the oval window. Thus the middle ear functions to match the acoustic impedance of the airborne sound to that of fluid environment of the inner ear.
Motion of the basilar membrane ultimately produces movement of the stereocilia at the apical surfaces of the hair cells. As the stereocilia move, mechanically sensitive ion channels on the stereocilia open and shut in synchrony with the motion. As a result, the hair cells depolarize and repolarize with an electrical waveform that is similar to the mechanical motion. The outer hair cells possess resonance properties that are tonotopically organized to correspond to the maximum sensitivity of the basilar membrane, so that they in essence amplify the motion of the basilar membrane over a narrow range of frequencies, enhancing the frequency discrimination of the system. The inner hair cells respond to the outer hair cell-enhanced basilar membrane motion by releasing neurotransmitter from the base of the hair cell. This release activates the auditory nerve fibers.
There are a number electrophysiological parameters one can monitor to assess cochlear function, and some of these (distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs)) are often used clinically. Current flowing through the transduction channels in the hair cells will generate a cochlear microphonic (CM) potential that mimics the acoustic waveform. One can record the CM potential to get an indication of hair cell function or to assess the effects of drugs on the hair cells. The CM is dominated by response of the outer hair cells. Another monitor of hair cell function, DPOAEs, takes advantage of the mechanical motion induced in the basilar membrane by the outer hair cell resonance. This mechanical response by the outer hair cell is propagated back out through the middle ear as an acoustic signal that can be measured in the auditory canal. This mechanical response is inherently nonlinear and will generate distortion products that can be detected noninvasively in the ear canal. The distortion product corresponding to a particular frequency is quite robust and is commonly used as a metric of cochlear function, and in particular, outer hair cell function.
Responses of the auditory neurons can be monitored individually with microelectrodes, but it is also feasible to monitor the synchronous activity of groups of nerve fibers. The compound action potential (CAP) is measured with a ball electrode placed near the RWM in response to a click or a tone pip. In this case, a group of fibers discharge synchronously in response to the stimulus, producing a signal large enough to measure even at a distance. Tone pips of varying frequency allow the investigator to assess specific regions along the length of the cochlea, e.g. responses to high frequency tone pips are generated in the basal portion of the organ of Corti. This measure is surgically invasive but useful in animal experiments. Clinically, it is possible to monitor these responses with electrodes placed on the surface of the scalp by averaging responses to a large number of stimuli. These ABRs are clinically useful in providing objective assessment of cochlear function noninvasively.