Electroacoustic stimulation: now and into the future.

Cochlear implants have provided hearing to hundreds of thousands of profoundly deaf people around the world. Recently, the eligibility criteria for cochlear implantation have been relaxed to include individuals who have some useful residual hearing. These recipients receive inputs from both electric and acoustic stimulation (EAS). Implant recipients who can combine these hearing modalities demonstrate pronounced benefit in speech perception, listening in background noise, and music appreciation over implant recipients that rely on electrical stimulation alone. The mechanisms bestowing this benefit are unknown, but it is likely that interaction of the electric and acoustic signals in the auditory pathway plays a role. Protection of residual hearing both during and following cochlear implantation is critical for EAS. A number of surgical refinements have been implemented to protect residual hearing, and the development of hearing-protective drug and gene therapies is promising for EAS recipients. This review outlines the current field of EAS, with a focus on interactions that are observed between these modalities in animal models. It also outlines current trends in EAS surgery and gives an overview of the drug and gene therapies that are clinically translatable and may one day provide protection of residual hearing for cochlear implant recipients.

A partial hearing animal model for chronic electro-acoustic stimulation.

OBJECTIVE: Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. APPROACH: This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. MAIN RESULTS: Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. SIGNIFICANCE: This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual hearing following cochlear implantation. The ability to record CAPs via the CI has clinical direct relevance for obtaining objective measures of residual hearing.

Cochlear implantation for chronic electrical stimulation in the mouse.

The mouse is becoming an increasingly attractive model for auditory research due to the number of genetic deafness models available. These genetic models offer the researcher an array of congenital causes of hearing impairment, and are therefore of high clinical relevance. To date, the use of mice in cochlear implant research has not been possible due to the lack of an intracochlear electrode array and stimulator small enough for murine use, coupled with the difficulty of the surgery in this species. Here, we present a fully-implantable intracochlear electrode stimulator assembly designed for chronic implantation in the mouse. We describe the surgical approach for implantation, as well as presenting the first functional data obtained from intracochlear electrical stimulation in the mouse.

Anti-apoptotic gene Bcl2 is required for stapes development and hearing.

In this paper we describe novel and specific roles for the apoptotic regulators Bcl2 and Bim in hearing and stapes development. Bcl2 is anti-apoptotic while Bim is pro-apoptotic. Characterization of the auditory systems of mice deficient for these molecules revealed that Bcl2⁻/⁻ mice suffered severe hearing loss. This was conductive in nature and did not affect sensory cells of the inner ear, with cochlear hair cells and neurons present and functional. Bcl2⁻/⁻ mice were found to have a malformed, often monocrural, porous stapes (the small stirrup-shaped bone of the middle ear), but a normally shaped malleus and incus. The deformed stapes was discontinuous with the incus and sometimes fused to the temporal bones. The defect was completely rescued in Bcl2⁻/⁻Bim⁻/⁻ mice and partially rescued in Bcl2⁻/⁻Bim⁺/⁻ mice, which displayed high-frequency hearing loss and thickening of the stapes anterior crus. The Bcl2⁻/⁻ defect arose in utero before or during the cartilage stage of stapes development. These results implicate Bcl2 and Bim in regulating survival of second pharyngeal arch or neural crest cells that give rise to the stapes during embryonic development.

Fatigue in mammalian skeletal muscle stimulated under computer control.

Functional electrical stimulation (FES) is used to provide paralyzed human subjects with postural support and a limited range of movements. Problems encountered with FES include jerky movements from tension oscillations during stimulation and rapid muscle fatigue. In this paper, we report experiments on anesthetized cats that test a new, computer-controlled method of stimulation of the muscle nerve supply, distributed across several inputs, which reduces these problems. After 5 min of continuous, distributed stimulation of the medial gastrocnemius muscle at 6 pulses per second (pps) across 6 channels, tension fell to 55.9 +/- 3.9% (SE) of its original value. In comparison, after 5 min of synchronous stimulation of one muscle portion at 36 pps, tension fell to 11 +/- 3.7%. At higher stimulation rates, 10 pps per channel (distributed) and 60 pps (synchronous), the differences in fatigue were even greater. Similar results were obtained when an intermittent, rather than a continuous, stimulation protocol was used. These findings indicate that distributed stimulation has important advantages over other methods for applications such as FES.

Tension changes in the cat soleus muscle following slow stretch or shortening of the contracting muscle.

1. The permanent extra tension after a stretch and the deficit of tension after a shortening in the soleus muscle of the anaesthetised cat were measured using distributed nerve stimulation across five channels. At low rates of stimulation the optimum length for a contraction was several millimetres longer than that when higher rates of stimulation were used, so that movements applied over the same length range could be on the descending limb of the full activation curve but on the ascending limb of the submaximal activation curve. 2. The extra tension after stretch and the depression after shortening were present only near the peak and on the descending limb of the length-tension curve. Effects on final tension of changing the speed and amplitude of stretches or shortenings were found to be small. 3. Statistical analysis showed that variations in the tension excess or deficit due to changing stimulus rate could be entirely attributed to the effect of stimulus rate on the length-tension relation, as when length was expressed relative to optimum for each rate, stimulus rate was no longer a significant determinant of the tension excess or deficit. 4. The extra tension after stretch and the depression after shortening disappeared if stimulation was interrupted and tension briefly fell to zero. 5. These effects were explained in terms of a non-uniform distribution of sarcomere length changes at long muscle lengths. During stretch some sarcomeres are stretched to beyond overlap while others lengthen hardly at all. During shortening some sarcomeres shorten much further than others. 6. These mechanisms have important implications for exercise physiology and sports medicine.

The role of muscle receptors in the detection of movements.

This review discusses the role of muscle receptors, in particular, that of muscle spindles, in the detection of movements, both passive and active. Emphasis is placed on the importance of conditioning the muscles acting at a joint before making measurements of thresholds to passive movements, to take into account muscle's thixotropic property. The detection threshold:movement velocity relation is discussed and described for a number of different joints. Implications for muscle spindles are considered from the generalisation that, when expressed in terms of proportion of muscle fascicle length change, detection thresholds are about the same at different joints. It is concluded that the available data supports the view that muscle spindles lie in parallel with only a portion of a muscle fascicle and not the whole fascicle. At the elbow joint, where it has been tested, movement detection threshold is lower during passive movements than during contraction of elbow muscles. Both peripheral mechanisms and mechanisms operating within the central nervous system may be responsible for the rise in threshold. The signalling of movements by spindles during a contraction raises the question of how the central nervous system is able to extract the length signal under such circumstances, given that there is likely to be co-activation of alpha and gamma motoneurones. The evidence for a central subtraction of fusimotor-evoked impulses and some recent experiments relevant to this idea are described. In conclusion, a number of points of uncertainly have been revealed in this area and these should be the subject of future experiments.

The responses of muscle spindles to small, slow movements in passive muscle and during fusimotor activity.

We have previously shown that movement detection thresholds at the human elbow joint were less than a degree of joint rotation in the passive limb but were higher if they were measured while subjects co-contracted elbow muscles [A.K. Wise, J.E. Gregory, U. Proske, J. Physiol., 508 (1998) 325-330]. Here we report observations on the responses of muscle spindles of the soleus muscle of the anaesthetised cat to determine their ability to signal small length changes in the passive muscle and during a contraction, under conditions resembling those of the human experiments. After appropriate conditioning of the muscle to control for history effects, primary endings of muscle spindles showed thresholds to ramp stretch at 20 micrometers s-1 of between less than 5 micrometers and 15 micrometers, which translates to 0.05 degrees -0.15 degrees of human elbow joint rotation. Thresholds were much higher following conditioning to introduce slack in the muscle. Since during a voluntary contraction there is likely to be alpha:gamma co-activation, responses of spindles were also recorded during slow stretches (100 micrometers at 20 micrometers s-1) during static fusimotor stimulation, dynamic fusimotor stimulation, combined fusimotor stimulation and fusimotor plus skeletomotor stimulation. Invariably, responses to passive stretch were larger than during motor stimulation. It is concluded that spindles are sensitive enough to signal fractions of a degree of elbow joint rotation and that the rise in threshold observed during a voluntary contraction may be accounted for by the actions of fusimotor and skeletomotor axons on spindle stretch responses.

Muscle history, fusimotor activity and the human stretch reflex.

1. The previous history of contraction and length changes of a muscle influences the size of the stretch reflex and H reflex. Here we ask, is this dependence due to changes in mechanical properties of extrafusal fibres, intrafusal fibres of spindles, or both? 2. The soleus muscle of human subjects was conditioned using either a voluntary contraction or a contraction evoked by low-strength electrical stimulation, in the range 0-25 % of maximum. Following conditioning, reflexes were increased by more than twofold above the no-contraction value by a voluntary contraction of 5 % of maximum, or more, but not by electrical stimulation which presumably did not contract the intrafusal fibres of spindles. 3. When the muscle was conditioned with a contraction at a length shorter than the test length, rather than at the test length, a depressing effect on reflexes was attributed to both the burst of impulses generated in spindles when the muscle was stretched back to the test length and to a reduced stretch sensitivity of muscle spindles. 4. The experiments demonstrate the importance of keeping the muscle and its spindles in a defined mechanical state when measuring reflexes. They also point to the powerful facilitating influences of conditioning muscle contractions provided they recruit the intrafusal fibres of spindles.

Detection of movements of the human forearm during and after co-contractions of muscles acting at the elbow joint.

1. We report here observations on the effects of muscle contraction history on thresholds for the detection of movements at the elbow joint of human subjects. Detection thresholds were measured in the direction of flexion or extension to movements of the relaxed forearm at a speed of 0.2 deg s-1 with the elbow at 90 deg. 2. As reported previously, thresholds for movements in the direction of extension were lower than in the direction of flexion after a conditioning co-contraction of elbow muscles with the arm flexed by 30 deg from its mid-position (hold-short). After a co-contraction with the arm held extended by 30 deg (hold-long), thresholds were lower in the direction of flexion. 3. Here we have made two additional observations. Thresholds for movements of the passive forearm after a co-contraction at the 90 deg test position (hold-test) were low, both in the direction of flexion and extension. Secondly, when thresholds were measured while subjects were carrying out a co-contraction of forearm muscles (15-20 % maximum voluntary contraction), thresholds were much higher. 4. It is concluded that muscle contraction history is an important factor to consider when making measurements of movement thresholds at the relaxed elbow joint. It is speculated that during an active contraction increases in muscle spindle discharges evoked by fusimotor activity lead to the rise in movement detection threshold.

The effects of muscle conditioning on movement detection thresholds at the human forearm.

We have used the muscle history dependence of the sensitivity of muscle spindles to stretch, to provide evidence for their contribution to kinaesthesia, the sense of position and movement. Stretch sensitivity is altered depending on whether or not slack has been introduced in intrafusal fibres [13]. At the human elbow joint detection threshold was measured to passive movements applied at different speeds to the forearm after a conditioning co-contraction of muscles of the upper arm, with the arm held either flexed ('hold short') or extended ('hold long'). Test measurements were made with the elbow joint at 90 degrees. For the three speeds of movement, 2 degrees s-1, 0.2 degree s-1 and 0.02 degree s-1, after 'hold short' conditioning thresholds were lower for movements into extension, after 'hold long' conditioning they were lower for movements into flexion. It is concluded that when muscle conditioning introduces slack in the intrafusal fibres of muscle spindles, this must be taken up by the test movements before they can be detected by the subject. It means that whenever detection thresholds to passive movements are measured at a joint, the contraction history of the muscles acting at that joint must be taken into account.