The sciatic nerve of the toad Xenopus laevis as a physiological model of the human cochlear nerve

The response of single fibres of the human cochlear nerve to electrical stimulation by a cochlear implant has previously been inferred from the response of the cochlear nerve in other mammals. These experiments are hindered by stimulus artefact and the range of stimulus currents used is therefore much less than the perceptual dynamic range (from threshold to discomfort) of human subjects. We have investigated use of the sciatic nerve of the toad Xenopus laevis as a convenient physiological model of the human cochlear nerve. Use of this completely dissected nerve reduces the problems of stimulus artefact whilst maintaining the advantages of a physiological preparation. The validity of the model was assessed by measuring the refractory periods, excitation time-constant, and relative spread of single fibres using microelectrode recording. We have also investigated the response of nerve fibres to sinusoidal stimulation. Based on these measurements, we propose that the sciatic nerve may be a suitable model of the human cochlear nerve if the timescales of stimuli are decreased by a factor of about five to compensate for the slower dynamics of the sciatic nerve and if noise is added to the stimuli to compensate for the lower internal noise of sciatic nerve fibres.

The effect of Gaussian noise on the threshold, dynamic range, and loudness of analogue cochlear implant stimuli

The deliberate addition of Gaussian noise to cochlear implant signals has previously been proposed to enhance the time coding of signals by the cochlear nerve. Potentially, the addition of an inaudible level of noise could also have secondary benefits: it could lower the threshold to the information-bearing signal, and by desynchronization of nerve discharges, it could increase the level at which the information-bearing signal becomes uncomfortable. Both these effects would lead to an increased dynamic range, which might be expected to enhance speech comprehension and make the choice of cochlear implant compression parameters less critical (as with a wider dynamic range, small changes in the parameters would have less effect on loudness). The hypothesized secondary effects were investigated with eight users of the Clarion cochlear implant; the stimulation was analogue and monopolar. For presentations in noise, noise at 95% of the threshold level was applied simultaneously and independently to all the electrodes. The noise was found in two-alternative forced-choice (2AFC) experiments to decrease the threshold to sinusoidal stimuli (100 Hz, 1 kHz, 5 kHz) by about 2.0 dB and increase the dynamic range by 0.7 dB. Furthermore, in 2AFC loudness balance experiments, noise was found to decrease the loudness of moderate to intense stimuli. This suggests that loudness is partially coded by the degree of phase-locking of cochlear nerve fibers. The overall gain in dynamic range was modest, and more complex noise strategies, for example, using inhibition between the noise sources, may be required to get a clinically useful benefit. © 2006 Association for Research in Otolaryngology.

Estimating ECAP threshold from the variability of the response

Electrical compound action potentials (ECAPs) of the cochlear nerve are used clinically for quick and efficient cochlear implant parameter setting. The ECAP is the aggregate response of nerve fibres at various distances from the recording electrode, and the magnitude of the ECAP is therefore related to the number of fibres excited by a particular stimulus. Current methods, such as the masker-probe or alternating polarity methods, use the ECAP magnitude at various stimulus levels to estimate the neural threshold, from which the parameters are calculated. However, the correlation between ECAP threshold and perceptual threshold is not always good, with ECAP threshold typically being much higher than perceptual threshold. The lower correlation is partly due to the very different pulse rates used for ECAPs (below 100 Hz) and clinical programs (hundreds of Hz up to several kHz). Here we introduce a new method of estimating ECAP threshold for cochlear implants based upon the variability of the response. At neural threshold, where some but not all fibers respond, there is a different response each trial. This inter-trial variability can be detected overlaying the constant variability of the system noise. The large stimulus artefact, which requires additional trials for artefact rejection in the standard ECAP magnitude methods, is not consequential, as it has little variability. The variability method therefore consists of simply presenting a pulse and recording the ECAP, and as such is quicker than other methods. It also has the potential to be run at high rates like clinical programs, potentially improving the correlation with behavioural threshold. Preliminary data is presented that shows a detectable variability increase shortly after probe offset, at probe levels much lower than those producing a detectable ECAP magnitude. Care must be taken, however, to avoid saturation of the recording amplifier saturation; in our experiments we found a gain of 300 to be optimal.

Stochastic beamforming for cochlear implant coding

Cochlear implants are prosthetic devices used to provide hearing to people who would otherwise be profoundly deaf. The deliberate addition of noise to the electrode signals could increase the amount of information transmitted, but standard cochlear implants do not replicate the noise characteristic of normal hearing because if noise is added in an uncontrolled manner with a limited number of electrodes then it will almost certainly lead to worse performance. Only if partially independent stochastic activity can be achieved in each nerve fibre can mechanisms like suprathreshold stochastic resonance be effective. We are investigating the use of stochastic beamforming to achieve greater independence. The strategy involves presenting each electrode with a linear combination of independent Gaussian noise sources. Because the cochlea is filled with conductive salt solutions, the noise currents from the electrodes interact and the effective stimulus for each nerve fibre will therefore be a different weighted sum of the noise sources. To some extent therefore, the effective stimulus for a nerve fibre will be independent of the effective stimulus of neighbouring fibres. For a particular patient, the electrode position and the amount of current spread are fixed. The objective is therefore to find the linear combination of noise sources that leads to the greatest independence between nerve discharges. In this theoretical study we show that it is possible to get one independent point of excitation (one null) for each electrode and that stochastic beamforming can greatly decrease the correlation between the noise exciting different regions of the cochlea. © 2007 Copyright SPIE - The International Society for Optical Engineering.

Auditory stream segregation of tone sequences in cochlear implant listeners

Previous claims that auditory stream segregation occurs in cochlear implant listeners are based on limited evidence. In experiment 1, eight listeners heard tones presented in a 30-s repeating ABA-sequence, with frequencies matching the centre frequencies of the implant's 22 electrodes. Tone A always stimulated electrode 11 (centre of the array); tone B stimulated one of the others. Tone repetition times (TRTs) from 50 to 200 ms were used. Listeners reported when they heard one or two streams. The proportion of time that each sequence was reported as segregated was consistently greater with increased electrode separation. However, TRT had no significant effect, and the perceptual reversals typical of normal-hearing listeners rarely occurred. The results may reflect channel discrimination rather than stream segregation. In experiment 2, six listeners performed a pitch-ranking task using tone pairs (reference = electrode 11). Listeners reported which tone was higher in pitch (or brighter in timbre) and their confidence in the pitch judgement. Similarities were observed in the individual pattern of results for reported segregation and pitch discrimination. Many implant listeners may show little or no sign of automatic stream segregation owing to the reduced perceptual space within which sounds can differ from one another. © 2006 Elsevier B.V. All rights reserved.

Auditory stream segregation in cochlear implant listeners:measures based on temporal discrimination and interleaved melody recognition

The evidence that cochlear implant listeners routinely experience stream segregation is limited and equivocal. Streaming in these listeners was explored using tone sequences matched to the center frequencies of the implant’s 22 electrodes. Experiment 1 measured temporal discrimination for short (ABA triplet) and longer (12 AB cycles) sequences (tone/silence durations = 60/40 ms). Tone A stimulated electrode 11; tone B stimulated one of 14 electrodes. On each trial, one sequence remained isochronous, and tone B was delayed in the other; listeners had to identify the anisochronous interval. The delay was introduced in the second half of the longer sequences. Prior build-up of streaming should cause thresholds to rise more steeply with increasing electrode separation, but no interaction with sequence length was found. Experiment 2 required listeners to identify which of two target sequences was present when interleaved with distractors (tone/silence durations = 120/80 ms). Accuracy was high for isolated targets, but most listeners performed near chance when loudness-matched distractors were added, even when remote from the target. Only a substantial reduction in distractor level improved performance, and this effect did not interact with target-distractor separation. These results indicate that implantees often do not achieve stream segregation, even in relatively unchallenging tasks.

Simultaneous grouping in cochlear implant listeners:can abrupt changes in level be used to segregate components from a complex tone?

A sudden increase in the amplitude of a component often causes its segregation from a complex tone, and shorter rise times enhance this effect. We explored whether this also occurs in implant listeners (n?=?8). Condition 1 used a 3.5-s “complex tone” comprising concurrent stimulation on five electrodes distributed across the array of the Nucleus CI24 implant. For each listener, the baseline stimulus level on each electrode was set at 50% of the dynamic range (DR). Two 1-s increments of 12.5%, 25%, or 50% DR were introduced in succession on adjacent electrodes within the “inner” three of those activated. Both increments had rise and fall times of 30 and 970 ms or vice versa. Listeners reported which increment was higher in pitch. Some listeners performed above chance for all increment sizes, but only for 50% increments did all listeners perform above chance. No significant effect of rise time was found. Condition 2 replaced amplitude increments with decrements. Only three listeners performed above chance even for 50% decrements. One exceptional listener performed well for 50% decrements with fall and rise times of 970 and 30 ms but around chance for fall and rise times of 30 and 970 ms, indicating successful discrimination based on a sudden rise back to baseline stimulation. Overall, the results suggest that implant listeners can use amplitude changes against a constant background to pick out components from a complex, but generally these must be large compared with those required in normal hearing. For increments, performance depended mainly on above-baseline stimulation of the target electrodes, not rise time. With one exception, performance for decrements was typically very poor.

Large diameter optic nerve axon fibres in Alzheimer's disease

A variety of visual symptoms have been associated with Alzheimer's disease (AD). These include delays in flash visual evoked potentials which indicate a disruption of the integrity of the visual pathway. Examination of the visual cortex has revealed the presence of both senile plaques and neurofibrillary tangles. The purpose of this study was to determine whether there were differences in the number and/or size of optic nerve axons between AD patients and non-demented age-matched controls. Five optic nerves from AD patients and five from age-matched controls were embedded in epon resin and 1 micron sections prepared on a Reichert ultramicrotome. The sections were then stained in toluidine blue and examined at x400 magnification. The numbers of axons were counted in photographs of three fields taken at random from each section. To evaluate the axon diameters, 70 axons were chosen at random from each patient and measured using a calibrated eyepiece graticule. The total axon counts revealed no significant differences between the AD optic nerves and the age-matched controls. However, the frequency distribution of axon diameters was significantly different in the two groups. In particular, there were fewer larger diameter axons in patients with AD as previously reported. Degeneration of the large diameter axons suggests involvement of the magnocellular as opposed to the parvocellular pathways. Hence, there could be differences in visual performance of AD patients compared with normals which could be important in clinical diagnosis.

The incidence of corpora amylacea (CA) in the optic nerve of patients with Alzheimer's disease

Corpora amylacea (CA) are spherical or ovoid bodies 50-50 microns in diameter. They have been described in normal elderly brain as well as in a number of neurodegenerative disorders. In this study, the incidence of CA in the optic nerves of Alzheimer's disease (AD) patients was compared with normal elderly controls. Samples of optic nerves (MRC Brain Bank, Institute of Psychiatry) were taken from 12 AD patients (age range 69-94 years) and 18 controls (43-82 years). Optic nerves were fixed in 2% buffered glutaraldehyde, post-fixed in osmium tetroxide, embedded in epoxy resin and then sectioned to a thickness of 2 microns. Sections were stained with toluidine blue. CA were present in all of the optic nerves examined. In addition, a number of similarly stained but more irregularly shaped bodies were present. Fewer CA were found in the optic nerves of AD patients compared with controls. By contrast, the number or irregularly shaped bodies was increased in AD. In AD, there may be a preferential decline in the large diameter fibres which may mediate the M-cell pathway. Hence, the decline in the incidence of CA in AD may be associated with a reduction in these fibres. It is also possible that the irregualrly shaped bodies are a degeneration product of the CA.

Auditory grouping in cochlear implant listeners

This thesis describes a series of experiments investigating both sequential and concurrent auditory grouping in implant listeners. Some grouping cues used by normal-hearing listeners should also be available to implant listeners, while others (e.g. fundamental frequency) are unlikely to be useful. As poor spectral resolution may also limit implant listeners’ performance, the spread of excitation in the cochlea was assessed using Neural Response Telemetry (NRT) and the results were related to those of the perceptual tasks. Experiment 1 evaluated sequential segregation of alternating tone sequences; no effect of rate or evidence of perceptual ambiguity was found, suggesting that automatic stream segregation had not occurred. Experiment 2 was an electrode pitch-ranking task; some relationship was found between pitch-ranking judgements (especially confidence scores) and reported segregation. Experiment 3 used a temporal discrimination task; this also failed to provide evidence of automatic stream segregation, because no interaction was found between the effects of sequence length and electrode separation. Experiment 4 explored schema-based grouping using interleaved melody discrimination; listeners were not able to segregate targets and distractors based on pitch differences, unless accompanied by substantial level differences. Experiment 5 evaluated concurrent segregation in a task requiring the detection of level changes in individual components of a complex tone. Generally, large changes were needed and abrupt changes were no easier to detect than gradual ones. In experiment 6, NRT testing confirmed substantially overlapping simulation by intracochlear electrodes. Overall, little or no evidence of auditory grouping by implant listeners was found.

A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer's disease

Objective: To study the density and cross-sectional area of axons in the optic nerve in elderly control subjects and in cases of Alzheimer's disease (AD) using an image analysis system. Methods: Sections of optic nerves from control and AD patients were stained with toluidine blue to reveal axon profiles. Results: The density of axons was reduced in both the center and peripheral portions of the optic nerve in AD compared with control patients. Analysis of axons with different cross-sectional areas suggested a specific loss of the smaller sized axons in AD, i.e., those with areas less that 1.99 μm2. An analysis of axons >11 μm2 in cross-sectional area suggested no specific loss of the larger axons in this group of patients. Conclusions: The data suggest that image analysis provides an accurate and reproducible method of quantifying axons in the optic nerve. In addition, the data suggest that axons are lost throughout the optic nerve with a specific loss of the smaller-sized axons. Loss of the smaller axons may explain the deficits in color vision observed in a significant proportion of patients with AD.

The toxic effects of enzyme inhibitors on muscle and nerve

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Regression analysis of ranked segment parameters for optic nerve head classification:a pilot study

Purpose: To determine whether curve-fitting analysis of the ranked segment distributions of topographic optic nerve head (ONH) parameters, derived using the Heidelberg Retina Tomograph (HRT), provide a more effective statistical descriptor to differentiate the normal from the glaucomatous ONH. Methods: The sample comprised of 22 normal control subjects (mean age 66.9 years; S.D. 7.8) and 22 glaucoma patients (mean age 72.1 years; S.D. 6.9) confirmed by reproducible visual field defects on the Humphrey Field Analyser. Three 10°-images of the ONH were obtained using the HRT. The mean topography image was determined and the HRT software was used to calculate the rim volume, rim area to disc area ratio, normalised rim area to disc area ratio and retinal nerve fibre cross-sectional area for each patient at 10°-sectoral intervals. The values were ranked in descending order, and each ranked-segment curve of ordered values was fitted using the least squares method. Results: There was no difference in disc area between the groups. The group mean cup-disc area ratio was significantly lower in the normal group (0.204 ± 0.16) compared with the glaucoma group (0.533 ± 0.083) (p < 0.001). The visual field indices, mean deviation and corrected pattern S.D., were significantly greater (p < 0.001) in the glaucoma group (-9.09 dB ± 3.3 and 7.91 ± 3.4, respectively) compared with the normal group (-0.15 dB ± 0.9 and 0.95 dB ± 0.8, respectively). Univariate linear regression provided the best overall fit to the ranked segment data. The equation parameters of the regression line manually applied to the normalised rim area-disc area and the rim area-disc area ratio data, correctly classified 100% of normal subjects and glaucoma patients. In this study sample, the regression analysis of ranked segment parameters method was more effective than conventional ranked segment analysis, in which glaucoma patients were misclassified in approximately 50% of cases. Further investigation in larger samples will enable the calculation of confidence intervals for normality. These reference standards will then need to be investigated for an independent sample to fully validate the technique. Conclusions: Using a curve-fitting approach to fit ranked segment curves retains information relating to the topographic nature of neural loss. Such methodology appears to overcome some of the deficiencies of conventional ranked segment analysis, and subject to validation in larger scale studies, may potentially be of clinical utility for detecting and monitoring glaucomatous damage. © 2007 The College of Optometrists.

Human intervertebral disc cells promote nerve growth over substrata of human intervertebral disc aggrecan

Study Design. Coculture assays of the migration and interaction of human intervertebral disc cells and chick sensory nerves on alternate substrata of collagen and aggrecan. Objective. To examine the effects of aggrecan on disc cell migration, how disc cells and sensory nerves interact, and whether disc cells affect previously reported inhibitory effects of aggrecan on sensory nerve growth. Summary of Background Data. Human intervertebral disc aggrecan is inhibitory to sensory nerve growth in vitro, suggesting that a loss of aggrecan from the disc may have a role in the increased innervation seen in disc degeneration. Endothelial cells that appear to co-migrate with nerves into degenerated intervertebral disc express neurotrophic factors, but the effects of disc cells on nerve growth are not known. Methods. Human disc cells were seeded onto tissue culture plates that had been coated with type I collagen and human intervertebral disc aggrecan. Explants of chick dorsal root ganglions (DRGs) were subsequently added to the plates and sensory neurite outgrowth stimulated by the addition of nerve growth factor. Time-lapse video and fluorescence microscopy were used to examine the migration and interaction of the disc cells and sensory neurites, in the context of the different matrix substrata. The effects of disc cell conditioned medium on nerve growth were also examined. Results. Disc cells spread and migrated on collagen until they encountered the aggrecan substrata, where some cells, but not all, were repelled. In coculture, DRG neurites extended onto the collagen/disc cells until they encountered the aggrecan, where, like the disc cells, many were repelled. However, in the presence of disc cells, some neurites were able to cross onto this normally inhibitory substratum. The number of neurite crossings onto aggrecan correlated significantly with the number of disc cells present on the aggrecan. In control experiments using DRG alone, all extending neurites were repelled at the collagen/aggrecan border. Conditioned medium from disc cell cultures stimulated DRG neurite outgrowth on collagen but did not increase neurite crossing onto aggrecan substrata. Conclusions. Human disc cells migrate across aggrecan substrata that are repellent to sensory DRG neurites. Disc cells synthesize neurotrophic factors in vitro that promote neurite outgrowth. Furthermore, the presence of disc cells in coculture with DRG partially abrogates the inhibitory effects of aggrecan on nerve growth. These findings have important implications for the regulation of nerve growth into the intervertebral disc, but whether disc cells promote nerve growth in vivo remains to be determined.