Practical model description of peripheral neural excitation in cochlear implant recipients: 3. ECAP during bursts and loudness as function of burst duration

In this, the third paper of the series, the loudness of low-rate bursts of electrical pulses was measured as a function of the burst duration, in subjects implanted with the Nucleus^® 24 cochlear implant system (three with straight and two with Contour™ electrode arrays). In order to help distinguish between the contributions of peripheral and more central effects, the ECAP was recorded to the individual pulses comprising the bursts, using the Neural Response Telemetry™ (NRT™) system. At a pulse rate of 250 pulses/s, the ECAP amplitude did not decrease greatly during the bursts: the mean reduction factor was 0.89. The time-constant for summation of the loudness contributions from the pulses comprising a burst was found to be larger than that associated with normal hearing. In addition, the first pulse of a pulse train was found to contribute much more to the overall loudness than did the subsequent pulses, although a corresponding difference was not observed in the ECAP recordings. These results establish a necessary connection between the essentially single-pulse model, developed in the fourth and fifth papers of the series, and the psychophysical data for pulse bursts, but they also have broader implications.     

Practical model description of peripheral neural excitation in cochlear implant recipients: 2. Spread of the effective stimulation field (ESF), from ECAP and FEA

This second paper of the series considers the spread of the “effective stimulation field” (ESF) produced by monopolar biphasic stimulation of an electrode within scala tympani, in subjects implanted with the Nucleus^® 24 cochlear implant system (three with straight and two with Contour™ electrode arrays). A novel measure of the ECAP was employed, using the Neural Response Telemetry™ (NRT™) system. The ESF provides a patient-specific measure of the “ability” of the stimulation field to excite neurons at differing locations around the cochlea. The results were interpreted with the aid of simple finite element computational models of the electric field. The finite element models were used to generate template field spread functions that differed with radial distance of the stimulated electrode from the modiolus. Relative to a template field function for the appropriate radial distance, the ESF spread on average approximately twice as broadly (a scaling factor of two). The magnitude of this scaling factor was considered to be indicative of the site of excitation on the neural fibers. The relationship between two ECAP measures, the spread of ESF and the “spread of excitation” (SOE), is discussed.     

Negative masking and the units problem in audition

Masking functions constructed from pedestal levels bracketing absolute threshold may exhibit negative masking, particularly when stimuli are defined in terms of amplitude (pressure). Three experimental conditions using 10-ms 1000-Hz tones in quiet, 1000-Hz tones embedded in continuous noise, and 6500-Hz tones in quiet, yielded negative masking when amplitudes were used to define the stimulus, with the greatest amount of negative masking occurring with 6500-Hz tones. Two models were applied to the data: the transduction model, which assumes direct coupling, and the sensory analytical model, which assumes differential coupling. Maximum likelihood estimates were derived to indicate goodness-of-fit, and the Akaike information criterion and Bayesian information criterion were utilised to adjust for model complexity. Overall, both models effectively accounted for the data, though the sensory analytic model provided the best fits to the data and has the added quality of being based on underlying physiological processes.     

The clinical features of patients with the homozygous 235delC and the compound-heterozygous Y136X/G45E of the GJB2 mutations (Connexin 26) in cochlear implant recipients

Objective

This study aimed to investigate the prevalence of GJB2 gene for the 235delC mutations, the clinical features and the outcomes of patients who had undergone cochlear implantation.

Methods

We have sequenced the coding region of GJB2 gene for 135 patients with sensorineural deaf from September 2000 to May 2009. Of the 135 patients, the patients with the homozygous 235delC and the compound-heterozygous Y136X/G45E were detected and were investigated clinically.

Results

The GJB2 gene for the 235delC mutations was found in 39 alleles of 270 alleles (14.4%), especially for the homozygous of 235delC was detected in 26 alleles (9.6%), the single heterozygous of 235delC was 1 allele (0.4%), the compound heterozygous of 235delC was found in 12 alleles (4.4%). Of 16 subjects (29 alleles) with the homozygous 235delC and the compound-heterozygous Y136X/G45E, 2 subjects (4 alleles) were found to have complications. All of the subjects were found to show severe hearing loss and some of them have indicated progressive hearing loss. However, they showed better performance regarding the thresholds after implantation. The subjects with complications, although, suggested poorer performance in the auditory speech performance.

Conclusion

The findings of poorer outcomes might depend on complications and brain functions. In addition, considering the blood test parameters, an independent elevated LDH and ChE at diagnosis were found to be associated with hereditary enzyme's metabolic disease. Therefore, the value of LDH measurements in patients might be a helpful predictive parameter in hereditary diseases.     

Prevalence of DFNB1 mutations in Argentinean children with non-syndromic deafness. Report of a novel mutation in GJB2

Objective

Mutations in DFNB1 locus, containing GJB2 (connexin 26) and GJB6 (connexin 30) genes, are the most common cause of autosomal recessive non-syndromic hearing loss. More than 100 mutations in GJB2 have been reported worldwide. Two deletions in GJB6, del(GJB6-D13S1830) and del(GJB6-D13S1854), have been found to be frequent in the Spanish population. The aim of this study was to determine the prevalence of GJB2 mutations and both GJB6 deletions in Argentinean children with non-syndromic deafness.

Methods

This study included 94 unrelated children with moderate to profound non-syndromic sensorineural hearing impairment. Molecular analysis was performed using a tiered approach. All DNA samples were screened for c.35delG mutation by PCR/RFLP. Samples from patients who were not homozygous for c.35delG were analysed for the presence of GJB6 deletions by PCR multiplex. The samples that remained unresolved after screening were further analysed by direct sequencing of GJB2 coding region. Finally, the splice site mutation IVS1 + 1G → A was analysed by PCR/RFLP.

Results

Sequence variations in the GJB2 and GJB6 genes were found in 49 of the 94 unrelated patients. The most prevalent GJB2 mutation, c.35delG, was found in 40 of the 68 pathogenic alleles with the second most common allele being p.R143W (4/68). Fourteen sequence variations other than c.35delG were identified. Seven already described mutations were present in more than one allele; among them, IVS1 + 1G → A, the rare splice site mutation flanking exon 1. In addition to known disease-related alterations, a novel GJB2 mutation, c.262G > C (p.A88P), was also identified. Six alleles were identified carrying GJB6 deletions; the most prevalent was del(GJB6-D13S1830). The frequency of the latter was found to be as high as that found in Spain from where Argentina has received one of its major immigration waves.

Conclusions

The overall frequency of GJB2/GJB6 mutations in the present sample is in agreement with other Caucasian populations. As expected, c.35delG was the most prevalent mutation. The deletion del(GJB6-D13S1830) was the second most common mutation. These findings reinforce the importance of the study of GJB2/GJB6 genes in diagnosis to provide early treatment and genetic counselling.