Dietary antioxidant intake is associated with the prevalence but not incidence of age-related hearing loss.

OBJECTIVES: Diet is one of the few modifiable risk factors for age-related hearing loss. We aimed to examine the link between dietary and supplement intakes of antioxidants, and both the prevalence and 5-year incidence of measured hearing loss. DESIGN: Cross-sectional and 5-year longitudinal analyses. SETTING: Blue Mountains, Sydney, Australia. PARTICIPANTS: 2,956 Blue Mountains Hearing Study participants aged 50+ at baseline, examined during 1997-9 to 2002-4. MEASUREMENTS: Age-related hearing loss was measured and defined as the pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz >25 dB HL. Dietary data were collected in a semi-quantitative food frequency questionnaire, and intakes of α-carotene; ß-carotene; ß-cryptoxanthin; lutein and zeaxanthin; lycopene; vitamins A, C and E; iron and zinc were calculated. RESULTS: After adjusting for age, sex, smoking, education, occupational noise exposure, family history of hearing loss, history of diagnosed diabetes and stroke, each standard deviation (SD) increase in dietary vitamin E intake was associated with a 14% reduced likelihood of prevalent hearing loss, odds ratio, OR, 0.86 (95% confidence interval, CI, 0.78-0.98). Those in the highest quintile of dietary vitamin A intake had a 47% reduced risk of having moderate or greater hearing loss (>40 dB HL) compared to those in the lowest quintile of intake, multivariable-adjusted OR 0.53 (CI 0.30-0.92), P for trend = 0.04. However, dietary antioxidant intake was not associated with the 5-year incidence of hearing loss. CONCLUSIONS: Dietary vitamin A and vitamin E intake were significantly associated with the prevalence of hearing loss. However, dietary antioxidant intake did not increase the risk of incident hearing loss. Further large, prospective studies are warranted to assess these relationships in older adults.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele.

INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT.

Previous studies of the gap-junction beta-2 subunit gene GJB2 (connexin 26) have suggested that the 101T-->C (M34T) nucleotide substitution may be a mutant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-junction assembly of the M34T allele product expressed in Xenopus oocytes and HeLa cells. The results of our current study of a family cosegregating the 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this phenotype did not cosegregate with the compound-heterozygous genotype M34T/167delT. Since 167delT is a null allele of GJB2, this result indicates that the in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observation raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importance of observing cosegregation with deafness in large families to confirm that these missense alleles are mutant DFNB1 alleles.

A review of objective methods of evaluating auditory neural pathways.

OBJECTIVES: Review physiological methods of evaluating function of the auditory neural pathways in infants, children, and adults. Present two case studies to demonstrate the usefulness of physiological measures in assessing abnormalities of the auditory neural pathways. STUDY DESIGN: Review of applications of physiological measures of auditory neural function. METHODS: Review otoacoustic emissions, auditory evoked potentials, and efferent reflexes, and discuss their use in identifying disorders of the auditory neural pathways from the cochlea to the cortex. RESULTS: Auditory disorders occur from peripheral to central areas of the neural system. Patients with disorders of the peripheral nerve and/or the input from the cochlear inner hair cells, such as the patients presently described as having auditory neuropathy, demonstrate abnormal efferent reflexes, including middle ear muscle reflexes and efferent suppression of otoacoustic emissions, as well as grossly abnormal brainstem evoked potentials. In contrast, patients with more central disorders can be differentiated by normal results on tests of the neural periphery and abnormal findings on cortical evoked potentials and other measures of central function. CONCLUSIONS: Physiological measures are sensitive, objective, and less variable in assessing neural disorders than traditional behavioral measures such as pure-tone or speech audiometry.

Development of human cochlear active mechanism asymmetry: involvement of the medial olivocochlear system?

To study the functional development of the medial olivocochlear system, transient-evoked otoacoustic emission suppression experiments were conducted in 73 ears of 38 pre-term and 11 full-term neonates. The continuous contralateral stimulation was a broad band white noise, presented at 70 dB SPL. Efferent suppression was determined by subtracting the without-contralateral stimulation condition from the with-contralateral stimulation condition. Across this population, a mean suppression effect of contralateral stimulation on transient-evoked otoacoustic emissions was found, with most of the suppression effect observed after 8 ms. The amount of suppression is linearly, positively correlated with the conceptional age. In the subgroup of bilaterally tested neonates, the suppression of transient-evoked otoacoustic emissions is similar in the right ear and the left ear in subjects whose conceptional age is less than 36 weeks and significantly higher in the right ear than in the left ear in older neonates. This last observation was seen at frequencies where transient-evoked otoacoustic emission amplitudes became higher in the right ear than in the left ear as the conceptional age increased, a finding already reported in adults. This study shows that the functional adult pattern of the medial efferent system, probably involved in the detection of signals in noise such as speech sounds, seems to appear gradually in neonates and represents one of the several arguments in favor of functional auditory lateralization in humans, with a right ear advantage.

An overview of neural function and feedback control in human communication.

The speech and hearing mechanisms depend on accurate sensory information and intact feedback mechanisms to facilitate communication. This article provides a brief overview of some components of the nervous system important for human communication and some electrophysiological methods used to measure cortical function in humans. An overview of automatic control and feedback mechanisms in general and as they pertain to the speech motor system and control of the hearing periphery is also presented, along with a discussion of how the speech and auditory systems interact.

Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness.

BACKGROUND: Mutations in the GJB2 gene cause one form of nonsyndromic recessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance of the 30delG mutant allele of GJB2. We assessed the contribution of mutations in GJB2 to the prevalence of the condition among Ashkenazi Jews. METHODS: We tested for mutations in GJB2 in DNA samples from three Ashkenazi Jewish families with nonsyndromic recessive deafness, from Ashkenazi Jewish persons seeking carrier testing for other conditions, and from members of other ethnic groups. The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions. RESULTS: Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence interval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservation of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. CONCLUSIONS: The high frequency of carriers of mutations in GJB2 (4.76 percent) predicts a prevalence of 1 deaf person among 1765 people, which may account for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggest that this site is a hot spot for recurrent mutations.

Reversing click polarity may uncover auditory neuropathy in infants.

OBJECTIVE: To identify patients with primary auditory neuropathies whose cochlear potentials to a 100 microsec click persist after click cessation and simulate synchronous auditory brain stem responses (ABRs) at high intensities. DESIGN: ABRs to condensation and rarefaction clicks, as well as Maximum Length Sequence ABRs and one transtympanic electrocochleogram (ECochG), were collected from five infants with absent middle ear muscle reflexes and normal or near normal otoacoustic emissions. These infants failed ALGO screens, which used alternating polarity clicks, and/or failed full ABRs done elsewhere with alternating polarity clicks. RESULTS: When ABRs were collected in response to a single polarity pulse, they revealed robust and reproducible wave forms over 4 to 6 msec that initially were mistaken for a normal ABR by the referring agents. However, when condensation and rarefaction click data are compared, the waveforms change polarity when the stimulus is inverted. Furthermore, the waveforms fail to shift in latency as the intensity of the stimulation is reduced. Transtympanic ECochG on one of the children revealed the same polarity reversal and fixed latency functions, confirming that they were cochlear rather than neural responses. CONCLUSIONS: Comparing responses with positive versus negative polarity clicks may help separate ABRs from cochlear potentials and alert clinicians to the possibility of an auditory neuropathy. Therefore, absent or abnormal ABRs in the presence of normal otoacoustic emissions need not always implicate a purely "central disorder," but might be consistent with dysfunction between outer hair cells and primary afferent fibers.

Contralateral suppression of transient-evoked otoacoustic emissions in humans: intensity effects.

Transient evoked otoacoustic emissions (TEOAEs) were recorded to clicks presented at peak sound pressures of 50, 55, 60, 65 and 70 dB while continuous contralateral white noise was varied from 10 dB below to 10 dB above the click level. Suppression increased predictably with suppressor noise level for any given click level. However, when the suppressor noise level was held constant, suppression was greater for lower click levels. This observation is consistent with the association of suppression of otoacoustic emissions with active cochlear processes and efferent function at low intensity levels.

Auditory neuropathy.

Ten patients presented as children or young adults with hearing impairments that, by behavioural and physiological testing, were compatible with a disorder of the auditory portion of the VIII cranial nerve. Evidence of normal cochlear outer hair cell function was provided by preservation of otoacoustic emissions and cochlear microphonics in all of the patients. Auditory brainstem potentials showed evidence of abnormal auditory pathway function beginning with the VIII nerve: the potentials were absent in nine patients and severely distorted in one patient. Auditory brainstem reflexes (middle ear muscles; crossed suppression of otoacoustic emissions) were absent in all of the tested patients. Behavioural audiometric testing showed a mild to moderate elevation of pure tone threshold in nine patients. The extent of the hearing loss, if due to cochlear receptor damage, should not have resulted in the loss of auditory brainstem potentials. The shape of the pure tone loss varied, being predominantly low frequency in five patients, flat across all frequencies in three patients and predominantly high frequency in two patients. Speech intelligibility was tested in eight patients, and in six was affected out of proportion to what would have been expected if the pure tone loss were of cochlear origin. The patients were otherwise neurologically normal when the hearing impairment was first manifest. Subsequently, eight of these patients developed evidence for a peripheral neuropathy. The neuropathy was hereditary in three and sporadic in five. We suggest that this type of hearing impairment is due to a disorder of auditory nerve function and may have, as one of its causes, a neuropathy of the auditory nerve, occurring either in isolation or as part of a generalized neuropathic process.

Binaural noise suppresses linear click-evoked otoacoustic emissions more than ipsilateral or contralateral noise.

We studied the efferent suppression of click-evoked otoacoustic emissions with 65 dB SPL of white noise presented to left, right, or sometimes both, ears for 408 ms. Each burst of noise preceded a series of four unipolar 80 microseconds 65 dB peak Sound Pressure clicks, presented to the left ear only. The first click of the four-click group followed the end of the noise by either 1, 2, 5, 10, 20, 50, 100 or 200 ms; each subsequent click was offset by 20 additional ms via an ILO88 system with special programming modifications. Conditions were alternated so that a 'without noise' condition preceded a 'with noise' condition for three repetitions of 600 clicks per trial. Seven subjects with normal hearing participated in the study, and three of the seven participated in a test-retest reliability study. Results showed the greatest suppression followed binaural stimulation ending within one to five ms of the first click in the pulse train. Somewhat less suppression was seen following ipsilateral stimulation. The least amount of suppression was seen following contralateral stimulation, suggesting that previous research using contralateral stimulation may underestimate efferent effects. We saw no effects when the end of the noise was 100 ms or more away from the beginning of the click train.

Cortical deafness: a longitudinal study.

We have studied a patient with MRI-confirmed bilateral absence of considerable portions of her temporal lobes resulting in cortical deafness. Although physiologic measures demonstrate normal peripheral hearing sensitivity, this patient's speech has the inflection and prosodic characteristics associated with profound peripheral hearing loss, and she is unable to understand spoken communication. Behaviorally obtained pure-tone thresholds taken over nearly 20 years range from normal to moderate hearing loss with normal middle ear muscle reflexes and normal ABRs; however, we consistently found abnormal middle latency and cortical evoked potentials. Because of her total inability to communicate auditorily, this patient was ultimately taught American Sign Language and educated at the Louisiana School for the Deaf. This rare case highlights the importance of using multiple audiologic measures sensitive to abnormalities at various levels of the auditory system.

The First Jerger Lecture. Contralateral suppression of otoacoustic emissions: an index of the function of the medial olivocochlear system.

We can now distinguish, in part, between nerve deafness and hair cell deafness through the use of otoacoustic emissions. We can also assess the efferent system by carefully quantifying the effects of contralateral stimulation on these same otoacoustic emissions. The suppression of transient evoked emissions by continuous contralateral white noise is an ostensibly small effect of 2 or 3 dB when studied over a 20-msec window. However, when subjected to microstructural analysis, the effect can exceed 6 to 8 dB in the zones from 10 to 20 msec after the stimulus has subsided. Temporal and spectral analyses reveal robust effects of contralateral lateral stimulation, although in any given normal subject it may be difficult to separate middle ear effects from efferent effects. Evidence is strong that the efferent effect is mediated in part by cholinergic-primarily nicotinic-receptors in the outer hair cell. However, a unique type of patient, who shows nearly normal pure-tone audiograms and absent ABRs, shows virtually no contralateral suppression of transient evoked emissions. Some other patients, with symptoms of Charcot-Marie-Tooth disease, may paradoxically show extremely poor audiograms, but perfectly normal evoked emissions along with absent contralateral suppression. The ABR, along with middle ear muscle reflexes and masking level differences, are all absent in these patients; we therefore think they have a disorder that desynchronizes most of their primary auditory nerve fibers and thereby disconnects them from any efferent activity or masking cancellation. The existence of such an auditory disorder, characterized by severe dysfunction in speech comprehension-especially when listening in noise-suggests that what appears to be a "central auditory imperception" might stem instead from a systemic peripheral primary neuropathy.

Contralateral suppression of non-linear click-evoked otoacoustic emissions.

Click-evoked otoacoustic emissions from nominal 80 dB pSP (peak sound pressure) 80-microseconds pulses presented at 50 pulses per second were collected from the right ears of eleven normal hearing subjects using an ILO88 Otodynamic Analyzer in the non-linear mode. Clicks, pure tones, and narrow bands of noise were then presented to their left ears through insert earphones. The 80-microseconds contralateral clicks ranged in intensity from 80 dB pSP in 5 dB steps down to 60 dB pSP but data on only 10 of the subjects were collected successfully. The pure tones and narrow bands of noise centered at 250, 500, 1000, 2000, and 4000 Hz were also presented through insert phones at 20, 40, 60 and 80 dB HL (Hearing Level) to all 11 subjects. The mean overall 'echo amplitude' without contralateral stimuli was 11 dB SPL and underwent more than 3 dB of overall suppression in response to the noises which were the most effective of the contralateral suppressors. When we analyzed the echo suppression to noise in 2-ms segments, we found consistent contralateral suppression of 3-4 dB concentrated in the time zones after 8 ms. Time shifts of more than 200 microseconds between the control and experimental traces were also observed in the same zones. The clicks were the next most effective suppressors, but showed their amplitude and time effects in somewhat earlier time zones. The tones were the least effective suppressors suggesting that efferent effects we measured in the human system are not strongly tonotopic. Because 'non-linear' mode high intensity clicks were deliberately selected as stimuli to evoke the TEOAE's, the emissions and their suppression can represent neither the 'true' TEOAE nor all of the efferent system's suppression abilities.

Does type I afferent neuron dysfunction reveal itself through lack of efferent suppression?

We present here two patients and three control subjects to demonstrate the clinical utility of studying evoked otoacoustic emissions and their contralateral suppression, as an aid to the delineation of afferent neuron dysfunction and possible lack of efferent suppression. The key patients here who fail to show contralateral suppression of their very robust otoacoustic emissions, concomitantly show paradoxically absent auditory brainstem responses (ABRs) and absence of middle ear muscle reflexes despite normal audiograms in the 2 kHz region and normal tympanograms. One of these patients has nearly normal pure tone sensitivity up to 3 kHz. The other has normal sensitivity in the 2 kHz region, but poor sensitivity on either side of that frequency. In addition, the two patients of interest show absent masking level differences and inordinately poor speech discrimination. Three 'foils' are presented: one patient with poor hearing on either side of 2 kHz, one with Bell's Palsy, and the third with bilateral temporal lobe disease. These patients show respectively that (1) isolated normal hearing at 2 kHz, (2) absence of middle ear muscle reflexes and (3) conscious cortical awareness of sound do not contribute directly to this intriguing clinical state. We propose that these patients with absent ABRs suffer from an auditory nervous system dysfunction which disrupts access to the efferent system. This condition also disables whatever systems contribute to the neural synchrony inherent in recording compound far-field action potentials such as the ABR. There are a number of hypotheses to be considered here. One suggests that the key patients are deficient in synchronous activation of Type I afferent fibers to the degree that they cannot activate efferent feedback, or they may be able to use only so-called Type II afferent neurons to support their normal zones of pure tone sensitivity. A less likely consideration focuses on the notion that discharge of primary neurons might be in some way synchronized by an efferent system which in these patients is the primary source of deficit.

Objective auditory threshold estimation using sine-wave derived responses.

A derived response method of acquiring frequency specific auditory evoked potentials that utilizes a pure tone in combination with a toneburst is applied to the measurement of hearing sensitivity in guinea pigs, chinchillas and pocket gophers. Two experiments which demonstrate that thresholds acquired via tone-derived responses are 10 to 15 dB more sensitive than thresholds to solitary tonebursts are described. The derived potentials approximate behaviorally acquired thresholds at frequencies of 0.5 kHz and above. This technique may provide a more rapid means of assessing hearing sensitivity in laboratory animals than by behavioral means.

Measurement of sound.

The measurement of sound involves the analysis of frequency, intensity, and temporal dimensions of acoustic signals. Each dimension of sound can be related directly to clinically observed phenomena. Frequency information, measured in Hz, can be extracted from pure-tone and complex stimuli. Intensity represents the physical energy of a signal and is described by using the decibel scale--a logarithmic scale of ratios. Temporal characteristics of sound include duration, phase, and repetition rate. In the analysis of human hearing sensitivity, the middle ear system and its impedance characteristics also must be considered. In this article, we have reviewed some major principles of sound and have presented a series of practical clinical applications. Such principles as these help to predict and explain frequency of laryngeal tones, middle ear mechanics, ear canal resonance, real-ear measurements of hearing aids, the Articulation Index, hearing loss, understanding of speech in quiet and in noise, and the relation between hearing and speech.

Derived guinea pig compound VIIIth nerve action potentials to continuous pure tones.

A technique is described which verifies neural activity to a very faint continuous sine wave through subtraction of two different far-field whole nerve action potentials from one another. A brief transient is presented to an animal in order to elicit a supra-threshold action potential. The technique is then repeated, but on the second trial a near-threshold sine wave is mixed with the transient and another action potential is collected. The resultant evoked is then subtracted from the evoked potential generated by the transient alone and a small but persistent difference potential is acquired that presumably represents the unit activity occupied by the continuous sine wave. Four experiments are presented to show the validity of this technique, along with a surprising stability of the derived-response latency despite a 30 dB range of the probes. The technique may have promise in predicting behavioral responses to sinusoids acquired from individual animals.

Myasthenia gravis: regimens and regimen-associated problems in adults.

Two hundred eighteen persons with myasthenia gravis (MG) responded to a mailed survey regarding experiences with their disease. The most commonly used regimen reported to control MG was taking medication on a regular schedule. One hundred ninety-four respondents reported using pyridostigmine bromide with 104 reporting experiencing diarrhea from their medication. Respondents reported situations that aggravated and alleviated adverse effects associated with their medication. Sixty-two respondents reported taking prednisone regularly for their MG. Forty-five of these respondents reported a weight gain. Seventy-seven respondents reported having had a thymectomy. The total remission rate was 11.6% for those who had undergone thymectomy and was 10.2% for those who had not undergone thymectomy. Thirty-one respondents reported having had plasmapheresis with only 3 respondents using plasmapheresis on a regular basis. Results generated by this study can provide useful information to assist nurses in the development of educational materials for persons with MG, their significant others and health care professionals.