Acoustic experience alters the aged auditory system.

OBJECTIVES: Presbyacusis, one of the most common ailments of the elderly, is often treated with hearing aids, which serve to reintroduce some or all of those sounds lost to peripheral hearing loss. However, little is known about the underlying changes to the ear and brain as a result of such experience with sound late in life. The present study attempts to model this process by rearing aged CBA mice in an augmented acoustic environment (AAE). DESIGN: Aged (22-23 months) male (n = 12) and female (n = 9) CBA/CaJ mice were reared in either 6 weeks of low-level (70 dB SPL) broadband noise stimulation (AAE) or normal vivarium conditions. Changes as a function of the treatment were measured for behavior, auditory brainstem response thresholds, hair cell cochleograms, and gamma aminobutyric acid neurochemistry in the key central auditory structures of the inferior colliculus and primary auditory cortex. RESULTS: The AAE-exposed group was associated with sex-specific changes in cochlear pathology, auditory brainstem response thresholds, and gamma aminobutyric acid neurochemistry. Males exhibited significantly better thresholds and reduced hair cell loss (relative to controls) whereas females exhibited the opposite effect. AAE was associated with increased glutamic acid decarboxylase (GAD67) levels in the inferior colliculus of both male and female mice. However, in primary auditory cortex AAE exposure was associated with increased GAD67 labeling in females and decreased GAD67 in males. CONCLUSIONS: These findings suggest that exposing aged mice to a low-level AAE alters both peripheral and central properties of the auditory system and these changes partially interact with sex or the degree of hearing loss before AAE. Although direct application of these findings to hearing aid use or auditory training in aged humans would be premature, the results do begin to provide direct evidence for the underlying changes that might be occurring as a result of hearing aid use late in life. These results suggest the aged brain retains significantly anatomical, electrophysiological, and neurochemical plasticity.

Effects of Calcitonin-Gene-Related-Peptide on Auditory Nerve Activity.

Calcitonin-gene-related peptide (CGRP) is a lateral olivocochlear (LOC) efferent neurotransmitter. Depression of sound-driven auditory brainstem response amplitude in CGRP-null mice suggests the potential for endogenous CGRP release to upregulate spontaneous and/or sound-driven auditory nerve (AN) activity. We chronically infused CGRP into the guinea pig cochlea and evaluated changes in AN activity as well as outer hair cell (OHC) function. The amplitude of both round window noise (a measure of ensemble spontaneous activity) and the synchronous whole-nerve response to sound (compound action potential, CAP) were enhanced. Lack of change in both onset adaptation and steady state amplitude of sound-evoked distortion product otoacoustic emission (DPOAE) responses indicated CGRP had no effect on OHCs, suggesting the origin of the observed changes was neural. Combined with results from the CGRP-null mice, these results appear to confirm that endogenous CGRP enhances auditory nerve activity when released by the LOC neurons. However, infusion of the CGRP receptor antagonist CGRP (8-37) did not reliably influence spontaneous or sound-driven AN activity, or OHC function, results that contrast with the decreased ABR amplitude measured in CGRP-null mice.

Cochlear damage changes the distribution of vesicular glutamate transporters associated with auditory and nonauditory inputs to the cochlear nucleus.

Integration of multimodal information is essential for understanding complex environments. In the auditory system, multisensory integration first occurs in the cochlear nucleus (CN), where auditory nerve and somatosensory pathways converge (Shore, 2005). A unique feature of multisensory neurons is their propensity to receive cross-modal compensation after deafening. Based on our findings that the vesicular glutamate transporters, VGLUT1 and VGLUT2, are differentially associated with auditory nerve and somatosensory inputs to the CN, respectively (Zhou et al., 2007), we examined their relative distributions after unilateral deafening. After unilateral intracochlear injections of kanamycin (1 and 2 weeks), VGLUT1 immunoreactivity (ir) in the magnocellular CN ipsilateral to the cochlear damage was significantly decreased, whereas VGLUT2-ir in regions that receive nonauditory input was significantly increased 2 weeks after deafening. The pathway-specific amplification of VGLUT2 expression in the CN suggests that, in compensatory response to deafening, the nonauditory influence on CN is significantly enhanced. One undesirable consequence of enhanced glutamatergic inputs could be the increased spontaneous rates in CN neurons that occur after hearing loss and that have been proposed as correlates of the phantom auditory sensations commonly called tinnitus.

Study of tracheal dyskinesia impact on the cardiac hemodynamics.

BACKGROUND: Tracheal dyskinesia (TD) was recently recognized as a possible mechanism for acute pulmonary edema (Elamin and Firdose, J Bronchol 2004;11:118-21; Khan and Elamin Eur Respir J 2005;26:319). This study was designed to evaluate possible impact of TD on cardiac hemodynamics. METHODS: Patients were prospectively assigned to either study "A" or control "B" groups (TD >50% or <50%, respectively) diagnosed by bronchoscopy or dynamic chest computed tomography. The cardiac hemodynamics was assisted by impedance cardiography (BioZ; CardioDynamics, San Diego, CA) at rest and during coughing. The latter was repeated after 5 minutes of rest. RESULTS: Thirteen patients were assigned to group A and 14 to group B. There was higher incidence of hypertension, diabetes mellitus, and history of congestive heart failure in group A compared with group B. The percentage of TD was 85% +/- 10.0% versus 25% +/- 2.5%, in the A and B groups, respectively (P < 0.05). Stroke volume index (normal = 35-65 mL/beat/body surface area) was significantly reduced in group A 29.68 [95% confidence interval (CI), 25.557-33.818] compared with group B 38.321 (95% CI, 35.199-41.444; P < 0.05). In addition, the velocity index (representative of aortic blood velocity) was 32.188 (95% CI, 20.841-43.534, P < 0.049) in group A compared with 46.786 (95% CI, 38.209-55.363) in group B, and the left ventricular ejection time measured in milliseconds was 265.813 (95% CI, 246.065-285.560 in group A, P < 0.004) compared with 303.821(95% CI, 288.894-318.749) in group B. CONCLUSION: This prospective study demonstrated the importance of recognizing TD as a pathologic entity and the need to consider TD in the workup of acute pulmonary edema especially if other tests were unrevealing.

Risks of allergy vial contamination: comparison of mixing in-office versus under ventilation hood.

OBJECTIVE: Compare the risk of bacterial contamination of allergy immunotherapy vials prepared in-office versus those mixed under a ventilation hood. STUDY DESIGN: Prospective single-blinded study. SETTING: Tertiary otolaryngology outpatient clinic. RESULTS: Five hundred thirty-seven vials were prepared and cultured for aerobes and anaerobes over an 11-month period. Three hundred twenty vials were arbitrarily assigned to in-office preparation and 217 to under-hood preparation. A total of two positive cultures occurred in vials prepared in-office and one from under-hood preparation. Follow-up cultures of these three vials were all negative. No patients receiving injections had signs or symptoms of skin or systemic infections from the injections. CONCLUSION: Our results suggest that the risk of bacterial contamination in immunotherapy vials in both groups is rare.

The safety of multi-dose vials in allergy immunotherapy.

OBJECTIVE: To prospectively evaluate the risks of vial contamination after routine clinical use of multiple-dose vials for immunotherapy. STUDY DESIGN: Prospective observational study of immunotherapy vial cultures from June 2007 to January 2008. SETTING: Tertiary care outpatient otolaryngology clinic. RESULTS: Over an 8-month period, 136 consecutive vials were cultured for aerobic and anaerobic bacteria at the 3-month expiration date after regular use in an outpatient allergy clinic and dispensation of multiple doses of injection immunotherapy from each vial. All vials had negative cultures. CONCLUSION: Immunotherapy vials are at low risk to undergo contamination in routine use. Important factors include aseptic technique, bacteriostatic agents, and expiration dating.

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma.

Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7-10 days after noise exposure. Reduction in cochlear blood flow as a result of free radical formation has also been described. Here we report that the antioxidant agents vitamins A, C, and E act in synergy with magnesium to effectively prevent noise-induced trauma. Neither the antioxidant agents nor the magnesium reliably reduced NIHL or sensory cell death with the doses we used when these agents were delivered alone. In combination, however, they were highly effective in reducing both hearing loss and cell death even with treatment initiated just 1 h before noise exposure. This study supports roles for both free radical formation and noise-induced vasoconstriction in the onset and progression of NIHL. Identification of this safe and effective antioxidant intervention that attenuates NIHL provides a compelling rationale for human trials in which free radical scavengers are used to eliminate this single major cause of acquired hearing loss.

Expression of striatal adenosine and dopamine receptors in mice deficient in the p50 subunit of NF-kappaB.

The striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) exhibit mutually antagonistic effects through physical interactions and by differential modulation of post-receptor signaling pathways. The expression of the A2AAR and the D2R is differentially regulated by nuclear factor-kappaB (NF-kappaB). In this report, we determined the role of NF-kappaB in regulation of these receptors by comparing mice deficient in the NF-kappaB p50 subunit (p50 KO) with genetically intact B6129PF2/J (F2) mice. Quantification of adenosine receptor (AR) subtypes in mouse striatum by real time PCR, immunocytochemistry and radioligand binding assays showed more A2AAR but less A1AR in p50 KO mice as compared with F2 mice. Striata from p50 KO mice also had less D2R mRNA and [(3)H]-methylspiperone binding than did striata from F2 mice. G(alphaolf) and G(alphas) proteins, which are transducers of A2AAR signals, were also present at a higher level in striata from the p50 KO versus F2 mice. In contrast, the G(alphai1) protein, which transduces signals from the A1AR and D2R, was significantly reduced in striata from p50 KO mice. Behaviorally, p50 KO mice exhibited increased locomotor activity relative to that of F2 mice after caffeine ingestion. These data are consistent with a role for the NF-kappaB in the regulation of A1AR, A2AAR, D2R and possibly their coupling G proteins in the striatum. Dysregulation of these receptors in the striata of p50 KO mice might sensitize these animals to locomotor stimulatory action of caffeine.

Prevention of noise- and drug-induced hearing loss with D-methionine.

A number of otoprotective agents are currently being investigated. Various types of agents have been found in animal studies to protect against hearing loss induced by cisplatin, carboplatin, aminoglycosides, or noise exposure. For over a decade we have been investigating D-methionine (D-met) as an otoprotective agent. Studies in our laboratory and others around the world have documented D-met's otoprotective action, in a variety of species, against a variety of ototoxic insults including cisplatin-, carboplatin-, aminoglycoside- and noise-induced auditory threshold elevations and cochlear hair cell loss. For cisplatin-induced ototoxicity, protection of the stria vascularis has also been documented. Further D-met has an excellent safety profile. D-met may act as both a direct and indirect antioxidant. In this report, we provide the results of three experiments, expanding findings in D-met protection in three of our translational research areas: protection from platinum based chemotherapy-, aminoglycoside- and noise-induced hearing loss. These experiments demonstrate oral D-met protection against cisplatin-induced ototoxicity, D-met protection against amikacin-induced ototoxicity, and D-met rescue from permanent noise-induced hearing loss when D-met is initiated 1h after noise exposure. These studies demonstrate some of the animal experiments needed as steps to translate a protective agent from bench to bedside.

Age-related changes in the inhibitory response properties of dorsal cochlear nucleus output neurons: role of inhibitory inputs.

Age-related hearing loss frequently results in a loss in the ability to discriminate speech signals, especially in noise. This is attributable, in part, to a loss in temporal resolving power and ability to adjust dynamic range. Circuits in the adult dorsal cochlear nucleus (DCN) have been shown to preserve signal in background noise. Fusiform cells, major DCN output neurons, receive focused glycinergic inputs from tonotopically aligned vertical cells that also project to the ventral cochlear nucleus. Glycine-mediated inhibition onto fusiform cells results in decreased tone-evoked activity as intensity is increased at frequencies adjacent to characteristic frequency (CF). DCN output is thus shaped by glycinergic inhibition, which can be readily assessed in recordings from fusiform cells. Previous DCN studies suggest an age-related loss of markers for glycinergic neurotransmission. The present study postulated that response properties of aged fusiform cells would show a loss of inhibition, resembling conditions observed with glycine receptor blockade. The functional impact of aging was examined by comparing response properties from units meeting fusiform-cell criteria in young and aged rats. Fusiform cells in aged animals displayed significantly higher maximum discharge rates to CF tones than those recorded from young-adult animals. Fusiform cells of aged rats displayed significantly fewer nonmonotonic CF rate-level functions and an age-related change in temporal response properties. These findings are consistent with an age-related loss of glycinergic input, likely from vertical cells, and with findings from other sensory aging studies suggesting a selective age-related decrement in inhibitory amino acid neurotransmitter function.

Gap detection deficits in rats with tinnitus: a potential novel screening tool.

The study describes a novel method for tinnitus screening in rats by use of gap detection reflex procedures. The authors hypothesized that if a background acoustic signal was qualitatively similar to the rat's tinnitus, poorer detection of a silent gap in the background would be expected. Rats with prior evidence of tinnitus at 10 kHz (n = 14) exhibited significantly worse gap detection than controls (n = 13) when the gap was embedded in a background similar to their tinnitus. No differences between tinnitus and control rats were found with 16 kHz or broadband noise backgrounds, which helped to rule out explanations related to hearing loss or general performance deficits. The results suggest that gap detection reflex procedures might be effective for rapid tinnitus screening in rats.

Age-related changes in the response properties of cartwheel cells in rat dorsal cochlear nucleus.

The fusiform cell and deep layers of the dorsal cochlear nucleus (DCN) show neurotransmitter and functional age-related changes suggestive of a downregulation of inhibitory efficacy onto DCN output neurons. Inhibitory circuits implicated in these changes include vertical and D-multipolar cells. Cartwheel cells comprise a large additional population of DCN inhibitory neurons. Cartwheel cells receive excitatory inputs from granule cell parallel fibers and provide a source of glycinergic inhibitory input onto apical dendrites of DCN fusiform cells. The present study compared the response properties from young and aged units meeting cartwheel-cell criteria in anesthetized rats. Single unit recordings from aged cartwheel cells revealed significantly higher thresholds, increased spontaneous activity and significantly altered rate-level functions characterized by hyperexcitability at higher intensities. Aged cartwheel cells showed a significant reduction in off-set suppression. Collectively, these findings suggest a loss of tonic and perhaps response inhibition onto aged DCN cartwheel neurons. These changes likely reflect a compensatory downregulation of synaptic inhibition in response to a loss of excitatory drive from auditory and non-auditory excitatory inputs via granule cells. The impact of increased excitability of cartwheel cells on DCN output neurons is likely to be complex, influenced by loss of glycinergic release and/or subunit receptor changes which would only partially off-set age-related loss of inhibition onto the somata and basal dendrites of fusiform cells.

Sleep and temperature responses of inbred mice with Candida albicans-induced pyelonephritis.

Human patients with renal disease frequently develop disturbed sleep and severe fatigue. To develop a model for studying factors that contribute to these symptoms, we characterized the sleep patterns of various strains of mice after acute challenge with the fungal organism Candida albicans. After intravenous administration to mice, C. albicans typically colonizes the kidney, producing acute pyelonephritis. Various strains of inbred mice demonstrate marked variation in the temperature and sleep responses that develop after challenge, with individual strains generally showing increased or reduced somnolence in association with fever or hypothermia, respectively. C. albicans-infected mice may be a useful model for identifying the genes and mechanisms that link sleep, temperature, fatigue, and the immune response.

Sleep, temperature, activity, and prolactin phenotypes of genetically epilepsy-prone rats.

Sleep-wake disturbances are common in epilepsy, yet the potential adverse effect of seizures on sleep is not well characterized. Genetically epilepsy-prone rats (GEPRs) are a well-studied model of genetic susceptibility to audiogenic seizures. To assess their suitability for investigating relationships between seizures and disordered sleep, we characterized the sleep, activity, and tempera ture patterns of 2 GEPR strains (designated 3 and 9) and Sprague-Dawley (SD) rats in the basal state, after forced wakefulness, and after exposure to sound-induced seizures at light onset and dark onset. Because of observed differences in rapid-eye-movement sleep (REMS), we also assessed serum levels of prolactin, which is implicated in REMS regulation. The data reveal that under basal conditions, the GEPR3 strain shows less SWS and REMS, higher core temperatures, and higher serum prolactin concentrations than do GEPR9 and SD strains. All 3 strains respond similarly to enforced sleep loss. Seizures induced at light onset delay the onset of SWS in both GEPR strains. Seizures induced at dark onset do not significantly alter sleep. Genotype assessment indicates that although both GEPR strains are inbred (that is, homozygous at 107 genetic markers), they differ from each other at 74 of 107 loci. Differences in basal sleep, temperature, and prolactin between GEPR3 and GEPR9 strains suggest different homeostatic regulation of these functions. Our detection of concurrent alterations in sleep, temperature, and prolactin in these 2 GEPR strains implicates the hypothalamus as a likely site for anatomic or physiologic variation in the control of these homeostatic processes.

Sleep during concanavalin-A-induced hepatitis and peritonitis in inbred mice.

STUDY OBJECTIVES: To assess the suitability of concanavalin-A-induced hepatitis as a model for investigating the relationships between hepatic disease and alterations in somnolence. DESIGN: We characterized the sleep patterns of various strains of inbred mice undergoing ConA-induced inflammation. SETTING: Southern Illinois University School of Medicine, Springfield, IL. INTERVENTION: Intravenous or intraperitoneal administration of concanavalin-A. PARTICIPANTS: Inbred mice. MEASUREMENTS AND RESULTS: Intravenous and intraperitoneal administration of concanavalin-A both elicited strain-dependent changes in slow-wave sleep. ConA treatment also reduced spontaneous locomotor activity. ConA-induced changes in slow-wave sleep varied with dose, route of administration, and circadian period of administration. As compared with the other strains, C57BL/6J mice had lower serum concentrations of interferon-gamma at 8 hours after ConA administration. CONCLUSIONS: These data provide the first demonstration that sleep enhancement and reduced locomotor activity accompany hepatic inflammation in mice.

Disruption of lateral olivocochlear neurons via a dopaminergic neurotoxin depresses sound-evoked auditory nerve activity.

We applied the dopaminergic (DA) neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the guinea pig cochlear perilymph. Immunolabeling of lateral olivocochlear (LOC) neurons using antibodies against synaptophysin was reduced after the MPTP treatment. In contrast, labeling of the medial olivocochlear innervation remained intact. As after brainstem lesions of the lateral superior olive (LSO), the site of origin of the LOC neurons, the main effect of disrupting LOC innervation of the cochlea via MPTP was a depression of the amplitude of the compound action potential (CAP). CAP amplitude depression was similar to that produced by LSO lesions. Latency of the N1 component of the CAP, and distortion product otoacoustic emission amplitude and adaptation were unchanged by the MPTP treatment. This technique for selectively lesioning descending LOC efferents provides a new opportunity for examining LOC modulation of afferent activity and behavioral measures of perception.

Divergent response properties of layer-V neurons in rat primary auditory cortex.

Layer-V pyramidal cells comprise a major output of primary auditory cortex (A1). At least two cell types displaying different morphology, projections and in vitro physiology have been previously identified in layer-V. The focus of the present study was to characterize extracellular receptive field properties of layer-V neurons to determine whether a similar breakdown of responses can be found in vivo. Recordings from 105 layer-V neurons revealed two predominant receptive field types. Thirty-two percent displayed strong excitatory V/U-shaped receptive field maps and spiking patterns with shorter stimulus-driven interspike intervals (ISIs), reminiscent of the bursting cells discussed in the in vitro literature. V/U-shaped maps remained relatively unchanged across the three sequential repetitions of the map run on each neuron. Neurons with V/U-shaped maps were also easily depolarized with extracellular current pulse stimulation. In contrast, 47% of the neurons displayed Complex receptive field maps characterized by weak and/or inconsistent excitatory regions and were difficult to depolarize with current pulses. These findings suggest that V/U-shaped receptive fields could correspond to previously described intrinsic bursting (IB) cells with corticotectal projections, and that neurons with Complex receptive fields might represent the regular spiking (RS) cells with their greater inhibitory input and corticocortical/corticostriatal projection pattern.

Hearing in laboratory animals: strain differences and nonauditory effects of noise.

Hearing in laboratory animals is a topic that traditionally has been the domain of the auditory researcher. However, hearing loss and exposure to various environmental sounds can lead to changes in multiple organ systems, making what laboratory animals hear of consequence for researchers beyond those solely interested in hearing. For example, several inbred mouse strains commonly used in biomedical research (e.g., C57BL/6, DBA/2, and BALB/c) experience a genetically determined, progressive hearing loss that can lead to secondary changes in systems ranging from brain neurochemistry to social behavior. Both researchers and laboratory animal facility personnel should be aware of both strain and species differences in hearing in order to minimize potentially confounding variables in their research and to aid in the interpretation of data. Independent of genetic differences, acoustic noise levels in laboratory animal facilities can have considerable effects on the inhabitants. A large body of literature describes the nonauditory impact of noise on the biology and behavior of various strains and species of laboratory animals. The broad systemic effects of noise exposure include changes in endocrine and cardiovascular function, sleep-wake cycle disturbances, seizure susceptibility, and an array of behavioral changes. These changes are determined partly by species and strain; partly by noise intensity level, duration, predictability, and other characteristics of the sound; and partly by animal history and exposure context. This article reviews some of the basic strain and species differences in hearing and outlines how the acoustic environment affects different mammals.

Assessing olfactory abilities with the University of Pennsylvania smell identification test: a Rasch scaling approach.

The strategy of delaying or retarding the progression of Alzheimer's disease requires early diagnosis and treatment. Previous research indicates that measurement of changes in olfaction and cognition will play an important role in the early detection of AD and in the monitoring of therapy effectiveness. Using the data of 177 subjects, our objective was to study the measurement properties of the University of Pennsylvania Smell Identification Test (UPSIT) using a Rasch scaling framework. The results indicate that the UPSIT can yield a linear, unbiased, and unidimensional Rasch measure of human smell recognition abilities. As expected, olfactory recognition ability decreased with age, and at the rate of about 0.05 Logits per year. Also, Alzheimer's patients showed a decrease in smell recognition equivalent to that experienced by healthy subjects over the course of 30 years. Hormone replacement therapy was not found to affect healthy women's olfactory recognition ability. Additional diagnostic information can be extracted from the analysis of incorrect responses patterns that is relevant to group membership.

Using a Rasch scale to characterize the clinical features of patients with a clinical diagnosis of uncertain, probable, or possible Alzheimer disease at intake.

OBJECTIVE: This study examined the clinical features of patients with clinical diagnoses of probable Alzheimer disease (AD), possible AD, and uncertain. DESIGN: Case study comparing three groups of AD patients diagnosed at their initial visit to an Alzheimer outpatient clinic. SETTING: Southern Illinois University School of Medicine's Center for Alzheimer Disease and Related Disorders (CADRD) assessment sites (20) in rural Illinois. PARTICIPANTS: 300 patients assessed at CADRD between January 1, 1994 and July 1, 2000. MEASUREMENTS: Patients were given an extensive clinical battery consisting of physical and neurologic examination, mental status testing including the Mini-Mental State Exam (MMSE), Short Blessed Dementia (SBD) and Blessed Dementia Scale (ADL), medical history evaluation, and laboratory tests. Other data included age at visit, gender, and medical history variables. RESULTS: Mean MMSE, SBD, and ADL scores differed significantly between groups (p's < 0.01). In all three cognitive tests, the uncertain group was the least impaired while the probable AD group was the most impaired. A Rasch model indicated that only the cognitive measures were useful in discriminating between the three diagnostic groups. CONCLUSION: In general, probable AD patients were distinguished from possible AD patients by the severity of their dementia as measured by the MMSE, ADL and SBD as well as Hachinski-Ischemic Score (HIS) scores. A Rasch model did well at predicting group membership based upon dementia measures only. The uncertain group differed from the AD groups in age and dementia severity as measured by the MMSE, ADL and SBD. Noting differences between this and previous studies, we speculate disparity may be related to differences in population ethnicity.