Ototoxic Substances Research Articles

Auditory Changes in Occupational Health Associated With Metabolic Diseases in Adult Workers

Introduction: The most common hearing losses in the population are associated with genetic conditions, use of ototoxic substances or medications, infectious diseases, metabolic diseases and chronic ear diseases and the association of exposure to occupational risks or the natural aging process. Objective: Verify the association between hearing loss in workers and metabolic diseases. Method: Retrospective cross-sectional study with analysis of secondary data of subjects exposed to occupational noise and undergoing drug treatment for metabolic disease, attended in two occupational health clinics (C1 and C2) from January 2020 to December 2022, considering the data of reference examinations from the year 2005. Results: Of the n = 97 subjects evaluated, 73.20% were male, exposed to occupational noise (64.90%), with medication use for treating cardiovascular diseases (89.70%). The most recurrent auditory complaint was tinnitus (28.90%), n = 53 subjects presented sensorineural hearing loss with a statistical association between the decline of hearing loss and medications used for metabolic and hormonal regulation. Conclusion: Here was a higher frequency in the use of medications for treating cardiovascular diseases with a risk of triggering or worsening hearing loss in these subjects and greater impairment and decline of hearing thresholds were observed in the results of C2.

A preliminary study of the mechanism of compound hearing loss caused by ototoxic drugs combined with impulse noise

AbstractBackgroundHearing loss (HL) is becoming increasingly common and is more commonly caused by noise, ototoxic substances, or a combination of ototoxic factors. However, so far, few studies have examined the mechanism by which compound factors cause HL. The only relevant study is about occupational ototoxic substances combined with environmental noise at 85–110 dB SPL. In this study, to address the shortcomings of existing research, we innovatively focused on HL induced by loud noise (impulse noise, >160 dB SPL) combined with common ototoxic drugs. The aim of this study was to establish and validate a mature animal model, and then to compare the characteristics of audiology, pathomorphology and molecular features, and to preliminarily predict pathogenesis in compound HL.Materials and MethodsWe selected guinea pigs to construct in vivo HL model groups for different extents of exposure, including a blank control group, a single‐drug group, a single‐impulse noise group, and a compound group. The animal model of the mature compound HL group was established using gentamicin combined with impulse noise. We then performed audiological and pathological verification. We analyzed the auditory brainstem response (ABR), pathological morphology of the cochlea, and molecules (including important self‐radicals, cytokines, and apoptosis signal transduction pathway proteins in the pathogenesis of drug‐ and noise‐induced HL), compared the effect of different extents of exposure on HL, and preliminarily predict the pathogenic mechanism of compound HL.ResultsFour groups of animal models were established successfully and verified by audiology and pathology. Regarding audiology, there were no significant differences in the ABR thresholds before exposure (p > 0.05), but differences emerged among the groups after exposure. Notably, after 3, 7, and 14 days of exposure, there were significant differences in the ABR thresholds between the compound group and both the drug and noise groups (p < 0.01), and after 14 days, the HL of the compound group was much more severe (greater than the linear sum of single‐factor HL group). Regarding the pathomorphology, compared with the control group, the cochleae were damaged to different degrees in the factor exposure groups. The drug group had the least severe HL, the noise group had serious HL (p < 0.05), and the compound group had the most severe HL (p < 0.01). The compound group's damage was greater than the linear sum of the single‐factor group in many ways, such as the loss and damage of hair cells and cilia, disturbed morphology and arrangement of hair cells, protein metabolism, cell function, and structural defects on the epidermal plate (p < 0.01). From a molecular perspective, the trend was similar to pathology and audiology, and the synergistic effect of ototoxic drugs and impulse noise significantly increased cytokine levels (IL‐6, ICAM‐1,8‐OHDG, IL‐1, and TNF‐α), free radicals Malondialdehyde ([MDA], ▪OH, LPO, O•2ˉ), and the apoptosis signal transduction pathway protein. There were significant differences between the compound group and single‐factor groups (p < 0.05).ConclusionGentamicin, impulse noise, and compound factors were used to induce HL in animal models, which were verified by audiology and pathology, laying a foundation for future studies. After constructing the animal models, we found that 50 mg/kg of gentamicin for 10 days was a subinjury dose, and 50× impulse noise caused partial HL, but the two factors combined had a significant synergistic ototoxicity effect, which increased the level of oxidative stress and the waterfall response of inflammatory cytokines in the cochleae and enhanced the expression of apoptosis‐related proteins, resulting in synergistic pathomorphological and audiological injury. We preliminarily analyzed the pathogenic mechanism of compound HL, establishing the basis for further study of the mechanism, prevention, and treatment of this increasing global problem.

Retesting of Neonatal Hearing Screening Before and During the COVID-19 Pandemic: A Longitudinal Study

Introduction: Universal Newborn Hearing Screening (UNHS) plays an essential role in the early identification of hearing loss in neonates. Risk factors for hearing impairment may include family history, prematurity, and exposure to ototoxic substances. Coronavirus Disease 2019 (COVID-19) might be a significant contributing factor affecting the structures of the inner ear. Objective: To assess the auditory follow-up process of retesting for UNHS before and during the COVID-19 pandemic among neonates from an Outpatient Auditory Health Service (SASA) in the state of Santa Catarina with SUS (Unified Health System) assistance. Methods: A retrospective longitudinal study analyzed data from neonates attended at a SUS Auditory Health Service (SASA) from January 2018 to December 2022. Information related to UNHS and retest outcomes was assessed. Data were analyzed using Microsoft Excel® and MedCalc® Statistical Software version 22.006, utilizing statistical measures and regression analyses to identify factors associated with UNHS failures and retesting. Results: A failure to retest rate of 2.6% in the right ear and 2.2% in the left ear was observed among evaluated neonates. The average age of mothers of neonates who did not pass the test was 33 years, while the overall average was 27 years. Failure to pass the retest and a longer interval between UNHS and retesting were associated with UNHS Initial Retest Default (IRD). There was an increase in dropout rates for UNHS retesting, and the time interval between UNHS and retesting was extended during the pandemic. Conclusion: Several factors, including the interval between tests, mothers' age, and medical conditions, influenced the retest outcomes. The pandemic led to a significant increase in dropout rates and extended time for retesting.

Hearing Loss and Urinary trans,trans-Muconic Acid (t,t-MA) in 6- to 19-Year-Old Participants of NHANES 2017-March 2020.

Hearing loss (HL) is associated with poorer language development and school performance. Ototoxic substances such as metals and solvents, including benzene, are a risk factor associated with HL. This study examines potential associations between the benzene metabolite trans,trans-muconic acid (t,t-MA) and HL in youth of the National Health and Nutrition Examination Survey (NHANES). Logistic regression calculated adjusted odds ratio (aOR) associations between HL and urinary t,t-MA quartiles, natural-log transformed, and doubled urinary t,t-MA. Hearing threshold pure-tone average (PTA) at speech frequencies (SF) 0.5, 1, 2, and 4 kHz and high frequencies (HF) 3, 4, and 6 kHz were analyzed for slight HL (PTA > 15 dB) and mild HL (PTA > 20 dB). Urinary t,t-MA was statistically significantly associated with both slight SF and HF HL. For each doubling of t,t-MA there were increased odds of having slight SFHL (aOR = 1.42; 95% CI: 1.05, 1.92), slight HFHL (aOR = 1.31; 95% CI: 1.03, 1.66), mild SFHL (aOR = 1.60; 95% CI: 1.10, 2.32), and mild HFHL (aOR = 1.45; 95% CI: 1.03, 2.04). To our knowledge, this is the first population-based report of an association between SFHL, HFHL, and the benzene metabolite t,t-MA in youth 6 to 19 years old.

Blood-Labyrinth Barrier in Health and Diseases: Effect of Hormetic Nutrients.

Significance: The stria vascularis, located in the inner ear, consists of three layers, one of which is the blood-labyrinth barrier (BLB). It is formed by endothelial cells, sealed together to prevent the passage of toxic substances from the blood to the inner ear, by pericytes and perivascular-resident macrophage-like melanocyte. Recent Advances: There are various causes that lead to hearing loss, and among these are noise-induced and autoimmune hearing loss, ear disorders related to ototoxic medication, Ménière's disease, and age-related hearing loss. For all of these, major therapeutic interventions include drug-loaded nanoparticles, via intratympanic or intracochlear delivery. Critical Issues: Since many pathologies associated with hearing loss are characterized by a weakening of the BLB, in this review, the molecular mechanisms underlying the response to damage of BLB cellular components have been discussed. In addition, insight into the role of hormetic nutrients against hearing loss pathology is proposed. Future Directions: BLB cellular components of neurovascular cochlear unit play important physiological roles, owing to their impermeable function against all ototoxic substances that can induce damage. Studies are needed to investigate the cross talk occurring between these cellular components to exploit their possible role as novel targets for therapeutic interventions that may unravel future path based on the use of hormetic nutrients. Antioxid. Redox Signal. 40, 542-563.

Can Assessment of Rheological Properties of Whole Blood and Plasma Be Useful in the Diagnosis of Tinnitus? A Pilot Study.

Tinnitus is a sensation of ringing in the ears in the absence of any physical source in the environment. Between 9-35% of adults experience some form of tinnitus. Common causes of tinnitus include noise, head injury, ototoxic substances, as well as disorders of blood and blood vessels. Vascular causes include: head-neck tumours, turbulent blood flow, problems with blood supply and inner ear cell damage. The aspect of rheology in terms of tinnitus has not been described yet. In the present study, which comprised 12 patients aged 30 to 74 years presenting with tinnitus, rheological properties of whole blood and plasma were assessed. All the subjects underwent audiological and neurological evaluation. The Quemada model was used to describe the variability of red blood cell shape, as well as their tendency to form aggregates. On the basis of the experimental study, statistically different results of haemorheological measurements were observed in the evaluated group in comparison to a reference group.

Hearing loss following the use of topical otitis therapeutics in dogs

Hearing loss occurring in temporal association with the topical application of otic medications is regularly reported to the Federal Office of Consumer Protection and Food Safety (Bundesamt für Verbraucherschutz und Lebensmittelsicherheit - BVL) in the form of adverse event (AE) reports. Although deafness or impaired hearing are listed as possible adverse reactions in the Summary of Product Characteristics of the otic medications approved in Germany little information about the underlying causes is available to date. A search for cases reporting impaired hearing following the use of otic medication was conducted in the national AE database. Subsequently, descriptive analysis was performed. Due to their small number, cases involving cats were excluded. Possible risk factors and causes of hearing loss were considered against the background of current literature. While dogs of all age groups were affected, the majority of reports referred to dogs older than 10 years of age. Besides crossbreds, dogs of the breeds West Highland White Terrier, Dalmatian, Miniature Poodle and French Bulldog were most frequently involved. The analysis of the available data does not point to specific products or active substances that could be associated with a more frequent occurrence of hearing loss. In addition to possible ototoxicity of a product, other causes of hearing loss should be considered. These include the underlying otitis itself, age-related hearing loss, previously undetected unilateral congenital deafness, or conductive deafness due to obstruction of the ear canal. Treatment options include discontinuation of potentially ototoxic substances or treatment of conductive deafness, e. g. by removal of drug residues and exudate or treatment of otitis media. In the case of hearing loss subsequent to the use of otic medication, the BVL should be notified of this event in as much detail as possible in order to further improve the data situation concerning this topic.

A Case Study about Joining Databases for the Assessment of Exposures to Noise and Ototoxic Substances in Occupational Settings

Evaluating risks associated with multiple occupational exposures is no easy task, especially when chemical and physical nuisances are combined. In most countries, public institutions have created databases, which gather extensive information on occupational exposures or work-related diseases. Unfortunately, these tools rarely integrate medical and exposure information, and, above all, do not take into account the possible adverse effects of co-exposures. Therefore, an attempt to exploit and join different existing databases for the assessment of the health effects of multiple exposures is described herein. This case study examines three French databases describing exposures to noise and/or ototoxic chemicals (i.e., toxic to the ear) and the incidence rate of occupational deafness in different sectors. The goals were (1) to highlight occupational sectors where the workers are the most (co)exposed and (2) to determine whether this approach could confirm the experimental data showing that this co-exposure increases the risk of developing hearing loss. The results present data per occupational sector exposing workers to noise only, ototoxic chemicals only, noise and ototoxic chemicals, and neither of these two nuisances. The ten sectors in which the proportion of exposed workers is the highest are listed. This analysis shows that the rate of hearing loss in these sectors is high but does not show an increased incidence of hearing loss in co-exposed sectors.

Bases genéticas, moleculares y bioquímicas del envejecimiento auditivo ¿Qué nos enseñan los modelos experimentales

Age-related hearing loss (ARHL) affects one in three people older than 65 years and is the most prevalent sensorineural deficit. This type of hearing loss precedes and accelerates the onset of cognitive impairment and is associated with an increased risk for neurodegenerative diseases such as dementia and Alzheimer disease. The onset and progression of ARHL is influenced by genetic factors, which are still poorly understood, and environmental factors, which in particular include exposure to excessive noise and ototoxic substances. At present, no effective drug treatments are available for ARHL prevention or treatment, and therefore research in this field is a priority. In the research field, animal models offer a crucial tool for i) identifying new genes associated with ARHL, ii) understanding the cellular and molecular basis of auditory ageing and iii) defining new therapeutic targets and evaluating candidate treatments.

Effect of noise and ototoxicants on developing standard threshold shifts at a U.S. Air Force depot level maintenance facility

Noise exposure has traditionally been considered the primary risk factor for hearing loss. However, ototoxicants commonly found in occupational settings could affect hearing loss independently, additively, or synergistically when combined with noise exposures. The purpose of this investigation was to determine the combined effect of metal and solvent ototoxicants, continuous noise, and impulse noise on hearing loss. Noise and ototoxicant exposure and pure-tone audiometry results were analyzed for U.S. Air Force personnel (n = 2,372) at a depot-level aircraft maintenance activity at Tinker Air Force Base, Oklahoma. Eight similar exposure groups based on combinations of ototoxicant and noise exposure were created including: (1) Continuous noise (reference group); (2) Continuous noise + Impulse noise; (3) Metal exposures + Continuous noise; (4) Metal exposures + Continuous noise + Impulse noise; (5) Solvent exposure + Continuous noise; (6) Solvent exposures + Continuous noise + Impulse noise; (7) Metal exposure + Solvent exposures + Continuous noise; and (8) Metal exposure + Solvent exposures + Continuous noise + Impulse noise. Hearing loss was assessed at center octave band frequencies of 500–6,000 Hz and using National Institute for Occupational Safety and Health Standard Threshold Shift (STS) criteria. Hearing changes were significantly worse at 2,000 Hz in the Metal exposure + Solvent exposure + Continuous noise group compared to the Continuous noise only reference group (p = 0.023). The Metal exposure + Solvent exposure + Continuous noise group had a significantly greater relative risk (RR) of 2.44; 95% CI [1.24, 4.83] for developing an STS at 2,000 Hz. While not statistically significant, the Solvent exposure + Continuous noise group had a RR of 2.32; 95%CI [1.00, 5.34] for developing an STS at 1,000 Hz. These results indicate that noise exposure may dominate hearing loss at ≥3,000 Hz while combined effects of concomitant exposure to ototoxic substances and noise are only noticeable at ≤2,000 Hz. These results also suggest combined exposures to ototoxicants and noise presents a greater hearing loss risk than just noise.

Prevalence of presbycusis in an otologically normal population

ObjectivePresbycusis or age-related hearing loss is a bilaterally symmetric sensorineural hearing loss associated exclusively with age, excluding any other causes of hearing loss. Presbycusis is very relevant because of its high prevalence, and its consequences (e.g., alterations in communication, social isolation, depression, dementia), and the economic impact. This paper reports the first attempt to estimate the prevalence of presbycusis in an otologically normal population, i.e., without previous ear disease, exposure to noise, or potentially ototoxic substances, or familial hearing loss. MethodsA total of 4290 subjects from 5 to 90 years old were included in the study. ResultsNo statistically significant differences were found between right and left ear, nor between males and females, in any of the age groups. Presbycusis was detected over 60 years following the WHO classification; although the results vary depending on the classification used. Moderate hearing loss (≥ 41dB) was detected in the population over 72 years. None of the subjects had severe or profound hearing impairment. The prevalence of presbycusis increased with age, being 100% in individuals aged 80 years and older. The prevalence of presbycusis is highly variable depending on the pure-tone averaged frequencies and the classification system used; therefore, a common classification system should be used. ConclusionsAn otologically normal population is needed to establish the prevalence of presbycusis as in non-screened populations it is the hearing level including all types of hearing loss that is measured, but not presbycusis itself.

Distortion product otoacoustic emission sensitivity to different solvents in a population of industrial painters

Objective: To evaluate the ototoxic effect of the exposure to different organic solvents and noise using distortion product otoacoustic emissions (DPOAEs).Design: The exposure to different solvents was evaluated by measuring, before and at the end of the work-shift, the urinary concentrations of solvent metabolites used as dose biomarkers. The urinary concentrations of DNA and RNA oxidation products were also measured as biomarkers of oxidative damage. The simultaneous exposure to noise was also evaluated. DPOAEs and pure tone audiometry (PTA) were used as outcome variables, and were correlated to the exposure variables using mixed effect linear regression models.Study sample: Seventeen industrial painters exposed to a solvent mixture in a naval industry. A sample size of 15 was estimated from previous studies as sufficient for discriminating small hearing level and DPOAE level differences (5 dB and 2 dB, respectively) at a 95% confidence level.Results: Statistically significant associations were found between the DPOAE level and the urinary dose biomarkers and the oxidative damage biomarkers. DPOAE level and the logarithm of the metabolite concentration showed a significant negative correlation.Conclusions: DPOAE are sensitive biomarkers of exposure to ototoxic substances and can be effectively used for the early detection of hearing dysfunction.

Prevalence of presbycusis in an otologically normal population

ObjectivePresbycusis or age-related hearing loss is a bilaterally symmetric sensorineural hearing loss associated exclusively with age, excluding any other causes of hearing loss. Presbycusis is very relevant because of its high prevalence, and its consequences (e.g., alterations in communication, social isolation, depression, dementia), and the economic impact. This paper reports the first attempt to estimate the prevalence of presbycusis in an otologically normal population, i.e., without previous ear disease, exposure to noise, or potentially ototoxic substances, or familial hearing loss. MethodsA total of 4290 subjects from 5 to 90 years old were included in the study. ResultsNo statistically significant differences were found between right and left ear, nor between males and females, in any of the age groups. Presbycusis was detected over 60 years following the WHO classification; although the results vary depending on the classification used. Moderate hearing loss (≥ 41dB) was detected in the population over 72 years. None of the subjects had severe or profound hearing impairment. The prevalence of presbycusis increased with age, being 100% in individuals aged 80 years and older. The prevalence of presbycusis is highly variable depending on the pure-tone averaged frequencies and the classification system used; therefore, a common classification system should be used. ConclusionsAn otologically normal population is needed to establish the prevalence of presbycusis as in non-screened populations it is the hearing level including all types of hearing loss that is measured, but not presbycusis itself.

Ototoxicity: Visualized in Concept Maps.

Ototoxicity refers to the damage to structures and function of the auditory-vestibular system caused by exogenous agents such as pharmaceuticals, chemicals, and ionizing radiation. There are many potentially ototoxic substances. For example, depending on how ototoxicity is defined, there are 200 to 600 medications that can cause damage to hearing and/or balance. Ototoxicity encompasses cochleotoxicity, vestibulotoxicity, and neurotoxicity. A variety of professional disciplines are involved in determining causation, prevention, and management of ototoxic effects. Research to identify and develop otoprotectants and otorescue agents is emerging and will translate basic scientific discovery into applications for use in hearing conservation programs, safety operations, and clinical care. Original concept maps are presented here to visually represent knowledge pathways, domains, and relationships essential to the understanding of ototoxicity.

I'm Wearing My Hearing Protection - Am I Still At Risk for Hearing Loss? Lurking Ototoxins in the Military Environment.

Information is summarized from the overall body of published literature regarding ototoxic chemicals encountered outside of clinical exposures, largely in occupational settings. While summarizing the most common non-pharmaceutical ototoxins, this review provides clinically relevant information and recommendations such that hearing health professionals may adopt a more comprehensive and appropriate diagnostic case history, test battery, documentation scheme, and education delivery. Solvents, metals, and asphyxiants literature was reviewed using PubMed, national and international agency websites, and communications with known ototoxicity experts. Initial intentions to summarize the existing programs for occupational ototoxicity monitoring fell short when it was discovered that such programs have not yet formalized across the major oversight agencies in the United States. Instead, recommended guidance documents and fact sheets, which highlight existing occupational exposure limits and suggest monitoring and education are discussed. While evidence in humans is limited, potentially ototoxic substances are worthy of improved surveillance and further research to understand their ototoxic mechanisms, effects, and possible mitigation strategies. A triad approach of monitoring, protecting, and educating is recommended for effective prevention of hearing loss: the Department of Defense Hearing Center of Excellence's Comprehensive Hearing Health Program model employs such an approach.

Bilateral vestibulopathy

The leading symptoms of bilateral vestibulopathy (BVP) are postural imbalance and unsteadiness of gait, deficits of spatial memory and navigation. The etiology of BVP remains unclear in more than 50% of patients: in these cases neurodegeneration is assumed. Frequent known causes are ototoxicity mainly due to gentamicin, bilateral Menière's disease, autoimmune diseases, meningitis and bilateral vestibular schwannoma, as well as an association with cerebellar degeneration. The diagnosis of BVP is based on a bilaterally reduced or absent function of the vestibulo-ocular reflex (VOR). Head impulse test (HIT), video-oculography system (vHIT), crvical/ocular vestibular-evoked myogenic potentials (c/oVEMP) and dynamic visual acuity is an additional test supporting the diagnosis. There are four different subtypes of BVP depending on the affected anatomic structure and frequency range of the VOR deficit: impaired canal function in the low-and/or high-frequency VOR range only and/or otolith function only; the latter is very rare. There are four treatment options: first, detailed patient counseling to explain the cause, etiology, and consequences, as well as the course of the disease; second, daily vestibular exercises and balance training; third, if possible, treatment of the underlying cause, as in bilateral Menière's disease, meningitis, or autoimmune diseases; fourth, if possible, prevention, i.e., being very restrictive with the use of ototoxic substances, such as aminoglycosides.

Cochlear Homocysteine Metabolism at the Crossroad of Nutrition and Sensorineural Hearing Loss.

Hearing loss (HL) is one of the most common causes of disability, affecting 360 million people according to the World Health Organization (WHO). HL is most frequently of sensorineural origin, being caused by the irreversible loss of hair cells and/or spiral ganglion neurons. The etiology of sensorineural HL (SNHL) is multifactorial, with genetic and environmental factors such as noise, ototoxic substances and aging playing a role. The nutritional status is central in aging disability, but the interplay between nutrition and SNHL has only recently gained attention. Dietary supplementation could therefore constitute the first step for the prevention and potential repair of hearing damage before it reaches irreversibility. In this context, different epidemiological studies have shown correlations among the nutritional condition, increased total plasma homocysteine (tHcy) and SNHL. Several human genetic rare diseases are also associated with homocysteine (Hcy) metabolism and SNHL confirming this potential link. Accordingly, rodent experimental models have provided the molecular basis to understand the observed effects. Thus, increased tHcy levels and vitamin deficiencies, such as folic acid (FA), have been linked with SNHL, whereas long-term dietary supplementation with omega-3 fatty acids improved Hcy metabolism, cell survival and hearing acuity. Furthermore, pharmacological supplementations with the anti-oxidant fumaric acid that targets Hcy metabolism also improved SNHL. Overall these results strongly suggest that cochlear Hcy metabolism is a key player in the onset and progression of SNHL, opening the way for the design of prospective nutritional therapies.

An optimized method to assess ototoxic effects in the lateral line of zebrafish (Danio rerio) embryos

In order to clarify the suitability of the lateral line of zebrafish (Danio rerio) embryos as a model for the screening of ototoxic (neurotoxic) effects, existing neuromast assays were adapted, improved and validated with a series of chemicals known or unknown for their ototoxic potential (caffeine copper sulfate, dichlorvos, 2.4-dinitrotoluene, neomycin, 4-nonylphenol, perfluorooctanesulfonic acid). Present methods were improved by (1) the introduction of a 4-step scoring system, (2) the selection of neuromasts from both the anterior and posterior lateral line systems, (3) a combined DASPEI/DAPI staining applied after both a continuous and pulse exposure scenario, and (4) an additional screening for nuclear fragmentation. Acute toxicities of the model substances were determined by means of the fish embryo test as specified in OECD TG 236, and EC10 concentrations were used as the highest test concentration in the neuromast assay. The enhanced neuromast assay identified known ototoxic substances such as neomycin and copper sulfate as ototoxic at sensitivities similar to those of established methods, with pulse exposure leading to stronger effects than continuous exposure. Except for caffeine, all substances tested (dichlorvos, 2.4-dinitrotoluene, 4-nonylphenol, perfluorooctanesulfonic acid) produced significant toxic effects in neuromasts at EC10 concentrations. Depending on the test substances and their location along the lateral line, specific neuromasts differed in sensitivity. Generally, neuromasts proved more sensitive in the pulse exposure scenario. Whereas for neomycin and copper sulfate neuromasts located along the anterior lateral line were more sensitive, posterior lateral line neuromasts proved more sensitive for the other test substances. Nuclear fragmentation could not only be associated with all test substances, but, albeit at lower frequencies, also with negative controls, and could, therefore, not be assigned specifically to chemical damage. The study thus documented that for a comprehensive evaluation of lateral line damage both neuromasts from the anterior and the posterior lateral line have to be considered. Given the apparently rapid regeneration of hair cells, pulse exposure seems more appropriate for the identification of lateral line neurotoxicity than continuous exposure.

Spontaneous activity is correlated with coding density in primary auditory cortex.

Sensory neurons across sensory modalities and specific processing areas have diverse levels of spontaneous firing rates (SFRs) in the absence of sensory stimuli. However, the functional significance of this spontaneous activity is not well-understood. Previous studies in the auditory system have demonstrated that different levels of spontaneous activity are correlated with a variety of physiological and anatomic properties, suggesting that neurons with differing SFRs make unique contributions to the encoding of auditory stimuli. Additionally, altered SFRs are a correlate of tinnitus, arising in several auditory areas after exposure to ototoxic substances and noise trauma. In this study, we recorded single-unit activity from primary auditory cortex of awake marmoset monkeys while delivering wide-band random-spectrum stimuli and white Gaussian noise (WGN) to examine any divergences in stimulus encoding properties across SFR classes. We found that higher levels of spontaneous activity were associated with both higher levels of activation relative to suppression across a variety of wide-band stimuli and higher driven rates in response to WGN. Moreover, response latencies to WGN were negatively correlated with the level of activation in response to both stimulus types. These findings are consistent with a novel view of the role spontaneous spiking may play during normal stimulus processing in primary auditory cortex and how it may malfunction in cases of tinnitus.

Chapter 17 - Bilateral vestibulopathy

The leading symptoms of bilateral vestibulopathy (BVP) are postural imbalance and unsteadiness of gait that worsens in darkness and on uneven ground. There are typically no symptoms while sitting or lying under static conditions. A minority of patients also have movement-induced oscillopsia, in particular while walking. The diagnosis of BVP is based on a bilaterally reduced or absent function of the vestibulo-ocular reflex (VOR). This deficit is diagnosed for the high-frequency range of the angular VOR by a bilaterally pathologic bedside head impulse test (HIT) and for the low-frequency range by a bilaterally reduced or absent caloric response. If the results of the bedside HIT are unclear, angular VOR function should be quantified by a video-oculography system (vHIT). An additional test supporting the diagnosis is dynamic visual acuity. Cervical and ocular vestibular-evoked myogenic potentials (c/oVEMP) may also be reduced or absent, indicating impaired otolith function. There are different subtypes of BVP depending on the affected anatomic structure and frequency range of the VOR deficit: impaired canal function in the low- and/or high-frequency VOR range only and/or otolith function only; the latter is very rare. The etiology of BVP remains unclear in more than 50% of patients: in these cases neurodegeneration is assumed. Frequent known causes are ototoxicity mainly due to gentamicin, bilateral Menière's disease, autoimmune diseases, meningitis and bilateral vestibular schwannoma, as well as an association with cerebellar degeneration (cerebellar ataxia, neuropathy, vestibular areflexia syndrome=CANVAS). In general, in the long term there is no improvement of vestibular function. There are four treatment options: first, detailed patient counseling to explain the cause, etiology, and consequences, as well as the course of the disease; second, daily vestibular exercises and balance training; third, if possible, treatment of the underlying cause, as in bilateral Menière's disease, meningitis, or autoimmune diseases; fourth, if possible, prevention, i.e., being very restrictive with the use of ototoxic substances, such as aminoglycosides. In the future vestibular implants may also be an option.