Characteristic Deviations of Auditory Evoked Potentials in Individuals with Autism Spectrum Disorder.

BACKGROUND: Neurological, structural, and behavioral abnormalities are widely reported in individuals with autism spectrum disorder (ASD); yet there are no objective markers to date. We postulated that by using dominant and nondominant ear data, underlying differences in auditory evoked potentials (AEPs) between ASD and control groups can be recognized. PURPOSE: The primary purpose was to identify if significant differences exist in AEPs recorded from dominant and nondominant ear stimulation in (1) children with ASD and their matched controls, (2) adults with ASD and their matched controls, and (3) a combined child and adult ASD group and control group. The secondary purpose was to explore the association between the significant findings of this study with those obtained in our previous study that evaluated the effects of auditory training on AEPs in individuals with ASD. RESEARCH DESIGN: Factorial analysis of variance with interaction was performed. STUDY SAMPLE: Forty subjects with normal hearing between the ages of 9 and 25 years were included. Eleven children and 9 adults with ASD were age- and gender-matched with neurotypical peers. DATA COLLECTION AND ANALYSIS: Auditory brainstem responses (ABRs) and auditory late responses (ALRs) were recorded. Adult and child ASD subjects were compared with non-ASD adult and child control subjects, respectively. The combined child and adult ASD group was compared with the combined child and adult control group. RESULTS: No significant differences in ABR latency or amplitude were observed between ASD and control groups. ALR N1 amplitude in the dominant ear was significantly smaller for the ASD adult group compared with their control group. Combined child and adult data showed significantly smaller amplitude for ALR N1 and longer ALR P2 latency in the dominant ear for the ASD group compared with the control group. In our earlier study, the top predictor of behavioral improvement following auditory training was ALR N1 amplitude in the dominant ear. Correspondingly, the ALR N1 amplitude in the dominant ear yielded group differences in the current study. CONCLUSIONS: ALR peak N1 amplitude is proposed as the most feasible AEP marker in the evaluation of ASD.

Behavioral Auditory Processing in Children and Young Adults with Autism Spectrum Disorder.

BACKGROUND: Auditory-processing deficits are common in children and adults who are diagnosed with autism spectrum disorder (ASD). These deficits are evident across multiple domains as exhibited by the results from subjective questionnaires from parents, teachers, and individuals with ASD and from behavioral auditory-processing testing. PURPOSE: Few studies compare subjective and behavioral performance of adults and children diagnosed with ASD using commercially available tests of auditory processing. The primary goal of the present study is to compare the performance of adults and children with ASD to age-matched, neurotypical peers. The secondary goal is to examine the effect of age on auditory-processing performance in individuals with ASD relative to age-matched peers. RESEARCH DESIGN: A four-group, quasi-experimental design with repeated measures was used in this study. STUDY SAMPLE: Forty-two adults and children were separated into four groups of participants: (1) 10 children with ASD ages 14 years or younger; (2) 10 age-matched, neurotypical children; (3) 11 adolescents and young adults with ASD ages 16 years and older; and (4) 11 age-matched, neurotypical adolescents or young adults. DATA COLLECTION AND ANALYSIS: Data from each participant were collected in one test session. Data were analyzed with analysis of variance (ANOVA), repeated measures ANOVA, or nonparametric analyses. Effect sizes were calculated to compare performance between those with ASD and those who were neurotypical within each age group. RESULTS: Across all the questionnaires and the majority of the behavioral test measures, participants with ASD had significantly poorer ratings or auditory-processing performance than age-matched, neurotypical peers. Adults had more favorable performance than children on several of the test measures. Medium to large effect sizes corroborated the significant results. CONCLUSION: Overall, the questionnaires and behavioral tests used in this study were sensitive to detecting auditory-processing differences between individuals diagnosed with ASD and those who are considered neurotypical. On most test measures, children performed more poorly than adults. The findings in this study support that both children and adults with ASD exhibit auditory-processing difficulties. Appropriate school and work accommodations will be necessary to ensure appropriate access to speech in challenging environments.

Effects of Auditory Training on Electrophysiological Measures in Individuals with Autism Spectrum Disorder.

BACKGROUND: Identifying objective changes following an auditory training program is central to the assessment of the program's efficacy. PURPOSE: This study aimed (1) to objectively determine the efficacy of a 12-week auditory processing training (APT) program in individuals with autism spectrum disorder using auditory evoked potentials (AEPs) and (2) to identify the top central AEP predictors of the overall score on the Test of Auditory Processing Skills-3 (TAPS-3), the primary behavioral outcome measure of the APT program published in our earlier article. RESEARCH DESIGN: A one-group pretraining, posttraining design was used. STUDY SAMPLE: The sample included 15 children and young adults diagnosed with autism spectrum disorder. Participants underwent the APT program consisting of computerized dichotic training, one-on-one therapist-directed auditory training, and the use of remote microphone technology at home and in the classroom. DATA COLLECTION AND ANALYSIS: All participants underwent pre- and posttraining auditory brain stem responses (ABRs), complex auditory brain stem responses (cABRs), and auditory late responses (ALRs). Test results from ABRs and ALRs were grouped based on scores obtained in their dominant and nondominant ears. Paired t-tests were used to assess the efficacy of the training program, and least absolute shrinkage and selection operator regression was used to assess the relationship between ALRs and the TAPS-3 overall summed raw score reported in our earlier article. RESULTS AND CONCLUSIONS: When compared with pretraining results, posttraining results showed shorter ABR latencies and larger amplitudes. The cABRs showed decreased latencies of the frequency following waves, a reduction in pitch error, and enhancement of pitch strength and phase shift. ALR results indicated shorter latencies and larger amplitudes. Our earlier article showed that the TAPS-3 overall score was significantly higher after training. This study showed that the top three ALR predictors of TAPS-3 outcomes were P1 amplitude in the dominant ear, and N1 amplitude in the dominant and nondominant ears.

Assessment of Safe Listening Intentional Behavior Toward Personal Listening Devices in Young Adults.

Recreational noise-induced hearing loss (RNIHL) is a highly preventable disorder that is commonly seen in teenagers and young adults. Despite the documented negative effects of RNIHL, it is still challenging to persuade people to adopt safe listening behaviors. More research is needed to understand the underlying factors guiding listeners' intentions to engage in safe listening habits. We used the Theory of Planned Behavior (TPB) to identify attitudes, social norms, and behavioral control in 92 young adults toward two intentional behaviors related to safe listening habits while listening to their personal listening devices: (1) lowering the intensity of loud music, and (2) shortening the listening duration of loud music. Using a Qualtrics survey, the major factors of the TPB model as they relate to the participants' intention to engage in risk-controlling behavior were assessed. Behavioral intentions to turn the music down and listen for shorter durations were thought to be predicted by the TPB factors (attitudes, social norms, and perceived behavioral control). Linear regression findings indicated that the overall TPB models were significant. Positive attitudes toward turning the music down and shortening the durations were significantly associated with intentions to engage in non-risky behavior, more so for the former behavior.

Effects of Auditory Training and Remote Microphone Technology on the Behavioral Performance of Children and Young Adults Who Have Autism Spectrum Disorder.

BACKGROUND: Individuals who have a normal pure-tone audiogram but are diagnosed with autism spectrum disorder (ASD) often exhibit poorer speech recognition and auditory processing when compared with neurotypical peers with normal pure-tone audiograms. PURPOSE: The purpose of this study was to determine the efficacy and effectiveness of a 12-week auditory processing training (APT) program that was designed to address the deleterious effects of background noise and auditory processing deficits that are common among individuals diagnosed with ASD. RESEARCH DESIGN: A repeated measures design was used. STUDY SAMPLE: The sample consisted of 15 high-functioning children and young adults who had a formal diagnosis of ASD and who were recruited from local clinics and school districts. INTERVENTION: Participants completed the 12-week APT program consisting of computerized dichotic training, one-on-one therapist-directed auditory training, and the use of remote microphone (RM) technology at home and in the classroom. DATA COLLECTION AND ANALYSIS: Participants completed a comprehensive test battery to assess general auditory processing skills, speech recognition in noise, acceptance of background noise, spatial processing, binaural integration abilities, self-perceived difficulties, and observed behaviors. Testing was conducted before (n = 15), immediately after (n = 15), and 12 weeks after (n = 7) the completion of the APT program. Paired t-tests, repeated measures analysis of variance, or nonparametric tests were used to analyze the data. RESULTS: On average, the APT program significantly enhanced general auditory processing abilities, including binaural integration and subjective listening abilities in the classroom. When the RM was used, significantly improved speech recognition and improved acceptance of background noise was measured relative to a condition with no technology. CONCLUSIONS: Following the APT program, the participants exhibited the greatest improvements in testing that required binaural integration and auditory working memory. The use of the RM technology was able to address the deleterious effects of noise on speech recognition in noise and acceptance of noise levels.

Risk Assessment of Recreational Noise-Induced Hearing Loss from Exposure through a Personal Audio System-iPod Touch.

BACKGROUND: Recreational noise-induced hearing loss (RNIHL) is a major health issue and presents a huge economic burden on society. Exposure to loud music is not considered hazardous in our society because music is thought to be a source of relaxation and entertainment. However, there is evidence that regardless of the sound source, frequent exposure to loud music, including through personal audio systems (PAS), can lead to hearing loss, tinnitus, difficulty processing speech, and increased susceptibility to age-related hearing loss. PURPOSE: Several studies have documented temporary threshold shifts (TTS) (a risk indicator of future permanent impairment) in subjects that listen to loud music through their PAS. However, there is not enough information regarding volume settings that may be considered to be safe. As a primary step toward quantifying the risk of RNIHL through PAS, we assessed changes in auditory test measures before and after exposure to music through the popular iPod Touch device set at various volume levels. RESEARCH DESIGN: This project design incorporated aspects of both between- and within-subjects and used repeated measures to analyze individual groups. STUDY SAMPLE: A total of 40 adults, aged 18-31 years with normal hearing were recruited and randomly distributed to four groups. Each group consisted of five males and five females. DATA COLLECTION AND ANALYSIS: Subjects underwent two rounds of testing (pre- and postmusic exposure), with a 30-min interval, where they listened to a playlist consisting of popular songs through an iPod at 100%, 75%, 50%, or 0% volume (no music). Based on our analysis on the Knowles Electronic Manikin for Acoustic Research, with a standardized 711 coupler, it was determined that listening to the playlist for 30 min through standard earbuds resulted in an average level of 97.0 dBC at 100% volume, 83.3 dBC at 75% volume, and 65.6 dBC at 50% volume. Pure-tone thresholds from 500-8000 Hz, extended high-frequency pure tones between 9-12.5 kHz, and distortion product otoacoustic emissions (DPOAE) were obtained before and after the 30-min music exposure. Analysis of variance (ANOVA) was performed with two between-subjects factors (volume and gender) and one within-subjects factor (frequency). Change (shift) in auditory test measures was used as the outcome for the ANOVA. RESULTS: Results indicated significant worsening of pure-tone thresholds following music exposure only in the group that was exposed to 100% volume at the following frequencies: 2, 3, 4, 6 and 8 kHz. DPOAEs showed significant decrease at 2000 and 2822 Hz, also only for the 100% volume condition. No significant changes were found between pre- and postmusic exposure measures in groups exposed to 75%, 50%, or 0% volume conditions. Follow-up evaluations conducted a week later indicated that pure-tone thresholds had returned to the premusic exposure levels. CONCLUSIONS: These results provide quantifiable information regarding safe volume control settings on the iPod Touch with standard earbuds. Listening to music using the iPod Touch at 100% volume setting for as little as 30 min leads to TTS and worsening of otoacoustic emissions, a risk for permanent auditory damage.

Potential Audiological and MRI Markers of Tinnitus.

BACKGROUND: Subjective tinnitus, or ringing sensation in the ear, is a common disorder with no accepted objective diagnostic markers. PURPOSE: The purpose of this study was to identify possible objective markers of tinnitus by combining audiological and imaging-based techniques. RESEARCH DESIGN: Case-control studies. STUDY SAMPLE: Twenty adults drawn from our audiology clinic served as participants. The tinnitus group consisted of ten participants with chronic bilateral constant tinnitus, and the control group consisted of ten participants with no history of tinnitus. Each participant with tinnitus was closely matched with a control participant on the basis of age, gender, and hearing thresholds. DATA COLLECTION AND ANALYSES: Data acquisition focused on systematic administration and evaluation of various audiological tests, including auditory-evoked potentials (AEP) and otoacoustic emissions, and magnetic resonance imaging (MRI) tests. A total of 14 objective test measures (predictors) obtained from audiological and MRI tests were subjected to statistical analyses to identify the best predictors of tinnitus group membership. The least absolute shrinkage and selection operator technique for feature extraction, supplemented by the leave-one-out cross-validation technique, were used to extract the best predictors. This approach provided a conservative model that was highly regularized with its error within 1 standard error of the minimum. RESULTS: The model selected increased frontal cortex (FC) functional MRI activity to pure tones matching their respective tinnitus pitch, and augmented AEP wave N1 amplitude growth in the tinnitus group as the top two predictors of tinnitus group membership. These findings suggest that the amplified responses to acoustic signals and hyperactivity in attention regions of the brain may be a result of overattention among individuals that experience chronic tinnitus. CONCLUSIONS: These results suggest that increased functional MRI activity in the FC to sounds and augmented N1 amplitude growth may potentially be the objective diagnostic indicators of tinnitus. However, due to the small sample size and lack of subgroups within the tinnitus population in this study, more research is needed before generalizing these findings.

Pharmacological response sensitization in nerve cell networks exposed to the antibiotic gentamicin.

Gentamicin is an aminoglycoside antibiotic that is used in clinical, organismic, and agricultural applications to combat gram-negative, aerobic bacteria. The clinical use of gentamicin is widely linked to various toxicities, but there is a void in our knowledge about the neuromodulatory or neurotoxicity effects of gentamicin. This investigation explored the electrophysiologic effects of gentamicin on GABAergic pharmacological profiles in spontaneously active neuronal networks in vitro derived from auditory cortices of E16 mouse embryos and grown on microelectrode arrays. Using the GABAA agonist muscimol as the test substance, responses from networks to dose titrations of muscimol were compared in the presence and absence of 100µM gentamicin (the recommended concentration for cell culture conditions). Spike-rate based EC50 values were generated using sigmoidal fit concentration response curves (CRCs). Exposure to 100µM gentamicin exhibited a muscimol EC50±S.E.M. of 80±6nM (n=10). The EC50 value obtained in the absence of gentamicin was 124±11nM (n=10). The 35% increase in potency suggests network sensitization to muscimol in the presence of gentamicin. Action potential (AP) waveform analyses of neurons exposed to gentamicin demonstrated a concentration-dependent decrease in AP amplitudes (extracellular recordings), possibly reflecting gentamicin effects on voltage-gated ion channels. These in vitro results reveal alteration of pharmacological responses by antibiotics that could have significant influence on the behavior and performance of animals.

Efficacy of carnitine in treatment of tinnitus: evidence from audiological and MRI measures-a case study.

BACKGROUND: Tinnitus, or ringing in the ears, is an extremely common ear disorder. However, it is a phenomenon that is very poorly understood and has limited treatment options. PURPOSE: The goals of this case study were to identify if the antioxidant acetyl-L-carnitine (ALCAR) provides relief from tinnitus, and to identify if subjective satisfaction after carnitine treatment is accompanied by changes in audiological and imaging measures. RESEARCH DESIGN: Case Study. PATIENT CASE: A 41-yr-old female with a history of hearing loss and tinnitus was interested in exploring the benefits of antioxidant therapy in reducing her tinnitus. The patient was evaluated using a standard audiological/tinnitus test battery and magnetic resonance imaging (MRI) recordings before carnitine treatment. After her physician's approval, the patient took 500 mg of ALCAR twice a day for 30 consecutive days. The audiological and MRI measures were repeated after ALCAR treatment. DATA COLLECTION AND ANALYSIS: Pure-tone audiometry, tympanometry, distortion-product otoacoustic emissions, tinnitus questionnaires (Tinnitus Handicap Inventory and Tinnitus Reaction Questionnaire), auditory brainstem response, functional MRI (fMRI), functional connectivity MRI, and cerebral blood flow evaluations were conducted before intake of ALCAR and were repeated 30 days after ALCAR treatment. RESULTS: The patient's pretreatment pure-tone audiogram indicated a mild sensorineural hearing loss at 6 kHz in the right ear and 4 kHz in the left ear. Posttreatment evaluation indicated marginal improvement in the patient's pure-tone thresholds, but was sufficient to be classified as being clinically normal in both ears. Distortion-product otoacoustic emissions results showed increased overall emissions after ALCAR treatment. Subjective report from the patient indicated that her tinnitus was less annoying and barely noticeable during the day after treatment, and the posttreatment tinnitus questionnaire scores supported her statement. Auditory brainstem response peak V amplitude growth between stimulus intensity levels of 40-80 dB nHL indicated a reduction in growth for the posttreatment condition compared with the pretreatment condition. This was attributed to a possible active gating mechanism involving the auditory brainstem after ALCAR treatment. Posttreatment fMRI recordings in response to acoustic stimuli indicated a statistically significant reduction in brain activity in several regions of the brain, including the auditory cortex. Cerebral blood flow showed increased flow in the auditory cortex after treatment. The functional connectivity MRI indicated increased connectivity between the right and left auditory cortex, but a decrease in connectivity between the auditory cortex and some regions of the "default mode network," namely the medial prefrontal cortex and posterior cingulate cortex. CONCLUSIONS: The changes observed in the objective and subjective test measures after ALCAR treatment, along with the patient's personal observations, indicate that carnitine intake may be a valuable pharmacological option in the treatment of tinnitus.

Botulinum toxin suppression of CNS network activity in vitro.

The botulinum toxins are potent agents which disrupt synaptic transmission. While the standard method for BoNT detection and quantification is based on the mouse lethality assay, we have examined whether alterations in cultured neuronal network activity can be used to detect the functional effects of BoNT. Murine spinal cord and frontal cortex networks cultured on substrate integrated microelectrode arrays allowed monitoring of spontaneous spike and burst activity with exposure to BoNT serotype A (BoNT-A). Exposure to BoNT-A inhibited spike activity in cultured neuronal networks where, after a delay due to toxin internalization, the rate of activity loss depended on toxin concentration. Over a 30 hr exposure to BoNT-A, the minimum concentration detected was 2 ng/mL, a level consistent with mouse lethality studies. A small proportion of spinal cord networks, but not frontal cortex networks, showed a transient increase in spike and burst activity with exposure to BoNT-A, an effect likely due to preferential inhibition of inhibitory synapses expressed in this tissue. Lastly, prior exposure to human-derived antisera containing neutralizing antibodies prevented BoNT-A induced inhibition of network spike activity. These observations suggest that the extracellular recording from cultured neuronal networks can be used to detect and quantify functional BoNT effects.

Pharmacodynamics of potassium channel openers in cultured neuronal networks.

A novel class of drugs - potassium (K(+)) channel openers or activators - has recently been shown to cause anticonvulsive and neuroprotective effects by activating hyperpolarizing K(+) currents, and therefore, may show efficacy for treating tinnitus. This study presents measurements of the modulatory effects of four K(+) channel openers on the spontaneous activity and action potential waveforms of neuronal networks. The networks were derived from mouse embryonic auditory cortices and grown on microelectrode arrays. Pentylenetetrazol was used to create hyperactivity states in the neuronal networks as a first approximation for mimicking tinnitus or tinnitus-like activity. We then compared the pharmacodynamics of the four channel activators, retigabine and flupirtine (voltage-gated K(+) channel KV7 activators), NS1619 and isopimaric acid ("big potassium" BK channel activators). The EC50 of retigabine, flupirtine, NS1619, and isopimaric acid were 8.0, 4.0, 5.8, and 7.8µM, respectively. The reduction of hyperactivity compared to the reference activity was significant. The present results highlight the notion of re-purposing the K(+) channel activators for reducing hyperactivity of spontaneously active auditory networks, serving as a platform for these drugs to show efficacy toward target identification, prevention, as well as treatment of tinnitus.

Antioxidants L-carnitine and D-methionine modulate neuronal activity through GABAergic inhibition.

Antioxidants are well known for their neuroprotective properties against reactive oxygen species in cortical neurons and auditory cells. We recently identified L-carnitine and D-methionine to be among agents that provide such protection. Here, we investigated their neuronal modulatory actions. We used cultured neuronal networks grown on microelectrode arrays to assess the effects of L-carnitine and D-methionine on network function. Spike production and burst properties of neuronal networks were used as parameters to monitor pharmacological responses. L-Carnitine and D-methionine reduced spike activity with 100% efficacy with EC50 values of 0.22 (± 0.01) mM and 1.06 (± 0.05) mM, respectively. In the presence of 1.0-40 µM of the GABAA antagonist bicuculline, the sigmoidal concentration-response curves of both compounds exhibited stepwise shifts, without a change in efficacy. Under a maximal bicuculline concentration of 40 µM, the EC50 increased to 3.57 (± 0.26) mM for L-carnitine and to 10.52 (± 0.97) mM for D-methionine, more than a tenfold increase. The agonist-antagonist interactions with bicuculline were estimated by Lineweaver-Burk plot analyses to be competitive, corroborated by the computed dissociation constants of bicuculline. For both compounds, the effects on the network burst pattern, activity reversibility, and bicuculline antagonism resembled that elicited by the GABAA agonist muscimol. We showed that the antioxidants L-carnitine and D-methionine modulate cortical electrical spike activity primarily through GABAA receptor activation. Our findings suggest the involvement of GABAergic mechanisms that perhaps contribute to the protective actions of these compounds.

Auditory risk assessment of college music students in jazz band-based instructional activity.

It is well-known that musicians are at risk for music-induced hearing loss, however, systematic evaluation of music exposure and its effects on the auditory system are still difficult to assess. The purpose of the study was to determine if college students in jazz band-based instructional activity are exposed to loud classroom noise and consequently exhibit acute but significant changes in basic auditory measures compared to non-music students in regular classroom sessions. For this we (1) measured and compared personal exposure levels of college students (n = 14) participating in a routine 50 min jazz ensemble-based instructional activity (experimental) to personal exposure levels of non-music students (n = 11) participating in a 50-min regular classroom activity (control), and (2) measured and compared pre- to post-auditory changes associated with these two types of classroom exposures. Results showed that the L eq (equivalent continuous noise level) generated during the 50 min jazz ensemble-based instructional activity ranged from 95 dBA to 105.8 dBA with a mean of 99.5 ± 2.5 dBA. In the regular classroom, the L eq ranged from 46.4 dBA to 67.4 dBA with a mean of 49.9 ± 10.6 dBA. Additionally, significant differences were observed in pre to post-auditory measures between the two groups. The experimental group showed a significant temporary threshold shift bilaterally at 4000 Hz (P < 0.05), and a significant decrease in the amplitude of transient-evoked otoacoustic emission response in both ears (P < 0.05) after exposure to the jazz ensemble-based instructional activity. No significant changes were found in the control group between pre- and post-exposure measures. This study quantified the noise exposure in jazz band-based practice sessions and its effects on basic auditory measures. Temporary, yet significant, auditory changes seen in music students place them at risk for hearing loss compared to their non-music cohorts.

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks.

Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus. d-Methionine (d-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatin-induced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of d-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with d-Met, at a concentration of 1.0mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5mM, and delayed cell death at 0.75 mM cisplatin. l-Methionine, the optical isomer, showed lower potency and less efficacy than d-Met, was less protective against 0.1mM cisplatin, and proved ineffective at a concentration of 0.5mM cisplatin. Pre-exposure time of d-Met was associated with the protective effects at 0.1 and 0.5mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that d-Met protects central nervous system tissue from acute cisplatin toxicity.

An in vitro model for testing drugs to treat tinnitus.

Tinnitus affects approximately 50 million people in the USA alone, with 10 million being highly debilitated. Pharmacotherapy for tinnitus is still in emerging stages due to time consuming clinical trials and/or animal experiments. We tested a new cellular model where induced rapid neuronal firing or spiking was used as a mimic for the type of aberrant activity that may occur in tinnitus. Spontaneously active auditory cortical networks growing on microelectrode arrays were exposed to pentylenetetrazol (PTZ), a proconvulsant and an antagonist of GABA(A) receptor, which is implicated in tinnitus. Auditory cortical networks were then exposed to experimental tinnitus drugs linopirdine (Dup966, a potassium channel blocker), L-carnitine (an antioxidant), or selective Ca(2+) channel antagonists pregabalin (Lyrica), or gabapentin (Neurontin) at various concentrations. PTZ increased spike rate by 139.6±27% and burst rate by 129.7±28% in auditory cortical networks with a phenotypic high firing of excitable neurons. Reductions of increased activity were observed to varying degrees using the experimental tinnitus drugs. The potency of the drugs was linopirdine (EC(50): 176±7.0 µM)>L-carnitine (EC(50): 1569±41 µM)>pregabalin (EC(50): 8360±340 µM), >gabapentin, with 34.2±7.5% efficacy (EC(50): 2092±980 µM). These studies provide proof of principle for the use of auditory cortical networks on microelectrode array as a feasible platform for semi-high throughput application for screening of drugs that might be used for the treatment of tinnitus.

Assessment of styrene oxide neurotoxicity using in vitro auditory cortex networks.

Styrene oxide (SO) (C8H8O), the major metabolite of styrene (C6H5CH=CH2), is widely used in industrial applications. Styrene and SO are neurotoxic and cause damaging effects on the auditory system. However, little is known about their concentration-dependent electrophysiological and morphological effects. We used spontaneously active auditory cortex networks (ACNs) growing on microelectrode arrays (MEA) to characterize neurotoxic effects of SO. Acute application of 0.1 to 3.0 mM SO showed concentration-dependent inhibition of spike activity with no noticeable morphological changes. The spike rate IC50 (concentration inducing 50% inhibition) was 511 ± 60 µM (n = 10). Subchronic (5 hr) single applications of 0.5 mM SO also showed 50% activity reduction with no overt changes in morphology. The results imply that electrophysiological toxicity precedes cytotoxicity. Five-hour exposures to 2 mM SO revealed neuronal death, irreversible activity loss, and pronounced glial swelling. Paradoxical "protection" by 40 µM bicuculline suggests binding of SO to GABA receptors.

Analysis of auditory measures in normal hearing young male adult cigarette smokers using multiple variable selection methods with predictive validation assessments.

Studies have shown that cigarette smoking is a risk factor for hearing loss; however, no information is available on auditory preclinical indicators in young chronic cigarette smokers. Cigarette smoking involves exposure to many harmful chemicals including carbon monoxide (CO). In this study, the CO level in 16 young normal hearing male chronic smokers was measured with a CO monitor, and was used as the outcome measure. Subjects were administered a battery of audiological tests that included behavioral and electrophysiologic measures. The goal was to investigate which auditory test measures can be used as potential predictors of the outcome measure. Using ordinary least squares estimation procedures with best-subsets selection and bootstrapped stepwise variable selection procedures, an optimal predictive multiple linear regression model was selected. Results of this approach indicated that auditory brainstem response peak V amplitudes and distortion product otoacoustic emissions had the highest predictive value and accounted for most of the variability.

Audiological findings in individuals exposed to organic solvents: case studies.

Millions of people around the world are exposed to industrial organic solvents such as toluene and xylene in the manufacturing sectors. Solvents are neurotoxic substances that are detrimental to the functioning of the nervous system, including the central auditory nervous system (CANS). This study investigated hearing and auditory processing in seven individuals with a history of exposure to industrial solvents. A battery of audiological tests was administered to all subjects: pure tone, speech, and impedance audiometry, otoacoustic emissions tests, auditory brainstem responses, middle latency responses, as well as the SCAN-A and R-SPIN tests with low predictability sentence lists. All individuals in this study exhibited findings consistent with retrocochlear and/or central abnormality. Two of the seven subjects in this study had normal pure tone thresholds at all frequencies bilaterally, yet showed abnormal retrocochlear/central results on one or more tests. The auditory test battery approach used in this study appears to be valuable in evaluating the pathological conditions of the CANS in solvent-exposed individuals.

Ototoxicity of organic solvents - from scientific evidence to health policy.

The scientific workshop, organized under the 6th European Framework Programme, the Marie Curie Host Fellowship for the Transfer of Knowledge "NoiseHear" Project, by the Nofer Institute of Occupational Medicine (Lódz, Poland, 15-16 November 2006), gathered world specialists in noise, chemicals, and ototoxicity, including hearing researchers, toxicologists, otolaryngologists, audiologists and occupational health physicians.The workshop examined the evidence and the links between isolated exposure to organic solvents, combined exposure to noise and solvents, and effects on the auditory system. Its main purpose was to review the key scientific evidence to gather the necessary knowledge for developing adequate occupational health policies. This paper summarizes the workshop sessions and subsequent discussions.

Selective serotonin reuptake inhibitors treatment effects on auditory measures in depressed female subjects.

The purpose of this study was to evaluate the auditory effects of selective serotonin reuptake inhibitors (SSRI), known to enhance serotonin (5-HT) transmission in the brain. The experimental group consisted of 14 clinically depressed female subjects, and the control group consisted of 11 non-depressed females. A battery of tests was administered to the experimental group while on and off of SSRI medication. The control group was also administered the test battery twice. Results indicated no significant differences in the control group between sessions. The experimental group showed significantly smaller transient evoked emissions, higher SCAN-A (auditory processing test) composite scores, and smaller amplitude growth functions for Auditory brainstem response peak V and Auditory late response peak N(1)P(2) while on SSRI medication. The increased 5-HT levels in the presence of SSRI (due to reduced reuptake of 5-HT) may be contributing to the significant changes seen in auditory measures with the experimental group.