Daniel B. Putterman

Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopa-induced dyskinesia in a rat model of Parkinson's disease.

Levodopa dose and severity of Parkinsons disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxy-dopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2–10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories (ρ > 0.7) and for each AIM category in regard to total AIM score (ρ > 0.7). In rats that received levodopa doses that were greater than the ED50, rates of amphetamine-induced rotation were significantly correlated with total AIM scores (ρ = 0.413). However, of those rotating >5 times/min, 34% had relatively low AIM scores (<8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores (ρ = 0.388). However, in those rats that had >85% TH loss, 30% had AIM scores <8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility.

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias.

Levodopa (L-DOPA) is the ‘gold standard’ to treat Parkinsons disease. Unfortunately, dyskinesias detract from its efficacy. Current dyskinesia treatments, including amantadine and dextromethorphan, are thought to work via N-methyl-D-aspartate (NMDA) antagonism, but this hypothesis has not been tested. The NMDA antagonists MK-801 and HA-966 failed to suppress expression of dyskinesias in the 6-hydroxydopamine rat. Dyskinesias, however, were suppressed by the NMDA and sigma (σ)-1 receptor ligand dextromethorphan and by the σ-1 antagonist BMY-14802. Antidyskinetic effects of dextromethorphan may be mediated via mechanisms other than NMDA, including the σ-1 receptor and other binding sites common to dextromethorphan and BMY-14802.

Normative wideband reflectance, equivalent admittance at the tympanic membrane, and acoustic stapedius reflex threshold in adults

Objectives: Wideband acoustic immittance (WAI) measures such as pressure reflectance, parameterized by absorbance and group delay, equivalent admittance at the tympanic membrane (TM), and acoustic stapedius reflex threshold (ASRT) describe middle ear function across a wide frequency range, compared with traditional tests employing a single frequency. The objective of this study was to obtain normative data using these tests for a group of normal-hearing adults and investigate test–retest reliability using a longitudinal design. Design: A longitudinal prospective design was used to obtain normative test and retest data on clinical and WAI measures. Subjects were 13 males and 20 females (mean age = 26 years). Inclusion criteria included normal audiometry and clinical immittance. Subjects were tested on two separate visits approximately 1 month apart. Reflectance and equivalent admittance at the TM were measured from 0.25 to 8.0 kHz under three conditions: at ambient pressure in the ear canal and with pressure sweeps from positive to negative pressure (downswept) and negative to positive pressure (upswept). Equivalent admittance at the TM was calculated using admittance measurements at the probe tip that were adjusted using a model of sound transmission in the ear canal and acoustic estimates of ear-canal area and length. Wideband ASRTs were measured at tympanometric peak pressure (TPP) derived from the average TPP of downswept and upswept tympanograms. Descriptive statistics were obtained for all WAI responses, and wideband and clinical ASRTs were compared. Results: Mean absorbance at ambient pressure and TPP demonstrated a broad band-pass pattern typical of previous studies. Test–retest differences were lower for absorbance at TPP for the downswept method compared with ambient pressure at frequencies between 1.0 and 1.26 kHz. Mean tympanometric peak-to-tail differences for absorbance were greatest around 1.0 to 2.0 kHz and similar for positive and negative tails. Mean group delay at ambient pressure and at TPP were greatest between 0.32 and 0.6 kHz at 200 to 300 &mgr;sec, reduced at frequencies between 0.8 and 1.5 kHz, and increased above 1.5 kHz to around 150 &mgr;sec. Mean equivalent admittance at the TM had a lower level for the ambient method than at TPP for both sweep directions below 1.2 kHz, but the difference between methods was only statistically significant for the comparison between the ambient method and TPP for the upswept tympanogram. Mean equivalent admittance phase was positive at all frequencies. Test–retest reliability of the equivalent admittance level ranged from 1 to 3 dB at frequencies below 1.0 kHz, but increased to 8 to 9 dB at higher frequencies. The mean wideband ASRT for an ipsilateral broadband noise activator was 12 dB lower than the clinical ASRT, but had poorer reliability. Conclusions: Normative data for the WAI test battery revealed minor differences for results at ambient pressure compared with tympanometric methods at TPP for reflectance, group delay, and equivalent admittance level at the TM for subjects with middle ear pressure within ±100 daPa. Test–retest reliability was better for absorbance at TPP for the downswept tympanogram compared with ambient pressure at frequencies around 1.0 kHz. Large peak-to-tail differences in absorbance combined with good reliability at frequencies between about 0.7 and 3.0 kHz suggest that this may be a sensitive frequency range for interpreting absorbance at TPP. The mean wideband ipsilateral ASRT was lower than the clinical ASRT, consistent with previous studies. Results are promising for the use of a wideband test battery to evaluate middle ear function.

Comparison of wideband and clinical acoustic reflex thresholds in patients with normal hearing and sensorineural hearing loss

Acoustic reflex thresholds (ARTs) obtained with a wideband (WB) probe and an adaptive threshold detection procedure were compared to ARTs using a clinical system. Ipsilateral and contralateral ARTs were elicited in a group of 79 adults with normal hearing (NH) and 51 adults with sensorineural hearing loss (SNHL). ARTs were obtained for both methods using activator tones of 0.5, 1.0, and 2.0 kHz and broadband noise (BBN) with a bandwidth extending to 4.0 kHz for the clinical and 8.0 kHz for the WB ART. Results were similar for ipsilateral and contralateral ARTs. Tonal ARTs with the clinical method were slightly elevated for the SNHL group for all three activator tones, but for the WB method were elevated at 2.0 kHz where the average hearing loss was greatest (47 dB HL). ARTs for BBN were higher for the clinical method than the WB method for both groups, and the difference between groups was around 5 dB for the clinical method but 12 dB for the WB method. This suggests that ARTs with the WB method and BBN activator extending to 8 kHz are a more sensitive indicator of high-frequency SNHL than the clinical method. Individual reflex patterns will also be presented.

High frequency transient-evoked otoacoustic emission measurements using chirp and click stimuli

Abstract Transient‐evoked otoacoustic emissions (TEOAEs) at high frequencies are a non‐invasive physiological test of basilar membrane mechanics at the basal end, and have clinical potential to detect risk of hearing loss related to outer‐hair‐cell dysfunction. Using stimuli with constant incident pressure across frequency, TEOAEs were measured in experiment 1 at low frequencies (0.7–8 kHz) and high frequencies (7.1–14.7 kHz) in adults with normal hearing up to 8 kHz and varying hearing levels from 9 to 16 kHz. In combination with click stimuli, chirp stimuli were used with slow, medium and fast sweep rates for which the local frequency increased or decreased with time. Chirp TEOAEs were transformed into equivalent click TEOAEs by inverse filtering out chirp stimulus phase, and analyzed similarly to click TEOAEs. To improve detection above 8 kHz, TEOAEs were measured in experiment 2 with higher‐level stimuli and longer averaging times. These changes increased the TEOAE signal‐to‐noise ratio (SNR) by 10 dB. Slower sweep rates were investigated but the elicited TEOAEs were detected in fewer ears compared to faster rates. Data were acquired in adults and children (age 11–17 y), including children with cystic fibrosis (CF) treated with ototoxic antibiotics. Test‐retest measurements revealed satisfactory repeatability of high‐frequency TEOAE SNR (median of 1.3 dB) and coherence synchrony measure, despite small test‐retest differences related to changes in forward and reverse transmission in the ear canal. The results suggest the potential use of such tests to screen for sensorineural hearing loss, including ototoxic loss. Experiment 2 was a feasibility study to explore TEOAE test parameters that might be used in a full‐scale study to screen CF patients for risk of ototoxic hearing loss. HighlightsTransient‐evoked otoacoustic emissions non‐invasively assess outer hair cell function upto 14.7 kHz.First report of TEOAE measurements in children above 8 kHz.Chirp stimuli elicit TEOAEs at higher sound exposure levels than possible with click stimuli.Subset of clinically useful TEOAE measures do not require reflectance calibration for satisfactory repeatability.High‐frequency TEOAEs show promise to detect ototoxic hearing loss in children and adults.

Chirp-Evoked Otoacoustic Emissions and Middle Ear Absorbance for Monitoring Ototoxicity in Cystic Fibrosis Patients

Objectives: The goal of this study was to investigate the use of transient-evoked otoacoustic emissions (TEOAEs) and middle ear absorbance measurements to monitor auditory function in patients with cystic fibrosis (CF) receiving ototoxic medications. TEOAEs were elicited with a chirp stimulus using an extended bandwidth (0.71 to 8 kHz) to measure cochlear function at higher frequencies than traditional TEOAEs. Absorbance over a wide bandwidth (0.25 to 8 kHz) provides information on middle ear function. The combination of these time-efficient measurements has the potential to identify early signs of ototoxic hearing loss. Design: A longitudinal study design was used to monitor the hearing of 91 patients with CF (median age = 25 years; age range = 15 to 63 years) who received known ototoxic medications (e.g., tobramycin) to prevent or treat bacterial lung infections. Results were compared to 37 normally hearing young adults (median age = 32.5 years; age range = 18 to 65 years) without a history of CF or similar treatments. Clinical testing included 226-Hz tympanometry, pure-tone air-conduction threshold testing from 0.25 to 16 kHz and bone conduction from 0.25 to 4 kHz. Experimental testing included wideband absorbance at ambient and tympanometric peak pressure and TEOAEs in three stimulus conditions: at ambient pressure and at tympanometric peak pressure using a chirp stimulus with constant incident pressure level across frequency and at ambient pressure using a chirp stimulus with constant absorbed sound power across frequency. Results: At the initial visit, behavioral audiometric results indicated that 76 of the 157 ears (48%) from patients with CF had normal hearing, whereas 81 of these ears (52%) had sensorineural hearing loss for at least one frequency. Seven ears from four patients had a confirmed behavioral change in hearing threshold for ≥3 visits during study participation. Receiver operating characteristic curve analyses demonstrated that all three TEOAE conditions were useful for distinguishing CF ears with normal hearing from ears with sensorineural hearing loss, with an area under the receiver operating characteristic curve values ranging from 0.78 to 0.92 across methods for frequency bands from 2.8 to 8 kHz. Case studies are presented to illustrate the relationship between changes in audiometric thresholds, TEOAEs, and absorbance across study visits. Absorbance measures permitted identification of potential middle ear dysfunction at 5.7 kHz in an ear that exhibited a temporary hearing loss. Conclusions: The joint use of TEOAEs and absorbance has the potential to explain fluctuations in audiometric thresholds due to changes in cochlear function, middle ear function, or both. These findings are encouraging for the joint use of TEOAE and wideband absorbance objective tests for monitoring ototoxicity, particularly, in patients who may be too ill for behavioral hearing tests. Additional longitudinal studies are needed in a larger number of CF patients receiving ototoxic drugs to further evaluate the clinical utility of these measures in an ototoxic monitoring program.

Assessing Sensorineural Hearing Loss Using Various Transient-Evoked Otoacoustic Emission Stimulus Conditions.

Objectives: An important clinical application of transient-evoked otoacoustic emissions (TEOAEs) is to evaluate cochlear outer hair cell function for the purpose of detecting sensorineural hearing loss (SNHL). Double-evoked TEOAEs were measured using a chirp stimulus, in which the stimuli had an extended frequency range compared to clinical tests. The present study compared TEOAEs recorded using an unweighted stimulus presented at either ambient pressure or tympanometric peak pressure (TPP) in the ear canal and TEOAEs recorded using a power-weighted stimulus at ambient pressure. The unweighted stimulus had approximately constant incident pressure magnitude across frequency, and the power-weighted stimulus had approximately constant absorbed sound power across frequency. The objective of this study was to compare TEOAEs from 0.79 to 8 kHz using these three stimulus conditions in adults to assess test performance in classifying ears as having either normal hearing or SNHL. Design: Measurements were completed on 87 adult participants. Eligible participants had either normal hearing (N = 40; M F = 16 24; mean age = 30 years) or SNHL (N = 47; M F = 20 27; mean age = 58 years), and normal middle ear function as defined by standard clinical criteria for 226-Hz tympanometry. Clinical audiometry, immittance, and an experimental wideband test battery, which included reflectance and TEOAE tests presented for 1-min durations, were completed for each ear on all participants. All tests were then repeated 1 to 2 months later. TEOAEs were measured by presenting the stimulus in the three stimulus conditions. TEOAE data were analyzed in each hearing group in terms of the half-octave-averaged signal to noise ratio (SNR) and the coherence synchrony measure (CSM) at frequencies between 1 and 8 kHz. The test–retest reliability of these measures was calculated. The area under the receiver operating characteristic curve (AUC) was measured at audiometric frequencies between 1 and 8 kHz to determine TEOAE test performance in distinguishing SNHL from normal hearing. Results: Mean TEOAE SNR was ≥8.7 dB for normal-hearing ears and ⩽6 dB for SNHL ears for all three stimulus conditions across all frequencies. Mean test–retest reliability of TEOAE SNR was ⩽4.3 dB for both hearing groups across all frequencies, although it was generally less (⩽3.5 dB) for lower frequencies (1 to 4 kHz). AUCs were between 0.85 and 0.94 for all three TEOAE conditions at all frequencies, except for the ambient TEOAE condition at 2 kHz (0.82) and for all TEOAE conditions at 5.7 kHz with AUCs between 0.78 and 0.81. Power-weighted TEOAE AUCs were significantly higher (p < 0.05) than ambient TEOAE AUCs at 2 and 2.8 kHz, as was the TPP TEOAE AUC at 2.8 kHz when using CSM as the classifier variable. Conclusions: TEOAEs evaluated in an ambient condition, at TPP and in a power-weighted stimulus condition, had good test performance in identifying ears with SNHL based on SNR and CSM in the frequency range from 1 to 8 kHz and showed good test–retest reliability. Power-weighted TEOAEs showed the best test performance at 2 and 2.8 kHz. These findings are encouraging as a potential objective clinical tool to identify patients with cochlear hearing loss.