Can Methotrexate Be Employed as Monotherapy for Bullous Pemphigoid? Analysis of Efficiency and Tolerance of Methotrexate Treatment in Patients with Bullous Pemphigoid.

The European Academy of Dermatology and Venerology (EADV) consensus states that the treatment of choice for bullous pemphigoid is systemic glucocorticosteroid therapy. Bearing in mind that long-term steroid therapy is associated with numerous side effects, an effective and safer treatment regimen for these patients is still being sought. A retrospective analysis was performed of the medical reports of patients with diagnosed bullous pemphigoid. The study included 40 patients with moderate or severe disease, and who had continued ambulatory treatment for at least six months. The patients were divided into two groups: one treated with methotrexate in monotherapy, or with combined methotrexate and systemic steroid therapy. A slightly better survival rate was noted in the methotrexate group. No significant differences were observed between the groups in time to achieve clinical remission. The combination therapy group demonstrated more frequent disease recurrence and exacerbations during treatment, and a higher mortality rate. None of the patients in either group presented with severe side effects related to methotrexate treatment. The treatment of bullous pemphigoid with methotrexate in monotherapy is an effective and safe therapeutic method for elderly patients.

Amplitude-modulation forward masking for listeners with and without hearing loss.

Amplitude-modulation (AM) forward masking was measured for listeners with normal hearing and sensorineural hearing loss at 4000 and 1000 Hz, using continuous and noncontinuous masker and signal carriers, respectively. A low-fluctuation noise (LFN) carrier was used for the "continuous carrier" conditions. An unmodulated low-fluctuation noise (U-LFN), an unmodulated Gaussian noise (U-GN), and an amplitude-modulation low-fluctuation noise (AM-LFN) were maskers for the "noncontinuous carrier" conditions. As predicted, U-GN yielded more masking than U-LFN and similar masking to AM-LFN, suggesting that U-GN resulted in AM forward masking. Contrary to predictions, no differences in masked thresholds were observed between listener groups.

The effects of data quantity on performance of temporal response function analyses of natural speech processing.

In recent years, temporal response function (TRF) analyses of neural activity recordings evoked by continuous naturalistic stimuli have become increasingly popular for characterizing response properties within the auditory hierarchy. However, despite this rise in TRF usage, relatively few educational resources for these tools exist. Here we use a dual-talker continuous speech paradigm to demonstrate how a key parameter of experimental design, the quantity of acquired data, influences TRF analyses fit to either individual data (subject-specific analyses), or group data (generic analyses). We show that although model prediction accuracy increases monotonically with data quantity, the amount of data required to achieve significant prediction accuracies can vary substantially based on whether the fitted model contains densely (e.g., acoustic envelope) or sparsely (e.g., lexical surprisal) spaced features, especially when the goal of the analyses is to capture the aspect of neural responses uniquely explained by specific features. Moreover, we demonstrate that generic models can exhibit high performance on small amounts of test data (2-8 min), if they are trained on a sufficiently large data set. As such, they may be particularly useful for clinical and multi-task study designs with limited recording time. Finally, we show that the regularization procedure used in fitting TRF models can interact with the quantity of data used to fit the models, with larger training quantities resulting in systematically larger TRF amplitudes. Together, demonstrations in this work should aid new users of TRF analyses, and in combination with other tools, such as piloting and power analyses, may serve as a detailed reference for choosing acquisition duration in future studies.

The search for correlates of age-related cochlear synaptopathy: Measures of temporal envelope processing and spatial release from speech-on-speech masking.

Older adults often experience difficulties understanding speech in adverse listening conditions. It has been suggested that for listeners with normal and near-normal audiograms, these difficulties may, at least in part, arise from age-related cochlear synaptopathy. The aim of this study was to assess if performance on auditory tasks relying on temporal envelope processing reveal age-related deficits consistent with those expected from cochlear synaptopathy. Listeners aged 20 to 66 years were tested using a series of psychophysical, electrophysiological, and speech-perception measures using stimulus configurations that promote coding by medium- and low-spontaneous-rate auditory-nerve fibers. Cognitive measures of executive function were obtained to control for age-related cognitive decline. Results from the different tests were not significantly correlated with each other despite a presumed reliance on common mechanisms involved in temporal envelope processing. Only gap-detection thresholds for a tone in noise and spatial release from speech-on-speech masking were significantly correlated with age. Increasing age was related to impaired cognitive executive function. Multivariate regression analyses showed that individual differences in hearing sensitivity, envelope-based measures, and scores from nonauditory cognitive tests did not significantly contribute to the variability in spatial release from speech-on-speech masking for small target/masker spatial separation, while age was a significant contributor.

Effects of Age on Cortical Tracking of Word-Level Features of Continuous Competing Speech.

Speech-in-noise comprehension difficulties are common among the elderly population, yet traditional objective measures of speech perception are largely insensitive to this deficit, particularly in the absence of clinical hearing loss. In recent years, a growing body of research in young normal-hearing adults has demonstrated that high-level features related to speech semantics and lexical predictability elicit strong centro-parietal negativity in the EEG signal around 400 ms following the word onset. Here we investigate effects of age on cortical tracking of these word-level features within a two-talker speech mixture, and their relationship with self-reported difficulties with speech-in-noise understanding. While undergoing EEG recordings, younger and older adult participants listened to a continuous narrative story in the presence of a distractor story. We then utilized forward encoding models to estimate cortical tracking of four speech features: (1) word onsets, (2) "semantic" dissimilarity of each word relative to the preceding context, (3) lexical surprisal for each word, and (4) overall word audibility. Our results revealed robust tracking of all features for attended speech, with surprisal and word audibility showing significantly stronger contributions to neural activity than dissimilarity. Additionally, older adults exhibited significantly stronger tracking of word-level features than younger adults, especially over frontal electrode sites, potentially reflecting increased listening effort. Finally, neuro-behavioral analyses revealed trends of a negative relationship between subjective speech-in-noise perception difficulties and the model goodness-of-fit for attended speech, as well as a positive relationship between task performance and the goodness-of-fit, indicating behavioral relevance of these measures. Together, our results demonstrate the utility of modeling cortical responses to multi-talker speech using complex, word-level features and the potential for their use to study changes in speech processing due to aging and hearing loss.

Effects of noise precursors on the detection of amplitude and frequency modulation for tones in noise.

Recent studies on amplitude modulation (AM) detection for tones in noise reported that AM-detection thresholds improve when the AM stimulus is preceded by a noise precursor. The physiological mechanisms underlying this AM unmasking are unknown. One possibility is that adaptation to the level of the noise precursor facilitates AM encoding by causing a shift in neural rate-level functions to optimize level encoding around the precursor level. The aims of this study were to investigate whether such a dynamic-range adaptation is a plausible mechanism for the AM unmasking and whether frequency modulation (FM), thought to be encoded via AM, also exhibits the unmasking effect. Detection thresholds for AM and FM of tones in noise were measured with and without a fixed-level precursor. Listeners showing the unmasking effect were then tested with the precursor level roved over a wide range to modulate the effect of adaptation to the precursor level on the detection of the subsequent AM. It was found that FM detection benefits from a precursor and the magnitude of FM unmasking correlates with that of AM unmasking. Moreover, consistent with dynamic-range adaptation, the unmasking magnitude weakens as the level difference between the precursor and simultaneous masker of the tone increases.

No effects of attention or visual perceptual load on cochlear function, as measured with stimulus-frequency otoacoustic emissions.

The effects of selectively attending to a target stimulus in a background containing distractors can be observed in cortical representations of sound as an attenuation of the representation of distractor stimuli. The locus in the auditory system at which attentional modulations first arise is unknown, but anatomical evidence suggests that cortically driven modulation of neural activity could extend as peripherally as the cochlea itself. Previous studies of selective attention have used otoacoustic emissions to probe cochlear function under varying conditions of attention with mixed results. In the current study, two experiments combined visual and auditory tasks to maximize sustained attention, perceptual load, and cochlear dynamic range in an attempt to improve the likelihood of observing selective attention effects on cochlear responses. Across a total of 45 listeners in the two experiments, no systematic effects of attention or perceptual load were observed on stimulus-frequency otoacoustic emissions. The results revealed significant between-subject variability in the otoacoustic-emission measure of cochlear function that does not depend on listener performance in the behavioral tasks and is not related to movement-generated noise. The findings suggest that attentional modulation of auditory information in humans arises at stages of processing beyond the cochlea.

Exploring the Role of Medial Olivocochlear Efferents on the Detection of Amplitude Modulation for Tones Presented in Noise.

The medial olivocochlear reflex has been hypothesized to improve the detection and discrimination of dynamic signals in noisy backgrounds. This hypothesis was tested here by comparing behavioral outcomes with otoacoustic emissions. The effects of a precursor on amplitude-modulation (AM) detection were measured for a 1- and 6-kHz carrier at levels of 40, 60, and 80 dB SPL in a two-octave-wide noise masker with a level designed to produce poor, but above-chance, performance. Three types of precursor were used: a two-octave noise band, an inharmonic complex tone, and a pure tone. Precursors had the same overall level as the simultaneous noise masker that immediately followed the precursor. The noise precursor produced a large improvement in AM detection for both carrier frequencies and at all three levels. The complex tone produced a similarly large improvement in AM detection at the highest level but had a smaller effect for the two lower carrier levels. The tonal precursor did not significantly affect AM detection in noise. Comparisons of behavioral thresholds and medial olivocochlear efferent effects on stimulus frequency otoacoustic emissions measured with similar stimuli did not support the hypothesis that efferent-based reduction of cochlear responses contributes to the precursor effects on AM detection.

Examining replicability of an otoacoustic measure of cochlear function during selective attention.

Attention to a target stimulus within a complex scene often results in enhanced cortical representations of the target relative to the background. It remains unclear where along the auditory pathways attentional effects can first be measured. Anatomy suggests that attentional modulation could occur through corticofugal connections extending as far as the cochlea itself. Earlier attempts to investigate the effects of attention on human cochlear processing have revealed small and inconsistent effects. In this study, stimulus-frequency otoacoustic emissions were recorded from a total of 30 human participants as they performed tasks that required sustained selective attention to auditory or visual stimuli. In the first sample of 15 participants, emission magnitudes were significantly weaker when participants attended to the visual stimuli than when they attended to the auditory stimuli, by an average of 5.4 dB. However, no such effect was found in the second sample of 15 participants. When the data were pooled across samples, the average attentional effect was significant, but small (2.48 dB), with 12 of 30 listeners showing a significant effect, based on bootstrap analysis of the individual data. The results highlight the need for considering sources of individual differences and using large sample sizes in future investigations.

Auditory enhancement under simultaneous masking in normal-hearing and hearing-impaired listeners.

Auditory enhancement, where a target sound within a masker is rendered more audible by the prior presentation of the masker alone, may play an important role in auditory perception under variable everyday acoustic conditions. Cochlear hearing loss may reduce enhancement effects, potentially contributing to the difficulties experienced by hearing-impaired (HI) individuals in noisy and reverberant environments. However, it remains unknown whether, and by how much, enhancement under simultaneous masking is reduced in HI listeners. Enhancement of a pure tone under simultaneous masking with a multi-tone masker was measured in HI listeners and age-matched normal-hearing (NH) listeners as function of the spectral notch width of the masker, using stimuli at equal sensation levels as well as at equal sound pressure levels, but with the stimuli presented in noise to the NH listeners to maintain the equal sensation level between listener groups. The results showed that HI listeners exhibited some enhancement in all conditions. However, even when conditions were made as comparable as possible, in terms of effective spectral notch width and presentation level, the enhancement effect in HI listeners under simultaneous masking was reduced relative to that observed in NH listeners.

Weak Middle-Ear-Muscle Reflex in Humans with Noise-Induced Tinnitus and Normal Hearing May Reflect Cochlear Synaptopathy.

Chronic tinnitus is a prevalent hearing disorder, and yet no successful treatments or objective diagnostic tests are currently available. The aim of this study was to investigate the relationship between the presence of tinnitus and the strength of the middle-ear-muscle reflex (MEMR) in humans with normal and near-normal hearing. Clicks were used as test stimuli to obtain a wideband measure of the effect of reflex activation on ear-canal sound pressure. The reflex was elicited using a contralateral broadband noise. The results show that the reflex strength is significantly reduced in individuals with noise-induced continuous tinnitus and normal or near-normal audiometric thresholds compared with no-tinnitus controls. Due to a shallower growth of the reflex strength in the tinnitus group, the difference between the two groups increased with increasing elicitor level. No significant difference in the effect of tinnitus on the strength of the middle-ear muscle reflex was found between males and females. The weaker reflex could not be accounted for by differences in audiometric hearing thresholds between the tinnitus and control groups. Similarity between our findings in humans and the findings of a reduced middle-ear muscle reflex in noise-exposed animals suggests that noise-induced tinnitus in individuals with clinically normal hearing may be a consequence of cochlear synaptopathy, a loss of synaptic connections between inner hair cells (IHCs) in the cochlea and auditory-nerve (AN) fibers that has been termed hidden hearing loss.

Rhythm judgments reveal a frequency asymmetry in the perception and neural coding of sound synchrony.

In modern Western music, melody is commonly conveyed by pitch changes in the highest-register voice, whereas meter or rhythm is often carried by instruments with lower pitches. An intriguing and recently suggested possibility is that the custom of assigning rhythmic functions to lower-pitch instruments may have emerged because of fundamental properties of the auditory system that result in superior time encoding for low pitches. Here we compare rhythm and synchrony perception between low- and high-frequency tones, using both behavioral and EEG techniques. Both methods were consistent in showing no superiority in time encoding for low over high frequencies. However, listeners were consistently more sensitive to timing differences between two nearly synchronous tones when the high-frequency tone followed the low-frequency tone than vice versa. The results demonstrate no superiority of low frequencies in timing judgments but reveal a robust asymmetry in the perception and neural coding of synchrony that reflects greater tolerance for delays of low- relative to high-frequency sounds than vice versa. We propose that this asymmetry exists to compensate for inherent and variable time delays in cochlear processing, as well as the acoustical properties of sound sources in the natural environment, thereby providing veridical perceptual experiences of simultaneity.

Stimulus Frequency Otoacoustic Emissions Provide No Evidence for the Role of Efferents in the Enhancement Effect.

Auditory enhancement refers to the perceptual phenomenon that a target sound is heard out more readily from a background sound if the background is presented alone first. Here we used stimulus-frequency otoacoustic emissions (SFOAEs) to test the hypothesis that activation of the medial olivocochlear efferent system contributes to auditory enhancement effects. The SFOAEs were used as a tool to measure changes in cochlear responses to a target component and the neighboring components of a multitone background between conditions producing enhancement and conditions producing no enhancement. In the "enhancement" condition, the target and multitone background were preceded by a precursor stimulus with a spectral notch around the signal frequency; in the control (no-enhancement) condition, the target and multitone background were presented without the precursor. In an experiment using a wideband multitone stimulus known to produce significant psychophysical enhancement effects, SFOAEs showed no changes consistent with enhancement, but some aspects of the results indicated possible contamination of the SFOAE magnitudes by the activation of the middle-ear-muscle reflex. The same SFOAE measurements performed using narrower-band stimuli at lower sound levels also showed no SFOAE changes consistent with either absolute or relative enhancement despite robust psychophysical enhancement effects observed in the same listeners with the same stimuli. The results suggest that cochlear efferent control does not play a significant role in auditory enhancement effects.

Exploring the role of feedback-based auditory reflexes in forward masking by schroeder-phase complexes.

Several studies have postulated that psychoacoustic measures of auditory perception are influenced by efferent-induced changes in cochlear responses, but these postulations have generally remained untested. This study measured the effect of stimulus phase curvature and temporal envelope modulation on the medial olivocochlear reflex (MOCR) and on the middle-ear muscle reflex (MEMR). The role of the MOCR was tested by measuring changes in the ear-canal pressure at 6 kHz in the presence and absence of a band-limited harmonic complex tone with various phase curvatures, centered either at (on-frequency) or well below (off-frequency) the 6-kHz probe frequency. The influence of possible MEMR effects was examined by measuring phase-gradient functions for the elicitor effects and by measuring changes in the ear-canal pressure with a continuous suppressor of the 6-kHz probe. Both on- and off-frequency complex tone elicitors produced significant changes in ear canal sound pressure. However, the pattern of results was not consistent with the earlier hypotheses postulating that efferent effects produce the psychoacoustic dependence of forward-masked thresholds on masker phase curvature. The results also reveal unexpectedly long time constants associated with some efferent effects, the source of which remains unknown.

Perception of across-frequency asynchrony by listeners with cochlear hearing loss.

Cochlear hearing loss is often associated with broader tuning of the cochlear filters. Cochlear response latencies are dependent on the filter bandwidths, so hearing loss may affect the relationship between latencies across different characteristic frequencies. This prediction was tested by investigating the perception of synchrony between two tones exciting different regions of the cochlea in listeners with hearing loss. Subjective judgments of synchrony were compared with thresholds for asynchrony discrimination in a three-alternative forced-choice task. In contrast to earlier data from normal-hearing (NH) listeners, the synchronous-response functions obtained from the hearing-impaired (HI) listeners differed in patterns of symmetry and often had a very low peak (i.e., maximum proportion of "synchronous" responses). Also in contrast to data from NH listeners, the quantitative and qualitative correspondence between the data from the subjective and the forced-choice tasks was often poor. The results do not provide strong evidence for the influence of changes in cochlear mechanics on the perception of synchrony in HI listeners, and it remains possible that age, independent of hearing loss, plays an important role in temporal synchrony and asynchrony perception.

Effects of temporal stimulus properties on the perception of across-frequency asynchrony.

The role of temporal stimulus parameters in the perception of across-frequency synchrony and asynchrony was investigated using pairs of 500-ms tones consisting of a 250-Hz tone and a tone with a higher frequency of 1, 2, 4, or 6 kHz. Subjective judgments suggested veridical perception of across-frequency synchrony but with greater sensitivity to changes in asynchrony for pairs in which the lower-frequency tone was leading than for pairs in which it was lagging. Consistent with the subjective judgments, thresholds for the detection of asynchrony measured in a three-alternative forced-choice task were lower when the signal interval contained a pair with the low-frequency tone leading than a pair with a high-frequency tone leading. A similar asymmetry was observed for asynchrony discrimination when the standard asynchrony was relatively small (≤20 ms) but not for larger standard asynchronies. Independent manipulation of onset and offset ramp durations indicated a dominant role of onsets in the perception of across-frequency asynchrony. A physiologically inspired model, involving broadly tuned monaural coincidence detectors that receive inputs from frequency-selective onset detectors, was able to accurately reproduce the asymmetric distributions of synchrony judgments. The model provides testable predictions for future physiological investigations of responses to broadband stimuli with across-frequency delays.

Forward masking of frequency modulation.

Forward masking of sinusoidal frequency modulation (FM) was measured with three types of maskers: FM, amplitude modulation (AM), and a masker created by combining the magnitude spectrum of an FM tone with random component phases. For the signal FM rates used (5, 20, and 40 Hz), an FM masker raised detection thresholds in terms of frequency deviation by a factor of about 5 relative to without a masker. The AM masker produced a much smaller effect, suggesting that FM-to-AM conversion did not contribute substantially to the FM forward masking. The modulation depth of an FM masker had a nonmonotonic effect, with maximal masking observed at an intermediate value within the range of possible depths, while the random-phase FM masker produced less masking, arguing against a spectrally-based explanation for FM forward masking. Broad FM-rate selectivity for forward masking was observed for both 4-kHz and 500-Hz carriers. Thresholds measured as a function of the masker-signal delay showed slow recovery from FM forward masking, with residual masking for delays up to 500 ms. The FM forward-masking effect resembles that observed for AM [Wojtczak and Viemeister (2005). J. Acoust. Soc. Am. 188, 3198-3210] and may reflect modulation-rate selective neural adaptation to FM.

Perception of across-frequency asynchrony and the role of cochlear delays.

Cochlear filtering results in earlier responses to high than to low frequencies. This study examined potential perceptual correlates of cochlear delays by measuring the perception of relative timing between tones of different frequencies. A brief 250-Hz tone was combined with a brief 1-, 2-, 4-, or 6-kHz tone. Two experiments were performed, one involving subjective judgments of perceived synchrony, the other involving asynchrony detection and discrimination. The functions relating the proportion of "synchronous" responses to the delay between the tones were similar for all tone pairs. Perceived synchrony was maximal when the tones in a pair were gated synchronously. The perceived-synchrony function slopes were asymmetric, being steeper on the low-frequency-leading side. In the second experiment, asynchrony-detection thresholds were lower for low-frequency rather than for high-frequency leading pairs. In contrast with previous studies, but consistent with the first experiment, thresholds did not depend on frequency separation between the tones, perhaps because of the elimination of within-channel cues. The results of the two experiments were related quantitatively using a decision-theoretic model, and were found to be highly correlated. Overall the results suggest that frequency-dependent cochlear group delays are compensated for at higher processing stages, resulting in veridical perception of timing relationships across frequency.

Forward masking in the amplitude-modulation domain for tone carriers: psychophysical results and physiological correlates.

Wojtczak and Viemeister (J Acoust Soc Am 118:3198-3210, 2005) demonstrated forward masking in the amplitude-modulation (AM) domain. The present study examined whether this effect has correlates in physiological responses to AM at the level of the auditory midbrain. The human psychophysical experiment used 40-Hz, 100% AM (masker AM) that was imposed on a 5.5-kHz carrier during the first 150 ms of its duration. The masker AM was followed by a 50-ms burst of AM of the same rate (signal AM) imposed on the same (uninterrupted) carrier, either immediately after the masker or with a delay. In the physiological experiment, single-unit extracellular recordings in the awake rabbit inferior colliculus (IC) were obtained for stimuli designed to be similar to the uninterrupted-carrier conditions used in the psychophysics. The masker AM was longer (500 ms compared with 150 ms in the psychophysical experiment), and the carrier and modulation rate were chosen based on each neuron's audio- and envelope-frequency selectivity. Based on the average discharge rates of the responses or on the temporal correlation between neural responses to masked and unmasked stimuli, only a small subset of the population of IC cells exhibited suppression of signal AM following the masker. In contrast, changes in the discharge rates between the temporal segments of the carrier immediately preceding the signal AM and during the signal AM varied as a function of masker-signal delay with a trend that matched the psychophysical results. Unless the physiological observations were caused by species differences, they suggest that stages of processing higher than the IC must be considered to account for the AM-processing time constants measured perceptually in humans.

The effect of carrier level on tuning in amplitude-modulation masking.

The effect of carrier level on tuning in modulation masking was investigated for noise and tonal carriers. Bandwidths of the modulation filters, estimated from the masked detection thresholds using an envelope power spectrum model, were independent of level for the noise carrier but seemed to decrease with increasing level for the tonal carrier. However, the apparently sharper tuning could be explained by increased modulation sensitivity and modulation dynamic range with increasing level rather than improved modulation-frequency selectivity. Consistent with this interpretation, the addition of a high-pass noise with a level adjusted to maintain the same threshold for the detection of the signal modulation for each carrier level used eliminated the effect of level on tuning. Overall, modulation filters estimated from psychophysical data do not depend on level in contrast to the modulation transfer functions obtained from neural recordings in the inferior colliculus in physiological studies. The results highlight differences between the characteristics of modulation processing obtained from neural data and perception. The discrepancies indicate the need for further investigation into physiological correlates of tuning in modulation processing.