Potential contamination effects of neuronal refractoriness on the speech-evoked mismatch negativity response

The mismatch negativity response (MMN) is an event-related potential that is believed to reflect the automatic (possibly preconscious) neural processing of changes in ongoing environmental sounds. The MMN involves a negative voltage shift of baseline electroencephalographic (EEG) activity in the approximate latency window of the N1 and P2 cortical potentials in response to new or novel sounds. The most commonly used laboratory tests for extracting the MMN from EEG activity all involve oddball stimulus presentation procedures in which the interstimulus intervals (ISIs) of the frequently occurring standard sounds are shorter in length then that of the infrequently occurring deviant sounds. This presents the possibility that the MMN response could be affected by neuronal refractory or recovery events. The present study tested 12 young females, using the syllabic events /da/ and /ga/ as standard and deviant stimuli, and found evidence that, with certain experimental protocols, ISI-dependent neural refractory effects can affect the morphology of the MMN, possibly resulting in misinterpretation of the underlying neural bases of the response.     

Towards optimal recording and analysis of the mismatch negativity

In this paper, the conceptual and practical issues related to the measurement of mismatch negativity (MMN) are discussed from the viewpoint of cost-efficiency. First, various criteria for efficiency or optimality of measurements are described, including reliability and signal-to-noise ratio. Then a critical look is taken at some currently used concepts and data analysis methods. Practical guidelines for the measurement and analysis of MMN are given, complementing the earlier reviews on the subject. Finally, reliability studies on MMN are critically reviewed.     

A Comparison of the mismatch negativity and a differential waveform response

A mismatch negativity response (MMN) and a new differential waveform were derived in an effort to evaluate a neural refractory or recovery effect in adult listeners. The MMN was elicited using oddball test runs in which the standard and deviant stimuli differed in frequency. To derive the differential waveform, the same standard and deviant stimuli were presented alone. MMN responses were obtained by subtracting the averaged responses to standards from the deviants. The differential waveforms were obtained by subtracting the averaged responses to standards presented alone from deviants presented alone. Scalp topography for the MMN and differential waveforms were similar. A significant (p<.05) positive and negative correlation was found between the earlier and later components of the bimodal MMN and the N1 and P2 component of the differential waveform, respectively. Further, N1 and P2 of the differential waveform were significant (p<.05) predictor variables of early and late peak amplitudes of the MMN. These results suggest that refractory effects may overlay/modify the morphology of the MMN waveform.

Sumario

Se obtuvo una respuesta de negatividad desigual (MMN) y una nueva onda “diferencial” en un esfuerzo por evaluar un efecto neural refractario o de recuperación en sujetos adultos. La MMN fue generada utilizando cursos peculiares de prueba en los que el estimulo estándar y el alterado tenían frecuencias diferentes. Para derivar la onda diferencial, se presentaron el mismo estímulo estándar y el alterado en forma aislada. Las respuestas MMN se obtuvieron restando las respuestas promediadas estándar de las alteradas. Las formas de onda diferenciales se obtuvieron restando las respuestas promediadas a estímulos estándar presentados aisladamente, de los estímulos alterados presentados también en forma aislada. La topografía craneana de los MMN y las onda diferenciales fueron similares. Se encontraron correlaciones positivas y negativas significativas (p<.05) entre los componentes tempranos y tardíos de la MMN bi-modal y de los componentes N1 y P2 de la onda diferencial, respectivamente. Más aún, los componentes N1 y P2 de la onda diferencial fueron variables de predicción significativas (p<.05) de los picos tempranos y tardíos de amplitud de las MMN. Estos resultados sugieren que los efectos refractarios pueden cubrir/modificar la morfología de las onda de la MMN.     

A comparison of the mismatch negativity and a differential waveform response

A mismatch negativity response (MMN) and a new differential waveform were derived in an effort to evaluate a neural refractory or recovery effect in adult listeners. The MMN was elicited using oddball test runs in which the standard and deviant stimuli differed in frequency To derive the differential waveform, the same standard and deviant stimuli were presented alone. MMN responses were obtained by subtracting the averaged responses to standards from the deviants. The differential waveforms were obtained by subtracting the averaged responses to standards presented alone from deviants presented alone. Scalp topography for the MMN and differential waveforms were similar. A significant (p <.05) positive and negative correlation was found between the earlier and later components of the bimodal MMN and the NI and P2 component of the differential waveform, respectively. Further, N1 and P2 of the differential waveform were significant (p <.05) predictor variables of early and late peak amplitudes of the MMN. These results suggest that refractory effects may overlay/modify the morphology of the MMN waveform.     

失匹配负波在高胆红素血症新生儿中的反应特性

目的:探讨失匹配负波(MMN)在高胆红素血症新生儿中的特征及应用前景。方法:将86例高胆红素血症新生儿以342μmol/L为界分成低浓度组和高浓度组,选取15例正常新生儿为对照组,均应用频率差异潜伏期及强度差异潜伏期2种刺激方式引发的MMN进行检测及组间比较,同时将检测结果与听性脑干反应(ABR)结果进行比较。42d复查比较MMN与ABR。结果:对照组与高、低浓度组间MMN频率差异潜伏期组间与强度差异潜伏期组间均差异有统计学意义(均P<0.01),随着胆红素浓度的升高潜伏期延长,胆红素浓度与潜伏期呈显著正相关(P<0.05),但相关关系不够密切(r<0.5);ABRⅤ波潜伏期、Ⅲ-Ⅴ及Ⅰ-Ⅴ波间期各浓度组之间差异有统计学意义(P<0.05);高浓度组与对照组相比明显延长,但高浓度组之间差异无统计学意义。高浓度组听阈异常率显著高于低浓度组(P<0.05)。复查前后MMN潜伏期及ABR各波潜伏期与波间期,除Ⅰ～Ⅲ,均差异有统计学意义(均P<0.05)。结论:高胆红素血症对新生儿传导通路及听觉辨别力均存在毒害作用,胆红素浓度越高,毒害作用越大,但大多数是可逆的。MMN可作为一种较为客观的判断听觉辨别能力和听觉中枢发...     

Reliability of the mismatch negativity in the responses of individual listeners

The mismatch negativity (MMN) was recorded from 12 normal adults during four biweekly sessions. Responses were elicited by a synthetically generated speech contrast (/dalpha/-/galpha/) that all listeners discriminated with at least 90 percent accuracy. Standard and deviant waveforms were replicable across sessions for all listeners; however, replicability of the derived difference waveforms was poor. Of greater importance, the MMN identification rate was too low (29%) to allow reliability to be evaluated. The implications that these findings may have on clinical applicability are discussed.     

Identification of the mismatch negativity in the responses of individual listeners

The mismatch negativity (MMN) was recorded from normal adults in three stimulus conditions: two contrast conditions and a control condition in which standard and deviant stimuli were identical. Averaged waveforms were analyzed by examiners blind to the evoking stimulus condition. Hit rates, a false alarm rate, and d' values were determined based on the number of MMNs identified in each condition. Hit rates were low and the false alarm rate was relatively high, resulting in unacceptably small d' values. The relationship between MMN findings and corresponding behavioral discrimination data for individual listeners was not systematic. Factors that may contribute to ambiguity and error in MMN data analysis are discussed.     

Mismatch negativity brain response as an index of speech perception recovery in cochlear-implant recipients

Speech-discrimination performance and the mismatch negativity (MMN) response elicited by vowel changes were used to track vowel-perception improvement of 5 adult cochlear-implant (CI) recipients. The MMN was recorded several times during the first 3 years after CI activation. Artefacts, presumably caused by CI, contaminated most of the brain responses until 1 year after CI activation. We found that speech discrimination improved over time and the MMN, observed in all patients after 2.5 years of CI use, was first seen for the larger vowel difference and later for the smaller one.     

The effect of different noise types on the speech and non-speech elicited mismatch negativity

The effect of different types of real-life noise on the central auditory processing of speech and non-speech sounds was evaluated by the means of mismatch negativity and behavioral responses. Subjects (19-34 years old; 6 males, 4 females) were presented, in separate conditions, with either speech or non-speech stimuli of approximately equal complexity in five background conditions: babble noise, industrial noise, traffic noise, wide band noise, and silent condition. Whereas there were no effects of stimuli or noise on the behavioral responses, the MMN results revealed that speech and non-speech sounds are processed differently both in silent and noisy conditions. Speech processing was more affected than non-speech processing in all noise conditions. Moreover, different noise types had a differential effect on the pre-attentive discrimination, as reflected in MMN, on speech and non-speech sounds. Babble and industrial noises dramatically reduced the MMN amplitudes for both stimulus types, while traffic noise affected only speech stimuli.     

健康青年人失匹配负波的提取及刺激偏差对波形的影响

目的 研究失匹配负波(mismatch negativity,MMN)波形提取的相关因素及刺激偏差对波形的影响,获得一套实验室标准值.方法 以oddBall序列给予21名健康青年志愿者短纯音刺激,分为频率偏差刺激和强度偏差刺激两组,每组中又包含3个刺激系列,共6个小组.用偏差刺激引出的事件相关电位(event-related potential,ERP)减去标准刺激引出的ERP即得到MMN波形.记录各组潜伏期与波幅并两两比较,分析听刺激偏差程度对MMN的影响.结果 本实验诱发出了健康青年人的MMN波形,并获得了潜伏期与波幅的正常值.频率偏差组中,频率差异为2 kHz时的MMN潜伏期[(155.81±29.08)ms]与频率差异为1 kHz时[(182.89±45.85)ms,(183.32±43.33)ms]相比,明显缩短(P值均<0.05);差异程度相同时,改变标准刺激与偏差刺激频率的绝对值,MMN潜伏期没有明显变化;各小组间MMN的波幅[(3.85±2.22)、(2.90±2.05)、(2.66±2.12)μV]差异无统计学意义(P值均>0.05).强度偏差组中,强度差异为加dB时MMN潜伏期[(157.04±34.87)ms]与强度差异为10 dB时[(184.46±38.05)ms,(186.24±42.36)ms]相比,明显缩短(P值均<0.05);差异程度相同时,改变标准刺激与偏差刺激强度的绝对值,MMN潜伏期没有明显变化;其中只有组4和组6的MMN波幅[(3.41±1.64)μV,(2.37±1.47)μV]差异有统计学意义(P<0.05),其余各组的波幅差异均无统计学意义.结论 MMN只与刺激差异程度有关,与受试者的注意无关,属于认知功能的产物,能够客观地反映大脑探测刺激特征变化的能力.     

Maturation of the mismatch negativity: effects of profound deafness and cochlear implant use

The use of cochlear implants to restore auditory sensation in deaf children is increasing, with a trend toward earlier implantation. However, little is known about how auditory deprivation and subsequent cochlear implant use affect the maturing human central auditory system. Our previous studies have demonstrated that the obligatory auditory evoked potentials (AEPs) of implanted children are very different from those of normal-hearing children. Unlike the obligatory potentials, which primarily reflect neural responses to stimulus onset, the mismatch negativity (MMN) provides a neurophysiological measure of auditory short-term memory and discrimination processes. The purpose of this investigation is to review our studies of the effects of auditory deprivation due to profound deafness and cochlear implant use on the maturation of the MMN in children, placed in the context of overall age-related changes in the AEPs. The development and application of a statistical technique to assess the MMN in individuals is also reviewed. Results show that although the morphology of the obligatory AEPs is substantially altered by the absence of a normal N(1) peak, the MMN is robustly present in a group of implanted children who have good spoken language perception through their device. Differences exist in the scalp distribution of the MMN between implanted and normal-hearing children. Specifically, the MMN appears to be more symmetrical in amplitude over both hemispheres, whereas it is initially much larger over the contralateral hemisphere in normal-hearing children. These findings suggest that, compared to N(1), the MMN is a better measure of basic auditory processes necessary for the development of spoken language perception skills in profoundly deaf children and adults who use a cochlear implant.     

Processing of English words with fine acoustic contrasts and simple tones: a mismatch negativity study

The purpose of this study was to compare the robustness of the event-related potential (ERP) response, called the mismatch negativity (MMN), when elicited by simple tone stimuli (differing in frequency, duration, or intensity) and speech stimuli (CV nonword contrast /de:/ vs. /ge:/ and CV word contrast /del/ vs. /gel/). The study was conducted using 30 young adult subjects (Groups A and B; n = 15 each). The speech stimuli were presented to Group A at a stimulus onset asynchrony (SOA) of 610 msec and to Group B at an SOA of 900 msec. The tone stimuli were presented to both groups at an SOA of 610 msec. MMN responses were elicited by the simple tone stimuli (66.7%-96.7% of subjects with MMN "present," or significantly different from zero, p < 0.05) but not the speech stimuli (10% subjects with MMN present for nonwords, 10% for words). The length of the SOA (610 msec or 900 msec) had no effect on the ability to obtain consistent MMN responses to the speech stimuli. The results indicated a lack of robust MMN elicited by speech stimuli with fine acoustic contrasts under carefully controlled methodological conditions. The implications of these results are discussed in relation to conflicting reports in the literature of speech-elicited MMNs, and the importance of appropriate methodological design in MMN studies investigating speech processing in normal and pathological populations.     

Use of the median method to enhance detection of the mismatch negativity in the responses of individual listeners

The median method was evaluated as an alternative way of expressing the mismatch negativity (MMN). Traditionally, signal averaging has been used to extract these event-related potentials from unwanted background noise. However, mean values are biased by unrejected artifact that skews the relatively small distribution of values on which the MMN is based. Because the median is a more valid measure of central tendency in asymmetric distributions, it may describe MMN data more accurately. Better representation of the signal in the median waveform might enhance detection of the MMN in the responses of individual listeners. Mean and median waveforms were computed from previously recorded MMN data. Visually identified MMNs were validated using area and onset latency criteria. Detectability of the MMN was not improved using median waveforms. Despite this result, a theoretical argument for use of the median is presented.     

Factors associated with active, refractory epistaxis

This study addresses the underlying causes responsible for the severity and persistence of active, refractory epistaxis. Seventy-five patients referred because of treatment failure by primary care physicians showed hypertension and aspirin and alcohol abuse to be major factors in the refractory nature of their epistaxis. The majority of bleeding was located near the posterior floor of the nasal cavity and just posterior to Kiesselbach's plexus and was only associated with septal deviation, spurring, or mucosal abnormalities in 16 of the 75 patients. Seventeen of 67 outpatients required hospitalization. Standard laboratory tests were often inadequate determinants of etiology. Intractable epistaxis should be a signal for a thorough investigation of factors that influence clotting.     

Automatic auditory processing of english words as indexed by the mismatch negativity, using a multiple deviant paradigm

OBJECTIVE: The aim of this study was to investigate mismatch negativity (MMN) responses to a variety of speech stimuli (/de:/, /ge:/, /deI/ "day", and /geI/ "gay") in a multiple deviant paradigm. It was hypothesized that all speech stimulus contrasts in the multiple deviant paradigm, including the fine acoustic speech contrast [d/g], would elicit robust MMN responses and that consonant vowel (CV) real word deviants (e.g., "day" and "gay") would elicit larger MMN responses than CV nonword deviants (e.g., "de" and "ge") within and across experimental contrasts. DESIGN: Ten healthy, right-handed, native English-speaking adults (23.4 +/- 2.27 yr) with normal hearing were presented with 12 blocks of stimuli, using a multiple deviant oddball paradigm. Each of the four speech stimuli were presented as standards (p = 0.7) in three blocks, with the remaining stimuli acting as deviants (p = 0.1 each). Subjects were also presented with the same stimuli in a behavioral discrimination task. RESULTS: MMN responses to the fine acoustic speech contrast [d/g] (e.g., "de" versus "ge", "day" versus "gay") did not reach significance. However, a significant and larger MMN response was obtained at an earlier latency to the real word deviants among nonword standards with the same initial consonant (i.e., de-->day, ge-->gay) when compared with the responses to nonword deviants among word standards (day-->de, gay-->ge). CONCLUSIONS: The results showed that MMN responses could be elicited by speech stimuli with large, single acoustic deviances, within a multiple deviant paradigm design. This result has positive clinical implications for the testing of subjects who may only tolerate short testing sessions (e.g., pathological populations) in that responses to a wider range of speech stimuli may be recorded without necessarily having to increase session length. The results also demonstrated that MMN responses were elicited by large, single acoustic deviances but not fine acoustic deviances within the speech stimuli. The poor results for the fine acoustic deviances support previous studies that have used single contrast paradigms and found that when carefully controlled methodological designs and strict methods of analysis are applied, robust responses to fine-grained CV syllable contrasts may be difficult to obtain. The enhanced MMN observed in response to the real word deviants among nonword standards may provide further evidence for the presence of long-term neural traces for words in the brain, however possible contextual effects limit the interpretation of these data. Further research is needed to investigate the ability of the MMN response to accurately reflect speech sounds with fine acoustic contrasts, as well as the ability of the MMN to reflect neural traces for words in the brain, before it can be reliably used as a clinical tool in the investigation of spoken word processing in pathological populations.     

Dupilumab therapy for patients with refractory eosinophilic otitis media associated with bronchial asthma

ObjectivesEosinophilic otitis media (EOM) is an intractable otitis media mostly associated with bronchial asthma. Dupilumab, an anti-interleukin (IL)-4 receptor (R)α, is effective and has been approved for use in patients with moderate to severe bronchial asthma, atopic dermatitis and chronic rhinosinusitis with nasal polyposis, whose diseases are not controlled by previous treatments including other molecular targeted drugs. We aimed to assess efficacy of dupilumab in three EOM patients with associated bronchial asthma, who were poor responders to previous topical and systemic corticosteroid therapy and molecular targeted therapies.Patients and methodsThree patients with severe, refractory EOM (two with a granulation type) associated with bronchial asthma received dupilumab as add-on therapy for at least 6 months. The efficacy of dupilumab therapy was evaluated using severity scores, symptom scores, hearing acuities, temporal bone computed tomography (CT) scores, and surrogate markers before and after therapy.ResultsSeverity scores in all patients were dramatically reduced to 2 points or less (full score: 16 points) after initiation of therapy. Air conduction hearing levels were improved in all patients. Temporal bone CT scores in two patients were reduced, and serum IgE levels in all three patients also decreased following therapy.ConclusionWe provide the first report that add-on dupilumab therapy was effective in patients with severe, refractory EOM who did not respond to the treatments including other molecular targeted therapy. Patients with severe middle ear mucosal change may benefit particularly from dupilumab therapy.     

Efficient stimuli for recording of the amplitude modulation following response.

Amplitude modulation following response (AMFR) is a promising tool for objective frequency-specific assessment of hearing thresholds in children. The stimulus generally used for AMFR recording (one amplitude-modulated carrier) activates only a small part of the basilar membrane. Therefore, the response amplitude is small. Combined frequency and amplitude modulation is not significantly more effective. A new stimulus is proposed that is composed of several carriers. All carriers are modulated with the same modulation frequency. The signal to noise ratio of the response to the multiple-carrier stimulus is significantly increased compared with the usual one-carrier stimulus. Therefore, response detection near threshold is expected to be improved. AMFR also seems to be well suited to newborn hearing screening. Simultaneous recording of six responses (three AMFRs from each ear) to 1-, 2-, and 4-kHz multiple-carrier stimuli of a 40 dB HL stimulus level is demonstrated in normally-hearing adults. Verification in babies will be necessary.