|Year : 2015 | Volume
| Issue : 2 | Page : 81-87
Himanshu Kumar Sanju, Akhil Mohanan, Prawin Kumar
Department of Audiology, All India Institute of Speech and Hearing, Mysore, Karnataka, India
|Date of Web Publication||20-Apr-2015|
Himanshu Kumar Sanju
Department of Audiology, All India Institute of Speech and Hearing, Mysore - 6, Karnataka
Source of Support: None, Conflict of Interest: None
Mismatch negativity (MMN) is a recent event-related potential to assess preattentive attention of the individuals. MMN has been gaining impetus as a measure to assess preattentive auditory discrimination. In the literature, the studies done on MMN have used different recording protocols. Various database such as Medline, PubMed, Google, and Google Scholar were searched for the reference related to the MMN. The different recording and analysis procedures from the literature have been summarized in the present article.
Keywords: Acquisition Parameter, Event-related Potential, Stimulus Parameter
|How to cite this article:|
Sanju HK, Mohanan A, Kumar P. Mismatch negativity. Indian J Otol 2015;21:81-7
| Introduction|| |
Mismatch negativity (MMN) was first described by Näätänen et al., in 1978. Our brain is able to perceive even a minute change in the acoustic environment. MMN has been gaining impetus as a measure to assess discrimination. Näätänen and Escera defined MMN as "an electric brain response, a negative component of the event-related potential (ERP), elicited by any discriminable change (deviant) in some repetitive aspect of auditory stimulation (standard), usually peaking around at 100-200 ms from onset".  An MMN is elicited, when a sound discriminable changes in intensity, duration, frequency, or phase of the tone burst stimuli. MMN also observed for complex change in phonemes.  MMN is the only objective measure of central auditory processing that may accurately correlate with behavioral perceptual measures.  MMN is an objective measure of the duration of echoic memory.  MMN is an objective index of general brain degeneration (Pekkonen, 2000), and the gross functional state of the brain can be obtained using MMN.  MMN can be evoked even in the absence of attention and easy to administer.  The MMN reflect central code of stimulus change; its amplitude and latency, are related to the degree to which the deviant stimuli differ from the standard stimuli, not the absolute levels of the deviant/standard stimuli. In general, larger the acoustic difference, the earlier and larger is the MMN although there may be ceiling the effect in amplitude with larger difference. 
Deouell and Bentin  compared the amplitude, latency, and spatial distribution of the MMN elicited by tones deviation in intensity, frequency, stimulus location, and onset asynchrony. They found that MMN evoked by frequency deviances was larger, and the MMN elicited by stimulus onset asynchrony (SOA) deviance was earlier than the other two types of MMN.
Mismatch negativity can also recorded by speech stimuli, like vowels and consonant-vowel syllables. MMN appears to show acoustic rather than phonetic difference.  MMN was present when the deviant stimuli were just discriminable from the standard stimuli but not when the difference was not perceptible.  The MMN is, therefore, the best test for an objective neurophysiological test of auditory discrimination. It usually occurs when the subject discriminates between stimuli at intensities similar to those used in normal speech, it can be recorded when the difference between the deviant and standard stimuli is close to discrimination limen and it occur whether or not the subject is attending to the stimuli. According to the current experimental evidence, the MMN gives a feature specific measure of the ongoing sensory analysis and auditory discrimination of various auditory stimuli. Because of this feature, MMN is an effective tool for testing person's perceptual abilities, maturation of acoustic discrimination or auditory dysfunction of various origin. MMN can also be an act as a promising tool in the assessment of intact and impaired processing in children as an objective, and early diagnosis of central hearing impairment would be of great significance. Attention insensitivity and its record ability in a broad range of consciousness make it a unique candidate for clinical application. MMN has been used in a variety of areas. MMN is a measure of consciousness, memory trace efficiency, lack of perceptual processing, processing accuracy. ,
Mismatch negativity reflects central processing of very fine acoustic differences in acoustic stimuli. It appears that MMN reflects a neuronal representation of the discrimination of numerous auditory stimulus attributes. MMN reflects the ability to discriminate between the acoustic stimuli, and then it may not only be of research interest but may have value clinically because speech perception depends on the response of neurons on stimulus change.
Some studies reported that MMN is not affected by pure tone thresholds when degree of hearing loss is <60 dB HL. There MMN can be used to see speech discrimination in individuals with sensorineural hearing loss. Kraus et al. have demonstrated that MMN can be used to evaluate the hearing aid benefit. 
The MMN can be evoked by a sudden change in stimulation, which have a negativity at about 100-250 ms from change onset.  MMN reflect the primitive intelligence in the auditory cortex because of its automatic nature, the MMN may be due to preattentive cognitive operation in audition.  MMN is also useful in understanding auditory perception and formation of sensory memory representations and auditory perception.  A study done by Baldeweg and Hirsh in 2014  showed that MMN is a sensitive and specific biomarker for detecting the early prodromal phase of schizophrenia and is well-suited for the exploration of novel cognition-enhancing agents in humans. Light and Braff  in 2005 showed that MMN deficits and their relationship to poor functional status are stable over time in patients with chronic schizophrenia, suggesting that MMN may be useful for assessing medication response and other factors in longitudinal studies [Figure 1].
Need for the present review
In the literature, there are few articles on MMN but none of which explain the method of recording procedure, acquisition parameter, stimulus variability, analysis and interpretation, subject related factor, and stimulus parameter in greater detail. An attempt is to review this article on the method of recording procedure, acquisition parameter, and subject-related factor in greater detail
| Anatomic Origin of the Mismatch Negativity Response|| |
Role of the prefrontal cortex in giving top-down modulation of the deviance detection system in the temporal cortices. The generator of MMN is located bilaterally in the temporal cortex.  Prefrontal cortex in the right hemisphere is mainly responsible for tone paradigm and prefrontal cortex for left hemisphere for language paradigm. 
| Roadmap of the Review|| |
- Stimulus parameter
- Acquisition parameter
- Analysis and interpretation
- Clinical implication.
We can evoke MMN with click trains, complex sound, and speech and tones. MMN can be evoked by a change in a tone to more complex stimuli, that is, rhythmic pattern, speech stimuli, and complex spatiotemporal patterns. 
- Tones: The MMN can be elicited by the change in frequency, intensity, duration or rise time which can be discriminable
- Complex stimuli (speech): MMN can be evoked by speech stimuli.  MMN can be elicited by speech stimuli that are difficult to discriminate psychophysically.  The MMN can be evoked by the stimuli that lie within as well as across phonetic category. MMN can be elicited in response to minimal acoustic stimulus difference in complex speech signal. MMN can be elicited by different unit of speech like phonological units (phonemes), larger speech segments (words), and even prosody, voice onset time, and the semantic features of the speech and language. The most commonly used paradigm for speech stimuli are interstimulus interval (ISI), interdevient interval, SOA, temporal order and probability of occurrence of deviant stimuli. The combination of parameter that elicits a robust MMN for tonal difference does not necessarily give the best MMN to complex stimuli. MMN to words was larger than pseudowords, reflects the presence of memory traces for spoken words. Categorically different speech use sounds (/da/vs/ga/) are used most commonly to elicit MMN
- Music: Music is also a good stimulus in evoking MMN. Tones, chords (music intervals), chord sequences and melodies can be used to evoke MMN responses. The individual who has experience in music show larger MMN to music related deviance than those who don't have such exposure.  A study done by Lappe et al.,  in 2013 having stimuli consisted of a six-tone melodic sequence comprising broken chords in C- and G-major. The musical sequence was presented within an oddball paradigm in which the last tone was lowered occasionally (20%) by a minor third. The results demonstrate that a deviant tone within a musical sequence recruits immediately a distributed neural network in frontal and prefrontal areas suggesting that top-down processes are involved when expectation violation occurs within well-known stimuli.
The MMN can be evoked by the difference between the deviant and standard which is near to just noticeable difference for the sounds. Greater the acoustic difference, the earlier and larger is the MMN.
- Frequency deviance: As the discrimination becomes easier, MMN is earlier in latency and greater in amplitude. MMN can be evoked even by frequency increment of 5% 
- Intensity deviance: As the difference in intensity increases, the latency decreases and amplitude increases.  MMN can be recorded even if the minimum difference between standard and deviant is just 3 dB.  As the stimulus level decreases is the amount of deviance is held constant, MMN latency increases and amplitude decreases
- Duration deviance: The time dimension plays an important role in the generation of MMN. Minimum stimulus duration for intensity coding is 20-30 ms and 10 ms for frequency deviation to elicit MMN. MMN will be better for greater duration deviance in the normal subject.  Changes in duration usually elicit MMN with the largest and most replicable amplitude 
- Spatial location: Spatial localization of a sound source is coded in the neuronal stimulus traces reflected by the MMN and that a change in this location is automatically detected by the brain by means of the MMN 
- Temporal order: When successive frequent and deviant differ either in frequency, intensity or duration in terms of temporal order also able to elicit MMN, which shows that sensory representations show contain precise temporal information about the sounds.
Hay et al., 2015  reported that that neurophysiological mechanisms underlying processing of auditory deviants are compromised early in the illness, and these deficiencies are not specific to the type of deviant presented.
Interstimulus interval and rate of stimulation
Mismatch negativity elicited by shortening ISI duration has been extensively studied. The ISI can be the interval between standard stimuli or the interval between the deviant and standard stimuli or the interval between the deviant stimuli. Increasing the rate of stimulus and decreasing the ISI lead to increase in amplitude of MMN and in differentiating it from the other cortical wave components.  ISI of 300 ms is appropriate for MMN when using simple or vowel stimuli. Sometimes, too short ISI also deteriorate the MMN.
Probability of the deviant stimuli
The MMN amplitude will reduce by increasing the number of deviant stimuli. Näätänen, opined that this phenomenon is due to the fact that when the repetition rate of the standard stimuli increases the memory trace evoked by it becomes more intense which in turn strengthens the MMN response generated by the comparison process. According to Picton et al. 2000,  there was an increase in amplitude as the inter deviant interval increases from 1 to more than 2.5 s.
According to a study done by Fisher et al.,  in 2011 reported that MMN attenuation following increased deviant presentation probability is due to the development of separate deviant memory traces, not due to a weakening of the standard memory trace.
Larger stimulus difference
When the deviance exceeds a certain limit, the highly deviant obtrusive stimulus causes a passive switch of attention (Giard, 1995).  Amplitude will be low, and signal-to-noise ratio (SNR) will be poor with a small deviance. In that situation, a large p3 component is superposed on the deviant waveform.
Acquisition parameter of mismatch negativity
Analysis time of 500-750 ms is commonly used to elicit MMN, with a prestimulus baseline period of 50-100 ms.
Electrode types and location in MMN measurement are similar as those for other cortical potentials like N1 and N2 and p300.
- Noninverting: Fz, Cz, Pz, C3, C4, F3, F4, Fpz
- Inverting: Nose tip or mastoid
- Common: Low forehead
- MMN has a frontocentral scalp distribution that can be detected good with midline electrode.
Filter setting and averaging
The filter setting mainly used in MMN is 0.1-30 Hz because MMN difference wave is limited to very low frequencies. Averaging of deviant response will decrease the noise level during recording. Because of limited recording duration, it is seldom possible to collect more than 200-300 deviant and 1200-27000 standard responses. One-quarter to one-half deviants of the total number of stimuli should be averaged for better SNR. If the acoustic difference between the standard and deviant is smaller than more number of sweeps should be required.
Mismatch negativity habituates over time. Hence, it is recommended to use short runs. When trials has two tones separated with long (5-10 s) intervals unable to elicit MMN, even though the subjects have no difficulty in discriminating the tones. To elicit an MMN at least two or three standard stimulus must be given before deviant.  If the two identical deviant stimuli presented one after another, then the second deviant elicited an MMN about half the size of the first deviant.
Mismatch negativity should be recorded for pairs of stimuli. Pair should have frequent and deviant with these two stimuli should differ. Stimuli should be presented in the oddball paradigm with the probability of standard and deviant stimulus as 80% and 20%, respectively. The participants should be seated comfortably in order to avoid muscular artifacts and made to watch a silent movie in order to promote passive listening. The skin surface of the target electrode sites should be cleaned, and disc electrodes should be placed. The recording should start only if the absolute impedance is <5 kΩ and the inter-electrode impedance is <2 kΩ. Apart from recording MMN in the conventional paradigm for each stimulus pair, late latency responses (LLRs) should be recorded for the respective infrequent stimulus. To eliminate the stimulus effects on MMN, the wave recorded for infrequent in the frequent-infrequent sequence will be compared with the wave recorded for the infrequent in the LLR paradigm. Difference waves will be then obtained by subtracting LLR of infrequent from the wave recorded infrequent in the frequent-infrequent sequence.
Analysis and interpretation
Detection of MMN response is a challenging task for audiologist because of following reasons:
- Amplitude (only 1 or 2 μV) of the MMN is very small in comparison to other auditory evoked potential
- Small number of trials is commonly used due to infrequent presentation of deviant stimuli
- MMN response is not having a repeatable and distinct peak or trough within a fixed latency region, but MMN is mainly a broad negativity in the waveform that extends latency region of 100 ms or more
- The subtract process to find MMN response leads to noisy waveform. Background response is more for deviant than standard
- The amplitude of MMN response is not always constant from one recording session to next or during a prolonged recording session
- Reliability of response is generally lower for MMN than other cortical auditory evoked response.
Responses of MMN can be detected by visual inspection of the difference waveform. More comprehensive objective and quantitative analysis approach are advisable because the amplitude of the MMN response is very small. Computation of the area of the MMN response is one of the clinically feasible techniques. The other technique is integral distribution technique.
- One parameter is not sufficient in the analysis of the difference waveform, so more than one parameter is required during the analysis of the difference waveform
- Latency of MMN is from the onset of deviant stimulus to the starting of the negative trough
- The amplitude analysis is more difficult for audiologists, as the problem is how to define the baseline or reference for the calculation of maximum MMN amplitude
- As there is no sharp peak or trough limits the usefulness of visual analysis and calculation of peak amplitude and latency.
Area under the curve
Area under the curve also taken into analysis of MMN response and it can also be considered as area above the curve since MMN wave is negative.
Integral distribution analysis
Here, the amplitude is integrated over the time period in place of calculating specific latency point within the waveform. The latency region analysis is determined in advance. This is applied separately for the waveform of the standard stimuli and the deviant stimuli, and then integrated waveform is compared statistically.
Principle component analysis
As we know that noise is randomly distributed whereas MMN will show a tendency in a single voltage direction. Through a common statistical procedure (two-tailed t-test) is applied to make sure that the response is present.
Näätänen  summarizes the clinical applications of the MMN as follows.
- The MMN is evoked by any discriminable change of a repetitive sound and can be evoked by stimulus differences that approximate the behavioral discrimination threshold. Therefore, it gives an objective measure of an individual's discrimination ability for different simple and complex (such as phonemic) sound features
- MMN can be elicited without attention; the MMN is free from attention variations that contaminate behavioral measures and attention dependent physiological measures of auditory function. In addition, auditory function can be studied even in individuals unable or unwilling to cooperate
- MMN gives a special window to observe the neurophysiological processes underlying normal hearing and an index to study the central nervous system maturation
- MMN also gives a means for finding auditory short-term memory which is very important for correct speech processing and understanding. MMN opens a view to the temporal dimension of auditory function which in contrast to the vision, is to a great extent sequential in nature
- Deficiencies in the MMN may be related to different forms of deficits in central auditory processing
- MMN indirectly gives a unique, objective measure of the central representation of a sound. This opens new possibilities for basic research as well as clinical and other applications
- MMN response with other cortical responses can be applied in documenting the benefit of hearing aid use for patients with hearing loss in the moderate through severe range.
Other clinical applications
- MMN is affected in children with auditory processing disorder (APD) and hence MMN can be clinically used to identify APD
- Schulte-Körne et al.,  reported that a difference between the dyslexic and control groups in the MMN (smaller amplitude) evoked by speech stimuli. Baldeweg et al.,  reported that smaller differences between the standard and deviant stimuli were more effective in differentiating the dyslexic subjects from the control group
- Abnormal MMN findings have been reported in children with specific language impairment (SLI). Friedrich et al.,  also found delayed latency of MMN response elicited by speech stimuli in infants who are risk for SLI
- Abnormal MMN responses elicited by speech stimuli appear to be characteristic finding in patients with aphasia
- According to Näätänen et al.,  in 2014 MMN has been used to index auditory processing capability in a range of neuropsychiatric, neurological, and neurodevelopmental disorders
- Cheour et al.,  confirmed progressive decrease in MMN latency and increases in amplitude associated with improvement in the ability to discriminate nonnative speech sounds
- MMN can be used in the determination of the capacity or talent for music and learning foreign languages
- MMN can be used in prognosis of outcome in comatose patients
- MMN can be used in the assessment of benefit from hearing aids and cochlear implants in children
- Baldeweg and Hirsh in 2014  reported that MMN is a sensitive and specific biomarker for detecting the early prodromal phase of schizophrenia and is well-suited for the exploration of novel cognition-enhancing agents in humans.
| Conclusion|| |
The present review provided information on different recording procedures to obtain MMN. The present article also gives the information about analysis and interpretation of MMN. The current review also focuses on stimulus and acquisition parameter of MMN. This article also focuses the procedure and clinical implications.
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