Aplicabilidade do mismatch negativity em crianças e adolescentes: uma revisão descritiva

Mismatch Negativity (MMN) is a cortical potential that occurs in response to a modification of an acoustic stimulus from a sequence of repeated stimuli, which reflects the brain capacity in relation to the discrimination of the sound passively, in other words, without the need of attention of the subject to the sound stimulus. Then, the aim of this study is to perform a descriptive review on MMN, in order to identify its applicability in children and teenagers, in the last five years. To this end, the search was performed in the Lilacs, SciELO, Medline and Pubmed databases by using the following descriptors: cortex auditivo, eletrofisiologia, potenciais evocados auditivos (the English version would be: auditory cortex, electrophysiology, auditory evoked potentials). In addition to, the words Mismatch and Negativity were used. In this review, we found 14 studies which evaluated children and/or teenagers with difficulty in speech articulation, specific language impairment, auditory processing disorder, Attention Deficit and Hyperactivity Disorder (ADHD), dyslexia, autism, risk for schizophrenia, psychosis, amusia, phenylketonuria and selective attention. So, it was possible to perform the descriptive review on the application of MMN in children and teenagers, concluding that in the last five years there were a reasonable article production about the theme. However, studies on this topic are not expressive in Brazil. Even though there is a variety of applications to MMN, in relation to the Brazilian population, there is a need for scientific evidences to use this potential in different age groups. We also verified that the search for MMN studies in the databases could be performed by only using the words Mismatch and Negativity.


INTRODUCTION
Negativity Mismatch (MMN), first described in 1978 1 , is a cortical potential that occurs in response to a modification of an acoustic stimulus (rare stimulus), from a sequence of repeated stimuli (frequent stimulus), reflecting the ability of the brain to discriminate the sound due to the fact that the stimuli are stored in memory 2 . MMN is considered an endogenous potential that occurs passively and automatically. In other words, it occurs without the need of attention of the subject to the sound stimulus 3,4 .
This potential is generated at the moment the subject discriminate a sound change automatically. This occurs because the auditory system is based on memory traces of the regularity of a stimulus, detecting a change, independent of the attention of the subject 5,6 . Such potential is represented by a negative deflection or a valley that happens after the identification response of the different stimulus, which may occur approximately between 150 and 250 milliseconds (ms) after the stimulus presentation, depending on the used stimulus, which can be, in general, a pure tone or a speech stimulus 5 .
MMN can be used to carry out an objective evaluation in patients with difficulty or impairment in communication or whose hearing is under investigation 7 . It can also be used in populations with difficulty in responding consistently to stimulation, or to subjects who do not cooperate, in order to evaluate the discrimination of different acoustic stimuli 2 .
Then, the aim of this study was to perform a descriptive review of MMN to identify its applicability in children and teenagers, according to scientific studies that were published in the last five years. The justification for performing this study consists on the importance of understanding the research that are being carried out with MMN in national and international context. This seems to be an objective evaluation that is not yet part of routine clinical practice in Brazil, but that might be helpful to complement the basic audiological and differential evaluation, as well as to motivate Brazilian researchers to carry out research on the topic.
It is believed, therefore, that in this context a descriptive review of the studies being carried out with MMN can be very useful to interpret the results associated to their use.

METHODS
This research presents a descriptive and retrospective approach. Data collection on MMN was performed from September to October 2015, by searching the following electronic databases: Lilacs, SciELO, Medline and Pubmed, which are databases used for searching articles in science health area, with free access.
The inclusion criteria for the selection of articles were: full text articles available in the aforementioned databases, written in Portuguese, Spanish and/ or English and published between 2011 and 2015. Exclusion criteria were: literature review articles, abstracts published in annals of congress, case reports, studies which did not mention the use of MMN in their methodology, research which involved animals, articles whose study population consisted of adults or elderly people, as well as articles that used the visual stimulus for carrying out the MMN.
The following descriptors in Portuguese and their corresponding in English were used to find the articles: córtex auditivo (auditory cortex), eletrofisiologia (electrophysiology) and potenciais evocados auditivos (auditory evoked potentials). The terms were chosen according to the Descriptors in Health Sciences (DeCS). In addition to these descriptors, the words Mismatch and Negativity were also used. The purpose of using other terms that are different from the words "Mismatch and Negativity" consisted of knowing if it was possible or not to find articles on MMN when performing a search with other descriptors. It is also important to highlight that the Boolean operator "and" was used.
As a didactic way to present search strategies with the descriptors and the selected words, Table 1 was generated.
The initial selection resulted from the previous reading of the titles and abstracts of articles in order to verify if they were about the proposed theme. After this first analysis, only those items related to the theme were selected for complete reading.
In the preliminary search for articles, it aimed to describe the applicability of MMN in different age groups, being selected a total of 359 articles for analysis, following the strategies mentioned above, as shown in Figure 1.  After analyzing the selected articles, 161 articles were excluded because they were duplicated and 32 did not meet the eligibility criteria, remaining 166 articles. After checking the impracticality of a review with a large number of articles, it was decided, in a second moment, to write about the applicability of MMN only in adults, which generated a new search filter. During this process, 137 articles were selected. Again, the review would be impractical. Then, it was decided to verify the applicability of MMN in children and teenagers, which led to the selection of 14 articles according to the eligibility criteria. In this last stage, 15 articles were excluded by comparing children or teenagers to adults. among the groups is due to the fact that MMN does not depend on the response of the subjects, thus not requiring their attention, which contributed to the normal results of MMN 4 . Corroborating this study, other researchers, by using stimuli that differed in frequency and also in verbal stimuli, did not identify differences in MMN when comparing a group of 15 children with ADHD and a control group with 16 children aged from six to 15 years 11 .
Disorders related to oral and written language development have been associated with deficits in processing of auditory information. With this in mind, a study was carried out by comparing 20 children with dyslexia and 20 children in the control group, with ages ranging from six to 14 years through MMN. For this purpose, they used frequent stimuli (1000 Hz), interspersed with rare stimuli (1200 Hz -stimulus of large deviation in the frequency -and 1030 Hz -stimulus of small deviation in the frequency). No significant differences were observed in MMN among the groups to stimuli for both large and small deviation in frequency. Therefore, the detection and the discrimination of change of auditory frequency were evidenced as regular in children with dyslexia 12 .
Another study, after evaluating 225 children, from the age group from 10 and 15 years, divided into three groups (comparing dyslexic children, their unaffected siblings, but with genetic risk for dyslexia and children from a control group), by using MMN with verbal stimuli (syllables), pointed out the potential presence in all groups. Furthermore, there was no significant difference between groups in relation to the first two components or peaks of MMN. However, it was identified significant differences between the groups for the late component, verifying an increase of the latency in the control group 13 .
When investigating the potential MMN in 31 children with autism, aged between six and 15 years (mean age of 11.3 years) and 30 children of the control group, aged between six and 17 years (mean age of 11.2 years), by using different auditory stimuli on the frequency (tone burst), researchers found significant differences between the groups, noting a decrease in amplitude and an increase in latency in the group of autistic subjects when compared to the control group. Therefore, the authors suggest that people with autism have hearing loss in pre-attentional level 14 .
In another study, MMN was used for the purpose of evaluating 22 children at risk for schizophrenia, compared to 24 children with normal development

LITERATURE REVIEW
With the descriptors used for the search in the selected databases, it was found 14 studies that used the MMN to evaluate children and teenagers in the last five years. From these ones, only five had children as the study population. The other nine studies were performed with teenagers.
One of these studies evaluated 12 children (six boys and six girls), Spanish speakers, aged from five years and two months to six years and three months. The children were then separated into two groups -with difficulty in articulation (five children) and without difficulty (seven children) -with the aim of verifying the features of MMN. For this purpose, they used word pairs in Spanish as stimulus. It was found that 83% of children had MMN as expected. Comparing the two groups, there was a reduction of latency and increase of MMN amplitude in the group with difficulty in articulation 8 .
Other researchers, after comparing the application of MMN through speech stimulus (syllables), evaluated 75 children in the age group of six to 12 years. These children were distributed into three equal groups: children with specific language impairment (SLI), children with auditory processing disorder (APD) and children with typical development (TD). The authors showed that all members of TD group showed response to MMN. In APD group and SLI group, the response rate was respectively 84% and 76%. It is also noteworthy that, for both APD group and for SLI group, there was an increase of latency and a decrease of amplitude in MMN in relation to TD group, which demonstrates the difficulty of children with APD and SLI in discriminating acoustic signals 9 .
Against the aforementioned study, researchers, with the aim of comparing the results obtained in MMN among 32 subjects with typical development and 32 individuals with SLI showed no significant difference in MMN in both groups, the group of children (seven to 11 years) and the group of teenagers (12 to 16). However, after submitting the groups to verbal and non-verbal stimuli (tone burst), differences in the tracing of waves among the age groups were identified 10 .
In order to understand the functioning of the central auditory pathway in children from eight to 12 years with ADHD, researchers compared 15 children with ADHD and 15 children with good school performance for reading and writing, by using the tone burst stimulation with different frequencies and lengths. However, they did not find significant difference among groups for MMN. The authors believe that the lack of difference the musical stimulation would benefit these children in relation to the cortical responses, participants were instructed to listen to 30 minutes of music every day during four weeks and, afterwards, they repeated MMN. The authors also did not find significant difference for both groups before and after stimulation, inferring that musical deprivation in childhood does not cause congenital amusia 18 .
Another study aimed to verify the applicability of MMN in 64 children who underwent treatment for phenylketonuria (PKU), with ages ranging from seven to 14 years, diagnosed with PKU in the first two weeks after birth and in continued treatment with food restriction. There was a decrease in the amplitude of MMN in children with PKU in the control group, but this difference was not significant. The authors relate this to the diet restriction. In relation to the latency, there was no significant difference 19 .
In order to verify the conditions of selective attention in 10 teenagers, aged from 13 to 17 years, using MMN with presentation of three stimulus of tone burst that range in relation to the frequency (a frequent stimulus; a rare stimulus with sequence every five frequent stimuli; and another rare stimulus that occurred in fewer moments) during the performance of three different tasks while receiving the same set of sounds, researchers observed that, in teenage years, selective attention changes the neural activity according to the goals of performance, thus indicating a specific neural adaptation modulated according to the behavior of the subject 20 .
As it was possible to observe, there are several possibilities of application of MMN, with the aim of studying the central auditory pathway, the attention and the discrimination for sound. Furthermore, it was possible to verify the relationship between changes in MMN and other difficulties faced by children, especially regarding language, which shows the importance of this test for this population. Then, it is possible to affirm that it can be used as a biomarker for the therapeutic processes and follow-up of cases of psychoses.
From this review, it was found that, in Brazil, there are few studies that are carried out with this approach. For the age group of adults, for example, there are no studies published in the period from 2011 to 2015 in Brazil. On the other hand, for the age group of children and teenagers, two Brazilian articles were found in the same period, which reinforces the importance of further research that use this potential in different age groups for understanding this topic, so that MMN can be part -both groups with ages ranging from nine to 12 years. The authors of this study identified some differences in the responses of MMN, which was evaluated with stimulus of tone bursts of different lengths. There was a significant increase in the amplitude of MMN in the group at risk for schizophrenia in relation to the group with normal development. In contrast, with regard to latency, there was no significant difference between groups 15 .
MMN was also applied to 14 teenagers with psychotic symptoms, without the use of medication, and to 22 teenagers of the control group, aged from 11 to 13 years in order to observe the difference in tone burst stimuli regarding length. As in schizophrenic subjects of the above study, no significant difference in the psychotic group was observed when compared to the control group regarding MMN latency. In contrast, it was noted a decrease in amplitude in the risk group, with significant difference 16 .
In other research, through MMN, 24 children from eight to 10 years old with no experience with music, native speakers of French, with verbal stimuli (syllables) were evaluated and with tone burst characterized by stimuli that differed in frequency and for length. These children were divided into two groups: those who received musical training (12 children) and those who received training for painting (12 children). MMN was performed at three different times: before training, six months after training and 12 months after training to evaluate brain plasticity. Before the training, there was no significant difference between the groups regarding the amplitude of MMN. After training, the authors verified a significant increase in the amplitude of MMN for the three types of stimuli (difference between frequency, difference between length and difference between syllables) which increased gradually from six months to 12 months after training. This significant difference happened only for the group that performed musical training. It is also noteworthy that the authors of this study support programs based on musical training for education, besides new treatment strategies for children with language and/or learning difficulty 17 .
Amusia is the inability of melodic perception or rhythm. However, it is not accompanied by peripheral hearing loss. Researchers, after evaluating six children with congenital amusia and eight children of the control group, aged between 10 and 13.2 years, through MMN, in a first moment, did not find significant difference for MMN using distinct tone burst regarding frequency stimuli. In a second moment, in order to verify whether on MMN in children and teenagers can be seen in