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The Mismatch Negativity and Its Magnetic Equivalent: An Index of Language Impairment or More General Cognitive Decline in Autism?
The Mismatch Negativity and Its Magnetic Equivalent: An Index of Language Impairment or More General Cognitive Decline in Autism? Risto Näätänen and Teija Kujala n this issue of Biological Psychiatry, Roberts et al. (1) show that the magnetic equivalent of the mismatch negativity (MMNm) or magnetic mismatch field (MMF) peak latency in response to changes in auditory streams of simple sinusoidal tones or vowels is prolonged in children with autism spectrum disorders (ASD) of 6 –15 years in age, relative to that of typically developing children at the same age. Previous studies (for a review, see Kujala [2]) have suggested a complex pattern of auditory processing abnormalities in ASD, involving mismatch negativities (MMNs) reflecting both hypersensitive and hyposensitive reactivity to sound changes. These MMN changes seem to be feature-specific: although MMNs for duration deviants were diminished, those for frequency changes were enhanced, consistent with previous clinical observations indicating elevated sensitivity to sound frequencies in ASD. Furthermore, the MMN peak latency was shown to be abnormally short or long in these previous studies, some of which suggesting speeded MMNs for frequency changes, whereas some others— using consonant changes in syllables—showing prolonged MMN peak latencies. Importantly, Roberts et al. (1) inspected the effect of concomitant language impairment in ASD, dividing children with ASD into two groups, one with and one without language impairment. They found that the MMNm peak-latency delay was considerably increased when an autistic child also suffered from language impairment, interpreted by the authors as suggesting a neurobiological basis as well as a clinical biomarker for language impairment in ASD. It is easy to imagine that a considerable delay in speech-sound processing and discrimination is detrimental to all the subsequent—in particular, semantic—stages of speech processing and hence to social communication of these children, as stated by the authors. These conclusions were backed up by a receiver operator characteristic analysis of the mean MMNm peak latency, indicating a sensitivity of 82.4% and a specificity of 71.2% for diagnosing language impairment on the MMNm peak latency. Roberts et al., however, wonder whether this additional MMNm peak latency delay, indexing language impairment, in ASD children is a signature of language impairment per se or only that of language impairment in the context of ASD. Several converging lines of electrophysiological research even outside the ASD context suggest that the MMN/MMNm is affected when speech-sound processing is not optimal (as reviewed in part by the authors themselves):
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From the Institute of Psychology (RN), University of Tartu, Tartu, Estonia; Centre of Integrative Neuroscience (RN), University of Aarhus, Aarhus, Denmark; and the Cognitive Brain Research Unit (RN, TK), Cognitive Science, Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland. Address correspondence to Teija Kujala, Ph.D., Cognitive Brain Research Unit, Cognitive Science, Institute of Behavioural Sciences, University of Helsinki, Siltavuorenpenger 1 B, 00014, Helsinki, Finland; E-mail: teija.m.kujala@ helsinki.fi. Received May 24, 2011; accepted May 24, 2011.
0006-3223/$36.00 doi:10.1016/j.biopsych.2011.05.024
1. The MMN/MMNm reflects the quality of speech-sound processing even in normal healthy school-age children. For instance, it was found by Kraus et al. (3) that the MMN for the /ba/ - /da/ contrast was much smaller in amplitude in children with learning difficulties than that in normally learning children (whereas the easier contrast used [/ba/ - /wa/] did not discriminate between the two groups). 2. Different training or rehabilitation procedures (2,4,5) increase the MMN/MMNm amplitude, along with improved languagerelated skills. For instance, audiovisual training of dyslexic children resulted in improved reading skills and the enhancement of early parts of the MMN (4). 3. The MMN/MMNm is also affected in several other pediatric patient groups, which often also disclose some language impairment (which usually correlates with MMN/MMNm deficit), such as children with benign Rolandic epilepsy. For instance, Boatman et al. (6) found that, in approximately one-half, the MMN to a speech-sound change was absent and its peak latency was prolonged in the rest of the patients. Moreover, in very prematurely born infants, too, the MMN deficiency for speech-sound change correlates with deficient speech-sound discrimination performance and predicts a delay in their later linguistic development. Corroborating results were also obtained in children with dysphasia, dyslexia, and specific language impairment (SLI) (for a review, see Kujala [2]). Finally, it is important to consider whether the MMNm delay found by Roberts et al. (1) in ASD patients with language impairment relative to those with no language impairment indexes affected speech-sound discrimination only or a more general cognitive decline (even though global cognitive delay was screened out and the nonverbal IQ did not correlate with the MMNm delay). Very recently, it was concluded by Näätänen et al. (7) that MMN/MMNm attenuation/delay also indexes, besides affected central auditory processing, cognitive decline irrespective of the specific etiology and symptomatology of different neuropsychiatric and neurological disorders. For example, MMN/MMNm attenuation reflects cognitive and functional decline in schizophrenia and cognitive decline in stroke, aphasia, epilepsy, multiple sclerosis, chronic alcoholism, Velo-Cardio-Facial (DiGeorge) syndrome, human immunodeficiency virus, Alzheimer’s disease, Parkinson’s disease, Down syndrome, the advanced phase of diabetes mellitus, and survivors of coma and persistent vegetative state (7). Näätänen et al. (7) further proposed that the MMN– cognition relationship is mediated by the deficient neuromodulatory status (e.g., N-methyl-D-aspartate receptor function) of the brain that would not be confined to the neural mechanisms of auditory discrimination only but rather involves the whole cortex (8), accounting for cognitive decline. It is well-established that the adequate functioning of the N-methyl-D-aspartate receptor system plays a crucial role in long-term and working memory functions (9) and in plastic changes in the brain in general (10). It is an important task of future research on autism to determine whether MMN/MMNm deficits in autism—in particular, when accompanied by language imBIOL PSYCHIATRY 2011;70:212–213 © 2011 Society of Biological Psychiatry
BIOL PSYCHIATRY 2011;70:212–213 213
Commentary pairments—are an expression of just auditory-cortex functional deficiencies or of that of more general functional abnormalities of the brain, as is the case with a large number of other brain disorders.
5. 6.
This work was supported by the Academy of Finland (Grants 122745 and 128840). The authors reported no biomedical financial interests or potential conflicts of interest. 1. Roberts TPL, Cannon KM, Tavabi K, Blaskey L, Khan SY, Monroe JF, et al. (2011): Auditory magnetic mismatch field latency: A biomarker for language impairment in autism. Biol Psychiatry 70:263–269. 2. Kujala T (2007): The role of early auditory discrimination deficits in language disorders. J Psychophysiol 21:239 –250. 3. Kraus N, McGee TJ, Carrell TD, Zecker SG, Nicol TG, Koch DB (1996): Auditory neurophysiologic responses and discrimination deficits in children with learning problems. Science 273:971–973. 4. Kujala T, Karma K, Ceponiene R, Belitz S, Turkkila P, Tervaniemi M, Näätänen R (2001): Plastic neural changes and reading improvement
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caused by audio-visual training in reading-impaired children. Proc Natl Acad Sci U S A 98:10509 –10514. Pihko E, Mickos A, Kujala T, Pihlgren A, Westman M, Alku P, et al. (2007): Group intervention changes brain activity in bilingual languageimpaired children. Cereb Cortex 17:849 – 858. Boatman, DF, Trescher WH, Smith C, Ewen J, Los J, Wied HM, et al. (2008): Cortical auditory dysfunction in benign rolandic epilepsy. Epilepsia 49: 1018 –1026. Näätänen R, Kujala T, Kreegipuu K, Carlson S, Escera C, Baldeweg T, Ponton C (2011): The mismatch negativity: An index of cognitive decline in neuropsychiatric and neurological diseases and in ageing [published online ahead of print May 30]. Brain. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D (1997): Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 154:805– 811. Javitt DC, Steinschneider, M, Schroeder CE, Arezzo JC (1996): Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: Implications for schizophrenia. Proc Natl Acad Sci U S A 93:11962–11967. Gu Q (2002): Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neurosci 111:815– 835.
www.sobp.org/journal
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From the Institute of Psychology (RN), University of Tartu, Tartu, Estonia; Centre of Integrative Neuroscience (RN), University of Aarhus, Aarhus, Denmark; and the Cognitive Brain Research Unit (RN, TK), Cognitive Science, Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland. Address correspondence to Teija Kujala, Ph.D., Cognitive Brain Research Unit, Cognitive Science, Institute of Behavioural Sciences, University of Helsinki, Siltavuorenpenger 1 B, 00014, Helsinki, Finland; E-mail: teija.m.kujala@ helsinki.fi. Received May 24, 2011; accepted May 24, 2011.
0006-3223/$36.00 doi:10.1016/j.biopsych.2011.05.024
1. The MMN/MMNm reflects the quality of speech-sound processing even in normal healthy school-age children. For instance, it was found by Kraus et al. (3) that the MMN for the /ba/ - /da/ contrast was much smaller in amplitude in children with learning difficulties than that in normally learning children (whereas the easier contrast used [/ba/ - /wa/] did not discriminate between the two groups). 2. Different training or rehabilitation procedures (2,4,5) increase the MMN/MMNm amplitude, along with improved languagerelated skills. For instance, audiovisual training of dyslexic children resulted in improved reading skills and the enhancement of early parts of the MMN (4). 3. The MMN/MMNm is also affected in several other pediatric patient groups, which often also disclose some language impairment (which usually correlates with MMN/MMNm deficit), such as children with benign Rolandic epilepsy. For instance, Boatman et al. (6) found that, in approximately one-half, the MMN to a speech-sound change was absent and its peak latency was prolonged in the rest of the patients. Moreover, in very prematurely born infants, too, the MMN deficiency for speech-sound change correlates with deficient speech-sound discrimination performance and predicts a delay in their later linguistic development. Corroborating results were also obtained in children with dysphasia, dyslexia, and specific language impairment (SLI) (for a review, see Kujala [2]). Finally, it is important to consider whether the MMNm delay found by Roberts et al. (1) in ASD patients with language impairment relative to those with no language impairment indexes affected speech-sound discrimination only or a more general cognitive decline (even though global cognitive delay was screened out and the nonverbal IQ did not correlate with the MMNm delay). Very recently, it was concluded by Näätänen et al. (7) that MMN/MMNm attenuation/delay also indexes, besides affected central auditory processing, cognitive decline irrespective of the specific etiology and symptomatology of different neuropsychiatric and neurological disorders. For example, MMN/MMNm attenuation reflects cognitive and functional decline in schizophrenia and cognitive decline in stroke, aphasia, epilepsy, multiple sclerosis, chronic alcoholism, Velo-Cardio-Facial (DiGeorge) syndrome, human immunodeficiency virus, Alzheimer’s disease, Parkinson’s disease, Down syndrome, the advanced phase of diabetes mellitus, and survivors of coma and persistent vegetative state (7). Näätänen et al. (7) further proposed that the MMN– cognition relationship is mediated by the deficient neuromodulatory status (e.g., N-methyl-D-aspartate receptor function) of the brain that would not be confined to the neural mechanisms of auditory discrimination only but rather involves the whole cortex (8), accounting for cognitive decline. It is well-established that the adequate functioning of the N-methyl-D-aspartate receptor system plays a crucial role in long-term and working memory functions (9) and in plastic changes in the brain in general (10). It is an important task of future research on autism to determine whether MMN/MMNm deficits in autism—in particular, when accompanied by language imBIOL PSYCHIATRY 2011;70:212–213 © 2011 Society of Biological Psychiatry
BIOL PSYCHIATRY 2011;70:212–213 213
Commentary pairments—are an expression of just auditory-cortex functional deficiencies or of that of more general functional abnormalities of the brain, as is the case with a large number of other brain disorders.
5. 6.
This work was supported by the Academy of Finland (Grants 122745 and 128840). The authors reported no biomedical financial interests or potential conflicts of interest. 1. Roberts TPL, Cannon KM, Tavabi K, Blaskey L, Khan SY, Monroe JF, et al. (2011): Auditory magnetic mismatch field latency: A biomarker for language impairment in autism. Biol Psychiatry 70:263–269. 2. Kujala T (2007): The role of early auditory discrimination deficits in language disorders. J Psychophysiol 21:239 –250. 3. Kraus N, McGee TJ, Carrell TD, Zecker SG, Nicol TG, Koch DB (1996): Auditory neurophysiologic responses and discrimination deficits in children with learning problems. Science 273:971–973. 4. Kujala T, Karma K, Ceponiene R, Belitz S, Turkkila P, Tervaniemi M, Näätänen R (2001): Plastic neural changes and reading improvement
7.
8. 9.
10.
caused by audio-visual training in reading-impaired children. Proc Natl Acad Sci U S A 98:10509 –10514. Pihko E, Mickos A, Kujala T, Pihlgren A, Westman M, Alku P, et al. (2007): Group intervention changes brain activity in bilingual languageimpaired children. Cereb Cortex 17:849 – 858. Boatman, DF, Trescher WH, Smith C, Ewen J, Los J, Wied HM, et al. (2008): Cortical auditory dysfunction in benign rolandic epilepsy. Epilepsia 49: 1018 –1026. Näätänen R, Kujala T, Kreegipuu K, Carlson S, Escera C, Baldeweg T, Ponton C (2011): The mismatch negativity: An index of cognitive decline in neuropsychiatric and neurological diseases and in ageing [published online ahead of print May 30]. Brain. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D (1997): Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry 154:805– 811. Javitt DC, Steinschneider, M, Schroeder CE, Arezzo JC (1996): Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: Implications for schizophrenia. Proc Natl Acad Sci U S A 93:11962–11967. Gu Q (2002): Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neurosci 111:815– 835.
www.sobp.org/journal