The mismatch negativity (MMN) â€“ A unique window to ... et al (2011... · Invited Review The...

Clinical Neurophysiology 123 (2012) 424–458

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Clinical Neurophysiology

journal homepage: www.elsevier .com/locate /c l inph

Invited Review

The mismatch negativity (MMN) – A unique window to disturbed centralauditory processing in ageing and different clinical conditions

R. Näätänen a,b,c,⇑, T. Kujala c,d, C. Escera e,f, T. Baldeweg g,h, K. Kreegipuu a, S. Carlson i,j,k, C. Ponton l

a Institute of Psychology, University of Tartu, Tartu, Estoniab Center of Integrative Neuroscience (CFIN), University of Aarhus, Aarhus, Denmarkc Cognitive Brain Research Unit, Cognitive Science, Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finlandd Cicero Learning, University of Helsinki, Helsinki, Finlande Institute for Brain, Cognition and Behavior (IR3C), University of Barcelona, Barcelona, Catalonia, Spainf Cognitive Neuroscience Research Group, Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Catalonia, Spaing Institute of Child Health, University College London, London, UKh Great Ormond Street Hospital for Sick Children NHS Trust, London, UKi Neuroscience Unit, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finlandj Brain Research Unit, Low Temperature Laboratory, Aalto University School of Science and Technology, Espoo, Finlandk Medical School, University of Tampere, Tampere, Finlandl Compumedics NeuroScan, Santa Fe, NM, USA

a r t i c l e i n f o

Article history:Accepted 20 September 2011Available online 13 December 2011

Keywords:The mismatch negativity (MMN)Central auditory processingEvent-related potentials (ERP)MagnetoencephalographyAuditory discriminationNeuropsychiatric disordersNeurological disordersNeurodevelopmental disordersThe NMDA-receptor system

1388-2457/$36.00 � 2011 International Federation odoi:10.1016/j.clinph.2011.09.020

⇑ Corresponding author at: Cognitive Brain ReseaInstitute of Behavioural Sciences, University of Helsink40 501 5740; fax: +358 9 191 29450.

E-mail address: [email protected] (R. Näät

h i g h l i g h t s

� The mismatch negativity (MMN) indexes different types of central auditory abnormalities in differentneuropsychiatric, neurological, and neurodevelopmental disorders.� The diminished amplitude/prolonged peak latency observed in patients usually indexes decreased audi-tory discrimination.� An MMN deficit may also index cognitive and functional decline shared by different disorders irrespec-tive of their specific aetiology and symptomatology.� MMN deficits index deficient N-methyl-D-aspartate (NMDA) receptor function affecting memory-traceformation and hence cognition in different disorders.

a b s t r a c t

In this article, we review clinical research using the mismatch negativity (MMN), a change-detectionresponse of the brain elicited even in the absence of attention or behavioural task. In these studies, theMMN was usually elicited by employing occasional frequency, duration or speech-sound changes inrepetitive background stimulation while the patient was reading or watching videos. It was found thatin a large number of different neuropsychiatric, neurological and neurodevelopmental disorders, as wellas in normal ageing, the MMN amplitude was attenuated and peak latency prolonged.

Besides indexing decreased discrimination accuracy, these effects may also reflect, depending on thespecific stimulus paradigm used, decreased sensory-memory duration, abnormal perception or attentioncontrol or, most importantly, cognitive decline. In fact, MMN deficiency appears to index cognitivedecline irrespective of the specific symptomatologies and aetiologies of the different disorders involved.� 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights

reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4252. The MMN as an index of decreased auditory discrimination accuracy (Table 1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4313. The MMN as an index of shortened sensory-memory duration (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

f Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

rch Unit, Cognitive Science,i, Helsinki, Finland. Tel.: +358

änen).

http://dx.doi.org/10.1016/j.clinph.2011.09.020

mailto:[email protected]

http://dx.doi.org/10.1016/j.clinph.2011.09.020

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R. Näätänen et al. / Clinical Neurophysiology 123 (2012) 424–458 425

4. The MMN as an index of abnormal auditory perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4345. The MMN as an index of increased backward masking (Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4346. The MMN as an index of abnormal involuntary attention switching: either too weak (Table 4) or too strong (Table 5). . . . . . . . . . . . . . . . . . . 4347. The MMN attenuation caused by cerebral grey-matter loss or other structural change (Table 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4358. The MMN as an index of pathological brain excitation/excitability (Table 7) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4379. The MMN as an index of cognitive and functional deterioration (Table 8) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43710. The MMN as an index of the level of consciousness (Table 9) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43811. The MMN as an index of the progression/severity of the illness (Table 10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43812. The MMN in predicting illness course/drug response (prognosis) (Table 11) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43913. The MMN as an index of genetic disposition to different pathologies (Table 12) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44014. The MMN as an index of central auditory processing improvement or recovery (Table 13) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44115. Concluding discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444

1. Introduction

Interestingly, central auditory processing is affected in a largenumber of different clinical conditions with very different aetiolo-gies and symptoms such as schizophrenia, dyslexia, stroke, specificlanguage impairment (SLI), multiple sclerosis (MS), amyotrophiclateral sclerosis (ALS), epilepsy and autism, suggesting someshared aetiology in these different abnormalities (see also Gottes-man and Gould, 2003; Bishop, 2009; Dolan et al., 1993; Hugdahland Calhoun, 2010; Reite et al., 2009). These effects on centralauditory processing in different clinical conditions and in ageingcan now be objectively evaluated, and hence their degree of simi-larity determined, by using the electrophysiological change-detec-

ig. 1. Grand average difference waveforms (9 subjects) for changes in duration, frequenectrode Fz and referenced to the mean of the two mastoid electrodes (upper panel). Theastoid (RM); lower panel. Sound onset is always at 0 ms (From Pakarinen et al., 2007)

tion (or regularity-violation) response, the mismatch negativity(MMN; Näätänen et al., 1978; Näätänen and Michie, 1979) andits magnetoencephalographic (MEG) equivalent, the MMNm (Hariet al., 1984; Sams et al., 1985b). The MMN can be reliably (Pekko-nen et al., 1995a,b; Escera and Grau, 1996; Tervaniemi et al., 1999;Escera et al., 2000b) recorded even in the absence of the subject orpatient’s attention or behavioural task, e.g., in sleeping infants(Ruusuvirta et al., 2009), stroke patients even at a very early poststroke-onset period (Ilvonen et al., 2001, 2004) and in comatose(Kane et al., 1993, 1996; Fischer et al., 1999; Fischer and Luauté,2005) and persistent-vegetative-state (PVS) patients (Wijnenet al., 2007).

cy, and perceived sound-source location for six different magnitudes of deviance atsame waveforms referenced to the nose electrode and shown from Fz and the right

.

Fig. 2. The differential effects of ethanol on MMN at the frontal (Fz) and left andright mastoid (LM and RM, respectively) electrode positions. MMN was reduced atthe frontal electrode but the polarity-inverted MMN recorded at the mastoids,suggesting the supratemporal MMN subcomponent, was not affected by ethanol(0.55 g/kg) whereas the frontal subcomponent was affected by ethanol. Adaptedfrom Jääskeläinen et al. (1996b).

426 R. Näätänen et al. / Clinical Neurophysiology 123 (2012) 424–458

The auditory MMN response is mainly generated by a change-detection process occurring bilaterally in auditory cortices, inwhich the current auditory input is found to differ from the repre-sentation of the preceding auditory events, including regularitiesgoverning consecutive stimulus events (for reviews, see Näätänenet al., 2001, 2007, 2010, 2011b; Duncan et al., 2009; Winkler,2007). For an illustration, see Fig. 1. In subjects performing someprimary, e.g., visual, task, this preconscious auditory-cortexchange-detection process reaches conscious perception by activat-ing, with a brief delay (Rinne et al., 2000; see also Rinne et al., 2005,2006), a right frontal-cortex process which, in turn, initiates furthercerebral processes which may lead to conscious change detection(Näätänen, 1990, 1992; Näätänen et al., 2011b; Alain et al., 1998;Berti and Schröger, 2001; Deouell et al., 2007; Giard et al., 1990;Schröger, 1996; Escera et al., 2000a). Hence, the MMN is composedof overlapping contributions from auditory- and frontal-cortex pro-cesses (the supratemporal and frontal MMN subcomponents,respectively) (Giard et al., 1990). These two subcomponents of theMMN can be inferred from the data presented in Fig. 2 showinghow ethanol selectively attenuates the MMN amplitude recordedover the frontal cortex, whereas the polarity-reversed MMN re-corded at the mastoids (with a nose reference) is unaffected. Thisdata pattern suggests that the frontally recorded MMN is composedof contributions from both the auditory and frontal cortices,whereas the mastoid ‘MMN’ gets a contribution from the audi-tory-cortex MMN generator only. Intracranial recordings in humansalso support both auditory- and frontal-cortex MMN generators(Halgren et al., 1995a,b, 1998; Baudena et al., 1995; Kropotovet al., 1995, 2000; Liasis et al., 1999, 2000a,b; Rosburg et al., 2005,2007).

The MMNm, in turn, selectively reflects the temporal-lobe com-ponent of the MMN because the MEG is insensitive to the radiallyoriented frontal generators (Hämäläinen et al., 1993) of the MMN.Therefore, the MMNm is particularly well suited for detecting cen-tral auditory processing deficits specific for the temporal lobes.Consequently, the combined use of the electroencephalography(EEG) and MEG recordings helps one to separately determine towhat extent the temporal and frontal MMN components are im-paired (Hämäläinen et al., 1993; Näätänen, 1992). Further, thesetwo components have their functional magnetic resonance imag-ing (fMRI) (Molholm et al., 2005; Celsis et al., 1999; Opitz et al.,2002; Schall et al., 2003), positron emission tomography (PET)(Tervaniemi et al., 2000; Dittmann-Balcar et al., 2001; Mülleret al., 2002) and optical-imaging (OI) (Rinne et al., 1999; Tse andPenney, 2008) equivalents as well. Moreover, there is event-relatedpotential (ERP; Paavilainen et al., 1991; Doeller et al., 2003; Frodl-Bauch et al., 1997; Escera et al., 2002), MEG (Levänen et al., 1993,1996; Rosburg, 2003) and fMRI evidence (Molholm et al., 2005) forthe attribute-specific organisation of the supratemporal MMNgenerator.

Moreover, the MMN has its equivalents in other sensory modal-ities, too [the visual MMN; vMMN (Alho et al., 1992; Amenedoet al., 2007; Astikainen and Hietanen, 2009; Tales et al., 1999,2002a,b, 2008; Tales and Butler, 2006; Maekawa et al., 2005,2009; Berti and Schröger, 2004, 2006; Stagg et al., 2004; Stefanicset al., 2011; Heslenfeld, 2003; Pazo-Alvarez et al., 2003, 2004; Fro-yen et al., 2010; Iijima et al., 1996; Kenemans et al., 2003; Kimuraet al., 2009; Czigler, 2007; Czigler and Csibra, 1990, 1992; Czigleret al., 2002, 2004, 2006a,b; Czigler and Pató, 2009; Nordby et al.,1996; Wei et al., 2002; Woods et al., 1992); the somatosensoryMMN; sMMN (Kekoni et al., 1997; Shinozaki et al., 1998; Akatsukaet al., 2005; Kida et al., 2001; Spackman et al., 2007, 2010; Astikai-nen et al., 2001; Näätänen, 2009); and the olfactory MMN; oMMN(Krauel et al., 1999; Pause and Krauel, 2000)]. The vMMN has aparieto-occipital scalp distribution but there is no convincing evi-dence for a frontal component analogous to that in the auditory

modality. By contrast, the sMMN appears to have, similar to theauditory MMN, sensory-specific (somatosensory cortex) and fron-tal subcomponents (Restuccia et al., 2009; Spackman et al.,2010), consistent with its fronto-central, contralaterally predomi-nant scalp distribution (Wei et al., 2002). Currently, it is not clearwhether the auditory and somatosensory modalities share thefrontal activation (generating the frontal MMN component) proba-bly serving attention switch to stimulus change (Näätänen, 1992;Näätänen et al., 2002; Schröger, 1997). In addition, there is alsoan oMMN, with a long peak latency (about 500–600 ms) and parie-tally predominant scalp distribution (Krauel et al., 1999).

The MMN can also be recorded in different animals [in monkey(Javitt et al., 1992); cat (Csépe et al., 1987, 1988, 1989; Pincze et al.,2001, 2002); rabbit (Astikainen et al., 2001); rat (Astikainen et al.,2006; Ruusuvirta et al., 1998, 2007; Roger et al., 2009; Tikhonravovet al., 2008, 2010); guinea pig (Kraus et al., 1994); and mouse(Umbricht et al., 2005; Ehrlichman et al., 2008, 2009)].

The MMN enables one to determine discrimination accuracy,usually with a good correspondence with behavioural discrimina-tion (Sams et al., 1985a; Amenedo and Escera, 2000; Gottseliget al., 2004; Lang et al., 1990; Näätänen et al., 1993, 2007; Leitmanet al., 2010; Kujala and Näätänen, 2010; Tremblay et al., 1998), sep-arately for each auditory dimension (such as frequency, intensityand duration) as well as for the different speech sounds (Krauset al., 1996), with the MMN vanishing at about the behavioural dis-crimination threshold (Sams et al., 1985a; Winkler and Näätänen,1994; Winkler et al., 1993). Therefore, it permits one to form objec-tive deterioration profiles covering all important auditory dimen-sions in different patient groups (Näätänen et al., 2004; Kujalaet al., 2005a, 2006, 2007, 2010; Pakarinen et al., 2007, 2009, 2010).In addition, these MMN-based objective tests can be extended toall aspects of short-term auditory sensory memory, too, such as its

Table 1The auditory MMN (MMNm) provides an objective index of affected auditory discrimination in:

– ADHD (Alexandrov et al., 2003; Barry et al., 2003; Gumenyuk et al., 2005; Huttunen et al., 2007; Huttunen-Scott et al., 2008; Kemner et al., 1996; Kilpeläinen et al., 1999; Oades et al., 1996; Rothenberger, 1995;Rothenberger et al., 2000; Satterfield et al., 1988; Sawada et al., 2010; Wild-Wall et al., 2005; Winsberg et al., 1993)

– Ageing (Alain and Woods, 1999; Alain et al., 2004; Amenedo and Diaz, 1998; Bellis et al., 2000; Bertoli et al., 2005; Cooper et al., 2006; Czigler et al., 1992; Fabiani et al., 2006; Gaeta et al., 1998, 1999, 2001, 2002; Gunteret al., 1996; Horváth et al., 2007; Iijima et al., 1996; Ikeda et al., 2004; Jääskeläinen et al., 1999a; Karayanidis et al., 1995; Kiang et al., 2007, 2009; Kisley et al., 2004a,b, 2005; Kok, 2000; Mager et al., 2005; Osawa et al.,1996; Pekkonen, 2000; Pekkonen et al., 1995a, 1996a, 2005; Schiff et al., 2008; Schroeder et al., 1995; Verleger et al., 1991; Woods, 1992; Woods and Clayworth, 1986)

– Alcohol intoxication, acute (Ahveninen et al., 2000a; Jääskeläinen et al., 1995, 1996a,b, 1998, 1999a,b; Kähkönen et al., 2001, 2004)Alcoholism (Ahveninen et al., 2000a,b; Fein et al., 2004; Grau et al., 2001; Holguin et al., 1998; Kathmann et al., 1995; Marco-Pallares et al., 2007; Pekkonen et al., 1998; Polo et al., 2003; Realmuto et al., 1993; Rodriguez et al.,

1998; van der Stelt and Belger, 2007; Zhang et al., 2001)

– Alzheimer’s disease and dementia (Engeland et al., 2002; Gaeta et al., 1999; Katada et al., 2004; Kazmerski et al., 1997; Missioner et al., 1999; Pekkonen, 2000; Pekkonen et al., 1994, 1996b, 1999, 2001a,b; Riekkinen et al.,1997; Schroeder et al., 1995; Yokoyama et al., 1995)

– Amusia(Congenital) (Moreau et al., 2009; Peretz et al., 2009)

– Amusia (Caused by Stroke) (Kohlmetz et al., 2001; Särkämö et al., 2010b)Amyotrophic Lateral Schlerosis (ALS) (Gil et al., 1993; Hanagasi et al., 2002; Pekkonen et al., 2004; Raggi et al., 2008)

Anaesthesis and sedation (Csepe et al., 1989; Heinke and Koelsch, 2005; Heinke et al., 2004; Koelsch et al., 2006; Astikainen et al., 2006; Yppärilä et al., 2002; Simpson et al., 2002; van Hooff et al., 1995, 1997)

– Anhedonia (Giese-Davis et al., 1993)– Aphasia and stroke (Aaltonen et al., 1993; Alain et al., 1998; Auther et al., 2000; Becker and Reinvang, 2007; Csépe et al., 2001; Ilvonen et al., 2003, 2004; Jacobs and Schneider, 2003; Kohlmetz et al., 2001; Peach et al., 1992,

1993, 1994; Pettigrew et al., 2004a, 2005; Särkämö et al. 2010a,b; Wertz et al., 1998)

– Asperger syndrome (Jansson-Verkasalo et al., 2003a, 2005; Korpilahti, 1995; Korpilahti et al., 2007; Kujala et al., 2005a, 2007, 2010; Lepistö et al., 2006, 2007)

– Autism (Bomba and Pang, 2004; Ceponiene et al., 2003; Dunn et al., 2008; Ferri et al., 2003; Gomot et al., 2002; Kasai et al., 2005; Kemner et al., 1995; Kuhl et al., 2005; Lepistö et al., 2005, 2008; Näätänen and Kujala, 2011;Oram Cardy et al., 2005a,b; Roberts et al., 2008, 2011; Seri et al., 1999, 2007; Siegal and Blades, 2003)

– Bipolar disorder (Hall et al., 2007, 2009; Takei et al., 2010)

– Bipolar II disorder (Andersson et al., 2008)– Blindness (early) (Alho et al., 1993; Kujala et al., 1995a,b, 1997, 2000b)– Brain lesions (Alain et al., 1998; Alho et al., 1994; Auther et al., 2000; Deouell et al., 2000a,b; Hämäläinen et al., 2007; Jacobs and Schneider, 2003; Kaipio et al., 1999, 2000, 2001; Kohlmetz et al., 2001; Kotchoubey, 2007;

Kotchoubey et al. 2003, 2005; Mäkelä et al., 1998b; Neumann and Kotchoubey, 2004; Polo et al., 2002; Reinvang et al., 2000; Tarkka et al., 2011; Woods and Knight, 1986); (see also Aphasia and Stroke)

– Brainstem auditory processing syndrome (Kraus et al., 1993a)

– CATCH-22 syndrome (Baker et al., 2005; Cheour et al., 1998a; Ceponiene et al., 2002)

– Central auditory processing disorder (CAPD) (Bamiou et al., 2000)

– Cerebellar degeneration (Moberget et al., 2008)

– Childhood cancer and brain radiation (Järvelä et al., 2011; Lähteenmäki, 1999)

– Chronic pain (Dick et al., 2003)

– Chronic primary insomnia (Wang et al., 2001)

– Cleft palate (different forms of) (Ceponiene et al., 2000, 2002; Cheour et al., 1998a, 1999)

– Closed-head injury (Kaipio et al., 1999, 2000, 2001; Polo et al., 2002)

– Cochlear-implant (CI) users (Groenen et al., 1996; Kelly et al., 2005; Kileny et al., 1997; Koelsch et al., 2004; Kraus et al., 1993b; Lonka et al., 2004; Nager et al., 2007; Ponton et al., 1996, 2000, 2009; Ponton and Don, 1995,2003; Ponton and Eggermont, 2007; Roman et al., 2005; Salo et al., 2002; Sandmann et al., 2010; Wable et al., 2000)

– Coma (Daltrozzo et al., 2007; Fischer et al., 1999, 2000, 2004, 2006a,b, 2008; Fischer and Luauté, 2005; Guérit et al., 1999; Kane et al., 1993, 1996, 2000; Kotchoubey et al., 2003; Laureys et al., 2005; Luauté et al., 2005;Morlet et al., 2000; Naccache et al., 2005; van der Stelt and van Boxtel, 2008; Vanhaudenhuyse et al., 2008)

– Conduct disorder (Rothenberger et al., 2000)

– Craniosynosthosis (Huotilainen et al., 2008)

– Deafness to musical dissonance ( Acquired) (Brattico et al., 2003)

– Dementia (Schroeder et al., 1995; Yokoyama et al., 1995; Osawa et al., 1996)

– Depression (He et al., 2010; Iv et al., 2010; Kähkönen et al., 2007; Lepistö et al., 2004; Ogura et al., 1991, 1993; Takei et al., 2009)

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Table 1 (continued)

– Developmental dysphasia (Holopainen et al., 1997, 1998; Korpilahti and Lang, 1994)– Diabetes mellitus (late phase) (Vanhanen et al., 1996)

– Distractibility (Escera et al., 2000a; Gumenyuk et al., 2004; Kaipio et al., 2000, 2001; Kilpeläinen et al., 1999; Mager et al., 2005)

– Down’s syndrome (Diaz and Zurron, 1995; Lalo et al., 2005)

– Drugs

–Antipsychotics/Neuroleptics:

– Clozapine (Horton et al., 2010; Schall et al., 1999; Umbricht et al., 1998)

– Haloperidol (Kähkönen and Ahveninen, 2002; Kähkönen et al., 2001, 2002; Pekkonen et al., 2002)– Olanzapine (Korostenskaja et al., 2005)– Risperidone (Umbricht et al., 1999)

– Alcohol:– (Hirvonen et al., 2000; Jääskeläinen et al., 1995, 1996a,b, 1998, 1999a; Kähkönen et al., 2001,2004,2005b; Kenemans et al., 2010)

– Acetylcholine:Tetrahydroaminoacridine (THA, Tacrine) (Engeland et al., 2002; Riekkinen et al., 1997)– (a) Muscarinic receptor antagonist:

– Glycopyrrolate (Pekkonen et al., 2001a)– Scopolamine (Pekkonen et al., 2001a)

– (b) Nicotinic receptor agonists:– Nicotine: (Baldeweg et al., 2006; Dulude et al., 2010; Engeland et al., 2002; Fisher et al., 2010; Harkrider and Hedrick, 2005; Inami et al., 2005, 2007; Knott et al., 2009; Martin et al., 2009; Pritchard et al., 2004)– AZD3480 (Dunbar et al., 2007)

– Benzodiazepines:– (Kivisaari et al., 2007; Murakami et al., 2002)– Triatzolam (Nakagome et al., 1998)– Lorazepam (Rosburg et al., 2004)

– GABA agonists/antagonists:– Bicuculline (Javitt et al., 1996)– Flumazenil (Smolnik et al., 1998)– Propofol (Heinke et al., 2004; Koelsch et al., 2006; Simpson et al., 2002)

– Monoamines– Review: (Kähkönen and Ahveninen, 2002)

– Adrenergic drugs:– Clonidine (Duncan and Kaye, 1987; Hansenne et al., 2003)– Atipamezole (Mervaala et al., 1993)– Noradrenergic agonist S 12024-4 (Missioner et al., 1999)

– Histamine:– Antihistamines: Chlorpheniramine (Serra et al., 1996)

– Dopamine:– Apomorphine (Hansenne et al., 2003)– Methamphetamine (Hosák et al., 2008)– Methylphenidate (Winsberg et al., 1993, 1997; Sawada et al., 2010; Verbaten et al., 1994)– Bromocriptine (Leung et al., 2007)– Domperidone (Leung et al., 2007)

– Serotonin:– Serotonin (Kähkönen et al., 2005a; Oranje et al., 2008)– Acute tryptophan depletion (Kähkönen and Ahveninen, 2002)– Dimethyltryptamine (Heekeren et al., 2008)– Escitalopram (Oranje et al., 2008; Wienberg et al., 2010)– Psilocybin (Umbricht et al., 2003)

– Neuropeptides/Hormones:– Vasopressin (Born et al., 1986, 1987a, 1998)– Oxytocin (Born et al., 1987a)– Cholecystokinin (Schreiber et al., 1995)– Desacetyl-alpha-MSH (Smolnik et al., 1999)

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– Hydrocortisone (Born et al., 1987a)– ACTH-related neuropeptides (Born et al., 1987b; Smolnik et al., 1999; Pietrowsky et al., 1990)

– NMDA/Glutamate:– Ketamine (Ehrlichman et al., 2008; Heekeren et al., 2008; Javitt et al., 2000; Kreitschmann-Andermahr et al., 2001; Umbricht et al., 2002)– MK-801 (Javitt et al., 1996; Tikhonravov et al., 2010)– Phencyclidine (PCP) (Javitt et al., 1996)– Memantine (Korostenskaja et al., 2007)– Nitrous oxide (Pang and Fowler, 1999)– Glycine (Leung et al., 2008)– N-acetyl-cysteine (NAC; Lavoie et al., 2007)

– Opiods:– Naltrexone (Jääskeläinen et al., 1998)– Opioid Dependence (Kivisaari et al., 2007; Näätänen, 2001)

– Other/alternative therapies:– Hiba odour (Hiruma et al., 2002)

– Purine nucleotides: – Adenosine (Hirvonen et al., 2000)– Caffeine (Rosburg et al., 2004)

– Dyslexia (Ahissar, 2007; Ahissar et al., 2006; Alonso-Búa et al., 2006; Baldeweg et al., 1999; Bishop, 2007a,b; Blitz et al., 2007; Bonte et al., 2005, 2007; Bradlow et al., 1999; Bruder et al., 2011a,b; Corbera et al., 2006; Csépe,2002; Czamara et al., 2011; Fisher et al., 2006; Froyen et al., 2008, 2009, 2010; Guttorm et al., 2005, 2001; Hämäläinen et al., 2008; Heim et al., 2000; Huttunen et al., 2007; Huttunen-Scott et al., 2008; Jansson-Verkasaloet al., 2010; Kujala, 2007; Kujala and Näätänen, 2001; Kujala et al., 2000a, 2001, 2003, 2006; Kurtzberg et al., 1995; Lachmann et al., 2005; Leppänen and Lyytinen, 1997; Leppänen et al., 1997, 1999, 2002, 2004, 2010;Lovio et al., 2010; Lyytinen et al., 2001, 2004, 2006, 2009; Maurer et al., 2003, 2009; Paul et al., 2006a,b; Pihko et al., 1999, 2008; Renvall and Hari, 2003; Richardson et al., 2003; Roeske et al., 2011; Schulte-Körne andBruder, 2010; Schulte-Körne et al., 1998, 1999, 2001; Sebastian and Yasin, 2008; Shankarnarayan and Maruthy, 2007; Sharma et al., 2005, 2006, 2007, 2009; Stoodley et al., 2006; van Leeuwen et al., 2006)

– Dysthymia (Giese-Davis et al., 1993)– Electromagnetic fields (Kwon et al., 2009, 2010)

– Epilepsy (Boatman et al., 2008; Borghetti et al., 2007; Duman et al., 2008; Gene-Cos et al., 2005; Korostenskaja et al., 2010b; Liasis et al., 2000; Liasis et al., 2001; Liasis et al., 2006; Lin et al., 2007; Metz-Lutz and Philippini,2006; Miyajima et al., 2011; Rosburg et al., 2005)

– Frontal-lobe injury (Alho et al., 1994; Woods and Knight, 1986)– Herpes Simplex Encephalitis (Mäkelä et al., 1998a)– Hippocampus-Amygdala Partial Temporal-Lobe Resection (Hämäläinen et al., 2007)– HIV (Schroeder et al., 1994)– Huntington’s disease (pathological enhancement of discrimination) (Beste et al., 2008)– Hyperkinetic disorder (Rothenberger, 1995)– Hypnosis (Jamieson et al., 2005; Kallio et al., 1999)– Insomnia (Wang et al., 2001)– Intellectual disability (Ikeda et al., 2004; Nakagawa et al., 2002; Kaga et al., 1999)– Introvert/extrovert personality (Sasaki et al., 2000)– Landau–Kleffner syndrome (Honbolygó et al., 2006; Metz-Lutz and Philippini, 2006)– Language-learning impairment (LLI) (Benasich and Tallal, 2002; Benasich et al., 2006; Bradlow et al., 1999; Choudhury and Benasich, 2011; Kraus et al., 1996; Kujala, 2007; Marler et al., 2002; Pihko et al., 2007; Shaferet al., 2005; Uwer et al., 2002; Weber et al., 2005)

– Late talkers (Grossheinrich et al., 2010)– Learning-disabled children (Banai and Ahissar, 2005; Bradlow et al., 1999; Kraus et al., 1996)– Left sylvian infarct in neonate (Dehaene-Lambertz et al., 2004)– Locked-in patients (Ragazzoni et al., 2000)– Meditation (Srinivasan and Baijal, 2007)– Mental work load (Kramer et al., 1995)– Mental retardation (Holopainen et al., 1998; Ikeda et al., 2004; Kaga et al., 1999; Nakagawa et al., 2002; Yokoyama et al., 1995; Zurrón and Díaz, 1997)– Migraine (de Tommaso et al., 2004; Korostenskaja et al., 2010a; Valeriani et al., 2008)– Multiple schlerosis (MS) (Gil et al., 1993; Jung et al., 2006; Santos et al., 2006)– Narcolepsy (Naumann et al., 2001)– Neglect (Hemifield inattention) and extinction (Deouell et al., 2000a,b; Tarkka et al., 2011)– Noise and distraction (Bertoli et al., 2005; Gumenyuk et al., 2004; Mikkola et al., 2010; Shtyrov et al., 1998, 1999; Simoens et al., 2007)– Noise, different types of (Kozou et al., 2005)– Noise, occupational (Mäntysalo and Salmi, 1989)– Noise, occupational, long-term exposure (Brattico et al., 2005; Kujala and Brattico, 2009; Kujala et al., 2004)– Obsessive–compulsive disorder (Towey et al., 1994; Oades et al., 1996)– Obstructive sleep apnea syndrome (OSAS) (Gosselin et al., 2006)– Opioid dependence (Kivisaari et al., 2007)– Parkinson’s disease (Brønnick et al., 2010; Karayanidis et al., 1995; Pekkonen et al., 1995c; Vieregger et al., 1994)– Perinatal asphyxia (Leipälä et al., 2011)

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Table 1 (continued)

– Perinatal intracerebral hemorrhage (Leipälä et al., 2011)– Persistent vegetative state (Boly et al., 2011; Fischer and Luauté, 2005; Kotchoubey, 2007; Kotchoubey et al., 2003, 2007, 2008; Laureys et al., 2005; Wijnen et al., 2007; Zarza-Lucianez et al., 2007)– Personality differences (Matsubayashi et al., 2008; Franken et al., 2005)– Phonological deficit (Blitz et al., 2007)– Plagiocephaly (Huotilainen et al., 2008)– Post-traumatic stress syndrome (PTSS) (Cornwell et al., 2007; Ge et al., 2011; Menning et al., 2008; Morgan and Grillon, 1999)– Psychosocial stress (Simoens et al., 2007)– Prematurely born (with very low birth weight, VLBW) infants (Bisiachi et al., 2009; Cheour-Luhtanen et al., 1996; Fellman and Huotilainen, 2006; Fellman et al., 2004; Gomot et al., 2007; Holst et al., 2005; Jansson-Verkasaloet al., 2004, 2010; Leipälä et al., 2011; Mento et al., 2010; Mikkola et al., 2007, 2010)

– REM-sleep deprivation (Zerouali et al., 2010)– Schizophrenia (Ahveninen et al., 2006; Baldeweg et al., 2002, 2004; Banati and Hickie, 2009; Bodatsch et al., 2011; Braff and Light, 2004; Brockhaus-Dumke et al., 2005; Catts et al., 1995; Davalos et al., 2003, 2005;Devrim-Ücok et al., 2008; Ehrlichman et al., 2008, 2009; Fisher et al., 2008, 2011; Grzella et al., 2001; Hermens et al., 2010; Hirayasu et al., 1998, 2000, 2001; Inami et al., 2007; Jahshan et al., 2011; Javitt, 1993, 2000,2009a,b; Javitt et al., 1996, 1998, 1999, 2000, 2008; Jessen et al., 2001; Kasai et al., 2001, 2002a,b,c, 2003a,b; Kathmann et al., 1995; Kaur et al., 2011; Kawakubo et al., 2006, 2007; Kiang et al., 2007, 2009; Kircher et al.,2004; Korostenskaja et al., 2005; Kreitschmann-Andermahr et al., 1999, 2001; Lavoie et al., 2007; Leitman et al., 2010; Light and Braff, 2005a,b; Luck et al., 2011; Magno et al., 2008; Matthews et al., 2007; Michie, 2001;Michie et al., 2002; Minami and Kirino, 2005; Morlet et al., 2000; Näätänen and Kähkönen, 2009; Niznikiewicz et al., 2009; Oades et al., 2006; Oknina et al., 2005; Park et al., 2002; Potts et al., 1998; Price et al., 2006;Rasser et al., 2011; Rissling et al., 2010; Salisbury et al., 2002, 2007; Sato et al., 1998, 2002; Schall et al., 1998, 1999, 2003; Schreiber et al., 1992; Shelley et al., 1991; Shin et al., 2009; Shinozaki et al., 2002; Stone et al.,2010; Thönnesen et al., 2008; Todd et al., 2008; Todd et al., in press; Todd et al., 2003, 2008; Turetsky et al., 2007, 2009; Umbricht et al., 1998, 1999, 2000, 2002, 2003, 2006; van der Stelt and Belger, 2007; Verbaten andvan Engeland, 1995; Wible et al., 2001; Wynn et al., 2010; Yamasue et al., 2004; Youn et al., 2003; for a meta-analysis of 32 studies, see Umbricht and Krljes, 2005)

– Serotonin transporter gene variants, individuals with (Sysoeva et al., 2009)– Sensorineural hearing loss (Oates et al., 2002; Stapells, 2002)– Sleep (Atienza et al., 1997, 2000, 2002; Atienza and Cantero, 2001; Campbell et al., 1991; Cheour et al. 2000,2002; Martynova et al., 2003; Nashida et al., 2000; Nittono et al., 2001; Ruby et al., 2008; Sallinen et al., 1994,1996; Sculthorpe et al., 2009)

– Sleep deprivation (Gumenyuk et al., 2010; Raz et al., 2001; Sallinen and Lyytinen, 1997; Salmi et al., 2005; Wang et al., 2001; Zerouali et al., 2010)– Socially withdrawn children (Bar-Haim et al., 2003)– Somatisation disorder (James et al., 1989)– Specific language impairment (SLI) (Barry et al., 2008; Bishop and McArthur, 2004; Friedrich et al., 2004; Korpilahti, 1995; Marler et al., 2002; Pihko et al., 2008; Rinker et al., 2007; Shafer et al., 2007; Uwer and vonSuchodoletz, 2000; Uwer et al., 2002; Weber et al., 2005)

– Stroke (see Aphasia)– Stuttering (Corbera et al., 2005; Wu et al., 1997)– Temporal-parietal brain lesions (Alain et al., 1998)– Thalamic infarction (Mäkelä et al., 1998b)– Tourette syndrome (TS) (Oades et al., 1996; Rothenberger et al., 2000; van Woerkom et al., 1988, 1994)– Tune deafness (Braun et al., 2008)– Velo-cardio-facial (DiGeorge) syndrome (Baker et al., 2005)

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Table 2THE MMN shows abnormally short auditory sensory-memory duration in:

– Alzheimer’s disease (Pekkonen et al., 1994)– Infants and children with cleft palate and CATCH-22 syndrome (Ceponiene et al., 2002; Cheour et al., 1997, 1998a, 1999)– Late talkers (Grossheinrich et al., 2010)– Chronic alcoholism (Grau et al., 2001; Marco-Pallares et al., 2007; Polo et al., 1999)– Normal ageing (Cooper et al., 2006; Grau et al., 2001; Jääskeläinen et al., 1999a; Pekkonen et al., 1996a)– Parents of children with specific language impairment (SLI) (Barry et al., 2008)

Table 3The MMN provides an index of increased backward masking (affecting speechperception) in:

– Chronic alcoholism (Ahveninen et al., 1999)– Dyslexia (Kujala et al., 2003)– Specific language impairment (SLI) (Marler et al., 2002)

3-5 days 10 days3 months

Lefthemisphere

Righthemisphere

Time

Am

plitu

de

MMNMMN

Fig. 3. MMN shows how frequency discrimination recovered to normal levelswithin 3 months from a stroke onset (averaged data of 8 patients). This MMNrecovery was slower for right-ear stimulation (with the main part of the auditoryinput going to the damaged left hemisphere) (curves on the left) than with left-earstimulation (curves on the right). During the MMN recording, the patient waswatching video-films. Adapted from Ilvonen et al. (2003).


duration, capacity and accuracy (Pekkonen et al., 1996a; Cooperet al., 2006; Polo et al., 1999; Grau et al., 2001). Furthermore, theauditory MMN can even index auditory long-term memory tracessuch as the language-specific memory traces, enabling one to cor-rectly perceive the speech sounds of the mother tongue and otherfamiliar languages (Dehaene-Lambertz, 1997; Näätänen, 2001;Näätänen et al., 1997; Pulvermuller et al., 2004; Shtyrov and Pulver-muller, 2007; Winkler et al., 1999c; Shtyrov and Pulvermüller,2007). This linguistic MMN subcomponent is usually left-hemi-spherically predominant and generated posteriorly to the bilateralMMN subcomponent for mere acoustic change (Näätänen et al.,1997; Shestakova et al., 2002).

The extensive MMN literature of clinical studies can be classi-fied according to the kind of clinically useful information thatcan be obtained by using the MMN. The MMN can index:

(1) Auditory discrimination accuracy (which is decreased in anumber of clinical groups and affected by different drugs)(Table 1);

(2) shortened sensory-memory duration (and hence possiblydecreased general brain plasticity) (Table 2);

(3) abnormal auditory perception;(4) increased backward masking (Table 3);(5) abnormal involuntary attention switching, either too weak

(Table 4) or too strong (Table 5);(6) cerebral grey-matter loss and other structural changes

(Table 6);(7) pathological brain excitation/excitability state (Table 7);(8) cognitive and functional decline (Table 8);(9) the level of consciousness (Table 9);

(10) the progression of illness (Table 10);(11) future clinical condition (prognosis) (Table 11);(12) genetic disposition to certain disorders (Table 12); and(13) recovery/improvement as a function of time or treatment

(Table 13).Moreover, recent studies using the vMMN (Iijima et al.,1996; Lorenzo-Lopez et al., 2004; Tales and Butler, 2006;Tales et al., 2002a,b; Kenemans et al., 2010; Tales and Butler,2006; Tales et al., 2002a, 2008; Maekawa et al., 2011; Froyenet al., 2010; Chang et al., 2010; Qiu et al., 2011; Horimotoet al., 2002; Hosák et al., 2008; Kremlácek et al., 2008, Ver-baten et al., 1994; Tales and Butler, 2006; Tales et al.,2008; Fisher et al., 2010; Urban et al., 2008; for a recentreview, see Kimura et al., 2011) and sMMN (Restucciaet al., 2007; Akatsuka et al., 2005, 2007; Näätänen, 2009)have also provided clinically important results.

The present review aims at covering all clinical MMN studies inthe auditory modality published in refereed international English-

language journals. Almost all these studies report, with only a fewexceptions, group-level results.

2. The MMN as an index of decreased auditory discriminationaccuracy (Table 1)

In several clinical conditions, the MMN amplitude is attenuated,usually indexing decreased behavioural discrimination accuracy(Javitt et al., 1998; Rabinowicz et al., 2000; Matthews et al.,2007). This amplitude reduction was usually found by recordingthe MMN to simple frequency or duration changes in sinusoidaltones, for instance, in schizophrenia (Todd et al., 2003; Javittet al., 2000; Michie et al., 2000; see also Javitt et al., 1998). Inschizophrenia, the duration MMN, in particular that to durationincrement, was even more affected than that to frequency change(Michie, 2001; Michie et al., 2000; for a meta-analysis, see Umb-richt and Krljes, 2005). The frequency MMN is attenuated in ampli-tude in several other clinical groups, too, such as children withdevelopmental dysphasia (Holopainen et al., 1997, 1998; Kor-pilahti and Lang, 1994), dyslexia (Baldeweg et al., 1999; Renvalland Hari, 2003; Kujala et al., 2003, 2006; Sebastian and Yasin,2008) and SLI (Mengler et al., 2005; Rinker et al., 2007).

In children and adults with dyslexia, the MMN to frequencychange but not that to duration change was considerably attenu-ated in amplitude (Baldeweg et al., 1999; Kujala et al., 2006). Fur-thermore, in keeping with this profile of MMN-amplitudereduction, the behavioural frequency but not duration discrimina-tion was affected (Baldeweg et al., 1999). In addition, thisfrequency-MMN deficit strongly correlated with the severity ofthe reading problem. Subsequently, Lachmann et al. (2005)

Table 4The MMN shows decreased involuntary attention switching in:

– Alcohol intoxication (Jääskeläinen et al., 1995, 1996a,b, 1999b)– Schizophrenia (Baldeweg et al., 2002; Catts et al., 1995; Matthews et al., 2007; Oades et al., 2006; Sato et al., 2003)– Closed-head injury (Polo et al., 2002)– Frontal-lesion patients (Alho et al., 1994)– Right-hemisphere damage (unilateral neglect) (Deouell et al., 2000a,b)– Children with major depression (Lepistö et al., 2004)


showed that the MMN-attenuation profile involving frequency andconsonant–vowel (CV) syllable changes could disentangle differentdiagnostic subgroups of developmental dyslexia from each other.Moreover, Shafer et al. (2005) and Uwer et al. (2002) found thatSLI children had attenuated MMN amplitudes for syllable change.

Using the new multi-feature MMN ‘optimum’ paradigm (Näätä-nen et al., 2004), permitting one to obtain five different MMNs in15 min, Lovio et al. (2010) found a widespread auditory discrimi-nation deficit in children at risk for dyslexia. Their MMNs for con-sonant, vowel, vowel duration and intensity changes of syllableswere diminished in amplitude. By contrast, Kujala et al. (2006),also using the multi-feature paradigm, found that in adult dyslex-ics, the frequency MMN was attenuated, whereas their locationMMN was in fact enhanced in amplitude. This shows that not allchanges in central auditory processing in dyslexia signify deterio-rated discrimination. However, the MMN data may also suggestthe presence of cognitive deficiencies associated with dyslexia, atleast deficient phonotactic processing (Bonte et al., 2007).

Furthermore, in children with autism, the MMN to durationchange (Lepistö et al., 2005) and the MMNm to speech-soundchange (Kasai et al., 2005; for recent corroborating results, see Rob-erts et al., 2011) were attenuated in amplitude. In addition, theMMN to CV-syllable change was prolonged in peak latency butonly in those children who preferred non-speech analogy signalsto speech (Kuhl et al., 2005). By contrast, the MMN to frequencychange was enhanced in amplitude (Lepistö et al., 2005; Ferriet al., 2003) and shortened in peak latency (Gomot et al., 2002)in autistic children, consistent with their better-than-average pitchdiscrimination and musical abilities (Bonnel et al., 2003; Heatonet al., 2001). Very recently, it was found by Roberts et al. (2011;

Fig. 4. Scatterplot of MMN amplitude at Fz versus age, for schizophrenia patients (operegression line) (From Kiang et al., 2009).

see also Näätänen and Kujala, 2011) that in autistic children of7–9 years, the MMNm peak latency for tone-frequency and vowelchanges was delayed, in comparison with that of normally devel-oping children of the same age, and, further, that this delay wasconsiderably increased if the child also suffered from a delay in lin-guistic development. This might contribute to their speech-under-standing difficulties and hence to their social isolation. In addition,in the Asperger syndrome, a condition belonging to the autismspectrum, the duration-increment MMN of children of about9 years of age was attenuated in amplitude over the left hemi-sphere, whereas it was enhanced over the right hemisphere(Lepistö et al., 2006). Moreover, in this syndrome, the MMN ampli-tude was also attenuated for changes in prosody (Kujala et al.,2005a). Recently, a shortened MMN peak latency for frequencychange and increased MMN amplitudes for duration and gapchanges were found in Asperger adults by Kujala et al. (2007).

In addition, the MMNs for frequency and duration changes wereattenuated in amplitude in patients with a left-hemispheric stroke(Csépe et al., 2001; Aaltonen et al., 1993; Auther et al., 2000; Ilvo-nen et al., 2001, 2003; Pettigrew et al., 2005). These two MMNsshowed somewhat different time courses of post-stroke recovery,however (Ilvonen et al., 2003) (Fig. 3). Importantly, the MMNrecovery indexed that of speech perception, there being a correla-tion between the duration-MMN amplitude and the Boston Diag-nostic Aphasia Examination Speech-Comprehension Test from10 days to 3 months post-stroke onset (Ilvonen et al., 2003). Subse-quently, Särkämö et al. (2010b) found that the MMNm recoveryand behavioural discrimination could be expedited with musicand speech stimulation. In addition, the MMNm recovery corre-

n circles; dashed regression line) and normal control subjects (solid circles; solid

Table 5The MMN shows increased involuntary attention switching in:

– Closed head injury (Kaipio et al., 2000)– Ageing (Gaeta et al., 2001)– Alcoholism (Ahveninen et al., 2000b; Polo et al., 2003)– Children with major depression (Lepistö et al., 2004)– Sleep disorder (Gumenyuk et al., 2010)

Younger Males (mean 22 yrs)

Older Males (mean 59 yrs)

0.5 s

4.5 s

MMN

Fz F3 F 4

Fig. 5. MMN to frequency change (700 ? 600 Hz) was normal in older males withan inter-stimulus interval (ISI) of 0.5 s but was considerably attenuated, relative tothat of younger males, with an ISI of 4.5 s, indexing faster auditory sensory-memorytrace decay with aging (From Pekkonen et al., 2001a).


lated with the recovery of behavioural speech-sounddiscrimination.

In epilepsy, the MMN is also affected. The MMN peak latencieswere abnormally long or no clear MMN response could be foundfor speech (but could for tones) in patients with benign childhoodepilepsy with contra-temporal spikes (Boatman et al., 2008; Du-man et al., 2008). Patients with such spikes with atypical featuresand learning difficulties also exhibit attenuated MMN amplitudes(Metz-Lutz and Philippini, 2006). In addition, in the Landau–Kleff-ner syndrome, an MMN was obtained for phoneme change but notfor prosodic change (Honbolygó et al., 2006). By contrast, Miyajimaet al. (2011), studying adult patients with temporal-lobe epilepsy,found that at fronto-central sites, their MMN amplitude for tone-frequency change was enhanced, interpreted by the authors asreflecting frontal-lobe hyperexcitability to compensate for tempo-ral-lobe dysfunction indexed, according to the authors, by pro-longed MMN peak latencies in patients relative to controls atboth fronto-central and mastoid sites, consistent with previous re-ports (Lin et al., 2007; Borghetti et al., 2007). Furthermore, in theMiyajima et al. (2011) temporal-lobe epilepsy patients, the fron-to-centrally recorded MMN persisted longer than that in controls,consistent with the results of Gene-Cos et al. (2005) who suggestedthat a prolonged MMN duration might point to difficulty in ‘theclosure mechanism of the MMN process’.

The MMN can also be used to evaluate the possible central-auditory-processing damage associated with a very prematurebirth. Studying very prematurely born children (mean gestationalage 29 weeks) with a very low birth weight (mean 1115 g), Jans-son-Verkasalo et al. (2003b, 2004) found that their MMN ampli-tude for consonant change at 4 years (from conception) wassmaller than that of controls and, further, that the absence of theMMN at 4–5 years of age predicted naming difficulties at 6 years.However, if the MMN amplitude nevertheless was normal at4 years, then there were no naming difficulties at 6 years.

Moreover, the MMN enables one to also determine central-auditory-processing damage caused by long-term exposure to loudoccupational noise. In workers exposed to such a noise for 2–17 years, the MMN to syllable change was attenuated in amplitude(even though their peripheral hearing was not affected), in keepingwith their increased speech-perception problems (Kujala et al.,2004). In addition, the Brattico et al. (2005) MMN data showed thatlong-term exposure to occupational noise altered the cortical orga-nisation of speech-sound processing in these workers (in the ab-sence of peripheral hearing loss) but did not alter that of non-speech processing. In addition, the discrimination of auditory stim-uli was generally slowed down, as indexed by prolonged MMN-peak latencies.

Furthermore, by using the MMN, one can also monitor age-re-lated changes in central auditory processing (Fabiani et al., 2006;Woods, 1992; Woods and Clayworth, 1986; Jääskeläinen et al.,1999a; Kiang et al., 2009; Cooper et al., 2006; Gaeta et al., 1998,2001, 2002; Kisley et al., 2005; Pekkonen, 2000; Pekkonen et al.,1995a, 1996a). A particularly convincing characterisation of theMMN–age relationship was provided by Kiang et al. (2009) whocarefully plotted the MMN and P3a amplitudes for tone-durationincrement across adulthood for 147 normal subjects and 253schizophrenic patients (Fig. 4). Along with an increasing age, the

level of performance in different cognitive tasks is gradually de-creased (Cansino, 2009). There is also evidence linking theseMMN changes to cognitive deterioration (Kisley et al., 2005). Evenin healthy elderly persons, the MMN to a short gap in the middle ofa tone (Desjardin et al., 1999) was attenuated in amplitude, index-ing their increased difficulties in correctly perceiving rapid speech-sound patterns such as consonants (Bertoli et al., 2002, 2005).

The MMN and MMNm are also affected by different drugs(Table 1).

3. The MMN as an index of shortened sensory-memory duration(Table 2)

The MMN elicitation depends on the presence of the sensory-memory trace representing the preceding stimuli and their regu-larities at the moment of the delivery of a deviant stimulus (for areview, see Näätänen et al., 2007). Hence, by gradually prolongingthe inter-stimulus interval (ISI), the MMN eventually vanishes,which enables one to assess sensory-memory duration in audition(a potential general index of brain plasticity; Näätänen and Kreegi-puu, 2011).

In young healthy adults, the trace duration, as estimated in thismanner, approximates 10 s (Böttcher-Gandor and Ullsperger,1992; Sams et al., 1993), but is gradually shortened with ageing.With short ISIs such as 0.5 s, the MMN amplitude for frequencychange was very similar in elderly (mean 59 years) and young(mean 25 years) male subjects, suggesting that the memory-traceformation for sounds and, thus, perception (see Näätänen and Win-kler, 1999) were not affected by ageing. By contrast, with a stimu-lus-onset asynchrony (SOA) of 4.5 s, the MMN amplitude of theelderly was much more attenuated than that of the young (Pekko-nen et al., 1996a) (Fig. 5), indicating that in ageing, the auditorysensory-memory duration is shortened. Moreover, correspondingMMN data for frequency change in chronic alcoholics suggestaccelerated age-related shortening of the memory-trace durationin these patients (Polo et al., 1999; see also Grau et al., 2001).

The memory-trace duration is particularly short in patientswith Alzheimer’s disease, of course. Their MMN was, however, nor-mal with short ISIs (0.5 s), suggesting normal memory-trace for-mation/perception (see Näätänen and Winkler, 1999) even inthese patients, but absent at long ISIs (3 s) (Pekkonen et al.,1994), indexing their extremely short sensory-memory duration.Interestingly, this data pattern is orthogonal to that observed in pa-tients with schizophrenia in whom no normal-amplitude MMN canbe obtained in any condition, not even with very short ISIs andwide frequency deviations (Javitt et al., 1998). This suggests thattheir memory-trace formation, and hence auditory perception

Table 6The MMN correlates with structural changes in:

– Schizophrenia (Hirayasu et al., 2000, 2001; Kasai et al., 2003a,b; Park et al.,2002; Rasser et al., 2011; Salisbury et al., 2002, 2007; Yamasue et al., 2004;Youn et al., 2003; for a review, see van der Stelt and Belger, 2007)

– Cleft palate (children with) (Ceponiene et al., 1999)

350-ms ISI700-ms ISI1400-ms ISI

-4 µV

+1 µV 350 ms

F4

Fig. 6. MMN for tone-frequency change was of normal amplitude in 7–9 year oldchildren with oral clefts when a short ISI (350 ms) was used but was considerablysmaller than that of controls when the ISI was prolonged to 700 ms and to 1400 ms,suggesting an accelerated sensory-memory trace in patients (From Ceponiene et al.,1999).


(Näätänen and Winkler, 1999), is abnormal, consistent with clini-cal observations (for a review, see Näätänen and Kähkönen,2009). By contrast, their sensory-memory duration, as judged fromthe ISI–MMN relationship in these patients, is unaffected (Javittet al., 1998; see also March et al., 1999).

The auditory memory-trace duration shows developmentalchanges also in the beginning of the life, but to the opposite direc-tion, of course, being only 0.5 s in newborns, as judged from MMNsrecorded during sleep (Cheour et al., 2002b), but is thereafter grad-ually prolonged during infancy and childhood. By using the Grauet al. (1998) MMN paradigm for effectively determining the sen-sory-memory duration, Glass et al., 2008a,b) found that this dura-tion was about 1–2 s at the age of 2–3 years but was prolonged to3–5 s by the age of 6 years (see also Gomes et al., 1999).

This memory-trace duration is affected in some child patientgroups, too. In children of 7–8 years with cleft palate, the MMNfor tone-frequency change was of normal amplitude with shortSOAs (350 and 700 ms), whereas the prolongation of the SOA to1400 ms attenuated this amplitude much more than it attenuatedthat of control children (Ceponiene et al., 1999) (Fig. 6). Further-more, an analogous data pattern was obtained in small infants withcleft palate, which was even more abnormal in children with theCatch-22 syndrome (Cheour et al., 1997, 1998a, 1999).

In addition, a short auditory sensory-memory duration even innormal healthy children is associated with delayed linguisticdevelopment. Late talkers had a shorter sensory-memory durationthan that of controls, as judged from MMN data for tone-frequencychange as a function of the ISI recorded at the age of 4 years7 months, even though the language development was normal bythat age (Grossheinrich et al., 2010).

Furthermore, the Barry et al. (2008) recent MMN data for tone-frequency change as a function of the ISI suggested a shorter audi-tory sensory-memory duration in parents of children with SLI thanthat in parents of normally developing children.

4. The MMN as an index of abnormal auditory perception

In the foregoing, it was already mentioned that in patients withschizophrenia, no normal-size MMN can be obtained irrespectiveof experimental manipulations, not even with very short SOAs (Ja-vitt et al., 1998). This suggests a fundamental abnormality in mem-ory-trace formation, and thus in auditory perception (see Näätänenand Winkler, 1999), in these patients (Näätänen and Kähkönen,2009). Moreover, a number of further studies in patients withschizophrenia (Oades et al., 1996; Hirayasu et al., 1998; Schallet al., 1999; Youn et al., 2003; Kasai et al., 2002a,b) showed thatthe frequency-MMN amplitude deficit tends to correlate with theseverity of auditory hallucinations. In addition, Youn et al. (2003)found that the abnormality of the left–right MMN-amplitudeasymmetry for frequency change of a tone correlated with the po-sitive scores of the positive-and-negative syndrome scale (PANSS),in particular with its hallucination subscale. For corroboratingMMNm data, see Thönnesen et al. (2008). Moreover, Fisher et al.(2008) found a smaller duration-MMN amplitude in patients withauditory hallucinations than in those with no hallucinations. Inaddition, the MMN amplitude for intensity change was also smallerin hallucinating than non-hallucinating patients. Furthermore,both patient groups showed an attenuated MMN amplitude for fre-quency change. This MMN deficiency however was differently dis-tributed in frontal areas in the two patient groups.

5. The MMN as an index of increased backward masking(Table 3)

Auditory masking refers to any observation such that informa-tion in a test auditory stimulus is reduced by the presentation ofanother (masking) auditory stimulus (Massaro, 1973). The percep-tion of sequentially presented auditory stimulation may be hin-dered by backward masking, with a sound preventing theperception of an immediately preceding sound, apparently byaffecting its memory-trace formation (Massaro, 1975), in particularwhen the later sound is stronger in intensity than the precedingsound (see Hawkins and Presson, 1986). Massaro (1975) concludesthat backward masking occurs because the masking stimulusessentially overwrites the auditory image of the test stimulusand, therefore, terminates the perceptual processing of the teststimulus.

Backward masking can be assessed both behaviourally and byusing the MMN: a masker presented shortly after each stimulusof the oddball paradigm causes the MMN to deviants and the sub-ject’s ability to discriminate them behaviourally to disappear inparallel (Winkler and Näätänen, 1994; Winkler et al., 1993). Byusing this type of paradigm, it was found by Kujala et al. (2003)that backward masking is enhanced in dyslexic individuals. In-creased backward masking, as reflected by MMN-data pattern,was also reported in chronic alcoholism (Ahveninen et al., 1999).Importantly, this MMN deficit in chronic alcoholism correlatedwith the amount of their alcohol consumption and predicted theirworking-memory performance deficit (Ahveninen et al., 1999).

6. The MMN as an index of abnormal involuntary attentionswitching: either too weak (Table 4) or too strong (Table 5)

As already mentioned, in addition to its auditory-cortex gener-ators, the MMN also has a frontal (usually right-hemisphericallypredominant (Giard et al., 1990)) generator contributing, togetherwith the auditory-cortex MMN generator (see Fig. 2), to the fron-tally and centrally recorded MMN amplitudes (Deouell, 2007;Giard et al., 1990; Rinne et al., 2000). The frontally recordedMMN amplitude is considerably attenuated, whereas the

Table 7The MMN indexes pathological brain excitation/excitability in:

– Alcoholism (Ahveninen et al., 2000a; Pekkonen et al., 1998)– ALS (with bulbar signs) (Pekkonen et al., 2004)– Chronic primary insomniacs (Wang et al., 2001)– Epilepsy (Miyajima et al., 2011)– Huntington’s disease, Syndromatic Phase (Beste et al., 2008)– Major depression, children with (Lepistö et al., 2004)– Pediatric migraine (Valeriani et al., 2008; see, however, de Tommaso et al.,

2004)– Schizophrenia (pathological microglia activation, indexing local disease

process and neuronal death) (Banati and Hickie, 2009)– Stuttering (Corbera et al., 2005; see also Wu et al., 1997)

Table 8The MMN indexes cognitive and functional decline in:

– Ageing (Gaeta et al., 2002; Kisley et al., 2005; Schroeder et al., 1995)– Alzheimer’s disease and dementia (Engeland et al., 2002; Schroeder et al.,

1995)– Amyotropic lateral schlerosis (ALS) (Raggi et al., 2008)– Autism (Seri et al., 2007; Roberts et al., 2008, 2011; Näätänen and Kujala,

2011)– CATCH-22 syndrome: children (for a review, see Ceponiene et al., 2002),

adults (Baker et al., 2005)– Children with cleft palate (Ceponiene et al., 2002)– Chronic alcoholism (Polo et al., 1999)– Coma, survivors of (Kane et al., 2000)– Developmental dysphasia (Holopainen et al., 1997, 1998; Korpilahti and

Lang, 1994)– Diabetes mellitus (advanced phase) (Vanhanen et al., 1996)– Down’s syndrome (Lalo et al., 2005)– Dyslexia (Bonte et al., 2007)– Epilepsy (Boatman et al., 2008; Liasis et al., 2000, 2001, 2006; Metz-Lutz and

Philippini, 2006)– HIV (Schroeder et al., 1994)– Intellectual disability (Ikeda et al., 2004; Nakagawa et al., 2002)– Multiple schlerosis (MS) (Gil et al., 1993; Jung et al., 2006; Santos et al., 2006)– Parkinson’s disease (Brønnick et al., 2010; Karayanidis et al., 1995; Pekkonen

et al., 1995c)– Persistent-vegetative-state (PVS), survivors of (Kotchoubey, 2007; Wijnen

et al., 2007; van der Stelt and van Boxtel, 2008; Zarza-Lucianez et al., 2007)– Preterm children with very low birth weight (Jansson-Verkasalo et al., 2004,

2010)– REM-sleep deprivation (Zerouali et al., 2010)– Schizophrenia (e.g., Baldeweg et al., 2004; Hermens et al., 2010; Kawakubo

et al., 2007; Light and Braff, 2005a,b; Rasser et al., 2011; Toyomaki et al.,2008)

– Sleep deprivation (Raz et al., 2001)– Stroke and aphasia (Auther et al., 2000; Ilvonen et al., 2003, 2004; Pettigrew

et al., 2005; Särkämö et al., 2009, 2010a,b; Wertz et al., 1998)– Velo-cardio-facial syndrome (Baker et al., 2005)


mastoid-recorded MMN (with nose reference) is unaffected in pa-tients with schizophrenia (Baldeweg et al., 2002, 2004; Sato et al.,1998, 2002), suggesting dampened involuntary attention switch-ing to auditory change and hence probably accounting forsome of their withdrawal (negative) symptoms, as proposed byNäätänen and Kähkönen (2009) (cf. Fig. 2). Consistent with this,Matthews et al. (2007) found that the MMN at fronto-central elec-trodes for change in the interaural time difference, one of the twomain cues for sound lateralisation, was attenuated in amplitude inpatients with schizophrenia. This result was attributed by theauthors to patients’ impaired ability to use temporal cues to soundlateralisation in natural settings, a deficit probably affecting,according to the authors, their ability to control the focus of atten-tion effectively. The dampened bottom-up attention-switchingfunction in schizophrenia patients might also contribute to theirgradual cognitive decline because of the resulting reduction of cog-nitive and social stimulation (cf. sensory deprivation) (Näätänenand Kähkönen, 2009). For further supportive MMN evidence, seeHermens et al. (2010).

A similar (but transient) dampening of involuntary attentionswitching can also be observed in acute alcohol intoxication(Jääskeläinen et al., 1995, 1996a,b, 1998, 1999b). Even a moderatedose of ethanol selectively weakened the frontal-MMN process,whereas the supratemporal MMN process (with most of it beingseparately observable in nose-referenced mastoid recordings)was unaffected (Jääskeläinen et al., 1996b) (Fig. 2). Furthermore,ethanol abolished the performance decrement caused by auditorydistraction in a visual task (Jääskeläinen et al., 1999b), i.e., damp-ened the effects of auditory distracting stimuli on brain mecha-nisms controlling for environment-driven involuntary attentionswitches in audition (Escera et al., 2000a; Escera and Corral,2007; Jääskeläinen et al., 1999b). This explains, in part, why alco-hol increases accident risk in traffic (cf. Näätänen and Summala,1976). In addition, the Alho et al. (1994) MMN data suggested de-creased involuntary attention switching to auditory changes as aconsequence of a frontal-lobe lesion (see Table 4).

Conversely, the frontal involuntary attention-switching mecha-nism may also become too sensitive, in this way disturbing pri-mary-task performance (Table 5). In patients with closed headinjury suffering from dramatically increased distractibility, thismechanism is abnormally sensitive, judging from their very largefrontally recorded MMN amplitudes at the presence of normalmastoid-recorded (nose-referenced) MMN amplitudes (Kaipioet al., 1999, 2000) (cf. Fig. 2). A subsequent study (Polo et al.,2002) did not confirm this finding, however, which might resultfrom the abnormally fast vigilance decrement of these patients(Kaipio et al., 2001).

Moreover, in children suffering from major depression, short-ened MMN latencies and increased P3a amplitudes (an index ofthe occurrence of an attention switch; Squires et al., 1975; Esceraet al., 2000a) might be associated with these patients’ increaseddistractibility and difficulties in concentrating on task perfor-mance, as shown by the Lepistö et al. (2004) MMN data for CV-syl-lable change. Analogous MMN evidence for increaseddistractibility was also obtained in chronic alcoholism (Ahveninenet al., 2000a,b) and ageing (Gaeta et al., 2001).

7. The MMN attenuation caused by cerebral grey-matter loss orother structural change (Table 6)

The MMN is also attenuated by structural damage in the centralauditory system and even elsewhere in the brain. In schizophreniapatients, a gradual loss of the left-hemisphere temporal grey-mat-ter volume has been observed, which was reflected by attenuatedMMN amplitudes for frequency change (Hirayasu et al., 1998).More recently, Salisbury et al. (2007) found, by using magnetic res-onance imaging (MRI), that at first hospitalisation, schizophreniapatients’ left Heschl-gyrus volume did not differ from that of bipo-lar-disorder patients and normal controls and, further, that thiswas reflected by similar MMN amplitudes for tone-frequencychange. However, in an 18-month follow-up, this volume was re-duced in schizophrenia patients only, and the magnitude of theHeschl’s gyrus volume reduction in these patients strongly corre-lated with the parallel attenuation of their MMN amplitude. Also,Yamasue et al. (2004) found that in schizophrenia patients, MMNmdeficiency for phoneme change in the left hemisphere correlatedwith the magnitude of the left planum-temporale grey-matter loss,suggesting that these structural abnormalities may underlie thefunctional abnormalities of fundamental language-related process-ing in these patients. In addition, very recently, Rasser et al. (2011)found that MMN-amplitude attenuation for frequency change inpatients with schizophrenia (reflecting their impaired day-to-dayfunctioning level) correlated with the magnitude of grey-matterloss in the left Heschl’s gyrus as well as in the motor and executive

Fig. 7. Post Hoc correlation analyses of reduced gray matter measures – averaged over specific gyri defined on the Deformed ‘‘Montreal Neurological Institute’’ brain template– with reduced frequency mismatch negativity (MMN) peak amplitudes recorded at fronto-central electrodes in control subjects (blue) and schizophrenia patients (Red).Solid regression lines indicate significant correlation (P < .05, uncorrected) (From Rasser et al., 2011).


Table 9The MMN can be used to on-line monitor the patient’s level-of-consciousness in:

– Anaesthesis: depth and recovery (Heinke et al., 2004; Heinke and Koelsch,2005; Koelsch et al., 2006; Yppärilä et al., 2002)

– Coma (Kane et al., 1993, 1996, 2000; Fischer and Luauté, 2005; Luauté et al.,2005; Morlet et al., 2000; Naccache et al., 2005)

– Persistent vegetative state (Kotchoubey, 2007; Kotchoubey, 2007; Wijnenet al., 2007)


regions of the frontal cortex while MMN reduction for durationdeviants also correlated with grey-matter loss in the right Heschl’sgyrus (Fig. 7).

It is possible that the MMN deficiency observed in schizophre-nia can be linked to grey-matter loss occurring in these patients.Olney and Farber (1995) suggested that N-methyl-D-aspartate(NMDA)-receptor (NMDAR) hypofunction accounts for structuralbrain changes in these patients. The data reviewed by the authorsshowed, among other things, that a repeated treatment with anNMDA antagonist during a 3- to 4-day period induces a patternof neurodegenerative changes distributed over several corticolim-bic brain regions. The authors concluded that these and other find-ings signify that the persistent suppression of the NMDAR functionlasting for a few days only can lead to relatively subtle but perma-nent structural changes that are distributed over the neocorticaland limbic brain regions in a pattern roughly similar to the patternof structural changes observed in schizophrenia (Bogerts, 1993).The fact that the MMN is an index of NMDAR dysfunction wouldthen explain the relationship between MMN deficiency and grey-matter loss (Salisbury et al., 2007; Rasser et al., 2011).

The MMN can also reflect structural changes (craniofacial mal-formations) associated with cleft palate (for a review, see Ceponi-ene et al., 2002). In children with cleft palate of 7–9 years of age, itwas found by Ceponiene et al. (1999) that the more posteriorlydelimited the cleft was, the smaller was the MMN amplitude fortone-frequency change and the more severe was the cognitivedefect.

8. The MMN as an index of pathological brain excitation/excitability (Table 7)

In some conditions, an increased MMN amplitude appears to in-dex pathologically increased central nervous system (CNS) or cen-tral-auditory-system excitation/excitability. For example, inabstinent chronic alcoholics, the MMN for frequency change wasabnormally enhanced in amplitude, which might be associatedwith their increased distractibility (Ahveninen et al., 2000a,b). Inaddition, in patients with persistent developmental stuttering,the MMN to phonetic contrasts was strongly enhanced in ampli-tude, whereas that to simple tone contrasts (both frequency andduration) was unaffected (Corbera et al., 2005). This might indexabnormal excitability located specifically in the speech-soundMMN generation region (Näätänen et al., 1997). This MMN findingcorrelated with the patients’ subjective appraisal of their speech-production problems. These results might indicate that properspeech production requires the presence of stable sensory refer-ence provided by the speech-sound-specific memory traces ofthe left temporal cortex (Näätänen, 2001; Näätänen et al., 1997;Shestakova et al., 2003).

In the same vein, an MMNm enhancement to tone-durationdecrement found by Pekkonen et al. (2004) in patients with ALSwith bulbar signs might result from cortical overactivity of excit-atory neurotransmitter glutamate observed in ALS (Rowland andShneider, 2001). Raggi et al. (2008), however, found MMN-ampli-tude decrement for frequency change in non-demented patientswith sporadic ALS.

Consistent with the Pekkonen et al. (2004) above-reviewed ALSresults, at late, symptomatic, stages of Huntington’s disease, theMMN to frequency change was considerably enhanced in ampli-tude, along with behavioural improvement in an auditory signal-detection task, compared to the control group and Huntingtonpatients in the early, presymptomatic, stage (Beste et al., 2008).This paradoxical effect, as contrasted to effects of neurodegenera-tive diseases in general, was attributed by the authors to toxic-le-vel overexcitability of the NMDAR system (due to increasedglutamate concentrations).

In addition, very importantly, Banati and Hickie (2009); (seealso Banati, 2003) found in patients in schizophrenic psychosis thatMMN deficiency for frequency and duration deviants indexedpathological microglia (the main constituent of the brain’s innateimmune system) activation, reflecting local ‘disease activity’ andneuronal death in these patients. The authors emphasised that thismicroglia activation is not a diagnostically specific pathologicalprocess but rather that this activation can serve as a generic mar-ker that relates more directly to disease progression and may becorrelated with other meaningful illness measures such as theMMN.

Pathological brain excitation, as suggested by increased MMNamplitudes, can also be found in temporal-lobe epilepsy (Miyajimaet al., 2011; Gene-Cos et al., 2005) even though MMN peak laten-cies may be prolonged, a possible sign of central-auditory-process-ing disturbance in these patients (Miyajima et al., 2011).

Pathological excitation might also explain some results in pa-tients suffering from post-traumatic stress disorder (PTSD), whoshowed considerably elevated MMN amplitudes for frequencychange (Morgan and Grillon, 1999; Ge et al., 2011), whereas Men-ning et al. (2008) could not confirm these results.

9. The MMN as an index of cognitive and functionaldeterioration (Table 8)

Baldeweg et al. (2004) found a relationship between the fron-tally recorded duration-increment MMN deficit and impairmentsin memory functions of patients with schizophrenia, which are evi-dent in these patients (Sullivan et al., 1995; Jahshan et al., 2010).Subsequently, Light and Braff (2005a) obtained a strong correlationbetween the global-assessment-of-functioning (GAF) ratings andthe fronto-central MMN amplitude for tone-duration prolongationin these patients. Furthermore, the MMN amplitude was highlypredictive of the patients’ level of independence in their domesticlife. This correlation was replicated in longitudinal studies 1–2 years later, indicating a stable relationship (Light and Braff,2005b). Subsequently, the relationship between the duration-increment MMN amplitude and patients’ functional status was alsofound by Kawakubo et al., 2007; social skills acquisition) and byToyomaki et al. (2008; executive functioning). (For corroboratingresults with the frequency-MMN amplitude, see Rasser et al.(2011).) Interestingly, this relationship for duration-incrementMMN amplitude is also present in normal healthy subjects (Lightet al., 2007). For previous analogous results with the frequency-MMN amplitude in normal healthy subjects, see Bazana and Stel-mack (2002) and Beauchamp and Stelmack (2006), and with theMMN amplitude for syllable change in children, Liu et al. (2007).For recent corroborating results, see Troche et al. (2009, 2010).

In a similar vein, Jung et al. (2006) found that the MMN-ampli-tude attenuation for duration decrement in patients with MS in-dexed cognitive decline occurring in part of these patients, beinglarger in magnitude for greater cognitive loss. For corroborating re-sults, see Gil et al., 1993) and Santos et al. (2006). Furthermore,MMN (MMNm) deficit indexes cognitive decline also in chronicalcoholism (Polo et al., 1999, 2003), stroke (Ilvonen et al., 2003;

Table 10The MMN can be used to monitor the patient’s state in:

– Stroke: recovery (Ilvonen et al., 2003; Särkämö et al., 2010a,)– Schizophrenia: illness progression (Banati and Hickie, 2009; Bodatsch et al.,

2011; Javitt et al., 2000; Oades et al., 2006; Oknina et al., 2005; Salisburyet al., 2007; Umbricht and Krljes, 2005; Umbricht et al., 2003, 2006) andtemporary recovery (Shinozaki et al., 2002)


Särkämö et al., 2009, 2010a,; Auther et al., 1998, 2000; Pettigrewet al., 2005; Wertz et al., 1998), epilepsy (Boatman et al., 2008; Lia-sis et al., 2006), velo-cardio-facial (DiGeorge) syndrome (Bakeret al., 2005), Down’s syndrome (Lalo et al., 2005), children withcertain forms of cleft palate and those with the Catch-22 syndrome(Ceponiene et al., 2002) and, of course, in Alzheimer’s disease(Pekkonen et al., 1994; vMMN: Tales and Butler, 2006; Taleset al., 2008), dementia (Schroeder et al., 1995), intellectual disabil-ity (Nakagawa et al., 2002; Ikeda et al., 2004) and mild cognitiveimpairment (MCI) (vMMN: Tales and Butler, 2006; Tales et al.,2008).

MMN-amplitude attenuation (at least for frequency change) canalso index cognitive and functional degeneration in patients withan advanced stage of diabetes mellitus (Vanhanen et al., 1996),Parkinson’s disease (Karayanidis et al., 1995; Pekkonen et al.,1995b; Brønnick et al., 2010), HIV (Schroeder et al., 1994) and alsoin normal ageing (Gaeta et al., 2001; Kisley et al., 2005; Cooperet al., 2006). In addition, the MMN amplitude indexes decreasedcognition in different subnormal states such as sleep deprivation(Raz et al., 2001), rapid eye movement (REM)-sleep deprivation(Zerouali et al., 2010) and in patients in the comatose (Fischeret al., 1999, 2006b) or PVS (Wijnen et al., 2007) state.

Recently, Bisiachi et al. (2009) found smaller-amplitude MMNresponses to tone-frequency change in newborns of less than 30gestational weeks than in those with a longer gestational period.This amplitude strongly correlated with several maturational fac-tors (gestational age, weight, length and cranial circumference).These results suggest, according to the authors, the role of the ges-tational age as the main factor explaining cortical functioning atthe early age.

10. The MMN as an index of the level of consciousness (Table 9)

In patients in the comatose state, no MMN can usually be re-corded unless a latent recovery process has started, leading tothe return of consciousness and cognitive capacities in the near fu-ture. Therefore, the MMN can be used as a tool in coma-outcomeprediction (Kane et al., 1993, 1996; Fischer et al., 1999, 2004,2006a,b; Luauté et al., 2005; Morlet et al., 2000; Fischer andLuauté, 2005; Daltrozzo et al., 2007; Vanhaudenhuyse et al.,2008). Moreover, the MMN peak latency measured at hospitalisa-tion of survivors of coma caused by a severe head injury predicted,to some extent, their expressive language ability and visuo-spatialperformance 1 year after the injury (Kane et al., 2000). Kotchoubey(2007) stressed that in using the MMN for the objective assessmentof the patient’s remaining cognitive capacity, it is better to usecomplex rather than simple sound stimuli which may result in se-vere underestimation of the remaining capacity. For a meta-analy-sis of studies on the MMN in coma, see Daltrozzo et al. (2007).Recently, it was concluded by Vanhaudenhuyse et al. (2008) thatMMN results in comatose patients converge to the conclusion thatMMN is a very good predictor of recovery from coma, in particularin anoxic coma.

In patients in the PVS, the frequency-MMN recovery occurred inparallel with the recovery of consciousness (Wijnen et al., 2007;Kotchoubey, 2007; Kotchoubey, 2007), showing a step-wise ampli-

tude increase when the patient crossed the boundary from uncon-sciousness to consciousness. In addition, in locked-in patients, thefrequency MMN can give evidence for the presence of at least somelevel of consciousness (Ragazzoni et al., 2000). Moreover, the MMNcan also index anaesthesia depth (for a review, see Heinke andKoelsch, 2005): a small-amplitude MMN was recorded to fre-quency change during deep sedation, whereas in complete uncon-sciousness, this MMN was absent. It, however, returned while thepatient was recovering from anaesthesia (Heinke et al., 2004).Interestingly, an MMN type of response was also elicited by mu-sic-syntactic violations in deep sedation (Heinke et al., 2004; Koe-lsch et al., 2006), indicating that this kind of complex analysisfollowing the rules of Western music can occur even in deepsedation.

Very recently, it was found by Boly et al. (2011) that in the veg-etative state, feed-forward processes are preserved whereas top-down processes are impaired. The effective connectivity wasmeasured by using the MMN for tones presented in a roving para-digm (Baldeweg et al., 2004). The authors found that the only dif-ference between patients in the vegetative state and controls wasan impairment of backward connectivity from frontal to temporalcortices, suggesting that a selective disruption of top-down pro-cesses from high levels of a cortical hierarchy can lead to loss ofconsciousness in brain-damaged patients, and can clearly differen-tiate the vegetative state from minimally conscious state. In addi-tion to its neuroscientific relevance, the present approach could,according to Boly et al. (2011), constitute a new diagnostic toolto quantify the level of consciousness electrophysiologically atthe patients’ bedside.

The MMN can also reflect effects of hypnosis (Jamieson et al.,2005; Kallio et al., 1999) and concentrative meditation (Srinivasanand Baijal, 2007).

11. The MMN as an index of the progression/severity of theillness (Table 10)

In patients with schizophrenia, the MMN amplitude in particu-lar to frequency change is attenuated concomitantly with diseaseprogression (for a meta-analysis, see Umbricht and Krljes, 2005).Consistent with this, several studies (Salisbury et al., 2002, 2007;Umbricht et al., 2006; Devrim-Ücok et al., 2008; Todd et al.,2008) showed that the frequency MMN deficit was more robustin chronic patients than in first-episode patients in whom the ef-fect was smaller in size or had not yet emerged. In addition, Shino-zaki et al. (2002) found that a temporary recovery of acutesymptoms of schizophrenia patients was accompanied by anMMN amplitude increase for tone-frequency change recorded atmastoids as polarity-reversed MMN (whereas the frontally re-corded MMN did not correlate with this temporary recovery). Inaddition, Urban et al. (2008), using the vMMN, found that thereduction of its amplitude for motion-direction deviants was largerfor a more severe state and longer duration of the illness of thepatient.

Moreover, MMN data also reflected clinical severity in patientswith persistent developmental stuttering (Corbera et al., 2005),dyslexia (Baldeweg et al., 1999; Stoodley et al., 2006), PTSD (Men-ning et al., 2008) and in newborns and 6-month-old infants withcleft palate (with clinical severity being determined as the ante-rior–posterior extent of the cleft; Ceponiene et al., 1999, 2000a,b,2002). In a similar vein, Moberget et al. (2008) found that patientsexhibiting the most severe symptoms of ataxia, a sign of cerebellarcortical atrophy, produced smaller-amplitude MMN responses totone-duration change than other patients.

Studying stroke patients, Särkämö et al. (2008, 2009, 2010a, ad-dressed amusia caused by a left or right middle cerebral artery

Table 11The MMN predicts:

– Recovery from coma (Daltrozzo et al., 2007; Fischer and Luauté, 2005;Fischer et al., 1999, 2002, 2004, 2006a,b; Morlet et al., 2000; Naccacheet al., 2005; Vanhaudenhuyse et al., 2008 (with the MMN being the bestpredictor of positive outcome, i.e., recovery without getting into thepersistent vegetative state: Fischer and Luauté, 2005; Luauté et al., 2005);for a meta analysis, see Daltrozzo et al., 2007)

– Recovery from the persistent vegetative state (Kotchoubey, 2007; Kotchoubeyet al., 2007; Wijnen et al., 2007 (with the MMN recorded at hospilizationalso predicting the level of consciousness at discharge and even the extentof cognitive recovery during the next 2 years; Wijnen et al., 2007))

– Recovery from locked-in state (Ragazzoni et al., 2000)– Recovery from alcoholism (Kathmann et al., 1995; Pekkonen et al., 1998)– Social-skills learning in schizophrenia Kawakubo et al., 2007)– Social cognition in schizophrenia (Wynn et al., 2010)– Schizophrenia (first-episode onset) risk (Bodatsch et al., 2011; Stone et al.,

2010)– Progression of schizophrenia (Bodatsch et al., 2011; Devrim-Ücok et al., 2008;

Kawakubo et al., 2007; Kiang et al., 2009; Light and Braff, 2005b; Salisburyet al., 2007; Umbricht and Krljes, 2005; Umbricht et al., 2006)

– Dyslexia (Blitz et al., 2007; Leppänen et al., 2010; van Leeuwen et al., 2006;Stoodley et al., 2006)

– Language development (Choudhury and Benasich, 2011; for a review, seeStix, 2011)

– Language development in prematurely born children (Jansson-Verkasalo et al.,2003b, 2004, 2010)

– Drug-therapy outcome in schizophrenia (Horton et al., 2010; Javitt et al.,2008; Lavoie et al., 2007; Schall et al., 1999)

– Working-memory performance decrement in chronic alcoholism (Ahveninenet al., 1999)

Fig. 8. Grand-average difference waves showing the duration mismatch negativityin the frontal (upper row) and central electrodes (lower row) for converting (dashedline) and nonconverting subjects (solid line). AR-C = at risk – coinversion, AR-NC = at risk – no conversion (From Bodatsch et al., 2011).

Table 12The MMN shows increased genetic risk of:

– Alcoholism (Rodriguez et al., 1998; Zhang et al., 2001)– Asperger syndrome (Jansson-Verkasalo et al., 2005; Korpilahti et al., 2007)– Dyslexia (Blitz et al., 2007; Friedrich et al., 2004; Leppänen et al., 2002,

2010; Leppänen and Lyytinen, 1997; Lyytinen et al., 2001, 2004, 2006;Maurer et al., 2009; Pihko et al., 1999; Richardson et al., 2003; vanLeeuwen et al., 2006)

– Language learning impairment (LLI) (Benasich et al., 2006; Choudhury andBenasich, 2011; Friedrich et al., 2004; Weber et al., 2005)

– Schizophrenia in children (Schreiber et al., 1992), adults (Ahveninen et al.,2006; Bodatsch et al., 2011; Brockhaus-Dumke et al., 2005; Hall et al.,2007, 2009; Jessen et al., 2001; Magno et al., 2008; Michie et al., 2002;Shin et al., 2009), and in Individuals with the CATCH syndrome (with ahigher risk in individuals carrying the COMT108/158Val than COMT108/

158Met allele) (Baker et al., 2005)– Specific language impairment (SLI) (Barry et al., 2008; Benasich and Tallal,

2002; Benasich et al., 2006; Friedrich et al., 2004; Weber et al., 2005)


stroke. They found that amusia caused by a right-hemisphere dam-age, especially that to temporal and frontal areas, was more severethan that caused by a left-hemisphere damage. Furthermore, inamusic right-hemisphere patients, the severity of amusia corre-lated with weaker frequency-MMNm responses. Additionally,within the right-hemisphere-damaged group, the amusic patientswho had damage in the auditory cortex showed worse recoveryfrom amusia as well as weaker MMNm responses throughout the6-month follow-up than did the non-amusic patients or the amusicpatients with no auditory-cortex damage. Also, the amusic patients(both with and without auditory-cortex damage) performed worsethan did the non-amusic patients on a number of tests of differentaspects of cognitive performance (including working memory,attention and cognitive flexibility). These findings suggested,according to the authors, domain-general cognitive deficits as theprimary mechanism underlying amusia without auditory-cortexdamage, whereas amusia with auditory-cortex damage is associ-ated with both auditory and cognitive deficits.

In conclusion, because of the large number of different disor-ders affecting the MMN, it appears that the MMN provides a gen-eric illness measure, useful for assessing illness severity, assuggested by Banati and Hickie (2009) for both the MMN andmicroglia activation.

12. The MMN in predicting illness course/drug response(prognosis) (Table 11)

A striking finding was that the recovery of the MMN in a coma-tose patient strongly predicted, as already mentioned, the recoveryof consciousness in the near future (Kane et al., 1993, 1996; Fischeret al., 2000, 2006a,b; see also Fischer et al., 2008; Luauté et al.,2005; Vanhaudenhuyse et al., 2008; for a meta-analysis, see Dal-trozzo et al., 2007). In addition, the MMN in patients in the PVS re-corded at hospitalisation predicted the magnitude of cognitiverecovery even 2 years ahead (Wijnen et al., 2007; see also Kotchou-bey, 2007; Kotchoubey et al., 2007).

Furthermore, in patients with schizophrenia, MMN data canpredict future developments of the patient’s state and the effi-ciency of different treatments. For example, Umbricht et al.(2006) found that MMN deficiency at illness onset may index thepresence of a more pervasive brain pathology and be observed onlyin a subgroup of patients, possibly in those with more precursors ofschizophrenia or with an elevated risk of developing chronicschizophrenia. In addition, Kawakubo et al. (2007) found that theMMN in patients with schizophrenia was predictive of the acquisi-tion of social skills during a 3-month social skills trainingprogramme.

Importantly, it was recently found by Lavoie et al. (2007) thatthe deficient MMN amplitude for frequency change in patientswith schizophrenia was corrected towards normal levels by a glu-tathione precursor, N-acetyl-cysteine (NAC), which improved theirNMDAR function, supporting the role of the NMDARs in MMNgeneration.

The MMN improvement was, however, found in the absence ofany robust changes in clinical-severity indices, even though theywere observed in a larger and more prolonged clinical study (La-voie et al., 2007; Berk et al., 2008a,b; for supporting evidence,

Table 13MMN indexes central-auditory-processing improvement in:

– Autistic patients (with frequency processing better than in Controls; Gomot et al., 2002)– Children with specific language impairment (SLI) receiving language and speech training (Pihko et al., 2007)– Cochlear-implant (CI) patients as a function of time since CI installation (Kraus et al., 1993b; Lonka et al., 2004; Ponton et al., 2000; Ponton and Eggermont, 2001) and

training (Ponton et al., 2009)– Dyslexic children presented with consonant–vowel syllables with lengthened formant-transition duration (Bradlow et al., 1999)– Dyslexic children receiving audio-visual rehabilitation (Kujala et al., 2001)– Early Child development, mainly speech-sound learning (Alho and Cheour-Luhtanen, 1997; Alho et al., 1990; Carral et al., 2005; Cheour et al., 1998b, 2002a,b; Cheour-

Luhtanen et al., 1996; Choudhury and Benasich, 2011; Draganova et al., 2005, 2007; Gomes et al., 2000; Gomot et al., 2000; Fellman and Huotilainen, 2006;Huotilainen et al. 2005, 2007; Kraus and Cheour, 2000; Kraus et al., 1992, 1993a, 1999; Kuhl, 2004; Kujala et al., 2004; Kushnerenko et al., 2002, 2007; Leppänenet al., 2004; Lovio et al., 2009; Lyytinen et al., 2001, 2006; Molholm et al., 2004; Novitski et al., 2007; Oades et al., 1996; Pang et al., 1998; Pihko et al., 2005; Tanakaet al., 2001; Trainor et al., 2001, 2003; Uwer and von Suchodoletz, 2000)

– Early-onset blindness (Kujala et al., 1995a,b, 2000b, 2005b; Alho et al., 1993)– Epileptic patients with vagus-nerve stimulation (Borghetti et al., 2007)– Infants operated for craniosynosthosis (Huotilainen et al., 2008)– Patients with hearing aids (Rudner et al., 2008)– Patients with ultrasound hearing aids (Hosoi et al., 1998)– Schizophrenic patients progressing from the Acute to Post-Acute Phase (Shinozaki et al., 2002)– Sleeping infants exposed to auditory discrimination training (Cheour et al., 2002a)– Stroke patients as a function of time since stroke onset (Ilvonen et al., 2003; Särkämö et al., 2010a,)– Stroke patients receiving music or audio-book stimulation (Särkämö et al., 2010a,)


see Coyle, 2006; Schwieler et al., 2008). Hence, an MMN enhance-ment may precede improvement in clinical severity, which,according to the authors, highlights the possible utility of theMMN as a biomarker of treatment efficacy, and, therefore, also asa tool in drug development (see also Javitt, 2007, 2009; Javittet al., 2008). Previously, in the Schall et al. (1999) study, theMMN predicted the outcome of clozapine therapy in patients withschizophrenia. Moreover, more recently, Horton et al. (2011) foundthat clozapine increased the MMN amplitude for tone-frequencychange, with increasing doses being associated with increasing fre-quency-MMN amplitudes (but attenuated that for tone-durationincrements and decrements).

Very recently, it was found by Bodatsch et al. (2011) that inindividuals with a high schizophrenia risk, the MMN for tone-dura-tion decrement (but not for tone-frequency change) was lower inamplitude (resembling that of first-episode patients) in those pa-tients who subsequently, during an observation period of 2 years,converted to the first-episode psychosis than that in those whodid not convert to psychosis during that period (Fig. 8). This resultwas remarkable as these groups were thought to share a similarclinical risk of psychosis at baseline. The authors proposed thatthe duration-MMN reduction in their converters might reflect bothstructural and neurochemical alterations associated with the con-version to psychosis. Furthermore, such results do not, according tothe authors, only contribute to the prediction of conversion andlead time to it but also contribute to a more individualised riskassessment and hence also to risk-adapted prevention. In addition,recently, Stone et al. (2010) found in subjects at risk of psychosis,an attenuated frontal-MMN amplitude for tone-duration incre-ment and, further, that this MMN deficit was related to reducedthalamic glutamate plus glutamine and NMDA levels.

Further, a phonological deficit in young elementary-school chil-dren, reflected by a reduced MMN amplitude to syllable change(but not that to simple frequency change), appeared to predicttheir dyslexia risk (Blitz et al., 2007). Also, in very prematurelyborn children, the MMN amplitude for consonant change at 4 yearsof age predicted, as already mentioned, naming performance at theage of 6 years (Jansson-Verkasalo et al., 2003b, 2004). Furthermore,Jansson-Verkasalo et al. (2010) found that the perceptual narrow-ing for non-native phoneme contrasts occurring in normal healthyinfants from 6 to 12 months of age (Kuhl et al., 1991; Kuhl, 2004),reflected by attenuated MMNs for non-native phoneme contrastsin these infants (Cheour et al., 1998b), does not occur in very pre-maturely born infants who showed large MMNs even for non-na-tive phoneme contrasts. This indicates that the ability to

discriminate non-native phonemes was preserved in prematurelyborn infants. Moreover, it was also found that the better this abilitywas preserved (reflected by larger MMN-amplitudes for non-na-tive contrasts) at the age of 1 year, the worse was the performancein native-language tests at the age of 2 years. Thus, decline in sen-sitivity to non-native phonemes, as reflected by MMN attenuationfor non-native phoneme contrasts, served as a positive predictorfor further age-appropriate language development.

Moreover, the Weber et al. (2005) MMN data showing a deficitof prosodic perception in 5-month-old infants suggested that theMMN might be taken as an early marker of SLI risk.

13. The MMN as an index of genetic disposition to differentpathologies (Table 12)

Some studies suggest that in schizophrenia there is a geneticcontribution to its aetiology. An MMN-amplitude attenuation forduration increment was found by Michie et al. (2002) and thatfor frequency change by Jessen et al. (2001) in symptom-freefirst-order relatives of patients with schizophrenia but studies withlarger samples have either not confirmed these findings (Bramonet al., 2004) or showed a trend only (Price et al., 2006). However,Hall et al. (2006) recently found a significant, although modest, ge-netic correlation between the duration-increment MMN-ampli-tude deficit and schizophrenia, and therefore suggested that theMMN is a potentially valid endophenotype in schizophrenia. Bycontrast, Ahveninen et al. (2006), using the MMN to tone-fre-quency changes in their study of twin pairs discordant for schizo-phrenia, obtained results suggesting, according to the authors, thatMMN abnormalities in patients with schizophrenia might reflectpredominantly state-dependent neurodegeneration. A similar con-clusion was made by Magno et al. (2008) on the basis of their dura-tion- and frequency-MMN amplitude results.

In patients with the 22q11 deletion syndrome, the considerablyincreased rates of schizophrenia are attributed to the loss of one al-lele containing the catechol-O-methyl transferase (COMT) gene.Symptom-free carriers showed attenuated MMN amplitudes forboth simple auditory (duration and frequency) and syllabicchanges as well as corresponding decrements in behavioural sounddiscrimination (Baker et al., 2005). Moreover, these MMN andbehavioural effects were stronger in subjects carrying the COMT108/158Met allele on their single intact chromosome (associatedwith a greater risk of schizophrenia) than in those carrying theCOMT 108/158Val allele (a smaller schizophrenia risk). The authors


concluded that because the MMN depends on the NMDAR function(Javitt et al., 1996), the MMN modification by the COMT Val 108/158Met polymorphism points towards abnormal dopamine–gluta-mate interactions in the MMN-generator system.

Furthermore, children with a parent or sibling with dyslexiahave an increased risk of dyslexia, and this is reflected by theirattenuated MMN amplitudes to simple frequency (Maurer et al.,2003) or duration changes (Friedrich et al., 2004; Leppänen et al.,2002) or to phoneme-category change (van Leeuwen et al.,2006). Similarly predictive were the lack of a left-hemisphereMMN response to speech-sound change (Maurer et al., 2003) andthe bilateral distribution of this MMN response (Maurer et al.,2009).

Also, studying 6-month-old infants with a family history of lan-guage-related learning difficulties, Benasich et al. (2006) foundthat these infants had smaller mismatch responses (MMRs; the po-sitive-polarity analogue of MMN; Maurer et al., 2003) than those ofcontrol infants with no such family history. In addition, as alreadymentioned, Barry et al. (2008) obtained MMN data suggesting thatparents of children with SLI have a shorter auditory sensory-mem-ory duration than that of control parents.

Very recently, a major breakthrough in the research of the ge-netic background of dyslexia was made by Roeske et al. (2011)who found that a certain marker (rs4234898), located on chromo-some 4q32.1, was associated with the MMN deficit for a CV-sylla-ble change. Moreover, this MMN was also associated with atwo-marker haplotype of rs4234898 and rs11100040, one of itsneighbouring single-nucleotide polymorphisms. The authors con-cluded that their results suggest a possible transregulation effecton SLC2A3, the predominant facilitative glucose transporter inneurons, which might lead to glucose deficits in dyslexic childrenand could explain their attenuated MMN in passive listening tasks,as observed in this study. Moreover, in a very recent study of thesame group, Czamara et al. (2011) obtained results pointing toan association between the late MMN for speech-sound changeand rare variants in a candidate region for dyslexia.

14. The MMN as an index of central auditory processingimprovement or recovery (Table 13)

Spontaneous and training-induced improvement. A number ofstudies in normal healthy subjects (Atienza and Cantero, 2001;Kraus et al., 1995; Gottselig et al., 2004; Menning et al., 2000;Tremblay et al., 1997, 1998; Näätänen et al., 1993; for a review,see Kujala and Näätänen, 2010) demonstrated that the MMN re-flects plastic neural changes associated with discrimination learn-ing. Therefore, it is a very attractive tool for following up recoveryand intervention effects in various patient groups, for instance, instroke, coma, PVS or cochlear-implant (CI) patients or in childrenwith developmental disorders.

In stroke and other brain-injured patients, it would be impor-tant to determine the changes in perceptual abilities very soonafter the damage. However, such patients are often unable to coop-erate or to understand instructions, particularly if the neural net-work involved in speech perception is affected. Aaltonen et al.(1993), in an early study, found that the MMN to speech-soundchange was abolished in posterior left-hemispheric stroke patients,whereas an anterior left-hemispheric stroke had no such effect. Bycontrast, the tone-frequency MMN was normal in both patientgroups. Subsequently, as already mentioned, Ilvonen et al. (2003)followed up the recovery of left-hemisphere stroke patients,recording the MMN at 4 and 10 days, and then at 3 and 6 monthsafter stroke onset. Language-comprehension tests (Boston Diag-nostic Aphasia Examination and Token tests) were also adminis-tered in all but the first session in which the patients could not

cooperate. The MMNs in the first two sessions were quite smallin amplitude for sound-duration and -frequency changes, but be-came larger thereafter, disclosing normal-like amplitudes at3 months post-stroke (Fig. 3). Furthermore, the duration-MMNamplitude increase correlated with the improvement in the BostonDiagnostic Aphasia Examination test scores from 10 days to3 months.

Subsequently, as already mentioned, it was found by Särkämöet al. (2010b) that the recovery of the MMNm and behavioural dis-crimination can be expedited with music and audio-book stimula-tion. Dividing their 60 middle cerebral artery stroke patients intomusic and audio-book listening and control groups, these authorsrecorded patients’ MMNm to frequency and duration changes ina binaurally delivered complex tone. (In addition, all patients re-ceived the normal hospital treatment and rehabilitation of strokepatients, of course.) It was found, as expected, that the MMNmamplitudes were, in general, smaller in the lesioned than oppositehemisphere. Importantly, the frequency-MMNm amplitude in-creased more in both music and audio-book groups than in thecontrol group during the 6-month post-stroke period. In addition,the duration-MMNm amplitude increased more in the audio-bookgroup than in the other groups. Moreover, the frequency-MMNmamplitude changes correlated with the behavioural improvementof verbal memory and focussed attention induced by music listen-ing. The authors interpreted their results as demonstrating that themere listening to music or speech starting soon post-stroke onsetcan induce long-term plastic changes in early sensory processing,as reflected by the MMNm enhancement, which, in turn, may facil-itate the recovery of higher cognitive functions. These remarkableresults encourage the use of music and speech stimulation in therehabilitation of stroke patients in particular in the early post-stroke period.

The deficit of the auditory/language system may be inborn, as isthe case in developmental dyslexia, SLI or in the autism spectrum.Because of the high prevalence of these disorders and their devas-tating effects on the individual’s academic success and therebyself-esteem, early identification and remediation methods shouldbe developed. Recent evidence fortunately shows that the aberrantneural substrate of language deficits can be ameliorated withappropriate intervention. For instance, Pihko et al. (2007) foundthat language-impaired children at the age of 5–6 years benefitedfrom language and speech exercises. Furthermore, this trainingalso changed the neural processing of speech sounds so that theMMNm for syllable changes became stronger in the lefthemisphere.

In dyslexic first-grade children, intervention, judging from anMMN-amplitude enhancement, induced neural plastic changesand ameliorated reading difficulties (Kujala et al., 2001). These 7-year-old school children were exposed to an audiovisual trainingprogramme with no linguistic items (Audilex Program; Karma,1999) for 7 weeks. Their reading skills as well as the MMN elicitedby tone-order reversals were assessed before and after this trainingperiod. After this period, the training group made fewer reading er-rors and tended to read faster than did the age-matched controlgroup of dyslexic children. Moreover, the MMN amplitude fortone-order reversals was increased in the training group but notin the control group. These results consequently showed that read-ing deficits can be ameliorated with audiovisual training and, fur-ther, that the improvement of reading skills is associated withplastic neural changes of the central auditory system as reflectedby the MMN enhancement. Furthermore, these positive trainingresults were obtained by using no linguistic stimuli, which sug-gests that impaired auditory-perceptual processes other than defi-cient phonology may also contribute to reading impairments.

Similar effects were also obtained with extremely low-birth-weight children of 6 years of age (Huotilainen et al., 2011). These


children were allocated to a 5-week training programme withAudilex (training group) or to a control group playing computergames. Before and after the intervention, auditory ERPs to soundchanges were recorded and reading-related skills were assessed.The MMN responses to frequency and duration deviants increasedin amplitude in the Audilex training group but not in the control-game group. However, the reading skills were similar in the twogroups after invention and 2 years later.

As already mentioned, the shortening of the abnormally longMMN-peak latency and the MMN-amplitude recovery in drug-resistant adult epilepsy patients after vagus-nerve stimulatorimplantation was recently found by Borghetti et al. (2007), sug-gesting a positive effect of vagus-nerve stimulation on centralauditory processing in these patients.

Drug-induced improvement. In Table 1, short-term effects of dif-ferent drugs are reviewed. In addition, in the foregoing, somefavourable drug effects in schizophrenia patients were alreadymentioned (NAC, Lavoie et al., 2007; clozapine, Schall et al.,1999; Horton et al., 2011). Moreover, very recently, Dulude et al.(2010) found that nicotine, relative to placebo, not only prolongedthe peak latency of the duration MMN but also increased its ampli-tude in patients to a level comparable with that seen in controls. Bycontrast, the frequency MMN was not affected. The authors con-cluded that these preliminary findings demonstrate that acute nic-otine can normalise temporal aspects of central auditoryprocessing in patients with schizophrenia, an effect that might bemediated by the activation of a7 nicotinic acetylcholine receptors,the functioning of which is diminished in schizophrenia. Theauthors further concluded that these ameliorating effects of nico-tine may have implications for understanding the increased tobac-co smoking in schizophrenic patients and for developing nicotinicpharmacotherapeutics to alleviate sensory-memory impairmentsin schizophrenia. In addition, a positive effect of nicotine in bothsmoking and non-smoking normal healthy subjects on temporal-interval processing (indexed by an MMN-amplitude enhancementto ISI deviants) was recently found by Martin et al. (2009).

Furthermore, very recently, it was found by Sawada et al. (2010)that in children of 7–13 years of age with attention deficit hyperac-tivity disorder (ADHD), the intake of osmotic-release methylpheni-date (MPH) increased the MMN amplitude for tone-frequencychange and simultaneously alleviated the severity of their ADHDsymptoms.

Central auditory discrimination and training in CI users. For pro-foundly deaf individuals, a sensation of hearing can be restoredby a CI. CIs are currently the most successful and widely used sen-sory neuroprotheses. In a large percentage of those individuals fit-ted with a CI, a remarkable degree of language communication viathe auditory domain is restored. Nevertheless, objective, non-behavioural measures of auditory discrimination such as theMMN remain a potentially powerful, but as yet under-utilised,application for this population.

The first MMN recordings from CI users were reported by Krauset al. (1993b) who employed speech-syllable contrasts. For thegroup of individuals investigated in that study, Kraus et al. foundthat the MMN elicited from CI users was remarkably similar to thatobtained from a group of normal-hearing listeners. These resultssuggested that despite the differences in peripheral input, the brainwas processing basic speech units in a very similar fashion.

Ponton et al. (2000; see also Ponton and Don, 1995, 2003; Pon-ton and Eggermont, 2007), recording the MMN evoked by a singlecontrast in stimulus duration from groups of normal-hearingadults and adult CI users, also found that MMNs of the two groupswere quite similar. In a more detailed study in which subjects wereseparated into groups based on benefit gained by using a CI, Groe-nen et al. (1996) reported that whereas the group classified as goodperformers showed an MMN, poor performers failed to generate a

comparable response. Furthermore, Kelly et al. (2005) reported asimilar failure to obtain the MMN from CI users defined as poorperformers. In addition, Lonka et al. (2004), in longitudinally track-ing the changes in the language function after a small group of deafadults received a CI, reported that while the MMN was absent forapproximately 12 months post-surgery, the response subsequentlyemerged, first for a large vowel contrast, and then later for moresubtle vowel distinctions. Converging behavioural improvementin a speech-discrimination test was also observed during the fol-low-up period.

Trautwein et al. (1998) and Ponton et al. (2000), who assessedthe CI users with non-speech stimuli, obtained results that relateback to both speech performance and training. First, Trautweinet al. (1998) found that while psychophysical thresholds weresuperior to MMN-estimated discrimination thresholds for durationcontrasts in the control group, the opposite was found for a groupof adult CI users. Thus, in several individuals, there was neuro-physiological evidence of discrimination based on the MMN, with-out the individual being able to behaviourally perceive thedifference. Based on the apparent separation of discrimination atthe level of sensation versus perception, Ponton et al. (2009) devel-oped a protocol based on pre-training MMN evaluation to deter-mine whether there was neurophysiological evidence ofdiscrimination in the absence of perceptual discrimination. Thisknowledge was then used to develop a training protocol which re-sulted in significant improvements in frequency discrimination aswell as combined consonant and vowel discrimination in a singlehighly trained adult implant user.

As noted by Roman et al. (2005), there is a clear application ofthe MMN in clinical testing and training of CI populations. How-ever, refinements are needed in methods and recording technique,to optimise the protocols for frequency discrimination and speechtesting.

Recently, music perception of CI users was also studied by usingthe MMN. Koelsch et al. (2004) found that CI users can perceivetimbre, judging from the MMN elicited by timbre deviants in them(the timbre MMN: Tervaniemi et al., 1997; Toiviainen et al., 1998).Moreover, music-syntactic violations elicited an early right ante-rior negativity which might be interpreted as a music-syntacticMMN in CI users, which again was considerably smaller in ampli-tude than that in controls but nevertheless showed that CI users’central neural mechanisms underlying music perception are acti-vated by musical stimulation (even though they reported that theyhad difficulties in discriminating musical information and thatthey were in general frustrated by their inability to accurately hearmusic). Consistent with this, subsequently, Sandmann et al. (2010),by using the multi-feature MMN paradigm with six different levelsof the magnitude of deviation for each feature (Pakarinen et al.,2007) (Fig. 1) found that CI users had difficulties in discriminatingsmall changes in the acoustic properties of musical sounds. It wasconcluded by Sandmann et al. (2010) that this type of paradigmcould be of substantial clinical value by providing a comprehensiveprofile of the extent of restored hearing in CI users. Moreover, aninverse relationship was found between the MMN amplitude andthe duration of profound deafness; however, there was also evi-dence for experience-related plastic changes as a function of theduration of CI use (Sandmann et al., 2010).

Ultrasonic hearing. Some profoundly deaf individuals can per-ceive ultrasound only, which occurs by bone conduction. Hosoiet al. (1998) found that in normal healthy subjects, ultrasoundmodulated by different speech sounds produces discriminablestimuli, which points to the possibility of developing ultrasonichearing aids as an alternative for CIs for those profoundly deaf indi-viduals who can sense ultrasound only. Hosoi and colleagues deliv-ered ultrasound to the right sterno-cleidomastoid through aceramic vibrator. Substantial N1m responses were elicited by both


audible air-conducted sound stimuli and bone-conducted ultra-sonic stimuli. Further, when the (40 kHz) ultrasound stimuli mod-ulated by vowels/i/ and/a/ were presented as standards anddeviants, respectively, substantial MMNm responses were ob-served for deviants, indicating that the two sounds were discrimi-nable. Moreover, the equivalent current dipole (ECD) for theMMNm was located within the auditory cortex, in the vicinity ofthe MMNm observed in a separate condition with the respectiveair-conducted stimuli. The authors also tested 53 profoundly deafindividuals behaviourally and found that 28 of them could detectultrasonic stimuli and, further, that 11 of them could discriminateultrasounds modulated by different speech signals. These resultsprovide, according to the authors, the rationale for developingultrasound hearing aids, which do not require surgery, for thoseprofoundly deaf who can sense ultrasound.

Improved discrimination in early blind individuals. A special caseof enhanced central auditory function of compensatory naturecan be encountered in early blinds. The MMN elicited by sound-location changes was larger in amplitude in early-blind individualsthan in sighted control subjects (Kujala et al., 1995a). (The MMNwas recorded while subjects’ attention was directed to the tactilemodality.) This suggests enhanced spatial auditory perceptionand discrimination in the blind. The result is consistent withbehavioural data showing that the blind are more accurate thanthe sighted in detecting loci of origin of sounds (Lessard et al.,1998; Röder et al., 1999). The scalp topography of MMN responseof Kujala et al., 1995a) did not differ between the two groups, how-ever. It, therefore, behaved differently from the N2b (Näätänenet al., 1982; for a review, see Näätänen and Gaillard, 1983) re-sponse elicited by auditory targets in an active discrimination con-dition, which had a scalp topography in the blind that wasposterior to that in the sighted (Kujala et al., 1992, 1995a,b). Thus,the MMN appears to be hard-wired in the central auditory systemof the blind, reflecting plastic changes within the auditory cortex,whereas the generators of the N2b, associated with attentionalprocesses in audition, may become part of the neural system nor-mally subserving vision. This was supported by imaging studiessuggesting occipital activity in the blind during auditory change-detection tasks (Kujala et al., 1995b, 2007, 2000b, 2005b).

15. Concluding discussion

This article has shown that central auditory processing, as in-dexed by the MMN and the MMNm, is affected in a wide rangeof different clinical conditions and in ageing. Most of these effectsare seen as indexing decreased auditory discrimination accuracy.In some cases, however, the duration of auditory short-term sen-sory memory, essential, for instance, in speech perception andunderstanding, is affected. This further decreases automatic dis-crimination when SOAs are prolonged. Moreover, these data alsoshow effects on mechanisms controlling for involuntary shifts ofattention (passive attention) or on those determining the charac-teristics of backward masking in different patient groups.

Consequently, this article has shown that the MMN provides aunique window to the neuropsychology of central auditory pro-cessing, and hence a possibility for the objective assessment ofauditory discrimination and sensory memory, in different patientgroups, which previously could be mainly inferred from behav-ioural performance only. This is a major improvement, in particularwhen considering the special communicational and motivationalproblems with patients, deducting from the reliability of the re-sults, and the fact that reliable behavioural measurements arenot at all possible in some clinical groups and often in small in-fants. These new possibilities in particular involve the improvedmonitoring of the patient’s state and the prediction of its future

development, for example, the prediction of coma or PVS outcomeand even that of the extent of the cognitive recovery of these pa-tients (during the next 2 years; Wijnen et al., 2007), or the moni-toring of, and predicting, the progress of schizophrenia.Moreover, importantly, very recent results of Bodatsch et al.(2011) showed that the duration MMN can predict, in individualsin schizophrenia-risk group, conversion to first-episode schizo-phrenia and even when this would occur in the period of 2 years.In addition, another recent study (Banati and Hickie, 2009) sug-gested that the duration and frequency MMNs might enable oneto online monitor local disease activity and neuronal death in pa-tients with schizophrenia.

Furthermore, in case of schizophrenia (see Lavoie et al., 2007;Horton et al., 2011; Javitt et al., 2008; Banati and Hickie, 2009;see also Berk et al., 2008a,b), and perhaps of other severe neuro-psychiatric, neurological and neurodevelopmental disorders, too,the MMN can be used as an online index of treatment efficacy.As far as dyslexia is concerned, such a use of the MMN in assessingthe effectiveness of different rehabilitation programmes is alreadywell established (Kujala et al., 2001). In addition, in the foregoing,we reviewed results of Särkämö et al. (2010a) demonstrating howthe MMNm can be used in evaluating the effectiveness of differentauditory stimulus material in an attempt at facilitating strokerecovery.

Some further clinically important uses of MMN data are, amongother things, the possibility to determine the dyslexia risk in new-borns and infants (Maurer et al., 2003; Leppänen et al., 2002; vanLeeuwen et al., 2006; Friedrich et al., 2004), the magnitude of cog-nitive and functional deficit associated with different clinical con-ditions (Näätänen et al., 2011a) and the degree of severity ofdifferent conditions (in Schizophrenia: Umbricht et al., 2006; Dev-rim-Ücok et al., 2008; Todd et al., 2008; Light and Braff, 2005a,b;Salisbury et al., 2002, 2007; Stuttering: Corbera et al., 2005; PTSD:Menning et al., 2008; Cleft Palate: Ceponiene et al., 1999, 2000,2002; Stroke and Aphasia: Ilvonen et al., 2003; Pettigrew et al.,2005; Särkämö et al., 2010b; Dyslexia: Baldeweg et al., 1999; Kuj-ala et al., 2001).

One might wonder why auditory discrimination is affected insuch a large number of different clinical conditions (Table 1),which indeed points to a possible common pathology shared bythese different conditions. A major part of this common pathologyappears to be found in the deficient functioning of the NMDAR sys-tem, as there is very strong evidence indicating that MMN defi-ciency reflects deficient NMDAR functioning (Javitt et al., 1996;Näätänen et al., 2011a). For example, sub-anaesthetic doses of ket-amine, an NMDAR antagonist, attenuated the MMN amplitude ofhealthy volunteers (Kreitschmann-Andermahr et al., 2001:MMNm; Umbricht et al., 2000, 2002), monkey (Javitt et al.,1996), rat (Tikhonravov et al., 2008, 2010) and mouse (Ehrlichmanet al., 2008), and caused schizophrenic kinds of psychotic experi-ences in normal subjects (Umbricht et al., 2000, 2002; see alsoSauer and Volz, 2000; Pang and Fowler, 1999). Furthermore, keta-mine disturbed the performance in a memory task in normal sub-jects in a manner similar to that normally observed inschizophrenia, as shown by Umbricht et al. (2000). Importantly,it was found by Umbricht et al. (2002) that the smaller was thesubject’s MMN amplitude for frequency and duration changes be-fore ketamine administration, the stronger were the psychoticexperiences caused by the drug. Therefore, the authors concludedthat the MMN in the normal state of consciousness indexes thevulnerability to disruption of the NMDAR system in normal healthysubjects. Consequently, the MMN appears to index the functionalstate of the NMDAR-mediated neurotransmission even in subjectsdemonstrating no psychopathology and may therefore ‘‘become auseful tool in studies on NMDAR functioning in humans’’ (Umb-richt et al., 2002).


Consequently, the MMN attenuation observed in a large num-ber of different clinical populations and conditions (Table 1) can,to a large extent, be accounted for by NMDAR dysfunction associ-ated with different clinical conditions. For instance, as already re-viewed, the dysfunction of the NMDAR system plays a centralrole in the brain pathology of schizophrenia and in particular inthe cognitive deficit in these patients (Javitt et al., 1996; Coyle,2006). Moreover, the cognitive decline occurring in several otherneurocognitive abnormalities might also be accounted for, at leastin part, by the dysfunctional NMDAR system (Näätänen et al.,2011a). Alzheimer’s disease, stroke, traumatic brain injury andeven normal ageing are accompanied by widespread dysfunctionsin the NMDAR system (Lipton and Rosenberg, 1994; Magnussonet al., 2010; Biegon et al., 2004; Dalkara et al., 1996; Izquidero,1991; McGeer and McGeer, 2010). For example, Dhawan et al.(2010) recently found that middle central artery occlusion in ratresulted in widespread decreases in NMDAR density in brain re-gions extending far beyond the infarct area, including even regionscontralateral to the lesion important to cognitive function. Dhawanet al. (2010), therefore, concluded that a persistent and widespreadloss of NMDARs may contribute to cognitive and other neurologicaldeficits in stroke patients, which cannot be localised to the side ofinfarction.

Importantly, this NMDAR functional deficiency may hence ac-count for, besides decreased discrimination accuracy, even the cog-nitive and functional decline occurring in a number of theseconditions (Table 8) (for a review, see Näätänen et al., 2011a). Itis, for instance, well established that the adequate functioning ofthe NMDAR system plays a crucial role in the initiation of long-term and working memories (Javitt et al., 1996; Newcomer et al.,1998). Therefore, the MMN and MMNm deficiency reflecting a defi-cient NMDAR function can also index cognition and its decrementin ageing and in different neurological and neuropsychiatric abnor-malities (Näätänen et al., 2011a). Consequently, as an easily acces-sible non-invasive measure of the functional condition of theNMDAR system, the MMN (MMNm) might play an important rolein future attempts at understanding what is common in the differ-ent neuropsychiatric diseases and abnormalities and what is spe-cific to each of them (Umbricht et al., 2003). These conclusionsare further supported by studies showing that pharmacologicalmanipulations enhancing cognition also enhance the MMN(MMNm) response (Baldeweg et al., 2006; Dunbar et al., 2007;Inami et al., 2005; Fisher et al., 2010; Harkrider and Hedrick,2005; Engeland et al., 2002; Knott et al., 2006, 2009) and vice versa(Pang and Fowler, 1999; Nakagome et al., 1998; Serra et al., 1996;Jääskeläinen et al., 1996a), and, further, that the MMN-cognitionrelationship holds even in normal adults (Light et al., 2007; Bazanaand Stelmack, 2002; Beauchamp and Stelmack, 2007; Troche et al.,2009, 2010) and children (Liu et al., 2007).

Optimising MMN protocols for clinical environments. Perhaps themost frequent issues associated with use of the MMN in clinicalenvironments are time required to record enough data to obtainan identifiable response and the expertise required to identifywhen a response is present or absent. By definition, the traditionalMMN protocol is very time consuming to obtain informationregarding even a single stimulus contrast. In a standard paradigm,the standard stimulus is presented 80–90% of the time, with devi-ant stimulus presentations, which evoke the MMN, randomlyinterspersed through the sequence. The introduction of the multi-ple-deviant paradigm for tones (Näätänen et al., 2004; Pakarinenet al., 2007, 2010; Fisher et al., 2011; Grimm et al., 2008; Jankowiakand Berti, 2007; see also Vaz Pato et al., 2002; Deacon et al., 1998)and for speech (Pettigrew et al., 2004b; Pakarinen et al., 2009;Sorokin et al., 2010; Lovio et al., 2009) and music (Vuust et al.,2011) provided a method for rapidly acquiring information on anumber of stimulus contrasts. This approach considerably in-

creases the amount of information that can be gathered within aspecific time period. Equally as important are methods that wouldfurther reduce the amount of time required to acquire sufficientdata that reach some objective criteria of identification.

One such approach has recently been described by Rahne et al.(2008). In this modification to standard averaging, individualepochs to stimulus presentation are sorted on the signal-to-noiseratio (SNR) to each individual epoch. This epoch with the highestSNR, that is, the lowest background noise, is added first to average.Individual epochs are then added to the average in rank orderbased on the background noise in each epoch. Thus, averaging iscontinued until the SNR is optimised. Objective or statistical detec-tion of these responses could then easily be achieved by using oneof a number of online algorithms involving randomisation or boot-strapping analyses such as those proposed by, for example, Pontonet al. (1997) or Fujioka et al. (2005). Moreover, further progress tothis end has been very recently made by Cong et al., 2009, 2010,2011); Burger et al. (2007); Kalyakin et al. (2007, 2008a,b, 2009)and Marco-Pallares et al. (2005).

Needless to say, a lot of work is still needed to bring the MMNmethodology to clinics as a tool of everyday patient work in whichreliable measurements have to be carried out at the level ofindividual patients (Bishop and McArthur, 2004; Boly et al.,2011; Taylor and Baldeweg, 2002; Lang et al., 1995), but studiesas those reviewed in the foregoing have shown that this goal isboth valuable and probably also attainable.

Acknowledgements

RN and KK were supported by Grant # 8332 from the EstonianScience Foundation. TK was supported by Grant # 128840 and RNby grant # 122745 from The Academy of Finland. CE was supportedby grants from ICREA Academia 2010 and CSD2007-00012,EUI2009-04806, PSI2009-08063, and SGR2009-11. We wish toacknowledge Ms. Piiu Lehmus’ skilful and patient text-editingwork.

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