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Brain Topogr (2014) 27:500–526

DOI 10.1007/s10548-013-0337-3


The Mechanisms and Meaning of the Mismatch Negativity
Yonatan I. Fishman

Received: 12 July 2013 / Accepted: 15 November 2013 / Published online: 26 November 2013 
Springer Science+Business Media New York 2013

Abstract The mismatch negativity (MMN) is a pre- cortex with potential implications for the debate. We
attentive auditory event-related potential (ERP) component conclude that the mechanisms and meaning of the MMN
that is elicited by a change in a repetitive acoustic pattern. are still unresolved and offer remarks on how to make
It is obtained by subtracting responses evoked by frequent progress on these important issues.
‘standard’ sounds from responses evoked by infrequent
‘deviant’ sounds that differ from the standards along some Keywords Auditory cortex  Adaptation  Sensory
acoustic dimension, e.g., frequency, intensity, or duration, memory  Predictive coding  N1  MMN  Event-
or abstract feature. The MMN has been attributed to neural related potentials (ERPs)  Multiunit activity (MUA) 
generators within the temporal and frontal lobes. The Current source density (CSD)  Monkey
mechanisms and meaning of the MMN continue to be
debated. Two dominant explanations for the MMN have
been proposed. According to the ‘‘neural adaptation’’ Introduction
hypothesis, repeated presentation of the standards results in
adapted (i.e., attenuated) responses of feature-selective The ability to rapidly and automatically detect changes in
neurons in auditory cortex. Rare deviant sounds activate an otherwise uniform environment is an important adaptive
neurons that are less adapted than those stimulated by the trait that is essential to survival for many organisms. For
frequent standard sounds, and thus elicit a larger ‘obliga- example, an animal living in the forest must be able to
tory’ response, which yields the MMN following the sub- distinguish a relatively constant background of sounds,
traction procedure. In contrast, according to the ‘‘sensory such as that of leaves blowing in the wind, from a sudden
memory’’ hypothesis, the MMN is a ‘novel’ (non-obliga- ‘novel’ sound, such as that of a cracking branch, which
tory) ERP component that reflects a deviation between may indicate the presence of a lurking predator. In humans,
properties of an incoming sound and those of a neural this auditory change-detection ability is thought to be
‘memory trace’ established by the preceding standard reflected by a distinct brain response called the mismatch
sounds. Here, we provide a selective review of studies negativity (MMN)—a middle-to-long-latency auditory
which are relevant to the controversy between proponents event-related potential/magnetic field (ERP/ERMF) com-
of these two interpretations of the MMN. We also present ponent that is elicited by an infrequent change in a repet-
preliminary neurophysiological data from monkey auditory itive series of sounds (Naatanen and Alho 1995a).
The MMN is typically investigated using an oddball
This is one of several papers published together in Brain Topography
paradigm in which infrequently occurring sounds (‘deviants’
in the ‘‘Special Issue: Mismatch Negativity’’. or ‘oddballs’) are randomly interspersed among frequent,
homogeneous sounds (‘standards’) that differ from the
Y. I. Fishman (&) deviants along some acoustic dimension, e.g., frequency,
Departments of Neurology and Neuroscience, Albert Einstein
intensity, or duration. The MMN is most prominently
College of Medicine, Kennedy Center, Room 322/915D,
1410 Pelham Parkway, Bronx, NY 10461, USA revealed in the difference-waveform obtained by subtracting
e-mail: responses to the standards from responses to the deviants.


Brain Topogr (2014) 27:500–526 501

The MMN appears in the ERP scalp distribution (using a of a violation of auditory patterns is considered ‘automatic’
nose reference) as a fronto-central negativity with a latency or ‘pre-attentive’, as the MMN can be elicited even when
of 100–200 ms. It has been attributed to neural generators subjects are ignoring the stimuli. Nonetheless, the ampli-
within auditory cortex, including primary auditory cortex tude of the MMN can be modulated by attention (Naatanen
(A1), located along the superior temporal gyrus (Hari et al. et al. 1993; Alain and Woods 1997; Woldorff et al. 1998;
1984; Giard et al. 1990; Naatanen and Alho 1995b; Alho Arnott and Alain 2002; Haenschel et al. 2005; see Sussman
et al. 1998; Molholm et al. 2005). Neural activity in the 2007 for a discussion of the effects of attention on the
frontal cortex may also contribute to the MMN (e.g., Giard MMN in the context of auditory scene analysis). Impor-
et al. 1990; Jemel et al. 2002; Opitz et al. 2002; Doeller et al. tantly, the MMN is thought to reflect activity in a popu-
2003; Molholm et al. 2005; Lappe et al. 2013) and be lation of neurons that is both anatomically and functionally
associated with involuntary switching of attention triggered distinct from that giving rise to the ‘obligatory’ N1 com-
by changes in the acoustic environment (Giard et al. 1990; ponent of the ERP/ERMF (Sams et al. 1991; Tiitinen et al.
Naatanen and Alho 1995b; Molholm et al. 2005). 1993; Korzyukov et al. 1999; Rosburg 2003), which is
The MMN has been studied extensively in humans; elicited by both ‘standard’ and ‘deviant’ sounds at a latency
indeed, a basic search of the scientific literature on the of about 100 ms and originates from multiple auditory
MMN returns well over 1,500 articles. Moreover, the cortical regions along the superior temporal plane,
MMN has been used as a promising diagnostic tool in including Heschl’s gyrus, the locus of primary auditory
clinical research on various brain disorders, such as cortex in humans (e.g., Vaughan and Ritter 1970; Wood
schizophrenia (e.g., Javitt 2000; Naatanen and Escera and Wolpaw 1982; Scherg and von Cramon 1985; Naata-
2000; for a recent review, see Naatanen et al. 2012). nen and Picton 1987; Liegeois-Chauvel et al. 1994; Fish-
Remarkably, however, the neural mechanisms and specific man et al. 2001a, b; Yvert et al. 2005; Brugge et al. 2008).
brain regions contributing to its generation remain unre- In contrast, according to the neural adaptation hypoth-
solved and continue to be actively debated. Two main esis, the MMN, as represented by the difference between
hypotheses have been proposed concerning the neural standard and deviant responses, does not reflect a higher-
mechanisms and meaning of the MMN. The first has been level comparison process or change-detection per se, but
variously referred to as the ‘‘sensory memory’’/‘‘predictive rather neural adaptation to the repeating standard sounds.
coding’’/‘‘regularity violation’’ hypothesis (except where Specifically, repeated presentation of the standards results
they are explicitly distinguished, these terms will be used in attenuated (‘adapted’) responses of feature-selective
interchangeably in this review). The second has been neurons in auditory cortex that are tuned to properties of
referred to as the ‘‘neural adaptation’’ hypothesis. the repeating sounds. Response attenuation is thought to be
According to the sensory memory hypothesis (Naatanen due primarily to mechanisms of synaptic depression and
and Alho 1995a; Naatanen et al. 2005), the MMN reflects lateral inhibition (May et al. 1999; May and Tiitinen 2010).
the outcome of a comparison process whereby features of Rare deviant sounds activate different populations of neu-
incoming sounds are compared with a neural ‘memory rons from those stimulated by the more frequent standard
trace’ established by prior exposure to a series of sounds sounds, owing to their differential tuning to properties of
(standards) that exhibit some form of perceptual regularity. the standards and deviants. As they are stimulated less
Incoming sounds which violate this regularity (deviants) frequently than neurons tuned to the standards, neurons
elicit an MMN, which indexes the brain’s detection of a tuned to the deviants (‘‘fresh afferents’’) are less adapted
‘mismatch’ between properties of the deviants and those of than those stimulated by the standards. Deviant sounds thus
the standards. A related interpretation of the MMN is the elicit larger responses than those elicited by standards.
‘‘predictive coding’’ hypothesis (e.g., Friston 2005; Win- Subtraction of the ERP/ERMF elicited by standards from
kler 2007; Garrido et al. 2009), according to which the that elicited by deviants yields a prominent negative
brain extracts the regularities in a sequence of sounds and component at a latency of 100–200 ms which matches the
forms a model or hypothesis regarding the ‘rule’ underly- classic MMN. Importantly, as the MMN is simply the
ing the regularity. Based on this rule, the brain generates a result of changes in the relative amplitude and latency of
prediction concerning what the next sound in the sequence the N1 response to standards and deviants, there is no
should be. When properties of the incoming sound fail to separate population of neurons, or distinct neural circuit,
agree with the prediction, a prediction ‘‘error’’ is registered. generating the MMN component; indeed, there is no dis-
According to the predictive coding framework, the MMN tinct MMN ‘‘component’’ apart from the N1 (May and
represents a prediction error signal indicating a violation of Tiitinen 2010). Thus, the MMN may simply reflect a
the hypothesized auditory pattern by the unexpected audi- ‘‘release from stimulus-specific adaptation’’ (SSA), rather
tory stimulus (see Winkler and Czigler 2012 for a recent than the detection of a violation of an auditory pattern (i.e.,
review). Under both of these interpretations, the detection ‘‘genuine’’ change or deviance detection).


if the MMN results from a output of a process which compares features of new sen. in fact. Details regarding animal According to May and Tiitinen (2010). Naatanen et al. here we provide a selective trasted by considering the example of a sound presented in (though representative) overview of studies supporting the isolation. sound cortex which have potential implications for the debate when it is presented as a deviant in an oddball context (and between proponents of the two competing models. In addition to highlighting several key studies which the features of the isolated sound can be compared. accordingly.g. Thus. We which yields the MMN following subtraction of the conclude with an assessment of where the debate currently response to the standard sounds). the onset of auditory stimuli. the sensory memory and neural adaptation acoustic pattern established by prior auditory stimulation. one would sory input with a neural representation of previously predict a larger/different response to deviant stimuli when encountered sounds (i.g. there are no prior ‘standard’ sounds adaptation and sensory memory/predictive coding models and hence there is no ‘sensory memory trace’ relative to of the MMN. 1 in May and Tiitinen 2010 for a helpful schematic describing and contrasting the two models of MMN). 2007. that bolster both the adaptation and the sensory memory/ lation (to which the auditory system would be minimally predictive coding hypotheses. Materials and Methods The question as to which of these two models is correct is crucial given the clinical significance attributed to the Neurophysiological data were obtained from two adult MMN. or it simply reflects the differential the same inter-stimulus intervals (May et al. we describe findings which have emerged in put. dimensional current source density (CSD). 2005.. N1) which can be elicited also reflect average local field potentials (LFPs) time-locked to by ‘standard’ sounds.. regard to clarifying the mechanisms and meaning of the efforts have been made in MMN research to exclude MMN. AEPs obligatory responses (e. surgery. The intracortical 123 . if adaptation were the underlying the years since the publication of their influential review mechanism. given the effort invested accredited Animal Institute of Albert Einstein College of in MMN research and the clinical utility of the MMN. they are presented in an oddball context than when they are tor’ neurons which detect a change in the pattern of audi. tation model. On the other hand. interpretations of the MMN are mutually exclusive (though This implies that they should remain inactive when the both mechanisms might still operate in the brain simulta. Elan. use of non-human primates. 2001.. deviant sound is presented as a standard or as a rare sound neously). MUA reflects the envelope of sumably responsible for generating the MMN should only spiking activity of local neural populations. Elangovan et al. erature (e. see Fig. These models can be con. and multiunit alent response component) reflects activity of neural pop. Bendixen et al. the activity of special ‘compara. two key training. 2012. 2005) and thereby reveal a ‘‘genuine’’ sensory 2009. govan et al. Jacobsen and Schro. All experimental dysfunction (Walker et al. 3). and (2) the neural populations pre. both conceptually and be activated by deviant sounds that violate the regular mechanistically.. e. the presented alone. Pa- memory-based MMN response (e. avilainen 2013.e. 2005). 1999. the two models of stands and with remarks on how progress can be made with the MMN are fundamentally different and. the response to a rare sound presented in iso. and equivalently rare. Guided by these two criteria.g. comparator neurons would produce no out. procedures were reviewed and approved by the AAALAC- As May and Tiitinen (2010) put it... We also present preliminary adapted) would resemble—or even markedly exceed—the neurophysiological data recorded from monkey auditory response elicited by the same. at least in part. activity (MUA) can be found in Fishman and Steinschne- ulations that are distinct from those contributing to ider (2012) and in the author’s previous publications. Discussion of other relevant work not mentioned potential ‘contamination’ of ERPs/ERMFs by neural here can be found in numerous reviews of the MMN lit- adaptation or refractory effects (Walker et al. of rare and frequent sounds. cited by May and Tiitinen (2010) in support of the adap- Consequently. May and Tiitinen 2010. ger 2001) (See Fig. 150-micron associated with certain forms of central nervous system inter-contact spacing. 2001.g. presented alone (without intervening standards present) at tory stimulation). one- the following: (1) the MMN (or some functionally-equiv. For instance. mechanism responding exclusively to change. May adaptation of neurons that are selectively tuned to features and Tiitinen 2010). Inc. In this case. Winkler and Czigler 2012). Garrido et al.502 Brain Topogr (2014) 27:500–526 It is important to note that. A lack of clarity as to whether the MMN reflects male macaque monkeys (Macaca fascicularis) and recor- ‘‘genuine’’ change detection or neural adaptation can lead ded using multi-contact electrodes consisting of 16 con- to erroneous interpretations of MMN waveform alterations tacts arranged in a linear fashion (Plexon. tional and federal guidelines governing the experimental measuring. and neurophysiological recordings of requirements of the sensory memory interpretation include intracortical auditory evoked potentials (AEPs). Medicine and were conducted in accordance with institu- it would be important to know what one is. Either the MMN reflects.

[Similarly. Schroeder et al. (EEG). Elangovan et al. Thus. The amplitude of middle-/long-latency responses to recording electrodes into A1. deviants. Rosburg et al. The MUA inhibition rather than a higher-level sensory memory-based recorded at each contact helps to distinguish these possi. Experiments in Human Subjects 2001. 1999. for a similar result. rating both adaptation and lateral inhibition. 1998). pure tone frequency tuning bandwidths. 2001). Indeed. response onset latencies. Thus. circuit-completing currents owing to differences in the amplitude and latency of the N1 associated with depolarizing synaptic potentials occurring elicited by the differentially adapted and inhibited at adjacent sites. (2004) examined whether differential cortical All recordings were performed under passive listening responses to standard and deviant tones in frequency conditions with the animals awake and comfortably seated oddball sequences reflected ‘‘genuine’’ deviance detection in custom-fitted primate chairs. the CSD profile is inherently responses to standards and deviants.. whereas current sources that are In a widely cited study using electroencephalography coincident with MUA reductions likely represent net syn. As of this writing. see Korzyukov et al. 1991. hence. Budd et al. Jaaske- et al. the MMN may ambiguous as to whether current sources and sinks reflect simply reflect lower-level mechanisms of SSA and lateral excitatory or inhibitory post-synaptic currents. comparison process indicative of ‘‘genuine’’ deviance bilities: current sinks that are coincident with MUA detection or ‘‘primitive intelligence’’ in the brain (Naatanen increases likely represent net synaptic depolarization of the et al. thus precluding the establishment of a ments. presented in the context of standard sounds (the inter- deviant stimulus onset asynchrony (SOA) being the Evidence for the ‘Adaptation’ Hypothesis same in both conditions. Their main findings were as from the animal’s head and 60-degrees from midline. Conversely. Current sinks occurring at a given electrode contact indi. owing to differential degrees of adaptation of posterior Campbell and Neuvonen 2007. and functional aptic hyperpolarization (for further discussion see Javitt magnetic resonance imaging (fMRI) in humans. 1998. MUA and CSD laminar elicited by deviants that were preceded by two to four response profiles. 1999. 123 .g. 2010). current sources indicate they concluded that the most parsimonious explanation for outward current flow associated with hyperpolarizing the MMN is that it is effectively a ‘subtraction artifact’ synaptic potentials or passive. Sams et al. 1999. circuit-completing currents responses to standards from the less-adapted responses to associated with hyperpolarizing synaptic potentials occur. (1999) and May and Tiitinen (2010) demonstrated how the cate net inward current flow associated with depolarizing classic MMN could arise by subtracting the more-adapted synaptic potentials or passive. Walker et al. Data obtained from the other deviants presented alone (with standards silenced) was animal have been histologically confirmed to originate equal to or greater than that of responses to deviants from A1 (see Fishman and Steinschneider 2012 for details). Other 1. difference-waveform component was greater than that However. Rosburg et al. one of the animals from even when deviants were preceded by a single which data were obtained is still participating in experi- standard. Auditory stimuli were processes or could be more simply explained by differ- delivered at 60 dB SPL from a speaker located 1 m away ences in neuronal adaptation. the amplitude of this non-primary auditory cortical fields) is not yet available. 1994. magnetoencephalography (MEG). and tonotopic gradients are all consistent with placement of 2.Brain Topogr (2014) 27:500–526 503 CSD profile characterizes the laminar pattern of net paradigms with predictions of neural simulations incorpo- transmembrane current flow that gives rise to the LFPs. May et al. lainen et al. 2005). Korzyukov the adaptation hypothesis.g. for distinct neuronal processes underlying the N1 and May and Tiitinen (2010) presented a compelling case for MMN components (e.. It is well-known that the N1 et al. and anterior sources of the N1 component in auditory Comparing actual MEG responses elicited in oddball cortex along the superior temporal plane. histological confirmation that neural sensory memory trace derived from a repetitive series responses originate from A1 (rather than from adjacent of identical sounds. Modeling of MEG data suggested that the apparent Is the MMN Due to N1 Adaptation? differences in N1 and MMN anatomical source locations—which have been interpreted as evidence In an extensive and critical examination of the literature. Pincze et al. 3. standards. Based on their analysis of the available literature ring at adjacent sites. 2006. May et al. 2001)—could be explained by component declines in amplitude with repeated auditory alterations in the ‘center of gravity’ of activation stimulation (e. follows: contralateral to the recorded brain hemisphere. local neuronal population. A robust negative-going difference-waveform compo- details regarding stimulus parameters are included in the nent consistent with the classic MMN was elicited figure captions.

these findings suggest that the MMN standards in the oddball condition). Recanzone et al. fMRI signal increases in the oddball conditions did not and deviant clicks. Con- changes in the latency and amplitude of the N1 component. As another example.. However. Contrary to the sensory memory interpretation of the Several more recent results are consistent with the con- MMN. the authors included a ‘many standards’ significantly exceed the sum of activations elicited by control condition in which clicks with seven different the standard and deviant sounds when they were intensities of 10. compared to when they were standards. Thus. responses to the repeating standards and the less-adapted could be similarly explained by the differential adaptation responses to the infrequently presented deviants. 1/7 ants in an oddball context and those elicited by probability). versely. rather than reflecting sensory memory or tory N1 component. based explanation for differences in responses to standard 4.g. 2000. these findings ical limitations of non-invasive EEG and MEG recordings constitute evidence against the sensory memory hypothesis. 5. 2005. (2004). Jaaskelainen et al. rather of neurons that are selectively tuned to those sound features than by the operation of a sensory memory-based com- (e.504 Brain Topogr (2014) 27:500–526 May et al. elicited by the repetitive standard sounds. the differences observed between detection per se. To rule out a refractoriness. deviants in an oddball context relative to the latency of more importantly. 50. explained by adaptation or lateral inhibition of deviant that were not also elicited by standards). and periodicity. intensity. their comparatively poor spatial resolution).. failed to find components in the latency responses to deviants presented alone could be well- range of the MMN that were uniquely elicited by deviants (i. 40. the delay in responses to with the N1s elicited by standard and deviant stimuli and. the was no statistically significant difference between respon- MMN simply reflects adaptation-related suppression and ses to deviants in the oddball condition and responses to the delay of N1 responses of neural populations that are tuned same stimuli presented in the ‘many standards’ control to acoustic features of the standards rather than change- condition. Lozano-Soldevilla et al.. they were presented in a context of equally probable varying-intensity stimuli (unlike the constant-intensity Taken together. (1999) found no difference between inferred at a higher intensity (50 dB SL. He et al. morphology and inferred intracerebral sources of responses applying independent component and model-based clustering to deviant stimuli in oddball paradigms compared with those analyses to scalp-recorded ERPs elicited by tones in an odd- of ‘obligatory’ responses to the same stimuli presented in ball paradigm. however. randomly presented. deviant clicks presented at a lower intensity (40 dB SL. hypothesis. they were not percep- arises through stimulus-specific adaptation of N1 activity tually recognizable as deviants. Specifically. Consistent with the MMN. 1997. Bendor and parison process. and thus provide further to provide evidence for anything ‘special’ with regard to the support for the adaptation model of the MMN. 6/7 probability) and source locations of MEG responses elicited by devi. see also May and Tiitinen 2010). Wang 2010. which proposes that the MMN is generated by in line with the arguments of May and Tiitinen (2010). Watkins and Barbour 2011a). Thus. the aforementioned studies have consistently failed clusions of Jaaskelainen et al. The authors inter- responses produced by the preceding standard stimuli preted their findings as lending support to the adaptation (Elangovan et al. ‘deviants alone’ and ‘many ference between independent component clusters associated standards’ conditions). (in particular. Moreover. Consistent with the MEG results. (2012) found no dif- non-oddball contexts (e. For instance. (2011) examined Thus. insofar as the sensory memory hypothesis presumes a However. the scalp-recorded MMN may the modulation of the amplitude and latency of the N1 com- simply be a ‘subtraction artifact’ owing to SSA-related ponent recorded at the scalp (May and Tiitinen 2010). one might expect that a response component middle-latency auditory evoked potentials elicited by reflecting ‘‘genuine’’ deviance detection (assuming it oddball sequences comprised of standard clicks presented 123 .g. the MMN is simply due to change-detection processes. 30. 20. Althen et al. these neural mechanisms similar to those associated with the audi- studies suggest that.or adaptation- deviants presented alone]. (2004) further specu- responses to deviants and standards in the oddball condi- lated that the MMN elicited by changes in other stimulus tion could be most parsimoniously explained by SSA of parameters. such as duration. each with a probability of 1/7. Thus. because contexts. 60 or 70 dB SL were presented in isolation. the fMRI data failed the control condition included clicks presented at the same to reveal additional change-specific activations beyond intensity and with the same probability as deviants in the those elicited by sounds presented in non-oddball oddball condition (50 and 40 dB SL).e. rather than being softer clicks elicited larger middle-latency responses generated by distinct neuronal populations in auditory (negative-going ERP deflections) when they were deviants cortex that are involved in change or ‘novelty’ detection. contrary to the sensory memory hypothesis. perhaps the inability to detect a unique neural fundamental distinction between neural processes contribut- signature of deviance detection is due to the methodolog- ing to the N1 and the MMN (as noted earlier). there Thus.

and intracranially-recorded ERPs strongly to loud deviants than to loud standards. suggesting major condition and in a ‘many standards’ control condition. sources along the superior temporal plane. These find. Farley et al. no ERP components were identified which were paradigms involving a change in tone frequency. Edwards et al.e. they recorded responses to deviants presented role of standards.g. (2010) recorded neural components. Farley uniquely elicited by deviants in the oddball context and and colleagues tested oddball paradigms involving a which are not also elicited by deviants presented alone. Under the control con- larger than those elicited by standards. in better dition (also used in earlier studies of MMN in humans: agreement with the adaptation hypothesis. 1991. several additional results cast alone at the same inter-deviant SOA as in the oddball doubt on the sensory memory interpretation of these dif- condition (i. no violation of a putative sensory memory trace can reliable differences between responses to deviants in the be detected. Umbricht et al. these studies to oddball sequences comprised of standard and deviant report larger neural responses to auditory stimuli when they tones differing in frequency (15 % deviant probability). anterior background of repeating standards relative to which a electrodes displayed roughly equal N1 responses to devi. 2009. 2010 for further details). change in sound intensity and duration. However. but did not fail to fulfill May and Tiitinen’s (2010) key requirements of respond more strongly to soft deviants than to soft stan- the sensory memory interpretation of the MMN. In contrast. Fishman and electrophysiological responses from the left frontal and Steinschneider 2012).e. Ulanovsky et al. 1994. however there is no by deviants in the oddball context. The investigators found that responses to tones oddball and non-oddball contexts were noted.Brain Topogr (2014) 27:500–526 505 exists) would be more readily observed in ERPs recorded Anderson et al. Consistent with both the sensory temporal cortex of 5 neurosurgical patients as they listened memory and adaptation models of the MMN. As the context are less adapted. the attenuated responses to the larger than responses to deviants in the oddball context. which the authors referred to as N1s. No other hence. inverted responses in A1 of awake rats to tones in both an oddball in polarity across the Sylvian fissure. Responses elicited in the intensity and are also better explained by adaptation of neural popula. In addition to oddball Moreover. 2010. 1996. dards (see Farley et al. Farley et al. Consistent with wherein the same tones presented as deviants in the oddball both the sensory memory and adaptation interpretations of condition were presented against a background of many the MMN. Thus. thalamus. with standard tones silenced). 2009. 2009. Jacobsen and Schroger 2001). conse.g. 2000). The most ferential responses and instead suggest that they can be prominent ERP components recorded from temporal lobe more simply explained by SSA. these findings suggest that neural 123 . et al. ants alone and deviants in the oddball context. NMDA receptor animal models at various levels of the auditory pathway. administration of NMDA Neural responses to classic oddball sequences used to elicit receptor antagonists suppressed standard and deviant the MMN in humans have been examined in a variety of responses to a roughly equal extent. However. frequently occurring standards). deviants. and therefore larger. as examined in Intracranial ERPs recorded in epileptic patients by Rosburg previous MMN studies in humans (e. antagonists did not affect the magnitude of SSA. it example. 2003. Taken together. as defined including the brainstem. than larger responses to deviants in the oddball condition could responses to standards.. and primary auditory by the difference between responses to standards and cortex (e. in all 5 patients N1s elicited by deviants were ‘standards’ of varying frequency. Malmierca et al. they found that A1 neurons responded more appears that both extra. infrequent. Sams et al... (2005) in response to frequent and infrequent tones Rosburg 2003). the differential responses in an oddball context (with standards present).. responses to deviants presented be ‘mimicked’ by the responses to the same. In play the role of deviants compared to when they play the addition. Moreover. For sensory memory-based comparison process. Javitt 2000. Javitt et al. electrodes occurred at a latency of about 100 ms. deviants alone at posterior electrodes along the superior tones are presented with the same low-probability as that of temporal gyrus were significantly larger than those elicited deviants in the oddball condition. N1s elicited by Schroger and Wolff 1996. duration oddball paradigms were again fully consistent tions tuned to the frequent tones than by the emergence of a with SSA and showed no evidence for the operation of new MMN-like component reflecting the outcome of a ‘‘genuine’’ deviance detection mechanisms in A1. given tone is perceptually distinguishable as a deviant. von der via intracranial electrodes.. Thus. contrary to the reported effects of N-methyl-D-aspartate Experiments in Animal Models (NMDA) receptor antagonists on the MMN (e. to standards and deviants in the oddball condition could be quently.g. elicited in the control condition were comparable to the ings can be easily accounted for by the adaptation enhanced responses elicited by the same tones when they hypothesis: obligatory responses to deviants in the oddball played the role of deviants in the oddball condition. responses to deviants alone will be equal to or fully explained by SSA (i. These For instance. (2005) recorded Behrens et al. alone are less adapted than responses to deviants presented tones under the control condition.

(1994.g. On the other hand. 1994). At first glance. responses to deviants range of the MMN in humans. it is well established that auditory cortex rat is not a suitable animal model for studying neural contains neurons that are non-monotonically tuned to par- mechanisms of change detection. Accordingly. Second. that adaptation did not play a significant present in A1 of awake rats. see von der Behrens et al. responses to ensemble responses (MUA and CSD) simultaneously deviants in the oddball context could be ‘mimicked’ by across cortical layers. Taaseh et al. importantly. cautious in drawing this conclusion.g. affected. Finally. may be generated in areas nation for the results cannot be ruled out for the following outside of A1. The failure to find clear evidence for sensory memory. fascicularis) using oddball sequences comprised generally smaller than responses to deviants when pre. such as forward sup. long. auditory cortex. but that ‘obligatory’ components that are evident also in responses the auditory N1 component did not. of loud and soft clicks suggested the existence of genuine sented alone at similar inter-stimulus intervals and were not deviance detection mechanisms in A1 (Javitt et al. role in the generation of the MMN. enhanced CSD components elicited by deviants may have been processed differently in the oddball and had latencies (100–150 ms) which overlapped the time ‘many standards’ conditions. they were deviants compared to when they were standards. if they indeed exist. indicating greater net extracellular dition. condition. Thus. 2009).g. deviant versus standard clicks (Javitt et al. 1992. whereas the N1 elicited by standards should be less frequency channels. 1994. Recording elicited by intensity deviants may reflect the differential AEPs elicited in a passive oddball paradigm from epidural adaptation of neural populations tuned to the louder and electrodes implanted over auditory cortex in awake cats.g. First. Using multi-contact electrodes to record neural in the ‘many standards’ condition.506 Brain Topogr (2014) 27:500–526 responses reflecting sensory memory processes. which only considered adaptation within narrow ants). as neural populations selectively tuned to the cal grounds the presence of ‘‘genuine’’ deviance detection standards should be adapted to a roughly similar extent in rat auditory cortex. Pincze et al. this conclusion was based on ably A1) of anesthetized rats to deviant tones presented in a measurements of the amplitude of the N1 elicited by frequency oddball paradigm were comparable to those standards rather than that elicited by deviants. Thus. Thus. are not and. ERPs recorded from epi- appeared to lack the characteristics needed to fulfill May dural electrodes in the same species also showed larger and Tiitinen’s (2010) criteria for demonstrating genuine negativities in the MMN latency range in response to deviance detection in the brain. as putatively reflected by ticular sound intensities (e. Recanzone et al. but rather enhanced deviant probability (which ranged from 2 to 10 %). this elicited by standards. These findings suggested on theoreti. neural correlate of ‘‘genuine’’ deviance detection in cat (2011) showed that responses in auditory cortex (presum. Thus. qualitatively different from those elicited by the same tones 1996). Taaseh and colleagues found as the N1 elicited by deviants should increase with that responses to deviants in the oddball condition were decreasing deviant probability (owing to reduced adapta- larger than those predicted by computational models of tion of neural populations selectively tuned to the devi- SSA. were not considered in these insofar as they demonstrate the operation of genuine sen- theoretical models.. Javitt et al. Earlier electrophysiological studies in non-human pri- responses to deviants presented in the oddball context were mates (M. On the other hand. 2000. While these findings are consistent with the sensory based responses in the aforementioned studies suggests that memory interpretation of the MMN. Hence. 1996) observed responses to the same tones in the ‘many standards’ con. softer sounds (e. the MMN in humans. ‘many standards’ condition remains unclear. deviant probability. the larger responses species might yield more promising results. an SSA-based expla- such signals. in response to loud and soft clicks when responded to the tones when they were presented as stan. First. these elicited by the same tones in a ‘many standards’ control findings might still be explained by SSA of N1 responses. responses to deviants in the oddball context transmembrane current flow. it is also possible that the reasons. commonly MMN and the N1 (which nonetheless overlapped in time) assumed to be represented by the MMN in humans. the larger current sinks elicited latency range) systematically increased with decreasing by deviants are not novel components. these findings remain inconclusive Bartlett and Wang 2005). predominantly in supragran- were elicited in essentially the same neural populations that ular layers of A1. Brosch and Schreiner 1997.. There are several reasons to remain across deviant probabilities (e. and their potential influence in the sory-memory based processes in cat auditory cortex. However. it should also be noted that result suggests a clear functional dissociation between the despite differences in extracellular current flow elicited by 123 . Watkins and Barbour 2011b). however... the amplitude of the N1 elicited by deviants varies with pression and facilitation (e. larger current sinks. studies utilizing other Watkins and Barbour 2011a). dards and as ‘deviants alone’. in the absence of information regarding how range spectral interactions in A1. Finally. Second. (2002) reported that the amplitude of the unlike the putatively distinct MMN component recorded MMN (deviant minus standard AEPs in the 40–80 ms noninvasively in humans. (2010). while deviant sounds Moreover. thereby revealing a Similar to the results of Farley et al.

Negative voltages are mechanisms contributing to the MMN recorded in humans. 1). such as ‘deviants alone’ or ‘many the MMN. plotted up. ERPs However. and P2 components. 1). and tone duration was nents (see Fig. and P2 compo. enhanced N1 and P2 components and distinct MMN and P3a components. An important lesson to take away from this example. and scalp topography in the two species. 2001) were observed in both human and monkey subjects (Fig. Umbricht et al. suggesting that they originate from similar neural generators and reflect homologous brain processes. 2013). but also together (soft and loud deviant responses were compared to that of ‘obligatory’ ERP components. It is these considerations. Figure modified from Gil-da-Costa et al. in part. consistent earlier in relation to the results of Farley et al. but also in the curves. inter-stimulus interval was 700 ms. ERPs elicited by standards and deviants (for the same are labeled. Javitt 2000).Brain Topogr (2014) 27:500–526 507 standards and deviants. Gil-da-Costa et al. The ‘obligatory’ P1. The shaded areas indicate the time windows during which control conditions. Difference waves (deviant ERPs minus standard ERPs) are represented by the thick black curves. worth noting that. the inherent ambiguity of current sources and sinks in the CSD profile with regard to whether they represent current flow associ- ated with excitatory or inhibitory post-synaptic potentials (see ‘‘Materials and Methods’’). was standards’. ERPs were potentially ideal animal model for elucidating neural recorded from a central scalp electrode (Cz). was 20 %. Thus. 2010. deviants elicited larger ERPs than standards elicited by standards and deviants are represented by the blue and red not only in the latency range of the MMN. respectively. in addition to the MMN.. Moreover. 123 .and P3a-like ERP components (the latter thought to reflect novelty detection and orienting of attention. With the aim of developing a in the deviant response and the difficulty in differentiating between pharmacological non-human primate model of schizo. (2013). Moreover. Gil-da-Costa and col. it appears that their effects on the scalp-recorded ERPs. Javitt et al. these components were comparable in morphology. and motivated by evidence suggesting that dys. N1. N1. The similarity between the scalp-recorded MMN and P3a in monkeys and humans supports the value of macaques as a Fig. In a recent study examining potential homologs of the human MMN in non-human primates. no significant differences in con- currently recorded MUA were reported by Javitt et al. as the study did not include 100 ms. as identified by the author. (2013) recorded ERPs from the scalp of both humans and macaque monkeys while they passively listened to tones presented in an intensity oddball paradigm.g. 2000). For reasons mentioned ketamine were not specific to the MMN or P3a. (1994). respectively. Finally. Deviant probability latency range of the ‘obligatory’ P1. This dissociation may reflect. the findings of Gil-da-Costa et al. Ketamine not the responses elicited by soft and loud sounds were pooled only reduced the amplitude of the MMN and P3a. 2000). as identified by the investigators. Friedman et al. latency. 1 Grand average ERPs elicited by standard and deviant tones in humans and monkeys (data from Gil-da-Costa et al. copyright Proceedings of the National Academy of Sciences function in NMDA receptor neurotransmission contributes (Color figure online) to the pathophysiology of the disorder (e. Note the enhancement of all three obligatory components reasons discussed above). MMN. The vertical dotted line indicates stimulus onset. 1999. phrenia. is that prominent differences between ERP or CSD components evoked by standard and deviant stimuli do not necessarily imply differences in neuronal firing at the location of the intracranial generators of scalp-recorded ERPs. Javitt and Zukin 1991. these obligatory leagues administered sub-anesthetic doses of the NMDA components are also reduced in schizophrenic patients receptor antagonist ketamine to the monkeys and examined (Shelley et al. especially as it relates to the interpretation of noninvasively recorded ERPs. potential explanation for the differences observed between and the MMN and P3a components. with results of previous studies in monkeys showing that combining responses to soft and loud stimuli may lead to NMDA receptor antagonists also reduce the amplitude of different conclusions from those obtained if responses to the P1 and N1 components of auditory ERPs recorded from soft versus loud stimuli are analyzed separately. Given epidural electrodes (Javitt 2000. as defined and quantified by the investigators. the effects of soft and loud standard responses). the data are unable to exclude adaptation as a statistically significant in the human and monkey subjects.

wherein tones used as devi. or duration). On the other hand.. Gil-da-Costa by Javitt et al. 1992). Furthermore. (2010) and intracortical for understanding the neural bases of the scalp-recorded neural population recording methods similar to those used MMN in humans (Javitt et al. 2008). Fishman and Steinschneider et al. However. Accordingly. fre- sensory memory-based interpretation of the human MMN. (2010) and suggest that differential responses in demonstrate (or at least aim to show) that the MMN is not monkey A1 to standard and deviant tones in a frequency merely a manifestation of adaptation or other ‘lower-level’ oddball paradigm reflect SSA (the reduced response to the neural processes. memory/predictive coding interpretation of the MMN. Unlike in the oddball which may be species-specific or may originate from brain paradigm. intensity. elicited by both oddball and appropriate control stimuli. 2005). and to the extent that intracortical AEPs (2012) examined whether evidence for ‘‘genuine’’ deviance elicited by oddball sequences in monkey A1 within the detection processes consistent with the sensory memory latency range of the human MMN are modulated by SSA interpretation of the MMN could be found in A1 of awake (Fishman and Steinschneider 2012) and are volume- monkeys. 1990.g. 2007. (1994. N1. be explained by such lower-level mecha- likely reside in cortical areas outside of A1. enhancement of ‘obligatory’ middle. Hari et al. (2011). et al. these results stimulus paradigm designed to control for neuronal adap- indicate that responses in monkey A1 to deviants presented tation and thereby to reveal an MMN component reflecting in a classic frequency oddball paradigm fail to fulfill May ‘‘genuine’’ sensory memory-based processing in the brain and Tiitinen’s (2010) criteria for demonstrating true devi.. condition (Fig. Hypothesis ing ‘‘error’’ signals. we will consider several studies which et al. but rather reflects sophisticated ‘cogni- repeating standards) rather than deviance or novelty tive’ operations of the auditory system that are sensitive to detection per se. and induced high-gamma band responses least indirectly) a contribution of SSA to the MMN across cortical layers were larger when elicited by deviant recorded from the scalp in humans.508 Brain Topogr (2014) 27:500–526 (2013) do not provide unequivocal support for a sensory A1 in several human studies (e. 1992. MUA. (e. 2013). 1975. these studies provide support for the sensory agreement with the findings of human MMN studies dis. P2) rather than the introduction of ‘novel’ components potentially Evidence for the ‘Sensory Memory’/‘Predictive Coding’ reflecting deviance-detection processes or predictive cod. Giard memory-based interpretation of the MMN.g. wherein the conclude that there is presently no clear evidence for stimulus playing the role of the deviant in the oddball ‘‘genuine’’ deviance detection or predictive coding signals paradigm is presented as one among many equi-probable in the animal models studied thus far. assuming that they exist. responses in the ‘many standards’ control condition. Maess et al. Additional recordings tones than by standard tones of the same frequency. in fact. Of course.. cannot.g. the stimuli that differ from each other along the auditory fea- findings of these studies do not necessarily count against a ture differentiating the standard and the deviant (e. However. Fishman and violations of patterns and abstract regularities in the Steinschneider concluded that neural mechanisms of acoustic environment. in nisms. ance detection in the brain. These results parallel those of Farley in this section. 3). insofar as their results ‘‘genuine’’ deviance detection.and longer-latency however. et al. 2). these findings do support (at ponents. 1996). cussed earlier and with the results of Taaseh et al. (1994. Based on these findings. Finally. cortical responses elicited by standard tones (including putative monkey homologs of the human P1. of ERPs from the scalp and dural surface in macaques. Using frequency oddball and control sequences similar insofar as the macaque is considered a good animal model to those tested by Farley et al. Molholm et al. This paradigm is similar to the ‘many Based on the studies reviewed in this section. are 1996) larger deviant responses were characterized by the needed in order to more firmly establish this conclusion. earlier and later AEP and CSD com. responses to deviants when presented in an Several non-invasive ERP studies in humans have used a oddball context (Fig. we may standards’ control condition discussed earlier. Horvath et al. 1994. quency. were similar niously explained by the well-established neural mecha- to the larger deviant responses elicited under the oddball nisms of neural adaptation and lateral inhibition. Taken together. The studies reviewed in the previous sections suggest that ants in the oddball condition were interspersed among many aspects of the MMN phenomenon can be parsimo- many ‘standard’ tones of variable frequency. Jacobsen and Schroger 2001. in the control paradigm the ‘deviant’ stimulus is regions outside of A1-notwithstanding its localization to presented against a changing background of ‘standard’ 123 . In agreement with both sensory memory and conducted to fronto-central regions of the scalp (Arezzo SSA interpretations. responses in monkey A1 to deviants presented alone (with Experiments in Human Subjects standards silenced) are larger than. similar to the findings of Javitt et al. Javitt et al. 1984. though not qualitatively different from.

2007. copyright Journal shown in the top and bottom plots. The extent of (BF) tones in the oddball and ‘many standards’ control conditions gray shading above and below the curves indicates ± SEM. Stimulus duration points displaying statistically significant differences (p \ . there would be going ERPs elicited by deviants in the oddball paradigm in greater adaptation of deviant responses by the repeating the latency range of the MMN are delayed relative to the 123 . In par- response to the deviant in the oddball paradigm should be ticular. responses to Responses to the BF tone in the ‘many standards’ control condition deviants are comparable in amplitude and morphology to those are plotted in blue. Maess et al.Brain Topogr (2014) 27:500–526 509 Fig. Fishman and Steinschneider oddball paradigm may be reduced compared with that in 2012). respectively. Corresponding of Neuroscience) (Color figure online) average difference waveforms (deviant minus standard responses) in stimuli and therefore cannot be perceptually differentiated standards in the oddball paradigm than in the control as an oddball. comparable to the response to the same stimulus in the which reported similar responses to deviants under both control paradigm. In fact. that they can be more simply explained by lower-level Accordingly. Thus. then the Horvath et al. left column). Responses to rected) are indicated by the black vertical lines beneath the difference the BF tone when it was presented as a standard and as a deviant in waveforms. if the adigm (Jacobsen and Schroger 2001. ulus presented with the same probability in the context of than the responses to the same stimuli in the control par- many different equi-probable stimuli. in the time range of both the N1 and MMN. neurons tuned to the ‘deviant’ would be effects of neuronal adaptation and lateral inhibition.]. the response to the deviant in the conditions (Farley et al. using simulations incorporating both adaptation and lateral compared with their partial activation by the constant inhibition. 2010. partially activated less frequently by the many ‘standards’.01. the control paradigm due to the larger (on average) acoustic While these findings appear to strongly support the separation between the many ‘standards’ and the ‘deviant’ sensory memory hypothesis. the genuine sensory memory-based MMN response. their interpretation has been in the control paradigm compared with the separation challenged by May and Tiitinen (2010). that if there exists a genuine sensory memory-based MMN Use of this control paradigm has yielded evidence for a that cannot be attributed to the effects of adaptation. 2008). respectively. Briefly. [Note that these results run contrary to response to the deviant in the oddball paradigm should be those of experimental animal studies discussed earlier. Responses elicited by deviants are larger than those the oddball condition are plotted in black and red. who have argued between standards and deviants in the oddball paradigm. MMN merely reflects a ‘release from adaptation’. uncor- (200 ms) is represented by the horizontal green bars. to be larger. Conversely. The rationale behind the control paradigm is paradigm. Lower lamina 3 multiunit activity (LL3 MUA) and elicited by the same tones when they are presented in the ‘many average rectified current source density (AVREC CSD) quantifying standards’ control condition (see text for discussion. responses to deviants in the oddball paradigm tend larger (and different) from the response to the same stim. adapted with total net extracellular current flow across cortical layers in A1 are permission from Fishman and Steinschneider 2012. However. 2 Average responses elicited in monkey A1 by best frequency the oddball condition are shown in the right column. elicited by standards in the oddball condition. May and Tiitinen (2010) showed that negative- standards in the oddball paradigm. Time- (n = 30 electrode penetrations.

Therefore. AEPs and MUA are recorded oddball condition was 658 ms. responses in the control paradigm. asterisk indicates a major negative deflection in AEP and CSD dimensional CSD profiles are derived from the AEP profiles. Major profiles in the latency range of the MMN. smaller than that elicited by the same tones in the control bition. 123 . Stimulus duration (200 ms) is column) response profiles elicited in A1 by a BF tone (950 Hz) in the represented by the horizontal green bars. as recorded in humans CSD response components are labeled. (100–200 ms). farther away acoustically from the the N1 elicited by deviants in the oddball condition was deviants. subtracting the control remain unclear (see May and Tiitinen 2010 for a possible response from the oddball response yields a larger nega. Responses elicited by the deviant are larger than those aries are indicated on the right of the figure. 3 AEP (left column). However. responses in the oddball and control paradigms (e. The reasons for this discrepancy the oddball condition. Interestingly. Consequently. respectively. (2008). One. Jac- tion of deviant responses by nearby standards in the oddball obsen and Schroger 2001) might be simply due to the paradigm compared with the weaker inhibition of ‘deviant’ combined effects of adaptation and lateral inhibition. the responses in the range of the N1 (100–125 ms) condition (as predicted by May and Tiitinen’s simulations).. Responses to the BF tone elicited by the standard in the oddball condition. Frequency separation between stan- by a multicontact electrode which samples activity at 16 laminar dard and deviant tones in the oddball condition was 37 %. 9 in May and inhibition within cortical networks occurring over the Tiitinen 2010). As a result of the delaying effect of lateral inhi. the putatively ‘‘genuine’’ course of prolonged auditory stimulation).g. SOA between tones in the oddball and ‘deviant alone’ conditions. The depths simultaneously (left. Responses to the elicited by the same tone when it is presented alone (‘deviant alone’ BF tone when it was presented alone (with standards silenced) at the condition) (Color figure online) same inter-deviant stimulus onset asynchrony (SOA) as in the oddball negativities elicited by the same tones in the control para. sensory memory-based MMN that is revealed by comparing digm. explanation involving synaptic plasticity and suppression of tivity in the MMN latency range (see Fig. on average. This delay is explained by the greater lateral inhibi. are larger in the control condition. inter-contact spacing: 150 lm). responses when it was presented as a standard and as a deviant in the oddball to the deviant are comparable in amplitude and morphology to those condition are plotted in black and red. Approximate laminar bound. in the study by Jacobsen and Schroger (2001) dards are. wherein the many stan. and subsequent responses whereas the reverse was the case in the comparable study by in the latency range of the MMN (150–200 ms) are larger in Horvath et al. CSD (center column).510 Brain Topogr (2014) 27:500–526 Fig. and MUA (right condition are plotted in blue.

On rare occasions tone A is repeated Sussman et al. with and has a similar scalp topography to that elicited in the an identical deviant probability of 20 %. caution needs to be exercised before drawing the lysis. as it should no longer be per. thereby breaking the alternating pattern and recorded ERPs from the scalp in humans to auditory violating the rule. However. for a similar paradigm using interpretation of the MMN would be provided if the MMN alternating intensity patterns.. Important for the present conclusion that a larger negativity in scalp-recorded ERPs discussion. and sequences occur randomly (unexpectedly) or predictably. indeed.. 4). an MMN continued to be elicited by ran. Cornella et al. when the five (assumed to reflect greater neuronal activation) elicited by tones are grouped into a perceptual unit. esis. Alain et al. because neurons tuned to the frequency of the deviant cally. tone B follows tone A. These findings were erating the differential responses observed in this para- interpreted to suggest that the mechanisms responsible for digm. This ‘repetition deviant’ (bolded ‘A’ sequences consisting of tones of different frequency (A and above) elicits an MMN. intensity. alternation) generated by involved in deviance detection and those contributing to prior auditory stimulation. On the other hand. 1988.e.Brain Topogr (2014) 27:500–526 511 MMN Elicited by Periodic Versus Random Oddball different frequency (pitch) in an alternating pattern. exposure to these improbable. which might affect responses to MMNs elicited by violations in auditory patterns. On the other hand. one would predict that the response to the repetition detecting deviance in auditory patterns depend upon the deviant would be smaller than the response to the standard perceptual grouping of tones in sensory memory. these deviants differently in the random and periodic oddball patterns were conveyed by stimuli with fixed acoustic conditions at rapid tone presentation rates—a possibility properties. and duration. Wacongne et al. To examine whether the appearance sequences results in a ‘rule’ being established in sensory of the MMN depends upon whether deviants in auditory memory according to which tone A follows tone B. Potentially convincing support for the predictive coding 2012. (1992). elicit an MMN (at shorter SOAs) when they occur unpre- dictably. see also Sussman 2007). Sculthorpe and Campbell 2011. interpretation of the MMN insofar as deviant tones only this inference may be unjustified. (1998) and Sussman and Gumenyuk (2005) (ABABAA). Accordingly. Considered from the perspective of the sensory larger than that elicited by expected. whereby the MMN reflects an ‘‘error’’ signal indi- (1998) and Sussman and Gumenyuk (2005) highlight an cating a violation of a prediction based on a stored model interesting interplay between neural processes putatively of the regularity (in this case. which occurs at a similar latency B) presented either in a random oddball paradigm or. Specifically. deviants. the findings of Sussman et al. On explained by adaptation or other lower-level mechanisms. Lanting et al. violations of abstract rules is that of Saarinen et al. One commonly used stim. Specifi. Thus. the other hand. tone. all of these studies supports the predictive coding hypoth- ceived as a ‘deviant’. though equally memory/predictive coding hypothesis. Horvath et al. A potentially repeating (periodic and predictable) pattern: …AAAA useful feature of this paradigm is that a larger negativity BAAAAB… Sussman et al. as we shall see later auditory perceptual organization (i. on. 2013). Sequences ABABAB (Nordby et al. at shorter SOAs listeners are more likely to hear the should be partially adapted by the identical tone which AAAAB sequences as a regularly repeating pattern of five precedes it. A potentially more powerful case for the sen- that should be explored in future studies. Whereas the studies mentioned above have reported 2009.g. if adaptation plays a significant role in gen- dom sequences at the shortest SOAs. see Macdonald and Campbell elicited by unexpected deviants in auditory sequences is 2011). in the following classic frequency oddball paradigm (Fig. 2012. 2001. auditory scene ana. standard: unbolded ‘As’ above) presumably cannot be but not when the SOA was short (200 ms and below). sory memory/predictive coding hypothesis would be made if the MMN could be elicited also by changes in abstract MMN Elicited by Violations of Auditory Patterns auditory features in addition to changes in basic acoustic attributes such as frequency. the larger negativity tones than at longer SOAs. 1994. ulus paradigm involves the presentation of two tones of The authors presented a series of tone pairs that randomly 123 . see von der Behrens et al. these findings might also be MMN Elicited by Violations of Abstract Rules partly explained by a non-linearity in the time course of recovery from adaptation (e. no MMN should the repetition deviant in the latency range of the MMN in be elicited by the B tone. they provide support for the predictive coding and ERMFs reflects greater neuronal activation. (1998) and Sussman and elicited by the same tone when it violates the alternating Gumenyuk (2005) found that an MMN was elicited by pattern (the repetition deviant) compared to that elicited deviants in the predictable condition when the SOA when it conforms to the alternating pattern (the alternating between consecutive tones was long (400 ms and above). A number of studies have examined the MMN elicited by One of the first studies examining MMNs elicited by violations of auditory patterns.

irrespective of the higher in frequency than the first). concept formation. simple embodied by the ‘standard’ abstract feature. 1992. Korzyukov et al. these neurons typ- frequency oddball paradigm. such as ‘rising pitch’ or ‘falling stimuli (for reviews of this literature. such dard pairs had an ascending pitch (i.. Accordingly. when they occur.. An MMN was elicited by the author’s knowledge. (1994). these findings would provide strong support for the predictive coding interpretation of the MMN. such neural populations have not yet deviant pair.. Tian and Rauschecker 2004.g. as lis- findings (e. respectively. 1999). given that the standard sounds are not that are selective to upward or downward frequency constant (e. responses of this neuron would not in the [100 ms latency range. Thus. Mendelson and Cynader 1985.000–2. In principle. Paavilainen 2013). 1993. Indeed.g. Frequency separation between the A and B their pure tone tuning curve. Mendelson et al. as in the aforementioned stimulus paradigms.g.. it can derive a common sory memory model. For instance. Adapted with permission from Alain be adapted by upward frequency changes occurring over et al. ‘rising pitch’) abstract feature (Paavilainen et al. Tones were 100 ms in duration and presented limited spectral range that overlaps excitatory regions of binaurally via headphone. Tervaniemi et al. ulations that respond to abstract features or patterns. Paavilainen et al.e. copyright Neuroreport different spectral ranges. whereas the deviant absolute frequency of the two tones. even when subjects were ignoring the stimuli. Atencio et al. On the other hand. 4 Scalp-recorded ERPs evoked by tones in an alternating vided by Hsieh et al. and can automatically detect violations of this associated with a given abstract feature (e. it is possible to devise an explanation for these findings based on adaptation of neurons whose responses are selective to particular upward or downward changes in frequency. pattern. such as generalization. However. in which tones either conformed to the alternating pattern (ABABAB). In the case of the sen- ing’ and ‘falling’ pitch). Schroger et al. it is reasonable to expect that A number of studies have replicated and extended these such populations do exist somewhere in the brain. However.g. but changes occurring in different absolute frequency ranges vary broadly along a physical (acoustic) dimension. 2012). selective to these abstract features. ‘falling pitch’) which violates the rule ‘‘cognitive’’ operations. Shamma et al. repetitive standard stimulus.. To the best of the pairs had a descending pitch. a comparison must be made between invariant feature from a set of physically varying acoustic responses of neurons that represent the memory trace events. 1994a. Under all stimulus conditions. teners can readily identify changes in such abstract features 1999. Heil et al. 1993. 5).e. the invariant ‘‘abstract’’ feature of the standard employing similar paradigms is if there exist neural pop- pairs was the direction of the frequency change: the stan. 2007. Gaese and Ostwald 1995. the existence of neurons selective to particular directions and speeds of frequency modulation in auditory cortex is well-documented in experimental animals (e. ERPs elicited by pattern-conforming and pattern- violating tones are represented by dashed and solid lines. it (Fig. pitch’ could be represented by higher-order neurons that 2012. tive coding interpretations of the MMN seem to require the These results suggest that the brain can extract an existence of neurons whose responses are sensitive and abstract attribute corresponding to a simple concept (‘ris. The plausibility of such a convergence is sup- would seem difficult to explain the differences in ERPs ported by evidence suggesting that neurons preferring 123 . And indeed the sensory memory/predic- ixen and Schroger 2008). upward frequency change occurring over the range of violating tones elicit a larger negativity than pattern-conforming tones 1. the audi.. confined to a limited frequency range). 2003. b. see Bendixen et al. respectively over the range of 500–1. a neuron tones and their presentation rate are indicated on the top and left of the that responds to an upward frequency change occurring figure. or violated the pattern by being ically only respond to frequency changes occurring over a repeated (ABABAA). Thus.512 Brain Topogr (2014) 27:500–526 elicited by ascending/descending standards and deviants by lower-level neural mechanisms such as adaptation.000 Hz. (1992) and others Instead. varied across a broad frequency range such that there was The only way that the adaptation hypothesis can account no physically identical.. receive convergent input from neurons in auditory cortex On the face of it.g. for the results of Saarinen et al. and prediction of future abstract auditory features. evidence for similar frequency modulation-selectivity in human auditory cortex is pro- Fig. the second tone was as ‘rising pitch’ and ‘falling pitch’.000 Hz may not respond to an (negative is plotted up). i. rule extraction. been identified. Bend. and responses of neurons that represent a different abstract tory system can automatically and pre-attentively perform feature (e. 2007.

neurons that are tuned to the abstract rule (e.Brain Topogr (2014) 27:500–526 513 population that is responsive to a change in auditory stimulation representing a deviation from a sensory mem- ory trace (Naatanen et al.g.e. stimulus) that are Fig. 1994a. 5 Hypothetical neurophysiological scheme whereby neural entrained to the rhythm of the previous stimuli. 1992). if not the direction of frequency change which violates the abstract rule will impossible.200 ms) and a tone was omitted 20 % of the time. in the predictive coding framework. (100 ms duration) occurred at regular temporal intervals quency sweeps in auditory cortex (Mendelson et al. Second-order animal models (e. there are several stimulus paradigms ‘‘falling pitch’’). separated selectively tuned to abstract auditory features remains to be by 100 ms) were presented at regular temporal intervals empirically determined in future studies. In some adaptation could account for the MMN elicited by abstract rule omission paradigms. These comparisons 123 . Tervaniemi et al. Russeler ciation cortex around the posterior temporal-parietal junc- et al. Yamashiro et al. (1. Neurons only respond to frequency changes Tiitinen 2010. tonotopic axis is represented by the vertical black arrow).. Responses of second-order neurons that are tuned to in which omission responses would be difficult. Indeed. 2013) and ‘second-order’ neurons (boxes) which represent the abstract features in electrophysiological recordings from auditory cortex in ‘‘rising pitch’’ (‘‘Up’’) and ‘‘falling pitch’’ (‘‘Down’’). Such ‘‘off’’ responses have occurring over a narrow spectral range surrounding their best been demonstrated in EEG and MEG recordings in humans frequency (BF.g. the authors were able to statistically MMN Elicited by Stimulus Omissions compare ERPs elicited by the omission of the second (expected) tone in a tone pair with that elicited at the same Perhaps the most convincing evidence for the sensory latency by single tones (Fig. stimulated more frequently. the MMN elicited by stimulus omis- violations (e. blue downward). (2001) recorded intracranial ERPs in epileptic patients while they passively upward frequency sweeps are clustered together and ana. 1993). (1. the omission MMN may represent an ‘‘error’’ signal elicited when a stimulus that is expected based on top-down predictions fails to occur (Wacongne et al. 1997. 2009.. i. Salisbury 2012). 2010). 2001.. Hughes et al. Bendixen et al.g. than second-order neurons that are tuned to the opposing abstract rule (e. May and Tiitinen (2010) have argued that the omission MMN can be explained instead by lower-level neural mechanisms. 2005). such as oscillatory responses of neural populations elicited by the sound preceding the stimulus omission. occur based on prior exposure to a regular series of sounds Most omission responses were recorded in auditory asso- (e. earlier ERP studies of May and Tiitinen (2001) showed automatic rebound responses occurring after the ending of auditory stimulation (and at the expected time of a subsequent. the omis. pairs of tones (100 ms duration. These ‘first-order’ neurons send convergent input (arrows) to (e.. 2011). ERPs elicited at the latency of the omitted stimulus omissions (physically absent stimuli) cannot second tone in each tone pair were statistically larger than activate afferent neurons giving rise to the N1. Lanting et al. As tion.g. For tuned to the direction of frequency change which conforms to the abstract rule (Color figure online) instance. tones tomically separated from those preferring downward fre. 2011. and will therefore be more adapted. In a Whether there are indeed neurons in the brain that are second sequence. Pelleg-Toiba and Wollberg 1989.g.g. On the other hand. In all 10 patients studied memory/predictive coding interpretation of the MMN they demonstrated localized cortical responses to the comes from studies showing that the MMN can be elicited missing (expected) tones that were topographically similar by the infrequent omission of stimuli that are expected to to the responses evoked by the physically present tones. those elicited by single tones at the same latency and sion MMN cannot be due to ‘release from adaptation’ and resembled those elicited by the second tone of each pair must instead result from the activity of some other neural when the tone was physically present.200 ms) and the second tone of the pair was omitted 20 % of the time.. though still compatible with the sensory memory interpretation. ‘‘rising pitch’’) will be Fishman and Steinschneider 2009. Alternatively. Salisbury 2012). though omitted. Scholl et al.. the N1-like enclose horizontal bars indicating their direction preference (red response to the ending of auditory stimulation (May and upward. 6). Saarinen et al. in a study examining responses elicited by the omission of expected stimuli. 2009. However. Yabe et al. Importantly.. Thus. to explain by lower-level phenomena such as therefore be larger than responses of second-order neurons that are ‘‘off’’ responses or oscillatory ‘‘rebound’’ responses. listened to two sequences of tones. Neurons tuned to different directions of frequency change are represented by circles which sions may simply reflect an ‘‘off’’ response. b. In one sequence.

as generally conceived responses. Auditory stimuli sound-the second tone in a pair of tones (represented by horizontal consisted of repeating sequences comprised of two complex tones bars at the top of the figure. (2001) for additional details. inter-pair SOA was 1. Occasionally (10 % of the time) the not mean that they were ignoring them (indeed. Fig. but rather ERP deflections from subjects while they attentively listened to repeating with a similar latency and morphology to those elicited by sequences of 5 tones. purple lines) which. the authors expected 5th tone (bolded A and B above) was omitted. inter-tone (‘XXXXY’.514 Brain Topogr (2014) 27:500–526 indicate that the omission ERP was not simply an ‘‘off’’ or A recent study by Wacongne et al.. Occasionally (10 % of SOA was 200 ms. 7). for which no second tone was expected (2011) for additional details.200 ms). this does mately 1 s of silence. whose omission was therefore unexpected. 50 ms in duration. In neural correlates of predictive coding in the auditory system demonstrating a robust and genuinely new intracranial provides another demonstration of responses elicited by the response to a predicted. MEG gradiometer (middle). elicitation of omission responses is not necessarily ‘‘auto. tone ‘Y’ was omitted (onset of ‘Y’ at 0 ms). An omission the time). (2001) seconds) of these signals as recorded from a sensor represented by a for detecting responses to the unexpected omission of an expected dot on the corresponding topographical map.. here we will focus exclusively on omission and colleagues were not ‘MMNs’. omission of expected sounds that cannot be explained by these studies provide compelling support for the sensory lower-level neural mechanisms. Impor- matic’’ or ‘‘pre-attentive’’ and may require attention to the tantly. The omitted response was detected (‘‘Double Omit’’) if there was a statistically tone elicited a response (condition ‘‘omiXY’’. was not elicited following the end of repeating sequences omitted) second tone which was not present at the same latency in the of complex tones (‘XXXX’). responses to stimulus omissions could not be simply explained by ‘‘off’’ or ‘‘rebound’’ responses elicited by the last tone in the 4-tone sequence (which would be present also in responses to the control sequences). (2011) examining ‘‘rebound’’ response elicited by the first tone of each pair.e. Three topographies (top row) show the scalp distribution of EEG (left). (2011). in frequently presented (100 % of the time) control sequences consisting of 4 tones. including Fig. Adapted from Wacongne et al. that the omission responses reported by Hughes hypothesis. AAAAA or AAAAB. 7 Topography and time course of brain responses to stimulus omissions. tones were 100 ms in duration. though physically absent. See Hughes et al. (‘‘Single’’). Hence. Omission responses were local- ized to generators in the superior temporal gyrus. stimulus. i.. this response was not elicited following the last tone sounds (as discussed below). from this study provide support for the predictive coding however.e. Graphs show the time course (in Fig. blue lines). The authors recorded EEG and MEG responses based on scalp-recorded ERPs. and MEG magnetometer (right) signals at the time indicated by the vertical dotted line in the graphs at the bottom of the figure. while the subjects sequences were separated from each other by approxi- were instructed to passively listen to the sounds. in which the omission of the 5th tone was expected). While several findings memory/predictive coding interpretation. AAAA (i. copyright Neuroimage figure online) 123 . Thus. 6 Quantitative statistical method used by Hughes et al. A referred to the subjects’ task as ‘‘passive attend’’). 5-tone physically present stimuli. for which the omission of tone ‘Y’ was response to auditory sequences in which only the first tone of the pair expected (condition ‘‘omi exp’’. was presented. It is worth noting. Moreover. (2001). 150 ms SOA). the response was elicited by the infrequently omitted tone (i.e. Adapted copyright Proceedings of the National Academy of Sciences (Color with permission from Hughes et al. significant ERP elicited at the latency of the expected (though importantly. See Wacongne et al.

Brain Topogr (2014) 27:500–526 515 123 .

then tones presented in the random to detect global pattern violations (e.. (1998) and Sussman and MMN.e. Deviant probability = 1/6 (16. 2011). These random signals would also be elicited under ‘‘ignore’’ conditions and periodic conditions are similar to those tested in and how they are related to the pre-attentively elicited the studies of Sussman et al. Furthermore. explained by short-term interactions between responses to pression of neural responses to repeated sounds in humans.500 Hz). incidentally. the roles of the BF and Non-BF tones were reversed. parietal. LFPs and MUA elicited by unexpected stimulus omissions generally have latencies and random sequences were larger than those elicited by peri- durations different from those of MMNs elicited by local odic sequences. this experiment has been conducted at 4 A few of these studies and their findings are described recording sites in monkey A1. Taken together. findings of Bekinschtein et al. In particular. described earlier. Recording from A1 of anesthetized rats. all of which show qualitatively similar briefly below. predictably) with respect to the standard tones (e.. The authors interpreted these results 123 . responses to global pattern violations and They found that. probability was 5 %. In a recent study. these findings larger responses in the random than in the periodic condi- indicate that the MMN and other putative predictive coding tion. the probability of the deviants. the subjects of Wacongne occurred at random intervals (i. Yaron and colleagues cate that while attention is not required for an MMN to be reasoned that if A1 is sensitive not only to the improba- elicited by local deviants in auditory sequences (e. while deviants were set to a frequency between the effects of attention and expectation on neural above the BF (Non-BF) which elicited a response that was half the signals associated with predictive coding is only beginning amplitude of the response elicited by BF tones (in this case.g. 2011. Wacongne et al.. Indeed. tion might elicit responses consistent with the sensory Note larger negativity in AEPs recorded in superficial layers in memory or predictive coding interpretations of the MMN. unpredictably)—as is et al. In a second stimulus block. ‘‘top-down’’ expectations can modulate sup. As of this writing. dards—but also to structure in oddball sequences (in this active listening is necessary in order for the auditory system case. unlike the responses to oddball sequences in which rare deviant tones majority of MMN investigations.e. responses and trends. Interestingly. to be explored (Arnal and Giraud 2012). response to deviants in the random condition (indicated by blue arrow). and in the precentral cortex. signals (responses to unexpected stimulus omissions and it was the deviants that evoked larger responses in the ran- global stimulus violations) may be differentially affected by dom than in the periodic condition.g. (2012) examined whether A1 tion ‘‘error’’ signals. standards were set equal to the BF sequences (Todorovic et al. which. Wacongne et al. (2009) indi. models concerning the sensitivity of the auditory system to MUA elicited by standards and deviants in the random condition is patterns and regularities in sound sequences whose viola- comparable to or smaller than that elicited in the periodic condition. periodicity).. 8. the predictive coding hypothesis. See text for discussion (Color figure online) Responses to Periodic Versus Random Oddball Sequences auditory cortex. On the other hand. standards and deviants. could deviants compared with responses to the frequent stan- potentially be explained by a ‘release from adaptation’. the pattern of differences in deviants.g. Experiments in Animal Models Responses to the tones when presented periodically (i. on average.e. in Thus. tem. 2011). (i. and appear to arise from a more widely distributed responses to random and periodic sequences depended on network of brain regions. CSD. when deviant probability was 20 %. To date. there have been very few investigations in animal respectively. Yaron et al..e. Additional analyses attention and likely involve different neural generators.000 Hz). when deviant poral.. rare (5. The complex interplay of the recording site (7. 2012). the standards evoked significantly 2009. but occurred periodically Todorovic and de Lange 2012. 8 Laminar profiles of AEPs. The authors interpreted the omission responses as representing predic. they compared It is important to emphasize again that. thereby providing neural evidence for is sensitive to structure in frequency oddball sequences. presented in a periodic condition. Gumenyuk (2005). as in typically the case in sequences used to examine SSA—with several other neurophysiological studies of predictive cod.. responses to sequences in which deviant tones were equally ing in the auditory system (e. cingulate.g. the BF tone played the role of standard in one block and the role of deviant in another. suggested that the reported effects could not be simply Finally. 3. the ‘B’ bility of sounds—displaying larger responses to the rare in repeating AAAAB sequences). 516 Brain Topogr (2014) 27:500–526 b Fig. or 20 % probability). predictably) and randomly (i. it is unclear whether these putative prediction ‘‘error’’ a repeating pattern …AAAABAAAAB…). including prefrontal. the last ‘A’ of the condition should be more ‘surprising’ and therefore evoke sequence AAAAA when it is infrequently presented in a larger responses than those evoked by the same same tones background of repeating AAAAB sequences). 10. and occipital cortices (Bekinschtein et al.. and MUA elicited in monkey thus indicating an important role for higher-level ‘‘cogni- A1 by standard (a) and by deviant (b) tones at the best frequency (BF) tive’’ operations in the neural processing of auditory in periodic versus random sequences.7 %). Thus. (2011) were instructed to attend to the sounds. Same conventions as in Fig. unpredictably) are plotted in black and red. Todorovic et al. Tones were 50 ms in duration (including 5 ms linear on/ off ramps) and were presented at 60 dB SPL at an SOA of 300 ms. In one stimulus block.

Brain Topogr (2014) 27:500–526 517 123 .

a continuous alternating tone sequence. in which tone A was occasion- results consistent with those of Yaron and colleagues. 8.g. this observation indirect support for the predictive coding hypothesis. automati. does responses and trends not necessarily imply an increase in underlying neural activity (contrary to what appears to be implicitly assumed as indicating a sensitivity of A1 to patterns in auditory in human MMN studies). Recall that in human scalp mechanisms and meaning of the MMN. we recorded neural popu- is smaller in the random condition than in the periodic lation responses (AEPs.. As noted earlier. Specifically. CSD. (2012). While no homologs of the MMN in the LFPs support the opposite inference: a larger superficial nega- were reported. despite the range of the MMN than that elicited by ‘standard’ tones fact that MUA elicited by deviants is smaller in the random which conform to the alternating pattern. Deviant probability = 1/12 (8. As illustrated in macaque studies was too long (300 ms) to demonstrate a Figs. this experiment has been conducted at 4 recording sites in monkey A1. these findings provide layers of auditory cortex. thereby vio- In any event. our preliminary results do not replicate the difference in MUA under these two conditions. 8). same inent negativity in superficial cortical layers compared with conventions as in Fig. Specifically. the lack of evi- random and periodic oddball sequences similar to those dence for enhanced responses to random sequences in A1 tested by Yaron et al. (2012). since differences in the MMN displayed response onset latencies. 518 Brain Topogr (2014) 27:500–526 b Fig. associated with excitatory or inhibitory post-synaptic cally elicit larger (or qualitatively different) responses con. we presented and Gumenyuk (2005) discussed above. As of this writing. we rea- condition than in the periodic condition when deviant soned that a larger response to the pattern-violating tone 123 . 1994. elicited by standards and deviants in the random condition is The lesson to be learned from this example. findings of Yaron et al. Sussman and colleagues were only observed at SOAs equal and tonotopic gradients consistent with their location in A1 to or below 200 ms. this example would sequences. sistent with a prediction ‘‘error’’ signal. neural population responses MMN is generated in auditory areas outside of A1. MUA that elicited by deviants in the periodic condition (Fig. 2001. while responses elicited by deviants are larger than those elicited Responses Elicited by Violations of Auditory Patterns by standards. 9 Laminar profiles of AEPs. we wished to between periodic and random conditions when deviant determine whether the MMN (or similar responses) elicited probability is 1/12 (8. It remains to be seen whether data obtained 2012). BF and Non-BF tone frequencies are the same as in Fig. 2012. MUA and CSD laminar elicited in the random and periodic conditions tested by response profiles. 1/6 (16. there are no appreciable differences in the amplitude of MUA elicited by standard or deviant tones In preliminary studies from our laboratory. ally repeated (ABABAA. 8). and MUA) in A1 to tones condition. relevant to the present discussion on the lating the alternating pattern.. from a larger sample of sites in monkey A1 will yield ABABAB. Sculthorpe stimulus parameters and deviant probabilities.3 %). and which will comparable to that elicited by the same tones in the periodic be emphasized later on. CSD. and species and Campbell 2011. Thus.3 %). of macaques (notwithstanding the small sample size) could tening macaque monkey. is that an increased negativity in condition. 10 % probability).7 %) MUA elicited by both standards and deviants Using multi-contact electrodes. Alain et al. potentials (see Materials and Methods). or that (AEPs. all of which show qualitatively similar the ERP. as exemplified by the scalp-recorded MMN. Moreover. which sequences. (1998) and Sussman In an attempt to replicate these results. As of this writing. Given the results of Sussman et al. it is instructive to recordings this pattern-violating ‘repetition deviant’ (bol- note the differences in intracortical AEPs elicited by ded ‘A’ above) elicits a larger negativity in the latency periodic and random sequences. (2012) to an awake. may reflect the fact that extracellular current flow giving according to which unexpected acoustic events. using linear. contrary to the by violations of auditory patterns in human scalp record- trends reported by Yaron et al. Wacongne et al. differences. Horvath et al. as findings include small sample size. 8. Cornella et al. pure tone frequency tuning bandwidths. was presented. Indeed. this homologs of the MMN elicited by random versus periodic experiment has been performed at 4 recording sites. Possible explanations for the difference in presented in an alternating frequency oddball paradigm. CSD. when deviant probability is ings could also be observed in A1 of the awake monkey. Alternatively. slight differences in 1988. effects of anesthesia in tested in previous MMN studies in humans (Nordby et al. Fishman and Steinschneider 2012). and the results were not explicitly considered tivity is associated with reduced neural activation across all from a predictive coding perspective. while recording. passively-lis. For instance. and MUA) simultaneously across multiple macaques are not a suitable animal model for investigating cortical layers in auditory cortex. and MUA elicited in monkey probability is 1/6. be interpreted to suggest that the putatively ‘‘genuine’’ array multi-contact electrodes. the laminar distribution of AEPs elicited A1 by standard (a) and by deviant (b) tones at the BF in periodic by deviants in the random condition shows a more prom- versus random sequences (data are from the same site as in Fig. the studies by Yaron et al. such as rise to the AEP is inherently ambiguous as to whether it is those comprising the random oddball sequences. it is possible that the SOA used in the (e. 8 and 9.

electrode penetrations into A1 (as defined by several lating tone would be consistent with SSA. CSD. In one stimulus larger negativities in AEPs and CSD recorded in superficial layers in block. See text for discussion (Color figure online) BF tone played the role of standard (pattern-conforming tone) in one (compared to the response to the same tone when it con. To date. Same conventions as in Fig. second stimulus block. including 10 ms alternating pattern are shown in red. the A tone (BF tone) was repeated consistent with the adaptation hypothesis. In a second stimulus in monkey A1. do not support the sensory memory/ capable of eliciting a neural response at the recording site).200 Hz). and MUA elicited in block and the role of deviant (pattern-violating tone) in another. tone ‘A’ was set equal to the BF of the recording site response to pattern-violating tones (indicated by blue arrows). 10. all deviant’ is immediately preceded by a physically identical yielding qualitatively similar results. which would adapt the responses of neural popula. Note thereby violating the alternating pattern (ABABAA). all of which show qualitatively similar responses and block. repeated. As illustrated in Fig. a smaller response to the pattern-vio. therefore. 3. Stimuli consisted of shown in black. the same tone when it conformed to the pattern (blue arrow). whereas in a forms to the pattern) would provide evidence for the sen. Interestingly. monkey A1 by best frequency (BF) tones in an alternating oddball Responses elicited by tones that conform to the alternating pattern are paradigm. As of (1. MUA elicited by the BF tone linear on/off ramps. 123 . 10 Laminar profiles of AEPs. average MUA elicited by BF tions that are tuned to it. the B tone (Non-BF tone) was sory memory/predictive coding interpretation of the MMN. Occasionally (10 % of the time) tone A was repeated. whereas responses elicited by tones that violate the continuous sequences of tones (100 ms in duration. The frequency of A tones was set tones that violate the alternating pattern (red curves) is to the best frequency (BF) of the recorded neurons while smaller than that elicited by physically identical tones that that of B tones was set to a frequency 6 semitones above conform to the alternating pattern (black curves). predictive coding interpretation of the MMN and are instead In one stimulus block. this paradigm has been tested in 5 On the other hand.697 Hz). as the ‘repetition physiological and anatomical criteria mentioned above). the roles of the BF and Non-BF tones were reversed. Thus. These that of the A tones (in all cases this frequency was also findings. this experiment has been conducted at 5 recording sites 6 semitones above that of tone ‘A’ (1. such that it violated the alternating pattern. 400 ms SOA) presented in an alternating pattern when it violated the pattern is diminished relative to that elicited by (ABABAB).Brain Topogr (2014) 27:500–526 519 Fig. the trends. tone. while tone ‘B’ was set to a frequency (Non-BF) that was this writing.

the larger responses to the Non-BF repetition in MUA. this example demonstrates responses to pattern-violating Non-BF tones observed in that enhanced negativities in superficially-recorded ERPs do the alternating condition cannot reflect violations of sen- not necessarily indicate an increase in underlying neural sory memory traces or predictive coding ‘‘error’’ signals. it turns out that tone. activity. pattern-violating tones elicit greater MUA than pattern. all of which show qualitatively similar tone is no larger than that elicited by the same tone when it is responses and trends. they correlate with a decrease Instead. CSD. than responses to Non-BF tones (see Fishman et al. some Non-BF tones occurring at the same SOA as tones in the which occur in the latency range of the MMN (100–200 ms) alternating sequences (400 ms. MUA elicited by the SOA between the first and second (repeated) Non-BF tone when the Non-BF tone when it violated the pattern is enhanced relative to the Non-BF tone violates the pattern in the alternating oddball that elicited by the same tone when it conformed to the pattern condition. the alternating pattern. 10. blue curves). 2001a. might seem to provide evidence for the sensory memory/ The pattern-conforming Non-BF tone is preceded by a BF predictive coding interpretation. pattern-violating BF tones elicit the enhanced response is no larger than the response to a larger AEP and CSD negativities in superficial layers of A1 control sequence consisting of repeating (non-alternating) than those elicited by pattern-conforming BF tones. 2004 for an account of how this differential suppression conforming tones. Same conventions as in Fig. compared to ‘‘forward maskers’’) of subsequent neural activity in A1 when they conform to. MUA elicited by the pattern-violating Non-BF recording sites in monkey A1. the enhanced AEP and CSD profiles). See text for discussion (Color figure online) despite the reduced MUA. deviant can be explained by differential forward suppres- Figure 11 shows average AEP. As of this writing.520 Brain Topogr (2014) 27:500–526 Fig. In this case. this experiment has been conducted at 5 (asterisk). 11 Laminar profiles of AEPs. CSD. Again. However. and MUA elicited in presented in a control condition (responses plotted in blue) consisting monkey A1 by non-best frequency (Non-BF) tones in an alternating of Non-BF tones presented with an SOA of 400 ms-which is equal to oddball paradigm. As there is no elicited by this stimulus paradigm in humans (blue arrows in pattern violation in the control sequence. At first glance. this enhanced response may operate in the context of auditory stream segregation). in this case. However. indeed. whereas the pattern-violating Non-BF tone is 123 . and MUA profiles sion: responses to BF tones are better suppressors (or elicited by Non-BF tones when they violate.

Hence. Instead. some of which may be provided by ward suppression (May and Tiitinen 2010). are either present only in areas outside of A1 (a 2. that lower-level neural mechanisms. are ambiguous in indicating whether the animal models demonstrate robust SSA in auditory cortex spiking activity of neural populations. On the other hand.. involving a violation of auditory patterns (alternating dictive coding interpretation of the MMN. May and Tiitinen Responses Elicited by Stimulus Omissions (2010) suggested two criteria: 1. The identification of neurons whose activity is consis- To the best of the author’s knowledge. in this review. On the for the apparently larger responses to deviants in pattern other hand. While these findings are preliminary. ological evidence. Similarly. given the non-primary auditory cor- when that stimulus is presented as a deviant in an tical anatomical location of omission responses in humans oddball setting and remain inactive when that stimulus reported by Hughes et al. not exclude the possibility that signals reflecting violations We may then ask. is enhanced or diminished. Using a well-studied paradigm evidence both for and against the sensory memory/pre. activity which is: models. including awake monkeys (unpublished observa- distinct from that giving rise to the ‘obligatory’ N1. the response hand. and One may interpret these negative findings as indicating that sufficiently robust to give rise to the MMN recorded predictive coding ‘‘error’’ signals. this representative example illustrates digms. tions. Moreover. Second.g. 2001). including adaptation pressed by the preceding activity. in which predicted sounds are unexpectedly omitted). temporally aligned with the latency of the MMN. 2009). MMN as reflecting obligatory responses modulated by particularly under active listening conditions. 2012 being one convincing case for the existence of neural responses possible exception). rather than deviance detection or predictive dictive coding hypothesis and the adaptation hypothesis coding processes per se. the MMN elicited by infrequent stimulus that differences between ERPs recorded in superficial omissions in some paradigms may reflect ‘‘off’’ or layers of A1 (and which are likely to be volume-conducted ‘‘rebound’’ responses. may (at least in principle) be able the response to the pattern-conforming Non-BF tone. as reflected by omission from the scalp. we have presented preliminary neurophysiological data from macaque A1 based on neural population response mea- Discussion sures (AEP. These neurons should respond to an auditory stimulus reasonable possibility. data not shown) and rats (von der Behrens et al. as represented by and subcortical structures in response to auditory oddball MUA. we concur with May and Tiitinen (2010) that a yet been found (the results of Yaron et al. lower-level processes alone cannot account for oddball paradigms. what would constitute definitive of sensory memory traces or prediction errors can be found evidence for the sensory memory/predictive coding inter- in brain regions outside of A1. no clear evidence for MMN-like or other While neural responses reported in several of the pre- neural signals reflecting violations of sensory memory dictive coding studies reviewed above seem to fulfill these traces or prediction ‘‘errors’’ in A1 of animal models has criteria. than and lateral suppression. On the one frequency oddball). yet provide no clear evidence for a genuine the importance of using appropriate controls to exclude MMN-like component representing violations of sensory more mundane or parsimonious alternative explanations memory traces or predictive coding ‘‘error’’ signals. responses. to account for the MMN elicited in classic oddball para- To summarize. MMN-like responses elicited in other stimulus paradigms they support May and Tiitinen’s (2010) account of the (e. To summarize. studies in experimental to the scalp). are not observed in these animal models. and hence larger. clearly they do remains unresolved. Accordingly. or alone. the lower-level neural mechanisms of adaptation and lateral debate between proponents of the sensory memory/pre- suppression. pretation of the MMN and against the adaptation hypoth- esis? Paraphrasing from the Introduction. it demonstrates sequences. Thus. are dependent on attention to is presented as a standard or as a rare sound presented the sounds or active engagement in sound-related tasks. there is presently no tent with the spatio-temporal properties of the nonin- evidence for responses to stimulus omissions in A1 of animal vasively measured MMN—that is. we have found no evidence for a 123 . animal model studies. responses elicited in oddball reflecting deviance detection or predictive coding ‘‘error’’ paradigms typically used in human MMN studies can be signals should rely on ‘‘local’’ intracortical electrophysi- best explained by lower-level processes of SSA and for. numerous non-invasive studies in humans indicate to the pattern-violating Non-BF tone will be less sup.Brain Topogr (2014) 27:500–526 521 preceded by an identical Non-BF tone. and MUA) which are comparable to ERPs recorded from the scalp in humans (although which Based on the studies and preliminary findings reviewed and do not suffer from the spatial resolution limitations of presented here we may conclude that there is substantive non-invasive recordings). CSD.

in the absence of instance. 2005. typically involving top-down connections within events from noninvasive recordings. neural offer good temporal resolution of neural responses.. 2009. latency. 2013). Friston 2005. N1). selectively detect such salient events. Rao and Ballard 1999.g. Muckli et al. 2011. contrary Even if the MMN can ultimately be explained by lower- to what is perhaps tacitly assumed in MMN research. and brain topographies regions are concurrently active (e.g. 2013). Nourski et al. Hughes et al. shaped by lower-level mechanisms of adaptation and lat- eral suppression (May and Tiitinen 2010). this so-called ‘‘inverse problem’’ is exacerbated the ‘‘pre-attentively’’ elicited MMN (Raij et al. 2009. as described (e. see Lutkenhoner from those of the MMN. level neural mechanisms. it may still provide an index of be volume-conducted to fronto-central regions of the scalp the salience of auditory stimulus representations in the brain. Simi- cesses rather than lower-level neural mechanisms. Whether it also Potential Pitfalls in MMN Research represents the output of a neural comparator detecting the violation of a sensory memory trace or a predictive coding While noninvasive recordings utilizing EEG and MEG ‘‘error’’ signal remains unclear. the brain might utilize a which are often absent in studies of MMN elicited by threshold that is set above the level of the spontaneous neural auditory pattern violations. durations. Muckli and in underlying neural activity. these considerations physiologically-inspired theoretical models have been severely hamper the ability to infer underlying neural proposed. in order to properly interpret activity (in the case of ‘deviants alone’) or above the more- MMN-like responses recorded from the scalp. Nonetheless. by the fact that the response to even a simple tone consists Bekinschtein et al. Wacongne et al. particularly when two or more brain have different latencies. 2012. and ‘‘top down’’ expectations and tend to signals is limited. 10). Denham and Winkler 2006. as reflected by MUA. at least in part. their responses supporting the predictive coding framework spatial resolution is comparatively poor and the ability to appear to rely on subjects’ attention to the sounds. associated with a decrease in MUA (see Fig. in the ‘many standards’ control condition effec- appropriate control conditions.. the results may be readily explained by lower.g. adapted responses to the repeating standards (in the case of 123 . sensitivity to the salience of auditory stimuli may suffice. As ERPs and ERMFs considerations) and animal models. Petro 2013. 2012). Chennu of multiple spatially distinct areas of activation distributed et al. Resolving the rela- along the superior temporal gyrus (e. perhaps the most conservative conclusion to be level processes of adaptation and forward suppression (as drawn from a consideration of the available evidence is that discussed earlier). 1994). hence. for the purposes of basic animal survival. these obser. such as differential neural adapta- Given that intracortical AEPs in monkey A1 are likely to tion and lateral suppression. Todorovic et al. 2005. (100–200 ms) does not unambiguously indicate an increase Garrido et al. ERPs recorded invasive neurophysiological recordings in humans (obvi- at these sites not only overlap in time. 2001. to To complicate matters further. Indeed. and accordingly clude that the enhanced response to a pattern-violating they elicit larger responses than those elicited by the Non-BF tone reflects ‘‘genuine’’ deviance detection pro. 2008. 1997. As noted earlier. For Finally. they may represent brain 2003). one might mistakenly con. and duration are in the next section. active reliably infer the intracranial generators of these neural task engagement. these negative findings do the MMN. 1975. tively all of the sounds are salient or ‘novel’. 2013. (Arezzo et al. components derived from scalp-recorded ERPs. 1992. such as larly. 11). In the context of MMN research relying on scalp processes that are distinct from those contributing to recordings. repeating standards in the classic oddball paradigm. Javitt et al. This example salient relative to the background context of silence. 1994. Yvert predictive coding in the brain will likely require continued et al. Moreover. we have seen how an explain how the brain might implement predictive coding increased negativity in LFPs recorded within superficial processes (e. While their description recorded from the scalp reflect the summed activity origi. Lee and Mumford layers of A1 in the latency range of the MMN in humans 2003.g. a ‘com- vations should inspire caution in interpreting MMN-like parator’ or deviance detection process may not be needed. Instead. we have also seen how. guide future research into neural mechanisms underlying violating tones in the alternating oddball paradigm was predictive coding in the auditory brain. Indeed. At present. a number of nating from multiple brain regions.522 Brain Topogr (2014) 27:500–526 ‘‘genuine’’ sensory memory-based homolog of the human Concluding Remarks MMN or for predictive coding ‘‘error’’ signals in A1. a hierarchical and bidirectional cortical architecture. To illustrates the need to include such control conditions. SanMiguel et al. but may have ously performed under circumstances mandated by clinical opposite polarities at adjacent sites.. is beyond the scope of the present review. Edwards et al. whose amplitude. sounds in the ‘deviants alone’ control condition are differential forward suppression (Fig. reflects an obligatory response have some implications for MMN research.. Liegeois-Chauvel tionship between the MMN and other neural signatures of et al. These models will help to the increased superficial negativity elicited by pattern.

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