Finding the missing stimulus mismatch negativity (MMN): emitted MMN to violations of an auditory gestalt.

The mismatch negativity (MMN) event related potential (ERP) is a neurophysiological signal of stimulus processing extracted from the electroencephalogram (EEG). The MMN elicited by simple changes in stimulus parameters (pitch, loudness, duration, location, etc) reflects activity of pre-conscious, pre-attentive sensory memory within sensory cortex, and serves as a metric of stimulus deviance likely sent to frontal lobe mechanisms that may engage an alerting orienting response to the source of change from a repetitive environmental pattern. MMN reflects the output of a low-level mechanism for detection of change from stimulus regularities in the environment. It occurs very early in perception within the information processing stream, and is little affected by top-down executive functions like attention (Naatanen 1990). Although for many years thought to be exclusively found in auditory echoic memory, a similar potential is evident within visual iconic memory (Winkler et al 2005, see Pazo-Alvarez et al 2003 for review). Still, the MMN to small stimulus deviations within the auditory system remains the most widely studied. Early MMN theory focused on the distinction between the MMN being a purely sensory response because the deviant tone recruited different sensory cortex populations, versus the MMN reflecting the difference between a memory trace of the specific single standard stimulus versus the current stimulus (Naatanen 1990). Simple stimulus parameter MMN studies (one repetitive identical tone and a physically different deviant) have been unable to show a MMN to a missing stimulus, unless the tones were played very rapidly (100 or 125 msec stimulus onset asynchrony (SOA), but not >150 msec, Yabe et al 1997. Herein SOA refers to onset-to-onset of tones, whereas inter-stimulus interval, ISI, refers to offset-to-onset). This suggested that the tones were within a critical temporal window of integration, and thus the missing stimulus represented a violation not simply because of its absence per se, but because it was not there to form a compound stimulus with the preceding stimulus. Using depth recordings, Hughes et al (2001) did not report MMN-like responses to omissions of tones regularly spaced 1.2 sec apart, although they did report MMN-like responses to a missing second tone of 100 msec duration tone pairs with a 200 msec SOA (100 msec tone duration + 100 msec ISI). Because omissions of tones at longer ISIs violate stimulus regularity, it remains paradoxical that omissions at SOAs > 150-200 msec do not elicit MMNs. As mentioned, stimulus parameter deviations are generally slight changes in the pitch, duration, or location of short tone pips (oddball stimuli), but MMN can also be elicited by stimuli that are affected by learning. For example, phonemes that deviate slightly from a repetitive train generate MMN only if that phoneme is relevant in one’s native language (Aaltonen et al 1987, see Naatanen 2001 for review). MMN is also elicited by deviations from learned patterns of sounds (see Kujala et al 2007 for review), exceptions from a purely bottom-up nature for MMN, indicating the influence of acquired knowledge in “automatic” perception. Hence, the simple stimulus parameter deviant MMN may only scratch the surface of the cortical processing that may be reflected in MMN activity. In the last several years, research in psychiatrically-well participants has changed the conceptualization of MMN, what it reflects, and the complexity of how it may be elicited. Rather than being elicited solely by low-level bottom-up analysis of repetitive stimulus patterns, physical parameter changes which can be analyzed mainly in primary auditory cortex, MMN can be elicited by a host of complex abstracted or second-order rules, and by deviations from complex learned rules. This “automatic auditory intelligence” can form rules based on stimulus change trends and learned tone patterns such as a melody (see review Naatanen et al 2010). The “complex memory MMN” depends on more sophisticated processing than the simple stimulus parameter MMN, necessitating the more complicated circuit architecture of secondary cortical association areas, and may include parietal and frontal processing modules in addition to secondary auditory cortex (see Schroger et al 2007). For example, if a rule that the second tone in a pair is always a higher pitch than the initial tone, a MMN is elicited if the second tone is lower (Saarinen et al 1992, Korzyukov et al 2003). Alho et al (1996) showed that complex MMN could be elicited by a deviation from a serial tone pattern (i.e., a tune). The melody E4, C5, G4, E5, C4 was the standard pattern, and a deviant was E4, C5, A4, E5, C4. The deviant A4 elicited a MMN, which could only occur if the overall melody had been abstracted as a complex rule. Atienza and Cantero (2001) claimed that the MMN to violations of an 8 tone pattern could also be evoked during REM sleep after learning. Standard stimuli were 365 msec long tones comprising 8 segments of different frequencies with no logical pattern from one segment to the next, resulting in an abstract sequence. The deviant was identical, except that the 6th segment was 15% higher in pitch. Responses to learned pattern violations was shown as well by Sculthorpe et al (2009) for an alternating 8 tone pattern, where the standard comprised alternating tones (ABABABAB) and the deviant comprised alternating tone with a repeat (ABABBBAB). These studies have supported a different model of MMN generation than the comparison of the current stimulus with a backward-looking memory trace of a previous standard stimulus. Rather, it seems more likely that MMN reflects a comparison of a forward-looking prediction of what should occur, be it based on a single repetitive tone or a complex pattern of tones, with what actually occurred (see Winkler 2007). The ability of the auditory system to use simpler abstracted rules to form groups of stimuli based on implicit patterns has been examined. At longer ISIs (1.3 sec, 50 msec duration tones), deviants presented regularly (every 5th tone) evoked a MMN. However, at short ISIs (100 msec), the deviants did not evoke a MMN, presumably forming a unit with the preceding tones (Sussman, 1998). van Zuijen et al (2004) presented subjects with a constant stream of 100 msec duration tones at an ISI of 87.5 msec. Four identical tones were played (an implicit group), with a new group at this constant rate indicated by a different pitch. An extra (fifth) tone elicited a MMN in both musicallly skilled and unskilled participants. Again, however, these groups appear to form only at relatively short ISIs. A crucial aspect of the simple grouping rule studies described immediately above is that the SOA and ISI were constant; that is, the groups were formed by implicit groupings of stimulus parameters or repetitive parameter changes. Using a somewhat more complex rule, Atienza et al (2003) examined the time course of this implicit grouping of 30 msec duration tones into a “larger acoustic event”, and suggested such an integration interval did not exceed ITIs of 240 msec. Subjects were presented 6 tones with a SOA of 120 msec. The ITI was varied between 150, 180, 240, and 360 msec. Within each train, tones alternated between 2 frequencies. Deviant trains began with a repetition of the same frequency (i.e., 2 standard trains: a,b,a,b,a,b a,b,a,b,a,b. Standard train followed by deviant train: a,b,a,b,a,b, b,a,b,a,b,a). Atienza et al argued that if a rule expecting alternating frequencies of 6 tones was developed, the first tone of a deviant train (where the frequency did not change) should elicit a MMN if it violated an expectancy for an alteration within the ~250 msec temporal integration interval described above. They described a MMN to the deviant under 240 msec, but not at 360 ITI, presumably outside the integration of the alternating rule expectancy. Although this may imply that the auditory system did not develop an overarching expectancy for the group of tones as a whole, it is important to note that the deviant always occurred every other train, and was thus predictable as a larger pattern. Here we describe a method to form overarching groups of a single repetitive stimulus via manipulation of the ISI, based on the gestalt grouping principle of proximity. As shown in Figure 1A, which illustrates the visual analog of the task, 6 stimuli which are close together and separated from other similar bunches of close together stimuli form implicit groups. This simple abstraction based on temporal proximity, forming groups of stimuli with constant ISIs separated by a longer ITI, was used to determine whether violation of such a grouping principle would elicit an MMN to an omitted stimulus (Figure 1B,C) at SOAs over 250 msec. Figure 1 Panel A. Stimuli separated by regularly spaced increases in ISI form implicit groups via the gestalt principle of proximity, here into groups of six notes. Most people see 3 groups of notes rather than a sequence of notes with variable SOAs. Panel B. ...