Mismatch Negativity Generation Research Articles

Unsupervised Characterization of Prediction Error Markers in Unisensory and Multisensory Streams Reveal the Spatiotemporal Hierarchy of Cortical Information Processing.

Elicited upon violation of regularity in stimulus presentation, mismatch negativity (MMN) reflects the brain's ability to perform automatic comparisons between consecutive stimuli and provides an electrophysiological index of sensory error detection whereas P300 is associated with cognitive processes such as updating of the working memory. To date, there has been extensive research on the roles of MMN and P300 individually, because of their potential to be used as clinical markers of consciousness and attention, respectively. Here, we intend to explore with an unsupervised and rigorous source estimation approach, the underlying cortical generators of MMN and P300, in the context of prediction error propagation along the hierarchies of brain information processing in healthy human participants. The existing methods of characterizing the two ERPs involve only approximate estimations of their amplitudes and latencies based on specific sensors of interest. Our objective is twofold: first, we introduce a novel data-driven unsupervised approach to compute latencies and amplitude of ERP components accurately on an individual-subject basis and reconfirm earlier findings. Second, we demonstrate that in multisensory environments, MMN generators seem to reflect a significant overlap of "modality-specific" and "modality-independent" information processing while P300 generators mark a shift toward completely "modality-independent" processing. Advancing earlier understanding that multisensory contexts speed up early sensory processing, our study reveals that temporal facilitation extends to even the later components of prediction error processing, using EEG experiments. Such knowledge can be of value to clinical research for characterizing the key developmental stages of lifespan aging, schizophrenia, and depression.

Spectral and phase-coherence correlates of impaired auditory mismatch negativity (MMN) in schizophrenia: A MEG study.

Reduced auditory mismatch negativity (MMN) is robustly impaired in schizophrenia. However, mechanisms underlying dysfunctional MMN generation remain incompletely understood. This study aimed to examine the role of evoked spectral power and phase-coherence towards deviance detection and its impairments in schizophrenia. Magnetoencephalography data was collected in 16 male schizophrenia patients and 16 male control participants during an auditory MMN paradigm. Analyses of event-related fields (ERF), spectral power and inter-trial phase-coherence (ITPC) focused on Heschl's gyrus, superior temporal gyrus, inferior/medial frontal gyrus and thalamus. MMNm ERF amplitudes were reduced in patients in temporal, frontal and subcortical regions, accompanied by decreased theta-band responses, as well as by a diminished gamma-band response in auditory cortex. At theta/alpha frequencies, ITPC to deviant tones was reduced in patients in frontal cortex and thalamus. Patients were also characterized by aberrant responses to standard tones as indexed by reduced theta-/alpha-band power and ITPC in temporal and frontal regions. Moreover, stimulus-specific adaptation was decreased at theta/alpha frequencies in left temporal regions, which correlated with reduced MMNm spectral power and ERF amplitude. Finally, phase-reset of alpha-oscillations after deviant tones in left thalamus was impaired, which correlated with impaired MMNm generation in auditory cortex. Importantly, both non-rhythmic and rhythmic components of spectral activity contributed to the MMNm response. Our data indicate that deficits in theta-/alpha- and gamma-band activity in cortical and subcortical regions as well as impaired spectral responses to standard sounds could constitute potential mechanisms for dysfunctional MMN generation in schizophrenia, providing a novel perspective towards MMN deficits in the disorder.

Mismatch negativity generation in subjects at risk for psychosis: source analysis is more sensitive than surface electrodes in risk prediction.

Deficits of mismatch negativity (MMN) in patients with schizophrenia have been demonstrated many times and there is growing evidence that alterations of MMN already exist in individuals at risk for psychosis. The present study examines differences in MMN between subjects fulfilling ultra-high risk (UHR) or only basic symptoms criteria and it addresses the question, if MMN source analysis can improve prediction of transition to psychosis. The MMN to duration, frequency, and intensity deviants was recorded in 50 healthy controls and 161 individuals at risk for psychosis classified into three subgroups: only basic symptoms (n = 74), only ultra-high risk (n = 13) and persons who fulfill both risk criteria (n = 74). Based on a three-source model of MMN generation, we conducted an MMN source analysis and compared the amplitudes of surface electrodes and sources among the three groups. Significant differences in MMN generation among the four groups were revealed at surface electrodes Cz and C4 (p < 0.05) and at the frontal source (p < 0.001) for duration deviant stimuli. The 15 subjects from the risk groups who subsequently developed a manifest psychosis had a significantly lower MMN amplitude at frontal source (p = 0.019) without showing significant differences at surface electrodes. Low activity at frontal MMN source increased the risk of transition to manifest disease by the factor 3.12 in UHR subjects. MMN activity differed significantly between subjects presenting only basic symptoms and subjects which additionally meet UHR criteria. The largest differences between groups as well as between individuals with and without transition were observed at the frontal source. The present results suggest that source analysis is more sensitive than surface electrodes in psychosis risk prediction by MMN.

Mismatch negativity as an early biomarker of cognitive impairment in schizophrenia

BackgroundDue to its disturbance in schizophrenic patients, mismatch negativity (MMN) generation is believed to be a potential biomarker for recognizing primary impairments in auditory sensory processing during the course of the disease. However, great controversy exists regarding the type and onset of MMN-related impairments, with the deficits to frequency deviants is more debatable. This cross-sectional, case–control study was conducted to assess the cognitive functions among 33 eligible Egyptian schizophrenics (15 early and 18 chronic), and 30 matched healthy controls by assessing their psychometric tests and correlating them to the coexisting frequency deviant MMN responses (using both tone and speech stimuli).ResultsDeficits in frequency MMN and neuropsychological tests were evident among early and chronic schizophrenics compared to their matched control counterparts, and also between early versus chronic schizophrenia in favor of the later. MMN deficits to speech stimuli were more elicited than tone stimuli among schizophrenics. Moreover, significant correlations were identified between MMN parameters and the results of psychiatric cognitive scales.ConclusionsWe demonstrated that frequency-deviant MMN deficits are evident feature among the enrolled Egyptian schizophrenics. The cognitive functions as indexed by MMN seem affected early, with the striking decrease of MMN amplitude and delay of latency point towards the progression of the illness. The normal lateralization of MMN was absent in chronic schizophrenia. These findings could be helpful in using the MMN as an additional objective tool for confirming cognitive impairments among schizophrenics and to differentiate between early- and chronic-schizophrenic patients for medico-legal purposes and clinical implication for medications.

Atypical prediction error learning is associated with prodromal symptoms in individuals at clinical high risk for psychosis

Reductions in the auditory mismatch negativity (MMN) have been well-demonstrated in schizophrenia rendering it a promising biomarker for understanding the emergence of psychosis. According to the predictive coding theory of psychosis, MMN impairments may reflect disturbances in hierarchical information processing driven by maladaptive precision-weighted prediction errors (pwPEs) and enhanced belief updating. We applied a hierarchical Bayesian model of learning to single-trial EEG data from an auditory oddball paradigm in 31 help-seeking antipsychotic-naive high-risk individuals and 23 healthy controls to understand the computational mechanisms underlying the auditory MMN. We found that low-level sensory and high-level volatility pwPE expression correlated with EEG amplitudes, coinciding with the timing of the MMN. Furthermore, we found that prodromal positive symptom severity was associated with increased expression of sensory pwPEs and higher-level belief uncertainty. Our findings provide support for the role of pwPEs in auditory MMN generation, and suggest that increased sensory pwPEs driven by changes in belief uncertainty may render the environment seemingly unpredictable. This may predispose high-risk individuals to delusion-like ideation to explain this experience. These results highlight the value of computational models for understanding the pathophysiological mechanisms of psychosis.

Effects of awareness and task relevance on neurocomputational models of mismatch negativity generation

Detection of regularities and their violations in sensory input is key to perception. Violations are indexed by an early EEG component called the mismatch negativity (MMN) – even if participants are distracted or unaware of the stimuli. On a mechanistic level, two dominant models have been suggested to contribute to the MMN: adaptation and prediction. Whether and how context conditions, such as awareness and task relevance, modulate the mechanisms of MMN generation is unknown. We conducted an EEG study disentangling influences of task relevance and awareness on the visual MMN. Then, we estimated different computational models for the generation of single-trial amplitudes in the MMN time window. Amplitudes were best explained by a prediction error model when stimuli were task-relevant but by an adaptation model when task-irrelevant and unaware. Thus, mismatch generation does not rely on one predominant mechanism but mechanisms vary with task relevance of stimuli.

P489. Cell-Type and Frequency-Specific Circuit for Mismatch Negativity in Mice

Processing sensory information in line with concurrent context is disrupted in schizophrenia. Mismatch negativity (MMN) is an EEG event related potential that indexes how early sensory cortical responses differ to contextually unexpected events. Importantly, reduced auditory and visual MMN is a biomarker of schizophrenia. Despite this disease relevance, a circuit-level understanding of MMN generation is missing. Our past work in mouse visual cortex (V1) shows that the generation of a rodent analogue of MMN relies on both local interneurons and feedback input from higher areas of cortex.

A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex–entorhinal cortex–hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

The Adaptation Model Offers a Challenge for the Predictive Coding Account of Mismatch Negativity.

An unpredictable stimulus elicits a stronger event-related response than a high-probability stimulus. This differential in response magnitude is termed the mismatch negativity (MMN). Over the past decade, it has become increasingly popular to explain the MMN terms of predictive coding, a proposed general principle for the way the brain realizes Bayesian inference when it interprets sensory information. This perspective article is a reminder that the issue of MMN generation is far from settled, and that an alternative model in terms of adaptation continues to lurk in the wings. The adaptation model has been discounted because of the unrealistic and simplistic fashion in which it tends to be set up. Here, simulations of auditory cortex incorporating a modern version of the adaptation model are presented. These show that locally operating short-term synaptic depression accounts both for adaptation due to stimulus repetition and for MMN responses. This happens even in cases where adaptation has been ruled out as an explanation of the MMN (e.g., in the stimulus omission paradigm and the multi-standard control paradigm). Simulation models that would demonstrate the viability of predictive coding in a similarly multifaceted way are currently missing from the literature, and the reason for this is discussed in light of the current results.

Acute effects of Δ9-tetrahydrocannabinol and cannabidiol on auditory mismatch negativity.

Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity. The current study investigated the acute effects of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN). In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8mg; (3) CBD 400mg; (4) THC 8mg + CBD 4mg [THC + CBDlow]; (5) THC 12mg + CBD 400mg [THC + CBDhigh]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each). Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users. The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure.

Electrophysiological Signatures of Perceiving Alternated Tone in Mandarin Chinese: Mismatch Negativity to Underlying Tone Conflict.

Although phonological alternation is prevalent in languages, the process of perceiving phonologically alternated sounds is poorly understood, especially at the neurolinguistic level. We examined the process of perceiving Mandarin 3rd tone sandhi (T3 + T3 → T2 + T3) with a mismatch negativity (MMN) experiment. Our design has two independent variables (whether the deviant undergoes tone sandhi; whether the standard and the deviant have matched underlying tone). These two independent variables modulated ERP responses in both the first and the second syllables. Notably, despite the apparent segmental conflict between the standard and the deviant in all conditions, MMN is only observed when neither the standard nor the deviant undergoes tone sandhi, suggesting that discovering the underlying representation of an alternated sound could interfere with the generation of MMN. A tentative model with three hypothesized underlying processing mechanisms is proposed to explain the observed latency and amplitude differences across conditions. The results are also discussed in light of the potential electrophysiological signatures involved in the process of perceiving alternated sounds.

Machine-learning-based diagnosis of drug-naive adult patients with attention-deficit hyperactivity disorder using mismatch negativity

Relatively little is investigated regarding the neurophysiology of adult attention-deficit/hyperactivity disorder (ADHD). Mismatch negativity (MMN) is an event-related potential component representing pre-attentive auditory processing, which is closely associated with cognitive status. We investigated MMN features as biomarkers to classify drug-naive adult patients with ADHD and healthy controls (HCs). Sensor-level features (amplitude and latency) and source-level features (source activation) of MMN were investigated and compared between the electroencephalograms of 34 patients with ADHD and 45 HCs using a passive auditory oddball paradigm. Correlations between MMN features and ADHD symptoms were analyzed. Finally, we applied machine learning to differentiate the two groups using sensor- and source-level features of MMN. Adult patients with ADHD showed significantly lower MMN amplitudes at the frontocentral electrodes and reduced MMN source activation in the frontal, temporal, and limbic lobes, which were closely associated with MMN generators and ADHD pathophysiology. Source activities were significantly correlated with ADHD symptoms. The best classification performance for adult ADHD patients and HCs showed an 81.01% accuracy, 82.35% sensitivity, and 80.00% specificity based on MMN source activity features. Our results suggest that abnormal MMN reflects the adult ADHD patients’ pathophysiological characteristics and might serve clinically as a neuromarker of adult ADHD.

A Critical Review of the Deviance Detection Theory of Mismatch Negativity

Mismatch negativity (MMN) is a component of the difference waveform derived from passive auditory oddball stimulation. Since its inception in 1978, this has become one of the most popular event-related potential techniques, with over two-thousand published studies using this method. This is a testament to the ingenuity and commitment of generations of researchers engaging in basic, clinical and animal research. Despite this intensive effort, high-level descriptions of the mechanisms theorized to underpin mismatch negativity have scarcely changed over the past four decades. The prevailing deviance detection theory posits that MMN reflects inattentive detection of difference between repetitive standard and infrequent deviant stimuli due to a mismatch between the unexpected deviant and a memory representation of the standard. Evidence for these mechanisms is inconclusive, and a plausible alternative sensory processing theory considers fundamental principles of sensory neurophysiology to be the primary source of differences between standard and deviant responses evoked during passive oddball stimulation. By frequently being restated without appropriate methods to exclude alternatives, the potentially flawed deviance detection theory has remained largely dominant, which could lead some researchers and clinicians to assume its veracity implicitly. It is important to have a more comprehensive understanding of the source(s) of MMN generation before its widespread application as a clinical biomarker. This review evaluates issues of validity concerning the prevailing theoretical account of mismatch negativity and the passive auditory oddball paradigm, highlighting several limitations regarding its interpretation and clinical application.

Perceptual Asymmetries and Auditory Processing of Estonian Quantities.

Similar to visual perception, auditory perception also has a clearly described “pop-out” effect, where an element with some extra feature is easier to detect among elements without an extra feature. This phenomenon is better known as auditory perceptual asymmetry. We investigated such asymmetry between shorter or longer duration, and level or falling of pitch of linguistic stimuli that carry a meaning in one language (Estonian), but not in another (Russian). For the mismatch negativity (MMN) experiment, we created four different types of stimuli by modifying the duration of the first vowel [ɑ] (170, 290 ms) and pitch contour (level vs. falling pitch) of the stimuli words (‘SATA,’ ‘SAKI’). The stimuli were synthesized from Estonian words (‘SATA,’ ‘SAKI’) and follow the Estonian language three-way quantity system, which incorporates tonal features (falling pitch contour) together with temporal patterns. This made the meaning of the word dependent on the combination of both features and allows us to compare the relative contribution of duration and pitch contour in discrimination of language stimuli in the brain via MMN generation. The participants of the experiment were 12 Russian native speakers with little or no experience in Estonian and living in Estonia short-term, and 12 Estonian native speakers (age 18–27 years). We found that participants’ perception of the linguistic stimuli differed not only according to the physical features but also according to their native language, confirming that the meaning of the word interferes with the early automatic processing of phonological features. The GAMM and ANOVA analysis of the reversed design results showed that the deviant with longer duration among shorter standards elicited a MMN response with greater amplitude than the short deviant among long standards, while changes in pitch contour (falling vs. level pitch) produced neither strong MMN nor asymmetry. Thus, we demonstrate the effect of language background on asymmetric perception of linguistic stimuli that aligns with those of previous studies (Jaramillo et al., 2000), and contributes to the growing body of knowledge supporting auditory perceptual asymmetry.

Auditory Mismatch Negativity in Clinical High Risk for Psychosis and Schizophrenia, and Association With Symptoms and Cognition

Primary Auditory Cortex processing deficits are a core feature of schizophrenia, reflected in impaired generation of auditory mismatch negativity (MMN), an EEG-derived event-related potential. Auditory MMN impairments in response to deviant stimuli can predict outcome among clinical high risk (CHR) for psychosis subjects. We hypothesized that auditory MMN deficits in CHR patients would be associated with symptom severity and cognitive dysfunction

Deficits in Pre-attentive Processing of Spatial Location and Negative Symptoms in Subjects at Clinical High Risk for Schizophrenia.

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

S25-4 Auditory processing and sensory memory related to the generation of auditory mismatch negativity

S25-4 Auditory processing and sensory memory related to the generation of auditory mismatch negativity

CDP-choline and galantamine, a personalized α7 nicotinic acetylcholine receptor targeted treatment for the modulation of speech MMN indexed deviance detection in healthy volunteers: a pilot study.

The combination of CDP-choline, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, with galantamine, a positive allosteric modulator of nAChRs, is believed to counter the fast desensitization rate of the α7 nAChRs and may be of interest for schizophrenia (SCZ) patients. Beyond the positive and negative clinical symptoms, deficits in early auditory prediction-error processes are also observed in SCZ. Regularity violations activate these mechanisms that are indexed by electroencephalography-derived mismatch negativity (MMN) event-related potentials (ERPs) in response to auditory deviance. This pilot study in thirty-three healthy humans assessed the effects of an optimized α7 nAChR strategy combining CDP-choline (500 mg) with galantamine (16 mg) on speech-elicited MMN amplitude and latency measures. The randomized, double-blinded, placebo-controlled, and counterbalanced design with a baseline stratification method allowed for assessment of individual response differences. Increases in MMN generation mediated by the acute CDP-choline/galantamine treatment in individuals with low baseline MMN amplitude for frequency, intensity, duration, and vowel deviants were revealed. These results, observed primarily at temporal recording sites overlying the auditory cortex, implicate α7 nAChRs in the enhancement of speech deviance detection and warrant further examination with respect to dysfunctional auditory deviance processing in individuals with SCZ.

Change in the Neural Response to Auditory Deviance Following Cognitive Therapy for Hallucinations in Patients With Schizophrenia.

Adjunctive psychotherapeutic approaches recommended for patients with schizophrenia (SZ) who are fully or partially resistant to pharmacotherapy have rarely utilized biomarkers to enhance the understanding of treatment-effective mechanisms. As SZ patients with persistent auditory verbal hallucinations (AVH) frequently evidence reduced neural responsiveness to external auditory stimulation, which may impact cognitive and functional outcomes, this study examined the effects of cognitive behavioral therapy for voices (CBTv) on clinical and AVH symptoms and the sensory processing of auditory deviants as measured with the electroencephalographically derived mismatch negativity (MMN) response. Twenty-four patients with SZ and AVH were randomly assigned to group CBTv treatment or a treatment as usual (TAU) condition. Patients in the group CBTv condition received treatment for 5 months while the matched control patients received TAU for the same period, followed by 5 months of group CBTv. Assessments were conducted at baseline and at the end of treatment. Although not showing consistent changes in the frequency of AVHs, CBTv (vs. TAU) improved patients' appraisal (p = 0.001) of and behavioral/emotional responses to AVHs, and increased both MMN generation (p = 0.001) and auditory cortex current density (p = 0.002) in response to tone pitch deviants. Improvements in AVH symptoms were correlated with change in pitch deviant MMN and current density in left primary auditory cortex. These findings of improved auditory information processing and symptom-response attributable to CBTv suggest potential clinical and functional benefits of psychotherapeutical approaches for patients with persistent AVHs.

Putative TAAR5 agonist alpha-NETA affects event-related potentials in oddball paradigm in awake mice

Trace amines have been reported to be neuromodulators of monoaminergic systems. Trace amines receptor 5 (TAAR5) is expressed in several regions of mice central nervous system, such as amygdala, arcuate nucleus and ventromedial hypothalamus, but very limited information is available on its functional role. The purpose of this study is to examine the effect of TAAR5 agonist alpha-NETA on the generation of mismatch negativity (MMN) analogue in C57BL/6 mice. Event-related potentials have been recorded from awake mice in oddball paradigms before and after the alpha-NETA administration. Alpha-NETA has been found to decrease N40 MMN-like difference, which resulted from the increased response to standard stimuli. An opposite effect has been found for the P80 component: the amplitude increased in response both to standard and deviant stimuli. A significant increase in N40 peak latency after the alpha-NETA administration has been found. This may suggest a reduced speed of information processing similar to the increase in P50 and N100 components latencies in schizophrenia patients. These results provide new evidence for a role of TAAR5 in cognitive processes.