Mismatch Negativity Generation Research Articles

Preattentive dysfunction in patients with bipolar disorder as revealed by the pitch-mismatch negativity: a magnetoencephalography (MEG) study.

Mismatch negativity (MMN) and its magnetic counterpart (MMNm) are thought to reflect an automatic process that detects a difference between an incoming stimulus and the sensory memory trace of preceding stimuli. In patients with schizophrenia, an attenuation of the MMN/MMNm amplitude has been repeatedly reported. Heschl's gyrus (HG) is one of the major generators of MMN and the functional alteration of HG has been reported in patients with bipolar disorder. The present study investigated the pitch-MMNm in patients with bipolar disorder using whole-head 306-ch magnetoencephalography (MEG). Twenty-two patients and 22 healthy controls participated in this study. Subjects were presented with two types of auditory stimulus sequences. One consisted of 1,000 Hz standards (probability = 90%) and 1,200 Hz deviants (probability = 10%), and the other consisted of 1,000 Hz standards (90%) and 1,200 Hz deviants (10%). These two tasks were each performed twice. Event-related brain responses to standard tones were subtracted from responses to deviant tones. Patients with bipolar disorder showed a significant bilateral reduction in magnetic global field power (mGFP) amplitudes (p = 0.02) and dipole moments of the MMNm (p = 0.04) compared with healthy controls. Patients with admission experience showed significantly reduced mGFP amplitudes of MMNm compared with patients without admission experience (p = 0.004). Additionally, patients with more severe manic symptoms had smaller mGFP amplitudes of MMNm (ρ = -0.50, p = 0.05). The results of this study suggest that patients with bipolar disorder may exhibit preattentive auditory dysfunction indexed by reduced pitch-MMNm responses. Pitch-MMNm could be a potential trait marker reflecting the global severity of bipolar disorder.

Mismatch negativity indexes illness-specific impairments of cortical plasticity in schizophrenia: A comparison with bipolar disorder and Alzheimer's disease

Cognitive impairment is an important predictor of functional outcome in patients with schizophrenia, yet its neurobiology is still incompletely understood. Neuropathological evidence of impaired synaptic connectivity and NMDA receptor-dependent transmission in superior temporal cortex motivated us to explore the correlation of in vivo mismatch negativity (MMN) with cognitive status in patients with schizophrenia. MMN elicited in a roving stimulus paradigm displayed a response proportional to the number of stimulus repetitions (memory trace effect). Preliminary evidence in patients with chronic schizophrenia suggests that attenuation of this MMN memory trace effect was correlated with the degree of neuropsychological memory dysfunction. Here we present data from a larger confirmatory study in patients with schizophrenia, bipolar disorder, probable Alzheimer's disease and healthy controls. We observed that the diminution of the MMN memory trace effect and its correlation with memory impairment was only found in the schizophrenia group. Recent pharmacological studies using the roving paradigm suggest that attenuation of the MMN trace effect can be understood as abnormal modulation of NMDA receptor-dependent plasticity. We suggest that the convergence of the previously identified synaptic pathology in supragranular cortical layers with the intracortical locus of MMN generation accounts for the remarkable robustness of MMN impairments in schizophrenia. We further speculate that this layer-specific synaptic pathology identified in supragranular neurons plays a pivotal computational role, by weakening the encoding and propagation of prediction errors to higher cortical modules. According to predictive coding theory such breakdown will have grave implications not only for perception, but also for higher-order cognition and may thus account for the MMN–cognition correlations observed here. Finally, MMN is a sensitive and specific biomarker for detecting the early prodromal phase of schizophrenia and is well suited for the exploration of novel cognition-enhancing agents in humans.

Temporo-frontal phase synchronization supports hierarchical network for mismatch negativity

ObjectiveWe performed an experiment designed to reveal the brain-regional network dynamics underlying both automatic and intentional auditory change detection as typically indexed by the mismatch negativity (MMN) event-related potential (ERP). MethodsHigh-density EEG was recorded while participants heard a stream of standard pure tones, into which occasional (14%) frequency deviants were inserted. In a first run they listened passively while watching a closed-captioned movie, whereas in a second run they pressed a button each time they detected a deviant while watching the movie with neither sound nor captioning. ResultsIndependent component analysis revealed independent components that we localized to temporal and frontal regional brain sources relevant to the generation of the MMN. Relative power in various oscillatory frequency bands, computed from a wavelet analysis on the time series of these independent components, was modulated by task demands and stimulus type, as was dynamic phase-locking between pairs of the independent components in those same frequency bands. ConclusionThese results support a hierarchical model of MMN generation that emphasizes information processing and transfer between temporal and frontal brain regions. SignificanceIn addition to enhancing the use of the MMN to evaluate some aspects of central auditory functioning, these results could be important for the evaluation of alterations in other cognitive functions or in consciousness.

Oscillatory Underpinnings of Mismatch Negativity and Their Relationship with Cognitive Function in Patients with Schizophrenia

BackgroundImpairments in mismatch negativity (MMN) generation have been consistently reported in patients with schizophrenia. However, underlying oscillatory activity of MMN deficits in schizophrenia and the relationship with cognitive impairments have not been investigated in detail. Time-frequency power and phase analyses can provide more detailed measures of brain dynamics of MMN deficits in schizophrenia.Method21 patients with schizophrenia and 21 healthy controls were tested with a roving frequency paradigm to generate MMN. Time-frequency domain power and phase-locking (PL) analysis was performed on all trials using short-time Fourier transforms with Hanning window tapering. A comprehensive battery (CANTAB) was used to assess neurocognitive functioning.ResultsMean MMN amplitude was significantly lower in patients with schizophrenia (95% CI 0.18 - 0.77). Patients showed significantly lower EEG power (95% CI -1.02 - -0.014) in the ~4-7 Hz frequency range (theta band) between 170 and 210 ms. Patients with schizophrenia showed cognitive impairment in multiple domains of CANTAB. However, MMN impairments in amplitude and power were not correlated with clinical measures, medication dose, social functioning or neurocognitive performance.ConclusionThe findings from this study suggested that while MMN may be a useful marker to probe NMDA receptor mediated mechanisms and associated impairments in gain control and perceptual changes, it may not be a useful marker in association with clinical or cognitive changes. Trial-by-trial EEG power analysis can be used as a measure of brain dynamics underlying MMN deficits which also can have implications for the use of MMN as a biomarker for drug discovery.

S12-4. Simultaneous fMRI-EEG-DTI recording of MMN in schizophrenia

Objectives: Here we investigated cognitive impairments reflected by omission mismatch negativity (MMN) aberration in schizophrenia. Methods: We recorded EEG during event-related functional MRI (fMRI) followed by diffusion tensor imaging (DTI) in 14 healthy volunteers and 12 schizophrenic patients. The fMRI data was analyzed on SPM08 and blood oxygenation level-dependent signals (BOLD) signal changes were calculated in region of interest analysis using MarsBaR software. In DTI analysis, the areas significantly deteriorated in patients compared to controls were detected with tract-based spatial statistics. Fractional anisotropy (FA) in white matter fibers related to each area was compared between groups using tract-specific analysis. The clinical manifestation in the patients was evaluated using the Positive and Negative Syndrome Scale (PANSS). Results: The correlation analysis on SPM revealed significant correlation between FA of the right uncinate fasciculus and BOLD activity in the left Insula. BOLD activity of the right anterior cingulate, the right corpus callosum and right insula significantly correlated with PANSS scores. Conclusion: The dysfunction of Insula, the uncinate fasciculus and the corpus callosum, as well as the temporal lobe and the anterior cingulate gyrus, may specifically contribute to MMN aberration of schizophrenic patients and clinical manifestations reflecting their impaired MMN generation.

Fronto-temporal interactions in the theta-band during auditory deviant processing

Mismatch negativity (MMN) is a negative component of event-related potential (ERP) that reflects auditory deviant detection. Previous studies repeatedly suggested that MMN is generated by the fronto–temporal network. However, it is still unclear how the frontal and temporal areas interact. To verify this, we observed the spatiotemporal pattern of inter-regional functional connectivity using phase synchrony and Granger causality, by analyzing event-related electroencephalograms (EEGs) elicited by standard and deviant tones in an oddball paradigm. Strong theta-band phase synchrony and bidirectional Granger causality were observed between the frontal and temporal areas during the processing of auditory deviants, especially at the temporal interval of MMN. Our results support the hypothesis that fronto–temporal interactions are crucial to the generation of MMN during auditory deviant processing.

Rhythmic and melodic deviations in musical sequences recruit different cortical areas for mismatch detection

The mismatch negativity (MMN), an event-related potential (ERP) representing the violation of an acoustic regularity, is considered as a pre-attentive change detection mechanism at the sensory level on the one hand and as a prediction error signal on the other hand, suggesting that bottom-up as well as top-down processes are involved in its generation. Rhythmic and melodic deviations within a musical sequence elicit a MMN in musically trained subjects, indicating that acquired musical expertise leads to better discrimination accuracy of musical material and better predictions about upcoming musical events. Expectation violations to musical material could therefore recruit neural generators that reflect top-down processes that are based on musical knowledge. We describe the neural generators of the musical MMN for rhythmic and melodic material after a short-term sensorimotor-auditory (SA) training. We compare the localization of musical MMN data from two previous MEG studies by applying beamformer analysis. One study focused on the melodic harmonic progression whereas the other study focused on rhythmic progression. The MMN to melodic deviations revealed significant right hemispheric neural activation in the superior temporal gyrus (STG), inferior frontal cortex (IFC), and the superior frontal (SFG) and orbitofrontal (OFG) gyri. IFC and SFG activation was also observed in the left hemisphere. In contrast, beamformer analysis of the data from the rhythm study revealed bilateral activation within the vicinity of auditory cortices and in the inferior parietal lobule (IPL), an area that has recently been implied in temporal processing. We conclude that different cortical networks are activated in the analysis of the temporal and the melodic content of musical material, and discuss these networks in the context of the dual-pathway model of auditory processing.

Visual mismatch negativity in the dorsal stream is independent of concurrent visual task difficulty.

The manipulation of attention can produce mismatch negativity-like components that are not necessarily connected to the unintentional sensory registration of the violation of probability-based regularity. For clinical purposes, attentional bias should be quantified because it can vary substantially among subjects and can decrease the specificity of the examination. This experiment targets the role of attention in the generation of visual mismatch negativity (vMMN). The visual regularity was generated by a sequence of two radial motions while subjects focused on visual tasks in the central part of the display. Attentional load was systematically varied and had three levels, no-load, easy, and difficult. Rare, deviant, and frequent standard motions were presented with a 10/60 ratio in oddball sequences. Data from 12 subjects was recorded from 64 channels and processed. vMMN was identified within the interval of 142–198 ms. The mean amplitude was evaluated during the aforementioned interval in the parietal and fronto-central regions. A general linear model for repeated measures was applied to the mean amplitude with a three-factor design and showed a significant difference [F(1, 11) = 17.40, p = 0.002] between standard and deviant stimuli and between regions [F(1, 11) = 8.40, p = 0.01]; however, no significant effect of the task [F(2, 22) = 1.26, p = 0.30] was observed. The unintentional detection of irregularity during the processing of the visual motion was independent of the attentional load associated with handling the central visual task. The experiment did not demonstrate an effect of attentional load manipulation on mismatch negativity (MMN) induced by the motion-sequence, which supports the clinical utility of this examination. However, used stimulation paradigm should be further optimized to generate mismatch negativity that is stable enough to be usable not only for group comparisons but also for a single subject assessment.

Modeling ketamine effects on synaptic plasticity during the mismatch negativity.

This paper presents a model-based investigation of mechanisms underlying the reduction of mismatch negativity (MMN) amplitudes under the NMDA-receptor antagonist ketamine. We applied dynamic causal modeling and Bayesian model selection to data from a recent ketamine study of the roving MMN paradigm, using a cross-over, double-blind, placebo-controlled design. Our modeling was guided by a predictive coding framework that unifies contemporary "adaptation" and "model adjustment" MMN theories. Comparing a series of dynamic causal models that allowed for different expressions of neuronal adaptation and synaptic plasticity, we obtained 3 major results: 1) We replicated previous results that both adaptation and short-term plasticity are necessary to explain MMN generation per se; 2) we found significant ketamine effects on synaptic plasticity, but not adaptation, and a selective ketamine effect on the forward connection from left primary auditory cortex to superior temporal gyrus; 3) this model-based estimate of ketamine effects on synaptic plasticity correlated significantly with ratings of ketamine-induced impairments in cognition and control. Our modeling approach thus suggests a concrete mechanism for ketamine effects on MMN that correlates with drug-induced psychopathology. More generally, this demonstrates the potential of modeling for inferring on synaptic physiology, and its pharmacological modulation, from electroencephalography data.

Delayed preattentional functioning in early psychosis patients with cannabis use

Cannabis use is prevalent among the early psychosis (EP) population. The event-related potentials, mismatch negativity (MMN) and P3a are reduced in EP. Cannabinoids have been shown to modulate N-methyl-D-aspartate receptors which are involved in MMN generation. This study is the first to investigate the effects of cannabis use on MMN/P3a in EP. EP was defined as a history of psychosis or psychotic symptoms with no progression to date to chronic schizophrenia. Twenty-two EP patients with cannabis use (EP + CANN), 22 non-cannabis-using EP patients (EP-CANN) and 21 healthy controls participated in this study. MMN/P3a was elicited using a two-tone, auditory paradigm with 8% duration deviants. As expected, EP-CANN showed marked reductions in MMN/P3a amplitudes compared to controls. However, EP + CANN showed evidence of a different pattern of neurophysiological expression of MMN/P3a compared to non-using patients, most notably in terms of delayed frontal MMN/P3a latencies. This study provides further evidence that MMN/P3a deficits are present during early psychosis and suggests that this biomarker may have utility in differentiating substance- from non-substance-related psychoses.

Spectrotemporal processing drives fast access to memory traces for spoken words

The Mismatch Negativity (MMN) component of the event-related potentials is generated when a detectable spectrotemporal feature of the incoming sound does not match the sensory model set up by preceding repeated stimuli. MMN is enhanced at frontocentral scalp sites for deviant words when compared to acoustically similar deviant pseudowords, suggesting that automatic access to long-term memory traces for spoken words contributes to MMN generation. Does spectrotemporal feature matching also drive automatic lexical access? To test this, we recorded human auditory event-related potentials (ERPs) to disyllabic spoken words and pseudowords within a passive oddball paradigm. We first aimed at replicating the word-related MMN enhancement effect for Spanish, thereby adding to the available cross-linguistic evidence (e.g., Finnish, English). We then probed its resilience to spectrotemporal perturbation by inserting short (20ms) and long (120ms) silent gaps between first and second syllables of deviant and standard stimuli. A significantly enhanced, frontocentrally distributed MMN to deviant words was found for stimuli with no gap. The long gap yielded no deviant word MMN, showing that prior expectations of word form limits in a given language influence deviance detection processes. Crucially, the insertion of a short gap suppressed deviant word MMN enhancement at frontocentral sites. We propose that spectrotemporal point-wise matching constitutes a core mechanism for fast serial computations in audition and language, bridging sensory and long-term memory systems.

The duration of predictive models underlying the generation of visual mismatch negativity

The duration of predictive models underlying the generation of visual mismatch negativity

Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia

Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia

Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia

Preclinical and clinical research suggests that the endogenous cannabinoid system is involved in cognitive impairments related to schizophrenia. In particular, the deficient generation of mismatch negativity (MMN) indicating auditory sensory memory is a characteristic finding in schizophrenic patients. Experimental studies implicate deficient N-methyl-D: -aspartate (NMDA) receptor functioning in such abnormalities. The primary aim of this study was to investigate the effects of the cannabinoid CB(1) receptor antagonist rimonabant on MMN deficits in the NMDA receptor antagonist model of schizophrenia by using ketamine. Twenty-four healthy male subjects participated in a randomized, double-blind, placebo-controlled cross-over study with subanesthetic doses of intravenous ketamine. The MMNs to frequency and duration deviants were elicited within an auditory oddball paradigm and recorded by a 32-channel EEG. Psychopathology was assessed using the Psychotomimetic States Inventory. Twenty subjects completed both experimental sessions. Ketamine infusion had no significant effect on MMN amplitudes in both deviance conditions. In contrast to placebo, co-administration of rimonabant produced significant deficits in MMN amplitudes to duration deviants at electrode position Fz. The results point to the involvement of the endogenous cannabinoid system in auditory sensory memory as a cognitive key feature in schizophrenia. They particularly suggest that CB(1) receptor antagonism may impair cognitive performance by a disturbed interaction between endocannabinergic activity and glutamatergic neurotransmission implied in schizophrenia.

Pitch Discrimination Learning: Specificity for Pitch and Harmonic Resolvability, and Electrophysiological Correlates

Multiple-hour training on a pitch discrimination task dramatically decreases the threshold for detecting a pitch difference between two harmonic complexes. Here, we investigated the specificity of this perceptual learning with respect to the pitch and the resolvability of the trained harmonic complex, as well as its cortical electrophysiological correlates. We trained 24 participants for 12 h on a pitch discrimination task using one of four different harmonic complexes. The complexes differed in pitch and/or spectral resolvability of their components by the cochlea, but were filtered into the same spectral region. Cortical-evoked potentials and a behavioral measure of pitch discrimination were assessed before and after training for all the four complexes. The change in these measures was compared to that of two control groups: one trained on a level discrimination task and one without any training. The behavioral results showed that learning was partly specific to both pitch and resolvability. Training with a resolved-harmonic complex improved pitch discrimination for resolved complexes more than training with an unresolved complex. However, we did not find evidence that training with an unresolved complex leads to specific learning for unresolved complexes. Training affected the P2 component of the cortical-evoked potentials, as well as a later component (250-400 ms). No significant changes were found on the mismatch negativity (MMN) component, although a separate experiment showed that this measure was sensitive to pitch changes equivalent to the pitch discriminability changes induced by training. This result suggests that pitch discrimination training affects processes not measured by the MMN, for example, processes higher in level or parallel to those involved in MMN generation.

Common or Redundant Neural Circuits for Duration Processing across Audition and Touch

Certain features of objects or events can be represented by more than a single sensory system, such as roughness of a surface (sight, sound, and touch), the location of a speaker (audition and sight), and the rhythm or duration of an event (by all three major sensory systems). Thus, these properties can be said to be sensory-independent or amodal. A key question is whether common multisensory cortical regions process these amodal features, or does each sensory system contain its own specialized region(s) for processing common features? We tackled this issue by investigating simple duration-detection mechanisms across audition and touch; these systems were chosen because fine duration discriminations are possible in both. The mismatch negativity (MMN) component of the human event-related potential provides a sensitive metric of duration processing and has been elicited independently during both auditory and somatosensory investigations. Employing high-density electroencephalographic recordings in conjunction with intracranial subdural recordings, we asked whether fine duration discriminations, represented by the MMN, were generated in the same cortical regions regardless of the sensory modality being probed. Scalp recordings pointed to statistically distinct MMN topographies across senses, implying differential underlying cortical generator configurations. Intracranial recordings confirmed these noninvasive findings, showing generators of the auditory MMN along the superior temporal gyrus with no evidence of a somatosensory MMN in this region, whereas a robust somatosensory MMN was recorded from postcentral gyrus in the absence of an auditory MMN. The current data clearly argue against a common circuitry account for amodal duration processing.

Mismatch negativity generation deficits and selective monoaminergic treatments in patients with major depression

Mismatch negativity generation deficits and selective monoaminergic treatments in patients with major depression

Electrophysiological evidence for the hierarchical organization of auditory change detection in the human brain

Auditory change detection has been associated with mismatch negativity (MMN), an event-related potential (ERP) occurring at 100-250 ms after the onset of an acoustic change. Yet, single-unit recordings in animals suggest much faster novelty-specific responses in the auditory system. To investigate change detection in a corresponding early time range in humans, we measured the Middle Latency Response (MLR) and MMN during a controlled frequency oddball paradigm. In addition to MMN, an early effect of change detection was observed at about 40 ms after change onset reflected in an enhancement of the Nb component of the MLR. Both MMN and the Nb effect were shown to be free from confounding influences such as differences in refractoriness. This finding implies that early change detection processes exist in humans upstream of MMN generation, which supports the emerging view of a hierarchical organization of change detection expanding along multiple levels of the auditory pathway.

Epidural Auditory Event-Related Potentials in the Rat to Frequency and duration Deviants: Evidence of Mismatch Negativity?

The capacity of the human brain to detect deviance in the acoustic environment pre-attentively is reflected in a brain event-related potential (ERP), mismatch negativity (MMN). MMN is observed in response to the presentation of rare oddball sounds that deviate from an otherwise regular pattern of frequent background standard sounds. While the primate and cat auditory cortex (AC) exhibit MMN-like activity, it is unclear whether the rodent AC produces a deviant response that reflects deviance detection in a background of regularities evident in recent auditory stimulus history or differential adaptation of neuronal responses due to rarity of the deviant sound. We examined whether MMN-like activity occurs in epidural AC potentials in awake and anesthetized rats to high and low frequency and long and short duration deviant sounds. ERPs to deviants were compared with ERPs to common standards and also with ERPs to deviants when interspersed with many different standards to control for background regularity effects. High frequency (HF) and long duration deviant ERPs in the awake rat showed evidence of deviance detection, consisting of negative displacements of the deviant ERP relative to ERPs to both common standards and deviants with many standards. The HF deviant MMN-like response was also sensitive to the extent of regularity in recent acoustic stimulation. Anesthesia in contrast resulted in positive displacements of deviant ERPs. Our results suggest that epidural MMN-like potentials to HF sounds in awake rats encode deviance in an analogous manner to the human MMN, laying the foundation for animal models of disorders characterized by disrupted MMN generation, such as schizophrenia.

Acute Effects of Δ9-Tetrahydrocannabinol on the Auditory Evoked Mismatch Negativity are Modulated by theNRG1Gene

Reduced amplitudes of auditory mismatch negativity (MMN) are a robust finding in schizophrenia, indicating deficient auditory information processing. Cannabis-induced psychotic states may resemble schizophrenic disorders. Yet, as previously reported, Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, has no effect on MMN generation. The aim of this study was to investigate whether variations in the potential susceptibility gene for schizophrenia, neuregulin 1 (NRG1), modulate the effects of Δ9-THC on MMN generation in 22 healthy subjects. Our analysis showed that NRG1 (rs783406) was significantly associated with the MMN amplitude, particularly at central electrodes. These data indicate that variations within NRG1 may alter the sensitivity to the cognitive effects of cannabinoids.