Duration Mismatch Negativity Amplitudes Research Articles

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.

Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT3R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.

Mismatch negativity in patients with major depressive disorder: A meta-analysis

ObjectiveDeficits of mismatch negativity (MMN), a general index of echoic memory function, have been documented in patients with schizophrenia. However, it remains controversial whether patients with major depressive disorder (MDD) demonstrate MMN defects compared with healthy controls (HC). MethodsAfter screening 41 potential studies identified in PubMed and Medline, 13 studies consisting of 343 HC and 339 patients with MDD were included in the present meta-analysis. The effect sizes (Hedges’s g) with a random-effect and inverse-variance weighted model were estimated for the MMN amplitudes and latencies. The effects of different deviant types (i.e., frequency and duration) and of different illness stages (i.e., acute and chronic) on MMN were also examined. ResultsWe found that 1) MMN amplitudes (g = 1.273, p < 0.001) and latencies (g = 0.303, p = 0.027) to duration, but not frequency deviants, were significantly impaired in patients with MDD compared to HC; 2), acute patients exhibited lower MMN amplitudes (g = 1.735, p < 0.001) and prolonged MMN latencies (g = 0.461, p = 0.007) for the duration deviants compared to HC. Only the attenuated duration MMN amplitudes were detected in patients with chronic MDD (g = 0.822, p = 0.027); and 3) depressive symptoms did not significantly correlate with MMN responses. ConclusionsPatients with MDD demonstrated abnormal MMN responses to duration deviants compared to HC. SignificanceDuration MMN may constitute an electrophysiological indicator to differentiate HC from patients with MDD, particularly those in the acute stage.

Features of Duration Mismatch Negativity Around the Onset of Overt Psychotic Disorders: A Longitudinal Study.

Reduced amplitude of duration mismatch negativity (dMMN) has been reported in psychotic disorders and at-risk mental state (ARMS); however, few longitudinal MMN studies have examined the amplitude changes during the course of psychosis. We compared dMMN amplitude between ARMS individuals with later psychosis onset and those without, and we longitudinally examined potential dMMN changes around psychosis onset. Thirty-nine ARMS subjects and 22 healthy controls participated in this study. Of the 39 ARMS subjects, 11 transitioned to psychosis (at-risk mental state with later psychosis onset [ARMS-P]) during follow-up and 28 did not (at-risk mental state without later psychosis onset [ARMS-NP]). dMMN was measured twice using an auditory oddball paradigm with a mean interval of 2years. Follow-up dMMN data were available for all but four ARMS-P subjects. dMMN amplitude at baseline was smaller in ARMS-P subjects compared with control and ARMS-NP subjects. Additionally, ARMS-P subjects displayed a longitudinal decline in dMMN amplitude, which was not present in control and ARMS-P subjects. We also observed a progressive decline in dMMN amplitude during the transition period, suggesting dynamic brain changes associated with the psychosis onset. Our findings implicate dMMN amplitude as a biological predictor of future psychosis onset in high-risk individuals, which may be used for early detection and intervention of psychosis.

Reduced Sensitivity to Non-Fear-Related Stimulus Changes in Panic Disorder

Panic disorder (PD) is associated with increased body vigilance and reduced cognitive resources directed at non-fear-related stimuli, particularly in the absence of stimulus-rich environments. To date, only few studies have investigated whether this deficit in PD is reflected in reduced mismatch negativity (MMN), an event-related potential indexing preattentive sensitivity to unexpected stimulus changes. We tested 35 patients affected by PD and 42 matched healthy controls in an oddball paradigm, using frequency and duration deviant stimuli to measure auditory MMN. PD patients displayed reduced duration MMN amplitudes in comparison to healthy controls. No group differences were detected for duration MMN latency, as well as frequency MMN indices. Results support the notion of reduced processing of non-fear-related stimuli in PD patients, particularly with regard to the preattentive processing of sound duration deviants. Additionally, our findings are in line with clinical studies reporting divergent deficits in preattentive processing of frequency and duration deviants.

F14. REDUCED DURATION MISMATCH NEGATIVITY ASSOCIATED WITH DECREASED GLUTAMATE+GLUTAMINE LEVEL IN SUBJECTS AT CLINICAL HIGH-RISK FOR PSYCHOSIS

BackgroundAbnormal mismatch negativity (MMN), thought to be a putative marker of glutamatergic function, has been reported in non-Asian, first episode schizophrenia and clinical high-risk for psychosis (CHR) individuals as indicative of impairments in pre-attentive processes. However, reports of abnormal MMN in Asian populations are sparse, as well as its relationships to glutamate and γ–aminobutyric acid (GABA) levels in medial prefrontal cortex. The present longitudinal study explored MMN differences between CHR subjects who will and who will not remit, and its relationships with prefrontal glutamate and GABA levels.MethodsAll subjects participated in the ShangHai At-Risk for Psychosis (SHARP) program. CHR subjects met the criteria defined by the Chinese version of the Structural Interview for Prodromal Syndromes (SIPS). From the SHARP sample, 76 CHR subjects (41 male, age 18.63 ± 5.02 years) and 53 HC (31 male, age 17.72 ± 3.18 years) completed both MMN test and proton magnetic resonance spectroscopy (1H MRS) scans using a MEGA-PRESS sequence at their initial visit. CHR subjects were divided into remitted (37) and non-remitted (34) individuals based on their clinical symptoms and functional scores at a one-year follow up. Duration MMN amplitude was measured at electrodes F1/2, Fz, FC1/2, FCz, C1/2 and Cz. Concentrations of glutamate+glutamine (Glx) and GABA in the medial prefrontal cortex (mPFC) were quantified using the LCModel software (version 6.3-0I).Repeated measures analysis of variance (ANOVA) with group (remitted CHR, non-remitted CHR and HC) as the between-group factor and electrodes (Fz, FCz and Cz) as the within-group factor were performed for the midline sites, and the ANOVA using F1/2, FC1/2 and C1/C2 with laterality (left and right hemisphere) as an additional within-group factor was performed for the lateral sites. Correlations of the dMMN amplitude (averaged over the 9 electrodes) and Glx and GABA concentrations were assessed by Pearson correlation tests for each group.ResultsThere was a significant main effect of group (F(2,121)=3.14, p<0.05) for the midline fronto-central dMMN amplitude. Post-hoc tests showed that non-remitted CHR subjects had lower baseline dMMN amplitude (-4.75 ± 0.37μv) than HC (-5.92 ± 0.30μv, p<0.05), whereas dMMN in remitted CHR (-5.22 ± 0.36μv, p=0.41) was comparable to dMMN in HC.The main effect of group was marginally significant at lateral sites (F(2,121)=2.83, p=0.06). DMMN amplitude in non-remitted CHR (-4.67 ± 0.37μv) tended to be lower than those in HC (-5.76 ± 0.29μv, p<0.1), while remitted CHR had dMMN amplitude (-5.11 ± 0.35μv, p=0.47) comparable to HC. There was no significant main effect of laterality or interaction of group × laterality.In non-remitted CHR subjects, dMMN amplitude was significantly correlated with Glx level (r=-0.47, p<0.01) and with GABA level (r=-0.38, p<0.05) in the mPFC. However, the correlation of dMMN amplitude with Glx or GABA levels was not significant among either HC or remitted CHR.DiscussionIn line with previous studies, reduced dMMN amplitude distinguished between remitted and non-remitted CHR subjects, with remitted CHR not different from HCs. Our finding further supports the idea that reduced dMMN amplitude could be a candidate biomarker for predicting outcome in CHR. More importantly, we linked the reduced dMMN amplitude in non-remitted CHR to their Glx and GABA levels in mPFC, the region identified as one of dMMN sources (responsible for attention switching) thus supporting the idea that NMDA-mediated disruptions may play a key role in predicting psychosis and functional outcome.

Pitch and Duration Mismatch Negativity and Premorbid Intellect in the First Hospitalized Schizophrenia Spectrum.

Mismatch negativity (MMN) is a robustly abnormal brainwave in chronically ill schizophrenia that has generated interest as a disease presence biomarker. Reports of MMN reduction in first-episode schizophrenia have been equivocal, raising uncertainty about its reduction at first psychotic break. Here we tested 29 schizophrenia-spectrum participants under 1 year from their first hospitalization for psychosis and 40 age-, gender-, parental socioeconomic status-, and Wechsler Adult Intelligence Scales III Information-matched healthy controls on both pitch and duration MMN. Participants performed a visual checkerboard tracking task while standard (1kHz, 50ms, 80%), pitch-deviant (1.2kHz, 50ms, 10%) and duration-deviant (1kHz, 100ms, 10%) tones were presented over headphones (75 dB) and EEG was recorded. Independent component analysis was used to remove eye movements and visual stimulus processing activity. Groups did not differ in pitch MMN or duration MMN amplitudes. Smaller pitch and duration MMN amplitudes were associated with lower estimates of premorbid intellect in all participants and independently with greater positive symptoms in first hospitalized schizophrenia. Overall MMN reduction was not present in these relatively high functioning individuals at the first episode of schizophrenia, and therefore is not a good disease presence biomarker for this sample. Future research is warranted to determine the degree of MMN reduction at the first episode of psychosis across a greater range of cognitive impairment, the utility of MMN as an indicator of risk or diagnosis, and its role for understanding pathophysiological mechanisms in emerging psychosis.

Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users.

Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process.

The separate and combined effects of monoamine oxidase A inhibition and nicotine on the mismatch negativity event related potential

The mismatch negativity (MMN) auditory event-related potential (ERP) has been extensively studied as a potential biomarker for abnormal auditory processing in schizophrenia (SZ), a population which exhibits abnormally high smoking rates. The relationship between nicotinic activation and cognition in SZ may be related to underlying nicotinic and NMDA receptor dysfunction within the disease. However, transient cognitive improvements via smoking in patients may also result from monoamine oxidase (MAO) inhibition, achieved through tobacco smoke. In 24 healthy non-smoking males, we investigated the separate and combined effects of nicotine and MAO-A inhibition via moclobemide (75mg) on the optimal-5 variation of the MMN paradigm. No significant drug effects were observed in our total sample, however, stratification of individuals into low (N=12) and high (N=12) baseline MMN amplitude groups revealed increases in duration MMN amplitude relative to placebo by nicotine, as well as moclobemide, but not after the combination of the two. Because previous research has shown there was no effect of monoamine modulation on MMN, this study shows an unexpected effect of moclobemide on duration MMN.

Event-related potentials and biomarkers of psychiatric diseases: the necessity to adopt and develop multi-site guidelines.

Higuchi et al. (2014) published a paper comparing healthy controls, schizophrenic patients and subjects with at-risk mental state (ARMS) during an event-related potential (ERP) auditory oddball task. Results showed that ARMS subjects who transitioned to schizophrenia (Converters) disclosed diminished duration mismatch negativity amplitudes (dMMN) as compared with non-Converters before onset of illness. As the reduction of dMMN is a common finding when schizophrenic patients are compared with healthy controls (e.g., Umbricht and Krljes, 2005), the authors concluded that decreased dMMN amplitudes are a trait biomarker of psychosis, present before and after the development of the disease.

Effects of auditory hallucinations on the mismatch negativity (MMN) in schizophrenia as measured by a modified ‘optimal’ multi-feature paradigm

The recently developed Optimal-3 multi-feature MMN paradigm, a shortened version of the ‘optimal’ multi-feature MMN paradigm, allows for the focused recording of the most widely reported MMN deviants (frequency, duration, intensity) within an efficient and time-saving paradigm. The objective of this study was to examine MMN acoustic change detection in schizophrenia (SZ), and elucidate its association with auditory verbal hallucinations (AH), using the Optimal-3. Methods MMN to duration, frequency and intensity deviants were recorded in 12 SZ outpatients (SZs) with persistent AHs and 12 matched healthy controls (HC). Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between groups and were correlated with trait (PSYRATS) and state measures of AH severity and Positive and Negative Syndrome Scale (PANSS) ratings in SZs. Results SZs showed a significantly smaller duration MMN compared to HCs. Furthermore, in SZs attenuated duration MMN amplitudes were correlated with increased PSYRATS scores, as well as increased PANSS positive symptom, hallucination item and general psychoticism ratings, while attenuated intensity MMN amplitudes were correlated with increased PSYRATS scores. Conclusions This is the first study to examine MMN in SZ within the modified (Optimal-3) multi-feature MMN paradigm. This study corroborates previous research reporting a robust duration MMN deficit in SZ and supports previous findings suggesting that AHs may contribute to MMN deficits in SZ.

The use of conditional inference to reduce prediction error—A mismatch negativity (MMN) study

The brain uses regularities in the sound environment to build inference models predicting the most likely attributes of subsequent sounds. When the inference model fails, a prediction-error signal (the mismatch negativity or MMN) is generated. This study is designed to explore the capacity to use information about when a deviant sound will occur to switch between inference models in memory. We measured MMN generated to rare frequency, duration, intensity and spatial deviant sounds randomly occurring in a stream of identical repeating “standard” sounds. We then measured MMN to the same deviants in a linked sequence where deviants were paired—duration deviants followed an intensity change and spatial deviants followed a frequency change. To minimise prediction error, the brain should use the occurrence of the intensity and frequency deviant to prompt a change in the dominant inference (“expect-the-standard”) to anticipate the characteristics of the linked deviant. Anticipation was quantified as the proportion decline in duration and spatial MMN in the linked versus random sequence. We report three main outcomes on a sample of 23 healthy adults: (1) a significant reduction in duration MMN amplitude in linked versus random sequence; (2) a subgroup of participants exhibited significant reduction in spatial MMN amplitude in linked versus random sequence; and (3) the capacity to anticipate a linked deviant (reduce MMN) was a related to performance on the Continuous Performance Task-Identical Pairs. The results are discussed with respect to a possible co-reliance of CPT-IP and inference models on the inferior frontal gyrus.

Mental ability and pre-attentive processing: An analysis of mismatch negativity

Event Abstract Back to Event Mental ability and pre-attentive processing: An analysis of mismatch negativity Stefan Troche1*, M. E. Houlihan2, R. M. Stelmack3 and Thomas Rammsayer1 1 Department of Psychology, University of Bern, Switzerland 2 Department of Psychology, St. Thomas University, Fredericton, Canada 3 School of Psychology, University of Ottawa, Canada The association of higher discrimination ability with higher mental ability is a well-established effect. In the present study, mismatch negativity (MNN) was derived during acoustic frequency and duration discrimination tasks to determine whether the mental ability effects are extant at a pre-attentive level of discrimination processing. MMN was recorded from 83 participants. Deviant tones were of a longer duration in one sequence and a higher frequency in the other. In both conditions, there were three levels of discrimination difficulty. Participants were instructed to ignore the tones and to attend to an animated movie. All three frequency MMN amplitudes but none of the duration MMN amplitudes were significantly related to MA. Larger frequency MMN amplitudes went with higher mental ability. Overall, frequency MMN amplitudes explained 18% of variance of the performance scores of the Multidimensional Aptitude Battery. Because MMN amplitude decreased with task difficulty, one could argue that the greater MMN amplitude for higher MA is indicative of their greater discrimination ability. However, this view is challenged by the failure to observe a relation between MMN amplitude and the 75% difference threshold in any condition. Conference: MMN 09 Fifth Conference on Mismatch Negativity (MMN) and its Clinical and Scientific Applications, Budapest, Hungary, 4 Apr - 7 Apr, 2009. Presentation Type: Poster Presentation Topic: Poster Presentations Citation: Troche S, Houlihan ME, Stelmack RM and Rammsayer T (2009). Mental ability and pre-attentive processing: An analysis of mismatch negativity. Conference Abstract: MMN 09 Fifth Conference on Mismatch Negativity (MMN) and its Clinical and Scientific Applications. doi: 10.3389/conf.neuro.09.2009.05.098 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Mar 2009; Published Online: 26 Mar 2009. * Correspondence: Stefan Troche, Department of Psychology, University of Bern, Bern, Switzerland, troche@psy.unibe.ch Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Stefan Troche M. E Houlihan R. M Stelmack Thomas Rammsayer Google Stefan Troche M. E Houlihan R. M Stelmack Thomas Rammsayer Google Scholar Stefan Troche M. E Houlihan R. M Stelmack Thomas Rammsayer PubMed Stefan Troche M. E Houlihan R. M Stelmack Thomas Rammsayer Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Acute high-dose glycine attenuates mismatch negativity (MMN) in healthy human controls

Schizophrenia is commonly associated with impairments in pre-attentive change detection as represented by reduced mismatch negativity (MMN). The neurochemical basis of MMN has been linked to N-methyl-D: -aspartate (NMDA) receptor function. Glycine augments NMDA receptor function via stimulation of the glycine modulatory site of the NMDA receptor and has been shown to effectively reduce negative symptoms in schizophrenia. However, no study has investigated the possible effects of high-dose glycine on MMN. Further, the physiological consequences of administering high-dose glycine in subjects with normal NMDA receptor function are unknown. The aim of the present project was to investigate the acute effects of a single large dose of glycine on the human MMN in healthy subjects. Sixteen healthy male subjects participated in a double blind, placebo-controlled, crossover design in which each subject was tested under two acute treatment conditions separated by a 1-week washout period; placebo and 0.8 g/kg glycine. The subjects were exposed to a duration-MMN paradigm with 50-ms standard tones (91%) and 100-ms deviant tones (9%). The results showed that glycine significantly attenuated duration MMN amplitude at frontal electrodes. There was no effect of glycine on MMN latencies or on amplitudes or latencies of N1, N2 and P3a. These findings suggest that an acute high dosage of glycine attenuates MMN in healthy controls, raising the possibility that optimal effects of glycine and other glycine agonists may depend on the integrity of the NMDA receptor system.