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Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study.

ABSTRACT: The lack of translation from basic research into new medicines is a major challenge in CNS drug development. The need to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology and (ii) quantitative biomarkers focusing on evolutionarily preserved neurobiological systems allowing back-translation from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN) response in schizophrenic (SZ) patients, Alzheimer's disease (AD) patients, and age-matched healthy controls. To evaluate back-translation of the MMN response, we developed EEG-based procedures allowing the measurement of MMN-like responses in a rat model of schizophrenia and a mouse model of AD. Our results indicate a significant MMN attenuation in SZ but not in AD patients. Consistently with the clinical findings, we observed a significant attenuation of deviance detection (~104.7%) in rats subchronically exposed to phencyclidine, while no change was observed in APP/PS1 transgenic mice when compared to wild type. This study provides new insight into the cross-disease evaluation of the MMN response. Our findings suggest further investigations to support the identification of neurobehavioral subtypes that may help patients clustering for precision medicine intervention. Furthermore, we provide evidence that MMN could be used as a quantitative/objective efficacy biomarker during both preclinical and clinical stages of SZ drug development.

SUBMITTER: Loiodice S

PROVIDER: S-EPMC8085207 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Rodent Mismatch Negativity/theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia.

Project description:Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and are linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatments, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency and duration deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks' treatment in rats treated with saline, phencyclidine (PCP, 15?mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (?)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and ?-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (?) and beta (?) frequency ranges. PCP treatment also significantly reduced ?-frequency response to standard stimuli while increasing ?-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro-oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to ?-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia.

| S-EPMC5770758 | biostudies-literature

Single-Trial EEG-fMRI Reveals the Generation Process of the Mismatch Negativity.

Project description:Although research on the mismatch negativity (MMN) has been ongoing for 40 years, the generation process of the MMN remains largely unknown. In this study, we used a single-trial electro-encephalography (EEG)-functional magnetic resonance imaging (fMRI) coupling method which can analyze neural activity with both high temporal and high spatial resolution and thus assess the generation process of the MMN. We elicited the MMN with an auditory oddball paradigm while recording simultaneous EEG and fMRI. We divided the MMN into five equal-durational phases. Utilizing the single-trial variability of the MMN, we analyzed the neural generators of the five phases, thereby determining the spatiotemporal generation process of the MMN. We found two distinct bottom-up prediction error propagations: first from the auditory cortex to the motor areas and then from the auditory cortex to the inferior frontal gyrus (IFG). Our results support the regularity-violation hypothesis of MMN generation.

| S-EPMC6546813 | biostudies-literature

Mismatch negativity: translating the potential.

Project description:The mismatch negativity (MMN) component of the auditory event-related potential has become a valuable tool in cognitive neuroscience. Its reduced size in persons with schizophrenia is of unknown origin but theories proposed include links to problems in experience-dependent plasticity reliant on N-methyl-d-aspartate glutamate receptors. In this review we address the utility of this tool in revealing the nature and time course of problems in perceptual inference in this illness together with its potential for use in translational research testing animal models of schizophrenia-related phenotypes. Specifically, we review the reasons for interest in MMN in schizophrenia, issues pertaining to the measurement of MMN, its use as a vulnerability index for the development of schizophrenia, the pharmacological sensitivity of MMN and the progress in developing animal models of MMN. Within this process we highlight the challenges posed by knowledge gaps pertaining to the tool and the pharmacology of the underlying system.

| S-EPMC3866657 | biostudies-literature

Stability of mismatch negativity event-related potentials in a multisite study.

Project description:ObjectivesMismatch negativity (MMN), an auditory event-related potential sensitive to deviance detection, is smaller in schizophrenia and psychosis risk. In a multisite study, a regression approach to account for effects of site and age (12-35?years) was evaluated alongside the one-year stability of MMN.MethodsStability of frequency, duration, and frequency?+?duration (double) deviant MMN was assessed in 167 healthy subjects, tested on two occasions, separated by 52?weeks, at one of eight sites. Linear regression models predicting MMN with age and site were validated and used to derive standardized MMN z-scores. Variance components estimated for MMN amplitude and latency measures were used to calculate Generalizability (G) coefficients within each site to assess MMN stability. Trait-like aspects of MMN were captured by averaging across occasions and correlated with subject traits.ResultsAge and site accounted for less than 7% of MMN variance. G-coefficients calculated at electrode Fz were stable (G = 0.63) across deviants and sites for amplitude measured in a fixed window, but not for latency (G = 0.37). Frequency deviant MMN z-scores averaged across tests negatively correlated with averaged global assessment of functioning.ConclusionMMN amplitude is stable and can be standardized to facilitate longitudinal multisite studies of patients and clinical features.

| S-EPMC7301288 | biostudies-literature

Mismatch Negativity is a Sensitive and Predictive Biomarker of Perceptual Learning During Auditory Cognitive Training in Schizophrenia.

Project description:Computerized cognitive training is gaining empirical support for use in the treatment of schizophrenia (SZ). Although cognitive training is efficacious for SZ at a group level when delivered in sufficiently intensive doses (eg, 30-50?h), there is variability in individual patient response. The identification of biomarkers sensitive to the neural systems engaged by cognitive training interventions early in the course of treatment could facilitate personalized assignment to treatment. This proof-of-concept study was conducted to determine whether mismatch negativity (MMN), an event-related potential index of auditory sensory discrimination associated with cognitive and psychosocial functioning, would predict gains in auditory perceptual learning and exhibit malleability after initial exposure to the early stages of auditory cognitive training in SZ. MMN was assessed in N=28 SZ patients immediately before and after completing 1?h of a speeded time-order judgment task of two successive frequency-modulated sweeps (Posit Science 'Sound Sweeps' exercise). All SZ patients exhibited the expected improvements in auditory perceptual learning over the 1?h training period (p<0.001), consistent with previous results. Larger MMN amplitudes recorded both before and after the training exercises were associated with greater gains in auditory perceptual learning (r=-0.5 and r=-0.67, respectively, p's<0.01). Significant pretraining vs posttraining MMN amplitude reduction was also observed (p<0.02). MMN is a sensitive index of the neural systems engaged in a single session of auditory cognitive training in SZ. These findings encourage future trials of MMN as a biomarker for individual assignment, prediction, and/or monitoring of patient response to procognitive interventions, including auditory cognitive training in SZ.

| S-EPMC5603809 | biostudies-other

Auditory Mismatch Negativity Response in Institutionalized Children.

Project description:The attunement of speech perception/discrimination to the properties of one's native language is a crucial step in speech and language development at early ages. Studying these processes in young children with a history of institutionalization is of great interest, as being raised in institutional care (IC) may lead to lags in language development. The sample consisted of 82 children, split into two age groups. The younger age group (<12 months) included 17 children from the IC and 17 children from the biological-family-care (BFC) group. The older group (>12 months) consisted of 23 children from the IC group, and 25 children from the BFC group. A double-oddball paradigm with three consonant-vowel syllables was used, utilizing native (Russian) and foreign (Hindi) languages. A Mismatch Negativity (MMN) component was elicited within a 125-225 ms time window in the frontal-central electrode. Findings demonstrate the absence of MMN effect in the younger age group, regardless of the living environment. Children in the older group are sensitive to native deviants and do not differentiate foreign language contrasts. No significant differences were observed between the IC and BFC groups for children older than 12 months, indicating that children in the IC have typical phonological processing. The results show that the MMN effect is not registered in Russian speaking children before the age of 12 months, regardless of their living environment. At 20 months of age, institutionally reared children show no evidence of delays in phonetic development despite a limited experience of language.

| S-EPMC6774417 | biostudies-literature

A neurocomputational model of the mismatch negativity.

Project description:The mismatch negativity (MMN) is an event related potential evoked by violations of regularity. Here, we present a model of the underlying neuronal dynamics based upon the idea that auditory cortex continuously updates a generative model to predict its sensory inputs. The MMN is then modelled as the superposition of the electric fields evoked by neuronal activity reporting prediction errors. The process by which auditory cortex generates predictions and resolves prediction errors was simulated using generalised (Bayesian) filtering--a biologically plausible scheme for probabilistic inference on the hidden states of hierarchical dynamical models. The resulting scheme generates realistic MMN waveforms, explains the qualitative effects of deviant probability and magnitude on the MMN - in terms of latency and amplitude--and makes quantitative predictions about the interactions between deviant probability and magnitude. This work advances a formal understanding of the MMN and--more generally--illustrates the potential for developing computationally informed dynamic causal models of empirical electromagnetic responses.

| S-EPMC3820518 | biostudies-literature

The Thalamocortical Circuit of Auditory Mismatch Negativity.

Project description:BackgroundMismatch negativity (MMN) is an extensively validated biomarker of cognitive function across both normative and clinical populations and has previously been localized to supratemporal auditory cortex. MMN is thought to represent a comparison of the features of the present stimulus versus a mnemonic template formed by the prior stimuli.MethodsWe used concurrent thalamic and primary auditory cortical (A1) laminar recordings in 7 macaques to evaluate the relative contributions of core (lemniscal) and matrix (nonlemniscal) thalamic afferents to MMN generation.ResultsWe demonstrated that deviance-related activity is observed mainly in matrix regions of auditory thalamus, MMN generators are most prominent in layer 1 of cortex as opposed to sensory responses that activate layer 4 first and sequentially all cortical layers, and MMN is elicited independent of the frequency tuning of A1 neuronal ensembles. Consistent with prior reports, MMN-related thalamocortical activity was strongly inhibited by ketamine.ConclusionsTaken together, our results demonstrate distinct matrix versus core thalamocortical circuitry underlying the generation of a higher-order brain response (MMN) versus sensory responses.

| S-EPMC7103554 | biostudies-literature

Measurement of mismatch negativity in individuals: a study using single-trial analysis.

Project description:Mismatch negativity (MMN) is measured by subtracting the averaged response to a set of standard stimuli from the averaged response to rarer deviant stimuli, and taking the amplitude of this difference wave in a given time window. This method is problematic when used to evaluate individuals, because there is no estimate of variance. We describe a new approach, in which independent components with high trial-by-trial variance are first removed. Next, each deviant response has the preceding standard response subtracted, giving a set of single trial difference waves. We illustrate this approach in analysis of MMN to brief tones in 17 adults. The best criterion for MMN combined t-test with an index of inter-trial coherence, giving significant MMN in 14 (82%) of individuals. Single-trial methods can indicate which people show MMN. However, in some clinically normal individuals there was no MMN, despite good behavioral discrimination of stimuli.

| S-EPMC2904495 | biostudies-literature

Neural mechanisms of mismatch negativity dysfunction in schizophrenia.

Project description:Schizophrenia is associated with cognitive deficits that reflect impaired cortical information processing. Mismatch negativity (MMN) indexes pre-attentive information processing dysfunction at the level of primary auditory cortex. This study investigates mechanisms underlying MMN impairments in schizophrenia using event-related potential, event-related spectral decomposition (ERSP) and resting state functional connectivity (rsfcMRI) approaches. For this study, MMN data to frequency, intensity and duration-deviants were analyzed from 69 schizophrenia patients and 38 healthy controls. rsfcMRI was obtained from a subsample of 38 patients and 23 controls. As expected, schizophrenia patients showed highly significant, large effect size (P=0.0004, d=1.0) deficits in MMN generation across deviant types. In ERSP analyses, responses to deviants occurred primarily the theta (4-7?Hz) frequency range consistent with distributed corticocortical processing, whereas responses to standards occurred primarily in alpha (8-12?Hz) range consistent with known frequencies of thalamocortical activation. Independent deficits in schizophrenia were observed in both the theta response to deviants (P=0.021) and the alpha-response to standards (P=0.003). At the single-trial level, differential patterns of response were observed for frequency vs duration/intensity deviants, along with At the network level, MMN deficits engaged canonical somatomotor, ventral attention and default networks, with a differential pattern of engagement across deviant types (P<0.0001). Findings indicate that deficits in thalamocortical, as well as corticocortical, connectivity contribute to auditory dysfunction in schizophrenia. In addition, differences in ERSP and rsfcMRI profiles across deviant types suggest potential differential engagement of underlying generator mechanisms.

| S-EPMC5547016 | biostudies-literature

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