Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Heekeren K
PROVIDER: S-EPMC2668652 | biostudies-other | 2008 Jul
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Clinical trial registrationRapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.
| S-EPMC8827377 | biostudies-literature
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
Project description:Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), N-methyl-D-aspartate (NMDA) antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: (1) placebo vs 10 mg of memantine or (2) placebo vs 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices, and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age dependent and most evident in older CPD patients, whereas those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.
| S-EPMC5130118 | biostudies-literature
Project description:Background:The declining transition rate to psychotic disorder and the increasing rate of nonpsychotic poor outcomes among subjects at clinical high risk (CHR) for psychosis have increased the need for biomarkers to predict remission regardless of transition. This study investigated whether mismatch negativity (MMN) predicts the prognosis of CHR individuals during a 6-year follow-up period. Methods:A total of 47 healthy control (HC) subjects and 48 subjects at CHR for psychosis participated in the MMN assessment. The clinical statuses of the CHR subjects were examined at baseline and regularly for up to 6 years. The CHR subjects were divided into remitter and nonremitter groups, and the baseline MMN amplitudes and latencies were compared across the remitter, nonremitter, and HC groups. Regression analyses were performed to identify the predictive factors of remission, the improvement of attenuated positive symptoms, and functional recovery. Results:CHR nonremitters showed reduced MMN amplitudes at baseline compared to CHR remitters and HC subjects. A logistic regression analysis revealed that the baseline MMN amplitude at the frontal electrode site was the only significant predictor of remission. In a multiple regression analysis, the MMN amplitude, antipsychotic use, and years of education predicted an improvement in attenuated positive symptoms. The MMN amplitude at baseline predicted functional recovery. Conclusions:These results suggest that MMN is a putative predictor of prognosis regardless of the transition to psychotic disorder in subjects at CHR. Early prognosis prediction and the provision of appropriate interventions based on the initial CHR status might be aided using MMN.
| S-EPMC5890455 | biostudies-literature
Project description:BackgroundReduced mismatch negativity (MMN) is observed in early psychosis (EP) and correlated with cognition and functioning, but few studies have examined their longitudinal relationships and diagnostic specificity. We examined MMN, neuro- and social-cognition, and functional measures in EP patients with schizophrenia-spectrum (SZ) or bipolar disorder (BD) over a 1-year follow-up.Methods54 EP patients (SZ: n = 24; BD: n = 30) and 42 healthy controls completed baseline measures: MMN, neuro- and social-cognition, and functional assessments. 30 EP patients completed 12-month follow-up assessments. Patients and controls were compared on MMN at baseline and follow-up, and diagnostic subgroup analyses were performed. Associations amongst MMN, neuro- and social cognition, and clinical measures were examined and predictive models of follow-up outcomes were conducted.ResultsEP patients showed significantly reduced MMN compared to controls at baseline (p = 0.023). MMN was impaired in SZ patients at baseline (p = 0.017) and follow-up (p = 0.003); BD patients did not differ from controls at either timepoint. MMN was associated with symptom severity and functioning at baseline, and with social cognition and functioning at follow up, but was not predictive of functional outcomes at follow-up.ConclusionsMMN abnormalities were evident in EP SZ-spectrum disorders at both timepoints, but not in BD at either timepoint. MMN was associated with functioning cross-sectionally, but did not predict future functional outcomes. However, deficits in MMN were associated with social cognition, which may have downstream effects on community functioning. Implications for targeted interventions to improve social processing and community outcomes are discussed.
| S-EPMC7987838 | biostudies-literature
Project description:The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task--for 24 patients with psychosis, 25 of their first-degree unaffected relatives, and 35 controls--and DCM was used to estimate the excitability (modeled as self-inhibition) of (source-specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent (condition-specific) and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis.
| S-EPMC4843949 | biostudies-literature
Project description:BackgroundIn the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR.Materials and methodsIndividuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function.ResultsCompared with the HC group, the UHR group had a significantly attenuated dMMN amplitude (p = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, p = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) (p = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, p = 0.030; fMMN, p = 0.041).ConclusionOur findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR.
| S-EPMC7416637 | biostudies-literature
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
Project description:ImportanceAlthough clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P).ObjectiveTo examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use.Design, setting, and participantsMMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021.Main outcomes and measuresElectroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured.ResultsThe CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity.Conclusions and relevanceThis study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.
| S-EPMC9178501 | biostudies-literature
Project description:The present study investigates the differences in auditory mismatch negativity (MMN) parameters given in a sample of young subjects with autism spectrum disorder (ASD, n = 37) with or without co-occurrent attenuated psychosis syndrome (APS). Our results show that ASD individuals present an MMN decreased amplitude and prolonged latency, without being influenced by concurrent APS. Additionally, when correlating the MMN indexes to clinical features, in the ASD + APS group, we found a negative correlation between the severity of autistic symptoms and the MMN latency in both frequency (f-MMN r = -0.810; p < 0.0001) and duration (d-MMN r = -0.650; p = 0.006) deviants. Thus, our results may provide a more informative characterization of the ASD sub-phenotype when associated with APS, highlighting the need for further longitudinal investigations.
| S-EPMC7732489 | biostudies-literature