Influence of GABAA and GABAB receptor activation on auditory sensory gating and its association with anxiety in healthy volunteers.

BACKGROUND: Dysfunctional sensory gating in anxiety disorders, indexed by the failure to inhibit the P50 event-related potential (ERP) to repeated stimuli, has been linked to deficits in the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). AIMS/METHODS: This study, conducted in 30 healthy volunteers, examined the acute effects of GABAA (lorazepam: 1 mg) and GABAB receptor (baclofen: 10 mg) agonists on P50 measures of auditory sensory gating within a paired-stimulus (S1-S2) paradigm and assessed changes in gating in relation to self-ratings of anxiety. RESULTS: Compared to placebo, lorazepam reduced ERP indices of sensory gating by attenuating response to S1. Although not directly impacting P50 inhibition, baclofen-induced changes in gating (relative to placebo) were negatively correlated with trait but not state anxiety. CONCLUSIONS: These preliminary findings support the involvement of GABA in sensory gating and tentatively suggest a role for GABAB receptor signaling in anxiety-associated gating dysregulation.

Auditory P50 Sensory Gating Alterations in Major Depressive Disorder and their Relationship to Clinical Symptoms.

Cognitive deficits in depression are pervasive and include impairments in attention and higher-order functions but the degree to which low-level sensory processes are affected is unclear. The present work examined event-related potential (P50 and N100) features of auditory sensory gating (i.e., the ability to inhibit P50/N100 responses to redundant stimuli) and their relationship to depressive symptoms, including ruminations and dysfunctional attitudes. In 18 patients with major depressive disorder (MDD) and 18 healthy volunteers, auditory sensory gating was measured using a paired-stimulus paradigm yielding ratio (rP50, rN100) and difference (dP50, dN100) gating indices, which reflected amplitude reductions from first (S1) to second (S2) stimulus. Patients with MDD exhibited diminished rP50 and dP50 gating scores and delayed S1-N100 latencies compared to healthy volunteers. These measures were positively associated with ruminative thoughts, negative attitudes and degree of depression. Study findings implicate aberrant sensory processing in depressed patients that is related to severity of maladaptive thinking.

Transcranial Alternating Current Stimulation Alters Auditory Steady-State Oscillatory Rhythms and Their Cross-Frequency Couplings.

Auditory cortical plasticity deficits in schizophrenia are evidenced with electroencephalographic (EEG)-derived biomarkers, including the 40-Hz auditory steady-state response (ASSR). Aiming to understand the underlying oscillatory mechanisms contributing to the 40-Hz ASSR, we examined its response to transcranial alternating current stimulation (tACS) applied bilaterally to the temporal lobe of 23 healthy participants. Although not responding to gamma tACS, the 40-Hz ASSR was modulated by theta tACS (vs sham tACS), with reductions in gamma power and phase locking being accompanied by increases in theta-gamma phase-amplitude cross-frequency coupling. Results reveal that oscillatory changes induced by frequency-tuned tACS may be one approach for targeting and modulating auditory plasticity in normal and diseased brains.

A Rapid Access Brief Psychotherapy Intervention to Respond to Healthcare Workers in Ontario Whose Mental Health was Negatively Impacted During the COVID-19 Pandemic.

OBJECTIVE: Although the coronavirus disease 2019 (COVID-19) pandemic has had widespread negative impacts on the mental health of healthcare workers (HCWs), there has been little research on psychological interventions during the pandemic for this population. The current study examines whether a brief coping-focused treatment intervention delivered in a virtual individual format would be associated with positive changes in Canadian HCWs' mental health during the pandemic. METHOD: Three hundred and thirty-three HCWs receiving the intervention at 3 large specialty tertiary care hospitals in Ontario, Canada, completed measures of anxiety, depression, perceived stress, work/social impairment, insomnia and fear of COVID-19. After completing treatment, HCWs rated their satisfaction with the treatment. RESULTS: The intervention was associated with large effect size improvements in anxiety, depression, perceived stress, insomnia and fear of COVID-19, and moderate effect size improvements in work/social impairment. At treatment session 1, prior mental health diagnosis and treatment were both significantly correlated with depression, anxiety, and work/social impairment scores. Secondary analyses of data from one of the sites revealed that treatment-related changes in anxiety, depression, perceived stress and work/social impairment were independent of age, gender, occupational setting, profession and the presence of a previous mental health diagnosis or treatment, with the exception that nurses improved at a slightly greater rate than other professions in terms of work/social impairment. HCWs were highly satisfied with the treatment. CONCLUSIONS: A large number of HCWs experiencing significant distress at baseline self-referred for assistance. Timely and flexible access to a brief virtual coping-focused intervention was associated with improvements in symptoms and impairment, and treatment response was largely unrelated to demographic or professional characteristics. Short-term psychological interventions for HCWs during a pandemic may have a highly positive impact given their association with improvement in various aspects of HCWs' mental health improvement.

Ethnoracial Inclusion in Clinical Trials of Ketamine in the Treatment of Mental Health Disorders.

OBJECTIVE: Despite strong evidence for the safety and efficacy of ketamine in the treatment of mood disorders, the enrollment of Black, Indigenous, and People of Color (BIPOC) has not been a focus of this research. Health disparities in the treatment of mood disorders in BIPOC indicate a strong need to understand the clinical, social, and pharmacological aspects of this novel treatment in people of color. METHOD: A comprehensive methodological search for double-blind, placebo-controlled, randomized ketamine clinical trials published from 1993 to 2020 was conducted across several databases to analyze the demographics of trial participants. Researchers contacted corresponding authors to obtain additional information. RESULTS: Only 10 studies provided sufficient information for quantitative analysis. Among these studies (n = 380 participants), 73.7% of the participants were non-Hispanic White, 9.2% were Black, 5.0% were Hispanic/Latinx, and 0.8% were Asian. Higher BIPOC inclusion was negatively correlated with the number of recruitment methods implemented across sites. The present study may underestimate the participation of BIPOC because of the lack of demographic information collected or published. CONCLUSIONS: BIPOC are greatly underrepresented in ketamine clinical trials despite high rates of mood disorders. Reported treatment outcomes may not generalize to all ethnic and cultural groups and significant disparities in access to such novel treatment paradigms exacerbate health disparities.

Synchronized Auditory Gamma Response to Frontal Transcranial Direct Current Stimulation (tDCS) and its Inter-Individual Variation in Healthy Humans.

In schizophrenia, a disorder associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction, auditory cortical plasticity deficits have been indexed by the synchronized electroencephalographic (EEG) auditory steady-state gamma-band (40-Hz) response (ASSR) and the early auditory evoked gamma-band response (aeGBR), both considered to be target engagement biomarkers for NMDAR function, and potentially amenable to treatment by NMDAR modulators. As transcranial direct current stimulation (tDCS) is likely dependent on NMDAR neurotransmission, this preliminary study, conducted in 30 healthy volunteers, assessed the off-line effects of prefrontal anodal tDCS and sham (placebo) treatment on 40-Hz ASSR and aeGBR. Anodal tDCS failed to alter aeGBR but increased both 40-Hz ASSR power, as measured by event-related spectral perturbations (ERSP), and phase locking, as measured by inter-trial phase consistency (ITPC). Inter-individual differences in tDCS-induced increases in ERSP were negatively related to baseline ERSPs. These findings provide tentative support for further study of tDCS as a potential NMDAR neuromodulatory intervention for synchronized auditory gamma response deficits.

N-methyl-D-aspartate receptor antagonism impairs sensory gating in the auditory cortex in response to speech stimuli.

Deficits in early auditory sensory processing in schizophrenia have been linked to N-methyl-D-aspartate receptor (NMDAR) hypofunction, but the role of NMDARs in aberrant auditory sensory gating (SG) in this disorder is unclear. This study, conducted in 22 healthy humans, examined the acute effects of a subanesthetic dose of the NMDAR antagonist ketamine on SG as measured electrophysiologically by suppression of the P50 event-related potential (ERP) to the second (S2) relative to the first (S1) of two closely paired (500 ms) identical speech stimuli. Ketamine induced impairment in SG indices at sensor (scalp)-level and at source-level in the auditory cortex (as assessed with eLORETA). Together with preliminary evidence of modest positive associations between impaired gating and dissociative symptoms elicited by ketamine, tentatively support a model of NMDAR hypofunction underlying disturbances in auditory SG in schizophrenia.

Depression Diagnosis Modeling With Advanced Computational Methods: Frequency-Domain eMVAR and Deep Learning.

Electroencephalogram (EEG)-based automated depression diagnosis systems have been suggested for early and accurate detection of mood disorders. EEG signals are highly irregular, nonlinear, and nonstationary in nature and are traditionally studied from a linear viewpoint by means of statistical and frequency features. Since, linear metrics present certain limitations and nonlinear methods have proven to be an efficient tool in understanding the complexities of the brain in the identification of underlying behavior of biological signals, such as electrocardiogram, EEG and magnetoencephalogram and thus, can be applied to all nonstationary signals. Various nonlinear algorithms can be used in the analysis of EEG signals. In this research paper, we aim to develop a novel methodology for EEG-based depression diagnosis utilizing 2 advanced computational techniques: frequency-domain extended multivariate autoregressive (eMVAR) and deep learning (DL). We proposed a hybrid method comprising a pretrained ResNet-50 and long-short term memory (LSTM) to capture depression-specific information and compared with a strong conventional machine learning (ML) framework having eMVAR connectivity features. The following 8 causality measures, which interpret the interaction mechanisms among spectrally decomposed oscillations, were used to extract features from multivariate EEG time series: directed coherence (DC), directed transfer function (DTF), partial DC (PDC), generalized PDC (gPDC), extended DC (eDC), delayed DC (dDC), extended PDC (ePDC), and delayed PDC (dPDC). The classification accuracies were 84% with DC, 85% with DTF, 95.3% with PDC, 95.1% with gPDC, 84.8% with eDC, 84.6% with dDC, 84.2% with ePDC, and 95.9% with dPDC for the eMVAR framework. Through a DL framework (ResNet-50 + LSTM), the classification accuracy was achieved as 90.22%. The results demonstrate that our DL methodology is a competitive alternative to the strong feature extraction-based ML methods in depression classification.

It's in the Timing: Reduced Temporal Precision in Neural Activity of Schizophrenia.

Studies of perception and cognition in schizophrenia (SCZ) show neuronal background noise (ongoing activity) to intermittently overwhelm the processing of external stimuli. This increased noise, relative to the activity evoked by the stimulus, results in temporal imprecision and higher variability of behavioral responses. What, however, are the neural correlates of temporal imprecision in SCZ behavior? We first report a decrease in electroencephalography signal-to-noise ratio (SNR) in two SCZ datasets and tasks in the broadband (1-80 Hz), theta (4-8 Hz), and alpha (8-13 Hz) bands. SCZ participants also show lower inter-trial phase coherence (ITPC)-consistency over trials in the phase of the signal-in theta. From these ITPC results, we varied phase offsets in a computational simulation, which illustrated phase-based temporal desynchronization. This modeling also provided a necessary link to our results and showed decreased neural synchrony in SCZ in both datasets and tasks when compared with healthy controls. Finally, we showed that reduced SNR and ITPC are related and showed a relationship to temporal precision on the behavioral level, namely reaction times. In conclusion, we demonstrate how temporal imprecision in SCZ neural activity-reduced relative signal strength and phase coherence-mediates temporal imprecision on the behavioral level.

Electrophysiological correlates and predictors of the antidepressant response to repeated ketamine infusions in treatment-resistant depression.

BACKGROUND: Sub-anesthetic ketamine doses rapidly reduce depressive symptoms, although additional investigations of the underlying neural mechanisms and the prediction of response outcomes are needed. Electroencephalographic (EEG)-derived measures have shown promise in predicting antidepressant response to a variety of treatments, and are sensitive to ketamine administration. This study examined their utility in characterizing changes in depressive symptoms following single and repeated ketamine infusions. METHODS: Recordings were obtained from patients with treatment-resistant major depressive disorder (MDD) (N = 24) enrolled in a multi-phase clinical ketamine trial. During the randomized, double-blind, crossover phase (Phase 1), patients received intravenous ketamine (0.5 mg/kg) and midazolam (30 µg/kg), at least 1 week apart. For each medication, three resting, eyes-closed recordings were obtained per session (pre-infusion, immediately post-infusion, 2 h post-infusion), and changes in power (delta, theta1/2/total, alpha1/2/total, beta, gamma), alpha asymmetry, theta cordance, and theta source-localized anterior cingulate cortex activity were quantified. The relationships between ketamine-induced changes with early (Phase 1) and sustained (Phases 2,3: open-label repeated infusions) decreases in depressive symptoms (Montgomery-Åsberg Depression Rating Score, MADRS) and suicidal ideation (MADRS item 10) were examined. RESULTS: Both medications decreased alpha and theta immediately post-infusion, however, only midazolam increased delta (post-infusion), and only ketamine increased gamma (immediately post- and 2 h post-infusion). Regional- and frequency-specific ketamine-induced EEG changes were related to and predictive of decreases in depressive symptoms (theta, gamma) and suicidal ideation (alpha). Early and sustained treatment responders differed at baseline in surface-level and source-localized theta. CONCLUSIONS: Ketamine exerts frequency-specific changes on EEG-derived measures, which are related to depressive symptom decreases in treatment-resistant MDD and provide information regarding early and sustained individual response to ketamine. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: Action of Ketamine in Treatment-Resistant Depression, NCT01945047.

N-methyl-d-aspartate receptor antagonism modulates P300 event-related potentials and associated activity in salience and central executive networks.

Impairments in auditory information processing in schizophrenia as indexed electrophysiologically by P300 deficits during novelty (P3a) and target (P3b) processing are linked to N -methyl- D -aspartate receptor (NMDAR) dysfunction. This study in 14 healthy volunteers examined the effects of a subanesthetic dose of the NMDAR antagonist ketamine on P300 and their relationship to psychomimetic symptoms and cortical source activity (with eLORETA). Ketamine reduced early (e- P3a) and late (l-P3a) novelty P300 at sensor (scalp)-level and at source-level in the salience network. Increases in dissociation symptoms were negatively correlated with ketamine-induced P3b changes, at sensor-level and source-level, in both salience and central executive networks. These P3a alterations during novelty processing, and the symptom-related P3b changes during target processing support a model of NMDAR hypofunction underlying disrupted auditory attention in schizophrenia.

Research abuses against people of colour and other vulnerable groups in early psychedelic research.

There is a growing resurgence in the study of psychedelic medicines for the treatment of mental health and substance use disorders. However, certain early investigations are marred by questionable research methods, abuses against research participants, and covert Central Intelligence Agency financial involvement. The purpose of this study was to understand how and to what extent people of colour and other vulnerable populations, specifically, individuals who were incarcerated or incapacitated due to mental health issues (inpatients with psychotic disorders), were exploited during the first wave of psychedelic research in the USA (1950-1980). To do so, we reviewed available empirical publications according to current ethical standards. Variables of interest included race and ethnicity of participants, population vulnerability, drug administration conditions, informed consent and undue influence. Our findings draw attention to the history of research abuses against people of colour in Western psychedelic research. In light of these findings, we urge a call-to-action to current psychedelic researchers to prioritise culturally inclusive and socially responsible research methods in current and future studies.

Ethnoracial health disparities and the ethnopsychopharmacology of psychedelic-assisted psychotherapies.

Emerging evidence from randomized, double-blind, placebo-controlled clinical trials suggests psychedelic compounds such as 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and lysergic acid diethylamide (LSD), when administered as an adjunct to psychotherapy, that is, psychedelic-assisted psychotherapy (PAP), may be beneficial for treating substance use disorders, posttraumatic stress disorder (PTSD), depression, anxiety, and other psychiatric conditions. Previous ethnopsychopharmacological research has identified ethnoracial differences in the metabolism, safety, and efficacy of psychotropic drugs, yet no studies have directly investigated the impact of ethnoracially based differences in psychedelic drug pharmacology. Although there is an extensive global history of psychedelic use among peoples of various cultures, ethnicities, and intersectional identities, psychedelic research has been conducted almost exclusively on White populations in North America and Western Europe. The failure to include Black, Indigenous, and People of Color (BIPOC) in psychedelic research trials neglects the ethnic, racial, and cultural factors that may impact individual responses to PAP and thereby prevents generalizability of findings. This article investigates the impact of biological and social factors related to culture, ethnicity, and race on pharmacological responses to PAP, as well as clinical outcomes. The limitations of ethnopsychopharmacology are discussed, and the authors present expected cultural, clinical, and public health benefits of expanding funding for this area. This work will draw attention to the unique and individualized needs of ethnoracially diverse clients in therapeutic settings and is intended to inform future PAP trials. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Resting-state functional EEG connectivity in salience and default mode networks and their relationship to dissociative symptoms during NMDA receptor antagonism.

N-methyl-d-aspartate receptor (NMDAR) antagonists administered to healthy humans results in schizophrenia-like symptoms, which are thought in part to be related to glutamatergically altered electrophysiological connectivity in large-scale intrinsic functional brain networks. Here, we examine resting-state source electroencephalographic (EEG) connectivity within and between the default mode (DMN: for self-related cognitive activity) and salience networks (SN: for detection of salient stimuli in internal and external environments) in 21 healthy volunteers administered a subanesthetic dose of the dissociative anesthetic and NMDAR antagonist, ketamine. In addition to provoking symptoms of dissociation, which are thought to originate from an altered sense of self that is common to schizophrenia, ketamine induces frequency-dependent increases and decreases in connectivity within and between DMN and SN. These altered interactive network couplings together with emergent dissociative symptoms tentatively support an NMDAR-hypofunction hypothesis of disturbed electrophysiologic connectivity in schizophrenia.

Using prefrontal and midline right frontal EEG-derived theta cordance and depressive symptoms to predict the differential response or remission to antidepressant treatment in major depressive disorder.

There is a growing need for optimizing treatment selection and response prediction in individuals with major depressive disorder (MDD). Prior investigations have shown that changes in electroencephalographic (EEG)-based measures precede symptom improvement and could serve as biomarkers of treatment outcome. One such method is cordance, a computation of regional brain activity based on a combination of absolute and relative resting EEG activity. Specifically, early reduction in prefrontal (PF) and midline right frontal (MRF) theta (4-8Hz) cordance has been shown to predict response to various antidepressants, though replication is required. Thus, this study examined early changes (baseline to week 1) in PF and MRF cordance in 47 MDD patients undergoing antidepressant treatment. Early changes in cordance and in Montgomery Åsberg Depression Rating Scale (MADRS) scores were assessed alone, and in combination, to predict eventual (by week 12) treatment response and remission. Models combining early changes in theta cordance (PF and MRF) and depressive symptoms were most predictive of response to treatment at week 12; remission models (cordance, MADRS, and their combination) were weaker, though provided modest prediction values. These results suggest that antidepressant response may be optimally predicted by combining both EEG and symptom-based measures after one week of treatment.

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.

Atypical Temporal Dynamics of Resting State Shapes Stimulus-Evoked Activity in Depression-An EEG Study on Rest-Stimulus Interaction.

Major depressive disorder (MDD) is a complex psychiatric disorder characterized by changes in both resting state and stimulus-evoked activity. Whether resting state changes are carried over to stimulus-evoked activity, however, is unclear. We conducted a combined rest (3 min) and task (three-stimulus auditory oddball paradigm) EEG study in n=28 acute depressed MDD patients, comparing them with n=25 healthy participants. Our focus was on the temporal dynamics of both resting state and stimulus-evoked activity for which reason we measured peak frequency (PF), coefficient of variation (CV), Lempel-Ziv complexity (LZC), and trial-to-trial variability (TTV). Our main findings are: i) atypical temporal dynamics in resting state, specifically in the alpha and theta bands as measured by peak frequency (PF), coefficient of variation (CV) and power; ii) decreased reactivity to external deviant stimuli as measured by decreased changes in stimulus-evoked variance and complexity-TTV, LZC, and power and frequency sliding (FS and PS); iii) correlation of stimulus related measures (TTV, LZC, PS, and FS) with resting state measures. Together, our findings show that resting state dynamics alone are atypical in MDD and, even more important, strongly shapes the dynamics of subsequent stimulus-evoked activity. We thus conclude that MDD can be characterized by an atypical temporal dynamic of its rest-stimulus interaction; that, in turn, makes it difficult for depressed patients to react to relevant stimuli such as the deviant tone in our paradigm.

Acute separate and combined effects of cannabinoid and nicotinic receptor agonists on MMN-indexed auditory deviance detection in healthy humans.

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.

NMDA Receptor Antagonist Effects on Speech-Related Mismatch Negativity and Its Underlying Oscillatory and Source Activity in Healthy Humans.

Background: Previous studies in schizophrenia have consistently shown that deficits in the generation of the auditory mismatch negativity (MMN) - a pre-attentive, event-related potential (ERP) typically elicited by changes to simple sound features - are linked to N-methyl-D-aspartate (NMDA) receptor hypofunction. Concomitant with extensive language dysfunction in schizophrenia, patients also exhibit MMN deficits to changes in speech but their relationship to NMDA-mediated neurotransmission is not clear. Accordingly, our study aimed to investigate speech MMNs in healthy humans and their underlying electrophysiological mechanisms in response to NMDA antagonist treatment. We also evaluated the relationship between baseline MMN/electrocortical activity and emergent schizophrenia-like symptoms associated with NMDA receptor blockade. Methods: In a sample of 18 healthy volunteers, a multi-feature Finnish language paradigm incorporating changes in syllables, vowels and consonant stimuli was used to assess the acute effects of the NMDA receptor antagonist ketamine and placebo on the MMN. Further, measures of underlying neural activity, including evoked theta power, theta phase locking and source-localized current density in cortical regions of interest were assessed. Subjective symptoms were assessed with the Clinician Administered Dissociative States Scale (CADSS). Results: Participants exhibited significant ketamine-induced increases in psychosis-like symptoms and depending on temporal or frontal recording region, co-occurred with reductions in MMN generation in response to syllable frequency/intensity, vowel duration, across vowel and consonant deviants. MMN attenuation was associated with decreases in evoked theta power, theta phase locking and diminished current density in auditory and inferior frontal (language-related cortical) regions. Baseline (placebo) MMN and underlying electrophysiological features associated with the processing of changes in syllable intensity correlated with the degree of psychotomimetic response to ketamine. Conclusion: Ketamine-induced impairments in healthy human speech MMNs and their underlying electrocortical mechanisms closely resemble those observed in schizophrenia and support a model of dysfunctional NMDA receptor-mediated neurotransmission of language processing deficits in schizophrenia. HIGHLIGHTS: -Neural effects of NMDA receptor blockade on speech processing were assessed in a ketamine model.-Ketamine reduced MMN, theta power, theta phase locking factor and regional cortical current density.-Psychosis-like symptoms induced by ketamine were related to baseline (placebo) neural measures of speech processing.