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.

Effect of GAD1 genotype status on auditory attention and acute nicotine administration in healthy volunteers.

OBJECTIVE: The effects of GABA modulating drugs and nicotine, the prototypical nicotinic cholinergic agonist, on attention have been investigated using subcomponents of the P300 event-related potentials (ERP), which index involuntary (P3a) and voluntary attention (P3b). However, investigations into how such pharmacologic effects interact with genetic features in the GABA system remain unclear. This study examined the moderating effects of a single nucleotide polymorphism (rs7557793) in the glutamic acid decarboxylase 67 (GAD1) gene, which is implicated in the conversion of glutamate to GABA, on P300-indices of auditory attentional processing; the influence of nicotine administration was also assessed. METHODS: The effects of GAD1 genotype (TT/CC/CT) were examined on the P3a/b in response to an auditory selective attention task in healthy, nonsmoking male volunteers (N = 126; 18-40 years). Participants responded to rare target stimuli (P3b-eliciting) and ignored frequent nontarget stimuli as well as rare distractor stimuli (P3a-eliciting). In a subsample (N = 59), P3a/b profiles to acute nicotine (vs. placebo) administration were examined as a function of GAD1 genotype. As a secondary aim, earlier sensory processes were assessed with N200 ERP subcomponents elicited by novel (N2a) and target (N2b) auditory stimuli. RESULTS: GAD1 allelic variation moderated early sensory processes, enhancing N2a amplitudes in CT versus TT carriers. Further, TT homozygotes exhibited larger P3b amplitudes than CC homozygotes in the placebo versus nicotine condition. Regardless of genotype, nicotine versus placebo moderated the N200 ERP. CONCLUSION: These findings expand our knowledge regarding the attentional effects of GAD1 genetic variants in relation to nicotine.

Effects of transcranial direct current stimulation on the auditory mismatch negativity response and working memory performance in schizophrenia: a pilot study.

Cognitive impairment has been proposed to be the core feature of schizophrenia (Sz). Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which can improve cognitive function in healthy participants and in psychiatric patients with cognitive deficits. tDCS has been shown to improve cognition and hallucination symptoms in Sz, a disorder also associated with marked sensory processing deficits. Recent findings in healthy controls demonstrate that anodal tDCS increases auditory deviance detection, as measured by the brain-based event-related potential, mismatch negativity (MMN), which is a putative biomarker of Sz that has been proposed as a target for treatment of Sz cognition. This pilot study conducted a randomized, double-blind assessment of the effects of pre- and post-tDCS on MMN-indexed auditory discrimination in 12 Sz patients, moderated by auditory hallucination (AH) presence, as well as working memory performance. Assessments were conducted in three sessions involving temporal and frontal lobe anodal stimulation (to transiently excite local brain activity), and one control session involving 'sham' stimulation (meaning with the device turned off, i.e., no stimulation). Results demonstrated a trend for pitch MMN amplitude to increase with anodal temporal tDCS, which was significant in a subgroup of Sz individuals with AHs. Anodal frontal tDCS significantly increased WM performance on the 2-back task, which was found to positively correlate with MMN-tDCS effects. The findings contribute to our understanding of tDCS effects for sensory processing deficits and working memory performance in Sz and may have implications for psychiatric disorders with sensory deficits.

Assessment of anodal and cathodal transcranial direct current stimulation (tDCS) on MMN-indexed auditory sensory processing.

Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which uses a very weak constant current to temporarily excite (anodal stimulation) or inhibit (cathodal stimulation) activity in the brain area of interest via small electrodes placed on the scalp. Currently, tDCS of the frontal cortex is being used as a tool to investigate cognition in healthy controls and to improve symptoms in neurological and psychiatric patients. tDCS has been found to facilitate cognitive performance on measures of attention, memory, and frontal-executive functions. Recently, a short session of anodal tDCS over the temporal lobe has been shown to increase auditory sensory processing as indexed by the Mismatch Negativity (MMN) event-related potential (ERP). This preliminary pilot study examined the separate and interacting effects of both anodal and cathodal tDCS on MMN-indexed auditory pitch discrimination. In a randomized, double blind design, the MMN was assessed before (baseline) and after tDCS (2mA, 20min) in 2 separate sessions, one involving 'sham' stimulation (the device is turned off), followed by anodal stimulation (to temporarily excite cortical activity locally), and one involving cathodal stimulation (to temporarily decrease cortical activity locally), followed by anodal stimulation. Results demonstrated that anodal tDCS over the temporal cortex increased MMN-indexed auditory detection of pitch deviance, and while cathodal tDCS decreased auditory discrimination in baseline-stratified groups, subsequent anodal stimulation did not significantly alter MMN amplitudes. These findings strengthen the position that tDCS effects on cognition extend to the neural processing of sensory input and raise the possibility that this neuromodulatory technique may be useful for investigating sensory processing deficits in clinical populations.

Effect of transcranial direct current stimulation (tDCS) on MMN-indexed auditory discrimination: a pilot study.

Membrane potentials and brain plasticity are basic modes of cerebral information processing. Both can be externally (non-invasively) modulated by weak transcranial direct current stimulation (tDCS). Polarity-dependent tDCS-induced reversible circumscribed increases and decreases in cortical excitability and functional changes have been observed following stimulation of motor and visual cortices but relatively little research has been conducted with respect to the auditory cortex. The aim of this pilot study was to examine the effects of tDCS on auditory sensory discrimination in healthy participants (N = 12) assessed with the mismatch negativity (MMN) brain event-related potential (ERP). In a randomized, double-blind, sham-controlled design, participants received anodal tDCS over the primary auditory cortex (2 mA for 20 min) in one session and 'sham' stimulation (i.e., no stimulation except initial ramp-up for 30 s) in the other session. MMN elicited by changes in auditory pitch was found to be enhanced after receiving anodal tDCS compared to 'sham' stimulation, with the effects being evidenced in individuals with relatively reduced (vs. increased) baseline amplitudes and with relatively small (vs. large) pitch deviants. Additional studies are needed to further explore relationships between tDCS-related parameters, auditory stimulus features and individual differences prior to assessing the utility of this tool for treating auditory processing deficits in psychiatric and/or neurological disorders.

Data mining EEG signals in depression for their diagnostic value.

BACKGROUND: Quantitative electroencephalogram (EEG) is one neuroimaging technique that has been shown to differentiate patients with major depressive disorder (MDD) and non-depressed healthy volunteers (HV) at the group-level, but its diagnostic potential for detecting differences at the individual level has yet to be realized. Quantitative EEGs produce complex data sets derived from digitally analyzed electrical activity at different frequency bands, at multiple electrode locations, and under different vigilance (eyes open vs. closed) states, resulting in potential feature patterns which may be diagnostically useful, but detectable only with advanced mathematical models. METHODS: This paper uses a data mining methodology for classifying EEGs of 53 MDD patients and 43 HVs. This included: (a) pre-processing the data, including cleaning and normalization, applying Linear Discriminant Analysis (LDA) to map the features into a new feature space; and applying Genetic Algorithm (GA) to identify the most significant features; (b) building predictive models using the Decision Tree (DT) algorithm to discover rules and hidden patterns based on the reduced and mapped features; and (c) evaluating the models based on the accuracy and false positive values on the EEG data of MDD and HV participants. Two categories of experiments were performed. The first experiment analyzed each frequency band individually, while the second experiment analyzed the bands together. RESULTS: Application of LDA and GA markedly reduced the total number of utilized features by ≥ 50 % and, with all frequency bands analyzed together, the model showed average classification accuracy (MDD vs. HV) of 80 %. The best results from model testing with additional test EEG recordings from 9 MDD patients and 35 HV individuals demonstrated an accuracy of 80 % and showed an average sensitivity of 70 %, a specificity of 76 %, and a positive (PPV) and negative predictive value (NPV) of 74 and 75 %, respectively. CONCLUSIONS: These initial findings suggest that the proposed automated EEG analytical approach could be a useful adjunctive diagnostic approach in clinical practice.

Modulation of auditory deviance detection by acute nicotine is baseline and deviant dependent in healthy nonsmokers: a mismatch negativity study.

OBJECTIVE: Cognitive enhancement resulting from nicotinic acetylcholine receptor stimulation may be evidenced by increased efficiency of the auditory-frontal cortex network of auditory discrimination, which is impaired in schizophrenia, a cognitive disorder associated with excessive tobacco use. Investigating automatic (preattentive) detection of acoustic change with the mismatch negativity (MMN) brain event-related potential in response to nicotine in individuals with varying baseline levels of auditory discrimination may provide useful insight into the cholinergic regulation of this neural network and its potential amelioration with novel nicotinic agents. METHODS: Sixty healthy, non-smoking male volunteers were presented with an 'optimal' multi-feature MMN paradigm in a randomized, placebo controlled double-blind design with 6 mg of nicotine gum. RESULTS: Participants with low, medium, and high baseline amplitudes responded differently to nicotine (vs. placebo), and nicotine response was feature specific. Whereas MMN in individuals with high amplitudes was diminished by nicotine, MMN increased in those with low amplitudes. Nicotine effects were not shown in medium amplitude participants. CONCLUSIONS: These findings provide preliminary support for the role of nicotinic neurotransmission in sensory memory processing of auditory change and suggest that nicotinic receptor modulation can both enhance and diminish change detection, depending on baseline MMN and its eliciting stimulus feature.

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.

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.

One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response.

Introduction: To date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response. Methods: Resting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients. Results: Responders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization. Discussion: Our single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability. Clinical trial registration: https://clinicaltrials.gov, identifier NCT00519428.

An α7 nAChR approach for the baseline-dependent modulation of deviance detection in schizophrenia: A pilot study assessing the combined effect of CDP-choline and galantamine.

BACKGROUND: Cognitive operations including pre-attentive sensory processing are markedly impaired in patients with schizophrenia (SCZ) but evidence significant interindividual heterogeneity, which moderates treatment response with nicotinic acetylcholine receptor (nAChR) agonists. Previous studies in healthy volunteers have shown baseline-dependency effects of the α7 nAChR agonist cytidine 5'-diphosphocholine (CDP-choline) administered alone and in combination with a nicotinic allosteric modulator (galantamine) on auditory deviance detection measured with the mismatch negativity (MMN) event-related potential (ERP). AIM: The objective of this pilot study was to assess the acute effect of this combined α7 nAChR-targeted treatment (CDP-choline/galantamine) on speech MMN in patients with SCZ (N = 24) stratified by baseline MMN responses into low, medium, and high baseline auditory deviance detection subgroups. METHODS: Patients with a stable diagnosis of SCZ attended two randomized, double-blind, placebo-controlled and counter-balanced testing sessions where they received a placebo or a CDP-choline (500 mg) and galantamine (16 mg) treatment. MMN ERPs were recorded during the presentation of a fast multi-feature speech MMN paradigm including five speech deviants. Clinical measures were acquired before and after treatment administration. RESULTS: While no main treatment effect was observed, CDP-choline/galantamine significantly increased MMN amplitudes to frequency, duration, and vowel speech deviants in low group individuals. Individuals with higher positive and negative symptom scale negative, general, and total scores expressed the greatest MMN amplitude improvement following CDP-choline/galantamine. CONCLUSIONS: These baseline-dependent nicotinic effects on early auditory information processing warrant different dosage and repeated administration assessments in patients with low baseline deviance detection levels.

Culture shapes spontaneous brain dynamics - Shared versus idiosyncratic neural features among Chinese versus Canadian subjects.

Environmental factors, such as culture, are known to shape individual variation in brain activity including spontaneous activity, but less is known about their population-level effects. Eastern and Western cultures differ strongly in their cultural norms about relationships between individuals. For example, the collectivism, interdependence and tightness of Eastern cultures relative to the individualism, independence and looseness of Western cultures, promote interpersonal connectedness and coordination. Do such cultural contexts therefore influence the group-level variability of their cultural members' spontaneous brain activity? Using novel methods adapted from studies of inter-subject neural synchrony, we compare the group-level variability of resting state EEG dynamics in Chinese and Canadian samples. We observe that Chinese subjects show significantly higher inter-subject correlation and lower inter-subject distance in their EEG power spectra than Canadian subjects, as well as lower variability in theta power and alpha peak frequency. We demonstrate, for the first time, different relationships among subjects' resting state brain dynamics in Chinese and Canadian samples. These results point to more idiosyncratic neural dynamics among Canadian participants, compared with more shared neural features in Chinese participants.

Acute tryptophan depletion effects on the vertex and late positive potentials to emotional faces in individuals with a family history of depression.

BACKGROUND: Depression, which is associated with dysfunctional serotonin (5-HT) activity, may be characterized by impaired emotional information processing. This study assessed the effects of acute tryptophan depletion (TRP-), which transiently lowers CNS 5-HT, on the emotion-sensitive vertex positive potential (VPP) and late positive potential (LPP) event-related potentials (ERPs) and mood in individuals with a family history of depression. The VPP and LPP are thought to index the early and later stages of motivated attentional processing, respectively. METHOD: Within a double-blind balanced design, ERPs were acquired in 18 individuals with a family history of depression (12 females) after TRP- and TRP+ (balanced) treatment while participants were presented with facial expressions (neutral, as well as sad, joy and surprise at 50 and 100% intensity) and responded to surprised faces. RESULTS: TRP- increased total mood disturbance and maintained depression scores. The VPP and LPP were larger to intense versus mild expressions. Enhanced processing of emotional versus neutral faces, as indexed by the VPP, was primarily evident with TRP-. Speeded and enhanced processing of intensely joyful versus mildly sad faces was found with TRP- (VPP indexed). Compared with TRP+, TRP also increased the VPP to mildly joyful faces. CONCLUSION: Transient 5-HT decreases in individuals with a family history of depression induce subtle changes in early stages of motivated emotional processing, though not in later ones.

Nicotine and the hallucinating brain: effects on mismatch negativity (MMN) in schizophrenia.

Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre-attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs.

A pilot study of electrocortical activity in dysfunctional anger: decreased frontocortical activation, impaired attention control, and diminished behavioral inhibition.

Dysfunctional anger, though not a primary clinical diagnosis per se, does present clinically as a pathological mood for which treatment is sought. Few studies have probed the neurocortical correlates of dysfunctional anger or assessed if cognitive processes, such as attention, are altered in dysfunctional anger. Though dysfunctional and high trait anger appears to be associated with biased processing of anger-eliciting information, few studies have examined if dysfunctional anger modulates attention more generally. This is a notable gap as volitional attention control is associated with effective emotive regulation, which is impaired in dysfunctional anger and in associated acts of aggression. In this pilot study, we examined performance and electroencephalographic (EEG) profiles during a 12-min continuous performance task (CPT) of sustained attention in 15 adults with dysfunctional anger (Anger group) and 14 controls (control group). The Anger group had fewer hits at the end of the CPT, which correlated with decreased frontocortical activation, suggesting decreased engagement of frontal circuits when attention is taxed. The Anger group had more false alarms overall indicating impaired response inhibition. Increased right cortical activation during the initial portion of CPT existed in the Anger group, perhaps reflecting greater engagement of frontal circuits (i.e. effort) during initial stages of the task compared to controls. Finally, increased overall beta1 power, suggesting increased cortical activation, was noted in the Anger group. These EEG patterns suggest a hypervigilant state in dysfunctional anger, which may interfere with effective attention control and decrease inhibition. Such impairments likely extend beyond the laboratory setting, and may associate with aggressive acts in real life.

The acute dose and baseline amplitude-dependent effects of CDP-choline on deviance detection (MMN) in chronic schizophrenia: A pilot study.

The detection of deviant auditory features is empirically supported as impaired in schizophrenia and has been shown to associate with functional outcome. Modulated by glutamate neurotransmission, this sensory process has also been shown to relate to the α7 nicotinic acetylcholine receptor (nAChR) system, a prioritized molecular target for the development of novel cognition targeted pharmacological treatments. This pilot study assessed the acute effects of CDP-Choline, a choline supplement with α7 nAChR agonist properties, on the mismatch negativity (MMN), an event-related potential index of the detection of an acoustic change, in a sample of individuals diagnosed with chronic schizophrenia. Utilizing a randomized, placebo-controlled, double-blind design, the dose-dependent (500 mg, 1,000 mg, 2,000 mg), baseline amplitude-dependent (low vs. high), and deviant feature-dependent effects of CDP-Choline on the MMN were examined. CDP-choline's effects interacted with dosage, deviance feature, and baseline amplitude with low baseline amplitude patients demonstrating enhanced MMNs, and high baseline amplitude patients demonstrating suppressed MMNs in response to CDP-Choline. These findings offer tentative support for the involvement of the α7 nAChR system in auditory MMN abnormalities in schizophrenia and supports further research assessing the effects of long-term treatment with CDP-Choline in the personalized treatment of auditory deviance processing impairments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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.

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.

Resting State EEG Activity Related to Impulsivity in People with Prescription Opioid Use Disorder.

Previous studies on EEG activity in prescription opioid use disorder (OUD) have reported neuronal dysfunction related to heroin use, most consistently reflected by increases in ß-brain oscillations. As similar research has yet to examine EEG associated with non-medical use of prescription opioid and as inhibitory deficits are associated with OUD, this pilot study compared quantitative EEGs of 18 patients with prescription OUD and 18 healthy volunteers and assessed relationships between oscillatory activity and impulsivity with the Barratt Impulsiveness Scale (BIS-11). Spectral EEGs showed greater amplitude density in ß1, ß2, and ß3 frequencies across frontal, temporal-central and posterior recording areas in patients. Similar abnormal amplitude density increases were seen in δ but not in θ or α frequency bands. Patients exhibited greater scores (impaired impulse control) on BIS-11 subscales (attention, motor, self-control) and impairment of these impulsive subtypes was associated with increases in ß and δ oscillations. In patients, ß1, ß2, and δ activity was positively associated with disorder severity. Taken together, the results suggest that altered brain oscillations in persons with prescription OUD show some similarities with reported oscillatory changes in heroin use and may indicate a chronic state of imbalance in neuronal networks regulating impulsive and inhibitory control systems.