Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction.

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35-45 Hz) power (n = 22, r = 0.613, P < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power (t13 = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.

Alpha3/alpha2 power ratios relate to performance on a virtual reality shopping task in ageing adults.

Background: Aspects of cognitive function decline with age. This phenomenon is referred to as age-related cognitive decline (ARCD). Improving the understanding of these changes that occur as part of the ageing process can serve to enhance the detection of the more incapacitating neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we employ novel methods to assess ARCD by exploring the utility of the alpha3/alpha2 electroencephalogram (EEG) power ratio - a marker of AD, and a novel virtual reality (VR) functional cognition task - VStore, in discriminating between young and ageing healthy adults. Materials and methods: Twenty young individuals aged 20-30, and 20 older adults aged 60-70 took part in the study. Participants underwent resting-state EEG and completed VStore and the Cogstate Computerised Cognitive Battery. The difference in alpha3/alpha2 power ratios between the age groups was tested using t-test. In addition, the discriminatory accuracy of VStore and Cogstate were compared using logistic regression and overlying receiver operating characteristic (ROC) curves. Youden's J statistic was used to establish the optimal threshold for sensitivity and specificity and model performance was evaluated with the DeLong's test. Finally, alpha3/alpha2 power ratios were correlated with VStote and Cogstate performance. Results: The difference in alpha3/alpha2 power ratios between age cohorts was not statistically significant. On the other hand, VStore discriminated between age groups with high sensitivity (94%) and specificity (95%) The Cogstate Pre-clinical Alzheimer's Battery achieved a sensitivity of 89% and specificity of 60%, and Cogstate Composite Score achieved a sensitivity of 83% and specificity of 85%. The differences between the discriminatory accuracy of VStore and Cogstate models were statistically significant. Finally, high alpha3/alpha2 power ratios correlated strongly with VStore (r = 0.73), the Cogstate Pre-clinical Alzheimer's Battery (r = -0.67), and Cogstate Composite Score (r = -0.76). Conclusion: While we did not find evidence that the alpha3/alpha2 power ratio is elevated in healthy ageing individuals compared to young individuals, we demonstrated that VStore can classify age cohorts with high accuracy, supporting its utility in the assessment of ARCD. In addition, we found preliminary evidence that elevated alpha3/alpha2 power ratio may be linked to lower cognitive performance.

Identifying Electroencephalography Biomarkers in Individuals at Clinical High Risk for Psychosis in an International Multi-Site Study.

Background: The clinical high-risk for psychosis (CHR-P) paradigm was introduced to detect individuals at risk of developing psychosis and to establish preventive strategies. While current prediction of outcomes in the CHR-P state is based mostly on the clinical assessment of presenting features, several emerging biomarkers have been investigated in an attempt to stratify CHR-P individuals according to their individual trajectories and refine the diagnostic process. However, heterogeneity across subgroups is a key challenge that has limited the impact of the CHR-P prediction strategies, as the clinical validity of the current research is limited by a lack of external validation across sites and modalities. Despite these challenges, electroencephalography (EEG) biomarkers have been studied in this field and evidence suggests that EEG used in combination with clinical assessments may be a key measure for improving diagnostic and prognostic accuracy in the CHR-P state. The PSYSCAN EEG study is an international, multi-site, multimodal longitudinal project that aims to advance knowledge in this field. Methods: Participants at 6 international sites take part in an EEG protocol including EEG recording, cognitive and clinical assessments. CHR-P participants will be followed up after 2 years and subcategorised depending on their illness progression regarding transition to psychosis. Differences will be sought between CHR-P individuals and healthy controls and between CHR-P individuals who transition and those who do not transition to psychosis using data driven computational analyses. Discussion: This protocol addresses the challenges faced by previous studies of this kind to enable valid identification of predictive EEG biomarkers which will be combined with other biomarkers across sites to develop a prognostic tool in CHR-P. The PSYSCAN EEG study aims to pave the way for incorporating EEG biomarkers in the assessment of CHR-P individuals, to refine the diagnostic process and help to stratify CHR-P subjects according to risk of transition. This may improve our understanding of the CHR-P state and therefore aid the development of more personalized treatment strategies.

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial.

BACKGROUND: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. AIMS: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. METHODS: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. RESULTS: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (p=0.04) and working memory-related theta oscillations (p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. CONCLUSIONS: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

Gamma band oscillations in the early phase of psychosis: A systematic review.

Abnormal gamma oscillations, measured by electroencephalography (EEG), have been associated with chronic psychotic disorders, but their prevalence in the early phase of psychosis is less clear. We sought to address this by systematically reviewing the relevant literature. We searched for EEG studies of gamma band oscillations in subjects at high risk for psychosis and in patients with first episode psychosis. The following measures of gamma oscillations were extracted: resting power, evoked power, induced power, connectivity and peak frequency. Forty-five studies with a total of 3099 participants were included. There were potential sources of bias in the study designs and potential artefacts. Although there were few consistent findings, several studies reported decreased evoked or induced power in both high risk subjects and first episode patients. Studies using larger samples with serial EEG measurements, and designs that minimise artefacts that occur at the gamma frequency may advance work in this area.

State-of-the-Art Analysis of High-Frequency (Gamma Range) Electroencephalography in Humans.

Gamma oscillations (>30 Hz) in the brain are involved in attention, perception and memory. They are altered in various pathological states, as well as by neuropharmaceuticals, so that they are of interest in drug and clinical investigations. However, when the human electroencephalogram is recorded on the scalp, this neural high-frequency signal is buried under a range of other electrical signals such that, without careful handling, recordings of the high-frequency electroencephalogram cannot be considered reliable. The artefacts of concern originate from: power line noise, saccade-associated contraction of the extra-ocular muscles, activity of muscles in the scalp, face and neck, screen refresh artefacts and activity of the muscles associated with blinking. Recent progress in dealing with these artefacts is described, including either noise cancellation or phased noise template subtraction for power line noise, regression or independent component analysis for correcting extra-ocular muscle activity and mathematical modelling for reducing scalp, face and neck muscle activity. If the artefacts are properly addressed, the neural gamma signal can be uncovered.

Delta-9-tetrahydrocannabinol, neural oscillations above 20 Hz and induced acute psychosis.

RATIONALE: An acute challenge with delta-9-tetrahydrocannabinol (THC) can induce psychotic symptoms including delusions. High electroencephalography (EEG) frequencies, above 20 Hz, have previously been implicated in psychosis and schizophrenia. OBJECTIVES: The objective of this study is to determine the effect of intravenous THC compared to placebo on high-frequency EEG. METHODS: A double-blind cross-over study design was used. In the resting state, the high-beta to low-gamma magnitude (21-45 Hz) was investigated (n = 13 pairs + 4 THC only). Also, the event-related synchronisation (ERS) of motor-associated high gamma was studied using a self-paced button press task (n = 15). RESULTS: In the resting state, there was a significant condition × frequency interaction (p = 0.00017), consisting of a shift towards higher frequencies under THC conditions (reduced high beta [21-27 Hz] and increased low gamma [27-45 Hz]). There was also a condition × frequency × location interaction (p = 0.006), such that the reduction in 21-27-Hz magnitude tended to be more prominent in anterior regions, whilst posterior areas tended to show greater 27-45-Hz increases. This effect was correlated with positive symptoms, as assessed on the Positive and Negative Syndrome Scale (PANSS) (r = 0.429, p = 0.042). In the motor task, there was a main effect of THC to increase 65-130-Hz ERS (p = 0.035) over contra-lateral sensorimotor areas, which was driven by increased magnitude in the higher, 85-130-Hz band (p = 0.02) and not the 65-85-Hz band. CONCLUSIONS: The THC-induced shift to faster gamma oscillations may represent an over-activation of the cortex, possibly related to saliency misattribution in the delusional state.

Resting EEG in psychosis and at-risk populations--a possible endophenotype?

BACKGROUND: Finding reliable endophenotypes for psychosis could lead to an improved understanding of aetiology, and provide useful alternative phenotypes for genetic association studies. Resting quantitative electroencephalography (QEEG) activity has been shown to be heritable and reliable over time. However, QEEG research in patients with psychosis has shown inconsistent and even contradictory findings, and studies of at-risk populations are scarce. Hence, this study aimed to investigate whether resting QEEG activity represents a candidate endophenotype for psychosis. METHOD: QEEG activity at rest was compared in four frequency bands (delta, theta, alpha, and beta), between chronic patients with psychosis (N=48), first episode patients (N=46), at-risk populations ("at risk mental state", N=33; healthy relatives of patients, N=45), and healthy controls (N=107). RESULTS: Results showed that chronic patients had significantly increased resting QEEG amplitudes in delta and theta frequencies compared to healthy controls. However, first episode patients and at-risk populations did not differ from controls in these frequency bands. There were no group differences in alpha or beta frequency bands. CONCLUSION: Since no abnormalities were found in first episode patients, ARMS, or healthy relatives, resting QEEG activity in the frequency bands examined is unlikely to be related to genetic predisposition to psychosis. Rather than endophenotypes, the low frequency abnormalities observed in chronic patients are probably related to illness progression and/or to the long-term effects of treatments.

Removing ballistocardiogram artifact from EEG using short- and long-term linear predictor.

In this paper, a novel source extraction method is proposed for removing ballistocardiogram (BCG) artifact from EEG. BCG appears in EEG signals recorded simultaneously with functional magnetic resonance imaging. The proposed method is a semiblind source extraction algorithm based on linear prediction technique. We define a cost function according to a joint short- and long-term prediction strategy to extract the BCG sources. We call this method SLTP-BSE standing for short- and long-term prediction blind source extraction. The objective of this work is to 1) model the temporal structure of the sources using short-term prediction and 2) impose the prior information about the BCG sources using long-term prediction. These two procedures are simultaneously implemented to optimize the system. The performance of the proposed method is evaluated using both synthetic and real EEG data. The obtained results show that the proposed technique is able to remove the BCG artifact while preserving the task-related parts of the signal. The results of SLTP-BSE are compared with those of well-known BCG removal techniques confirming the superiority of the proposed method.

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment.

Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

A novel method for reducing the effect of tonic muscle activity on the gamma band of the scalp EEG.

Neural oscillations in the gamma band are of increasing interest, but separating them from myogenic electrical activity has proved difficult. A novel algorithm has been developed to reduce the effect of tonic scalp and neck muscle activity on the gamma band of the EEG. This uses mathematical modelling to fit individual muscle spikes and then subtracts them from the data. The method was applied to the detection of motor associated gamma in two separate groups of eight subjects using different sampling rates. A reproducible increase in high gamma (65-85 Hz) magnitude occurred immediately after the motor action in the left central area (p = 0.02 and p = 0.0002 for the two cohorts with individually optimized algorithm parameters, compared to p = 0.03 and p = 0.16 before correction). Whilst the magnitude of this event-related gamma synchronisation was not reduced by the application of the EMG reduction algorithm, the baseline left central gamma magnitude was significantly reduced by an average of 23 % with a faster sampling rate (p < 0.05). In comparison, at left and right temporo-parietal locations the gamma amplitude was reduced by 60 and 54 % respectively (p < 0.05). The reduction of EMG contamination by fitting and subtraction of individual spikes shows promise as a method of improving the signal to noise ratio of high frequency neural oscillations in scalp EEG.

Disruption of frontal θ coherence by Δ9-tetrahydrocannabinol is associated with positive psychotic symptoms.

The main ingredient in cannabis, Δ(9)-tetrahydrocannabinol (THC), can elicit acute psychotic reactions in healthy individuals and precipitate relapse in schizophrenic patients. However, the neural mechanism of this is unknown. We tested the hypothesis that THC psychopathology is related to changes in electroencephalography (EEG) power or inter-regional coherence. In a within-subjects design, participants (n=16) were given intravenous THC (1.25 mg) or placebo under double-blind conditions, during EEG recordings. Using fast-Fourier transform, EEG data were analyzed for power and coherence in the delta (1-3.5 Hz), theta (3.5-7 Hz), alpha (8-13 Hz), beta (14-25 Hz), low-gamma (30-40 Hz), and high-gamma (60-70 Hz) bands during engagement in the n-back test of working memory (WM). Compared with placebo, THC evoked positive and negative psychotic symptoms, as measured by the positive and negative syndrome scale (p<0.001) and slowed WM performance (p<0.05). Under THC, theta power was specifically reduced, (p<0.001) regardless of WM load; however, the reduction showed no relationship with psychotic symptoms or WM impairment. Coherence between bi-frontal electrodes in the theta band was also reduced by THC (p<0.05) and these reductions correlated with the change-in positive psychotic symptoms (rho=0.79, p<0.001). Bi-frontal specificity was suggested by the absence of a relationship between psychotic symptoms and fronto-parietal coherence. The results reveal that the pro-psychotic effects of THC might be related to impaired network dynamics with impaired communication between the right and left frontal lobes.

Uncovering gamma in visual tasks.

Gamma is an important frequency band of the electroencephalogram (EEG), but its study has been impaired by problems with artefacts. This paper focuses on the artefacts caused by contraction of the extra-ocular muscles at the start of a saccade, which produces spurious gamma oscillations in the EEG. An algorithm was written and tested which detects and reduces the effect of this artefact. It involves novel adaptations of standard regression techniques which have traditionally been used to reduce blink artefacts, so as to render them applicable to the gamma band ocular artefact. Before the algorithm can be applied any power-line noise must be removed by noise cancellation and not notch filtering. The sharp, broadband gamma peak at around 200 ms was substantially reduced by the algorithm in all three subjects tested. However, there may be lower amplitude, task related, modulations in gamma which are uncovered when the artefact is reduced. The amplitude of the artefact had its largest positive value at the most anterior electrodes and its largest negative value at midline central and parietal electrodes, and these two sets of locations also showed the greatest reductions in gamma band magnitude after application of the algorithm. This study demonstrates the feasibility of reducing the saccade linked gamma band artefact.