Application of Electroencephalography to the Study of Cognitive and Brain Functions in Schizophrenia

The electroencephalogram (EEG) recorded from the human scalp is widely used to study cognitive and brain functions in schizophrenia. Current research efforts are primarily devoted to the assessment of event-related potentials (ERPs) and event-related oscillations (EROs), extracted from the ongoing EEG, in patients with schizophrenia and in clinically unaffected individuals who, due to their family history and current mental status, are at high risk for developing schizophrenia. In this article, we discuss the potential usefulness of ERPs and EROs as genetic vulnerability markers, as pathophysiological markers, and as markers of possible ongoing progressive cognitive and cortical deterioration in schizophrenia. Our main purpose is to illustrate that these neurophysiological measures can offer valuable quantitative biological markers of basic pathophysiological mechanisms and cognitive dysfunctions in schizophrenia, yet they may not be specific to current psychiatry's diagnosis and classification. These biological markers can provide unique information on the nature and extent of cognitive and brain dysfunction in schizophrenia. Moreover, they can be utilized to gain deeper theoretical insights into illness etiology and pathophysiology and may lead to improvements in early detection and more effective and targeted treatment of schizophrenia. We conclude by addressing several key methodological, conceptual, and interpretative issues involved in this research field and by suggesting future research directions

Differentiation of Schizophrenia Patients from Healthy Subjects by Mismatch Negativity and Neuropsychological Tests

BACKGROUND: Schizophrenia is a heterogeneous disorder with diverse presentations. The current and the proposed DSM-V diagnostic system remains phenomenologically based, despite the fact that several neurobiological and neuropsychological markers have been identified. A multivariate approach has better diagnostic utility than a single marker method. In this study, the mismatch negativity (MMN) deficit of schizophrenia was first replicated in a Han Chinese population, and then the MMN was combined with several neuropsychological measurements to differentiate schizophrenia patients from healthy subjects. METHODOLOGY/PRINCIPAL FINDINGS: 120 schizophrenia patients and 76 healthy controls were recruited. Each subject received examinations for duration MMN, Continuous Performance Test, Wisconsin Card Sorting Test, and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). The MMN was compared between cases and controls, and important covariates were investigated. Schizophrenia patients had significantly reduced MMN amplitudes, and MMN decreased with increasing age in both patient and control groups. None of the neuropsychological indices correlated with MMN. Predictive multivariate logistic regression models using the MMN and neuropsychological measurements as predictors were developed. Four predictors, including MMN at electrode FCz and three scores from the WAIS-III (Arithmetic, Block Design, and Performance IQ) were retained in the final predictive model. The model performed well in differentiating patients from healthy subjects (percentage of concordant pairs: 90.5%). CONCLUSIONS/SIGNIFICANCE: MMN deficits were found in Han Chinese schizophrenia patients. The multivariate approach combining biomarkers from different modalities such as electrophysiology and neuropsychology had a better diagnostic utility

Objective Quantification Of Selective Attention In Schizophrenia : A Hybrid TMS-EEG Approach

Schizophrenia is a brain disorder that exhibits effects on perception, way of thinking and behavior. Often, schizophrenia patients suffer from attention deficiency. Currently clinical interview is used to diagnose schizophrenia by doctors. There is no alternative way to diagnose schizophrenia in present. Thus, an objective approach by employing transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) is proposed. The aim of the study is to quantify objectively the neural correlate of selective attention that reflected in auditory late responses (ALRs) using signal processing techniques. TMS provides a means of stimulating neuronal structures within the cortex using brief time-varying magnetic pulses generated by a coil positioned over the scalp. Integrating it with electroencephalogram provides real-time information on cortical reactivity and connectivity through the analysis of TMS evoked potentials or induced oscillations. In this project, auditory oddball paradigm was used throughout the experiment. The experiment involved three sessions; 1) without TMS, 2) single pulse TMS (sTMS) and 3) repetitive TMS (rTMS). All sessions were conducted in attended (attention) and unattended (no attention) conditions. It is found that the amplitude of the grand averaged of ALR (the N1-P2 wave) is higher in control compared to schizophrenia in without TMS session at both conditions. However, the amplitude of ALR in schizophrenia subjects is higher than control subjects in sTMS and rTMS at both conditions. The attention level measure, i.e., the Wavelet Phase Stability (WPS) was used to extract and quantify the neural correlates of auditory selective attention reflected in ALRs. In particular, Complex Morlet was implemented (scales 50-100 corresponding to 4-8Hz). There are significant differences of the ALR between schizophrenia and control groups in without TMS (p<0.05) and sTMS at the attended condition (frontal electrodes). Meanwhile at the unattended condition, Significance difference is found between two groups of the subjects in without TMS but no significant difference in sTMS (frontal electrodes). Particularly, the WPS of controls are larger than schizophrenia patients for without TMS and sTMS at attended for frontal electrodes. These results were consistent for temporal electrodes. It is worth to note that the phase stability of ALR in single pulse TMS is lower than without TMS for controls during attended but showed reversed pattern in unattended. Besides, it is found that a large phase stability difference between without TMS and sTMS in schizophrenia (frontal and temporal electrodes) at unattended compared to attended. For control subjects, this difference is small at frontal and temporal electrodes in both conditions. In a further investigation, the C4.5 decision tree algorithm was implemented to classify the N1-P2 wave of control and schizophrenia subjects elicited by sTMS and rTMS. Four features (energy, power, variance and entropy) were extracted by continuous wavelet transform (CWT). The result shows high classification accuracy which is above 83% in all three sessions at both attended and unattended conditions. In conclusion, the combined TMS-EEG approach shows a promising way to study the selective attention in schizophrenia. By successfully quantifying the neural correlates of auditory selective attention reflected in ALRs using the WPS and discriminating the control and patient groups using C4.5 decision tree provides an objective way to diagnose schizophrenia in compliment to the current subjective method

Brief Monocular Deprivation as an Assay of Short-Term Visual Sensory Plasticity in Schizophrenia - The Binocular Effect

Background: Visual sensory processing deficits are consistently observed in schizophrenia, with clear amplitude reduction of the visual evoked potential (VEP) during the initial 50-150 of processing. Similar deficits are seen in unaffected first-degree relatives and drug-naïve first-episode patients, pointing to these deficits as potential endophenotypic markers. Schizophrenia is also associated with deficits in neural plasticity, implicating dysfunction of both glutamatergic and GABAergic systems. Here, we sought to understand the intersection of these two domains, asking whether short-term plasticity during early visual processing is specifically affected in schizophrenia. Methods: Brief periods of monocular deprivation (MD) induce relatively rapid changes in the amplitude of the early VEP - i.e., short-term plasticity. Twenty patients and 20 non-psychiatric controls participated. VEPs were recorded during binocular viewing, and were compared to the sum of VEP responses during brief monocular viewing periods (i.e., Left-eye + Right-eye viewing). Results: Under monocular conditions, neurotypical controls exhibited an effect that patients failed to demonstrate. That is, the amplitude of the summed monocular VEPs was robustly greater than the amplitude elicited binocularly during the initial sensory processing period. In patients, this binocular effect was absent. Limitations: Patients were all medicated. Ideally, this study would also include first-episode unmedicated patients. Conclusion: These results suggest that short-term compensatory mechanisms that allow healthy individuals to generate robust VEPs in the context of MD are not effectively activated in patients with schizophrenia. This simple assay may provide a useful biomarker of short-term plasticity in the psychotic disorders and a target endophenotype for therapeutic interventions

The development of the N1 and N2 components in auditory oddball paradigms: a systematic review with narrative analysis and suggested normative values

Auditory event-related potentials (AERPs) are widely used in diverse fields of today’s neuroscience, concerning auditory processing, speech perception, language acquisition, neurodevelopment, attention and cognition in normal aging, gender, developmental, neurologic and psychiatric disorders. However, its transposition to clinical practice has remained minimal. Mainly due to scarce literature on normative data across age, wide spectrumof results, variety of auditory stimuli used and to different neuropsychological meanings of AERPs components between authors. One of the most prominent AERP components studied in last decades was N1, which reflects auditory detection and discrimination. Subsequently, N2 indicates attention allocation and phonological analysis. The simultaneous analysis of N1 and N2 elicited by feasible novelty experimental paradigms, such as auditory oddball, seems an objective method to assess central auditory processing. The aim of this systematic review was to bring forward normative values for auditory oddball N1 and N2 components across age. EBSCO, PubMed, Web of Knowledge and Google Scholarwere systematically searched for studies that elicited N1 and/or N2 by auditory oddball paradigm. A total of 2,764 papers were initially identified in the database, of which 19 resulted from hand search and additional references, between 1988 and 2013, last 25 years. A final total of 68 studiesmet the eligibility criteria with a total of 2,406 participants from control groups for N1 (age range 6.6–85 years; mean 34.42) and 1,507 for N2 (age range 9–85 years; mean 36.13). Polynomial regression analysis revealed thatN1latency decreases with aging at Fz and Cz,N1 amplitude at Cz decreases from childhood to adolescence and stabilizes after 30–40 years and at Fz the decrement finishes by 60 years and highly increases after this age. Regarding N2, latency did not covary with age but amplitude showed a significant decrement for both Cz and Fz. Results suggested reliable normative values for Cz and Fz electrode locations; however, changes in brain development and components topography over age should be considered in clinical practice

S-ketamine’s effect changes the cortical electrophysiological activity related to semantic affective dimension of pain : a placebo- controlled study in healthy male individuals

Background: Previous studies using the electroencephalogram (EEG) technique pointed out that ketamine decreases the amplitude of cortical electrophysiological signal during cognitive tasks, although its effects on the perception and emotional-valence judgment of stimuli are still unknown. Objective: We evaluated the effect of S-ketamine on affective dimension of pain using EEG and behavioral measures. The hypothesis was that S-ketamine would be more effective than placebo, both within and between groups, to attenuate the EEG signal elicited by target and non-target words. Methods: This double-blind parallel placebo-controlled study enrolled 24 healthy male volunteers between 19 and 40 years old. They were randomized to receive intravenous S-ketamine (n = 12) at a plasmatic concentration of 60 ng/ml or placebo (n = 12). Participants completed a computerized oddball paradigm containing written words semantically related to pain (targets), and non-pain related words (standard). The volunteers had to classify the words either as “positive,” “negative” or “neutral” (emotional valence judgment). The paradigm consisted in 6 blocks of 50 words each with a fixed 4:1 target/non-target rate presented in a single run. Infusion started during the interval between the 3rd and 4th blocks, for both groups. EEG signal was registered using four channels (Fz, Pz, Pz, and Oz, according to the 10–20 EEG system) with a linked-earlobe reference. The area under the curve (AUC) of the N200 (interval of 100–200 ms) and P300 (300–500 ms) components of event-related potentials (ERPs) was measured for each channel. Results: S-ketamine produced substantial difference (delta) in the AUC of grand average ERP components N200 (P = 0.05) and P300 (P = 0.02) at Pz during infusion period when compared to placebo infusion for both targets and non-targets. S-ketamine was also associated with a decrease in the amount of pain-related words judged as negative from before to after infusion [mean = 0.83 (SD = 0.09) vs. mean = 0.73 (SD = 0.11), respectively; P = 0.04]. Conclusion: Our findings suggest that S-ketamine actively changed the semantic processing of written words. There was an increase in electrophysiological response for pain-related stimuli and a decrease for standard stimuli, as evidenced by the increased delta of AUCs. Behaviorally, S-ketamine seems to have produced an emotional and discrimination blunting effect for pain-related words

Neural Dynamics of Autistic Behaviors: Cognitive, Emotional, and Timing Substrates

What brain mechanisms underlie autism and how do they give rise to autistic behavioral symptoms? This article describes a neural model, called the iSTART model, which proposes how cognitive, emotional, timing, and motor processes may interact together to create and perpetuate autistic symptoms. These model processes were originally developed to explain data concerning how the brain controls normal behaviors. The iSTART model shows how autistic behavioral symptoms may arise from prescribed breakdowns in these brain processes.Air Force Office of Scientific Research (F49620-01-1-0397); Office of Naval Research (N00014-01-1-0624