Phase-locking Factor Research Articles

The Effects of Transcranial Alternating Current Stimulation on the Auditory Steady-State Response and its Association with Schizotypy

Background: Evidence for impaired neural oscillations associated with particular circuits in schizophrenia (e.g. gamma oscillations [30 to 100 Hz]) has been found in the observations of reduced amplitude and phase locking factor (PLF) aspects of the 40-Hz auditory steady-state response (ASSR). As both amplitude and PFL of the 40-Hz ASSR are associated with a particular phase of low frequency oscillations, we examined in healthy control subjects the acute effects of low (theta) and high frequency (gamma) transcranial alternating current stimulation (tACS) on the 40-Hz response and its relation to schizotypy.

Relationships between cognitive event-related brain potential measures in patients at clinical high risk for psychosis

Neurophysiological measures of cognitive functioning that are abnormal in patients with schizophrenia are promising candidate biomarkers for predicting development of psychosis in individuals at clinical high risk (CHR). We examined the relationships among event-related brain potential (ERP) measures of early sensory, pre-attentional, and attention-dependent cognition, in antipsychotic-naïve help-seeking CHR patients (n = 36) and healthy control participants (n = 22). These measures included the gamma auditory steady-state response (ASSR; early sensory); mismatch negativity (MMN) and P3a (pre-attentional); and N400 semantic priming effects - a measure of using meaningful context to predict related items - over a shorter and a longer time interval (attention-dependent). Compared to controls, CHR patients had significantly smaller P3a amplitudes (d = 0.62, p = 0.03) and N400 priming effects over the long interval (d = 0.64, p = 0.02). In CHR patients, gamma ASSR evoked power and phase-locking factor were correlated (r = 0.41, p = 0.03). Reductions in mismatch negativity (MMN) and P3a amplitudes were also correlated (r = −0.36, p = 0.04). Moreover, lower gamma ASSR evoked power correlated with smaller MMN amplitudes (r = −0.45, p = 0.02). MMN amplitude reduction was also associated with reduced N400 semantic priming over the shorter but not the longer interval (r = 0.52, p < 0.002). This pattern of results suggests that, in a subset of CHR patients, impairment in pre-attentional measures of early information processing may contribute to deficits in attention-dependent cognition involving rapid, more automatic processing, but may be independent from pathological processes affecting more controlled or strategic processing. Thus, combining neurophysiological indices of cognitive deficits in different domains offers promise for improving their predictive power as prognostic biomarkers of clinical outcome.

Sleep-like bistability, loss of causality and complexity in the cerebral cortex of unresponsive wakefulness syndrome patients

Unresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In most of these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) shows that structurally preserved cortical areas react to TMS, but fail to engage complex patterns of effective interactions, as assessed by the perturbational complexity index (PCI). Another condition during which thalamocortical circuits are intact, active and reactive, yet unable to generate complex responses, is non-rapid eye movement (NREM) sleep, in which cortical neurons become bistable and tend to fall into a silent state (OFF-period) upon receiving an input. Here we tested whether a pathological form of bistability may be responsible for the loss of cortical complexity in UWS patients. In eyes-open UWS patients (n=16) TMS evoked a slow wave-like EEG response that was associated with a suppression of high-frequency (above 20Hz) oscillations suggesting the occurrence of OFF-periods similar to the ones observed in healthy subjects (n=8) during NREM sleep. Crucially, this phenomenon was never detected in healthy awake subjects (n=20). In all targeted cortical areas (Brodmann areas 6 and 7, bilaterally) of UWS patients, pathological OFF-periods significantly impaired local causal interactions (as measured by the phase-locking factor) and prevented the build-up of global complexity (as measured by PCI). Our results draw a first link between neuronal events (OFF-periods) and global brain dynamics (complexity) in UWS patients. Detecting the presence of sleep-like bistability and tracking its evolution over time, may offer a valuable read-out to devise, guide and titrate therapeutic strategies aimed at restoring consciousness.

Test-retest reliability of time-frequency measures of auditory steady-state responses in patients with schizophrenia and healthy controls.

BackgroundAuditory steady-state response (ASSR) paradigms have consistently demonstrated gamma band abnormalities in schizophrenia at a 40-Hz driving frequency with both electroencephalography (EEG) and magnetoencephalography (MEG). Various time-frequency measures have been used to assess the 40-Hz ASSR, including evoked power, single trial total power, phase-locking factor (PLF), and phase-locking angle (PLA). While both EEG and MEG studies have shown power and PLF ASSR measures to exhibit excellent test-retest reliability in healthy adults, the reliability of these measures in patients with schizophrenia has not been determined.MethodsASSRs were obtained by recording EEG data during presentation of repeated 20-Hz, 30-Hz and 40-Hz auditory click trains from nine schizophrenia patients (SZ) and nine healthy controls (HC) tested on two occasions. Similar ASSR data were collected from a separate group of 30 HC on two to three test occasions. A subset of these HC subjects had EEG recordings during two tasks, passively listening and actively attending to click train stimuli. Evoked power, total power, PLF, and PLA were calculated following Morlet wavelet time-frequency decomposition of EEG data and test-retest generalizability (G) coefficients were calculated for each ASSR condition, time-frequency measure, and subject group.ResultsG-coefficients ranged from good to excellent (> 0.6) for most 40-Hz time-frequency measures and participant groups, whereas 20-Hz G-coefficients were much more variable. Importantly, test-retest reliability was excellent for the various 40-Hz ASSR measures in SZ, similar to reliabilities in HC. Active attention to click train stimuli modestly reduced G-coefficients in HC relative to the passive listening condition.DiscussionThe excellent test-retest reliability of 40-Hz ASSR measures replicates previous EEG and MEG studies. PLA, a relatively new time-frequency measure, was shown for the first time to have excellent reliability, comparable to power and PLF measures. Excellent reliability of 40 Hz ASSR measures in SZ supports their use in clinical trials and longitudinal observational studies.

Monaural 40-Hz auditory steady-state magnetic responses can be useful for identifying epileptic focus in mesial temporal lobe epilepsy

ObjectivePatients with mesial temporal lobe epilepsy (mTLE) often exhibit central auditory processing (CAP) dysfunction. Monaural 40-Hz auditory steady-state magnetic responses (ASSRs) were recorded to explore the pathophysiology of mTLE. MethodsEighteen left mTLE patients, 11 right mTLE patients and 16 healthy controls (HCs) were examined. Monaural clicks were presented at a rate of 40 Hz. Phase-locking factor (PLF) and power values were analyzed within bilateral Heschl’s gyri. ResultsMonaural 40-Hz ASSR demonstrated temporal frequency dynamics in both PLF and power data. Symmetrical hemispheric contralaterality was revealed in HCs. However, predominant contralaterality was absent in mTLE patients. Specifically, right mTLE patients exhibited a lack of contralaterality in response to left ear but not right ear stimulation, and vice versa in left mTLE patients. ConclusionThis is the first study to use monaural 40-Hz ASSR with unilateral mTLE patients to clarify the relationship between CAP and epileptic focus. CAP dysfunction was characterized by a lack of contralaterality corresponding to epileptic focus. SignificanceMonaural 40-Hz ASSR can provide useful information for localizing epileptic focus in mTLE patients.

Altered neural synchronization to pure tone stimulation in patients with mesial temporal lobe epilepsy: An MEG study

ObjectiveOur previous study of monaural auditory evoked magnetic fields (AEFs) demonstrated that hippocampal sclerosis significantly modulated auditory processing in patients with mesial temporal lobe epilepsy (mTLE). However, the small sample size (n = 17) and focus on the M100 response were insufficient to elucidate the lateralization of the epileptic focus. Therefore, we increased the number of patients with mTLE (n = 39) to examine whether neural synchronization induced by monaural pure tone stimulation provides useful diagnostic information about epileptic foci in patients with unilateral mTLE. MethodsTwenty-five patients with left mTLE, 14 patients with right mTLE, and 32 healthy controls (HCs) were recruited. Auditory stimuli of 500-Hz tone burst were monaurally presented to subjects. The AEF data were analyzed with source estimation of M100 responses in bilateral auditory cortices (ACs). Neural synchronization within ACs and between ACs was evaluated with phase-locking factor (PLF) and phase-locking value (PLV), respectively. Linear discriminant analysis was performed for diagnosis and lateralization of epileptic focus. ResultsThe M100 amplitude revealed that patients with right mTLE exhibited smaller M100 amplitude than patients with left mTLE and HCs. Interestingly, PLF was able to differentiate the groups with mTLE, with decreased PLFs in the alpha band observed in patients with right mTLE compared with those (PLFs) in patients with left mTLE. Right hemispheric predominance was confirmed in both HCs and patients with left mTLE while patients with right mTLE showed a lack of right hemispheric predominance. Functional connectivity between bilateral ACs (PLV) was reduced in both patients with right and left mTLE compared with that of HCs. The accuracy of diagnosis and lateralization was 80%–90%. ConclusionAuditory cortex subnormal function was more pronounced in patients with right mTLE compared with that in patients with left mTLE as well as HCs. Monaural AEFs can be used to reveal the pathophysiology of mTLE. Overall, our results indicate that altered neural synchronization may provide useful information about possible functional deterioration in patients with unilateral mTLE.

Gamma Band Phase Delay in Schizophrenia

BackgroundIn 1999, Kwon et al. reported several electroencephalographic gamma band auditory steady-state response (ASSR) abnormalities in schizophrenia, spawning approximately 100 subsequent studies. While many studies replicated the finding of reduced 40-Hz ASSR power in schizophrenia and extended this by showing that 40-Hz phase synchrony (phase-locking factor [PLF]) was also reduced, none attempted to replicate the original phase delay finding of Kwon et al. Accordingly, we measured the 40-Hz ASSR phase-locking angle (PLA) to assess phase delay and examined its differential sensitivity to schizophrenia, relative to power and PLF measures. MethodsTo obtain ASSRs, electroencephalography data were recorded from 28 patients with schizophrenia and 25 healthy control subjects listening to repeated 40-Hz 500-ms click trains. Evoked power, total power, PLF, and PLA were calculated after Morlet wavelet time-frequency decomposition of single trial data from electrode Fz. ResultsIn patients with schizophrenia, 40-Hz PLA was significantly reduced (i.e., phase delayed) (p < .0001) and was unrelated to reductions in their 40-Hz power or PLF. PLA discriminated patients from healthy control subjects with 85% accuracy compared with 67% for power and 65% for PLF. ConclusionsConsistent with the original Kwon et al. study, 40-Hz click train–driven gamma oscillations were phase delayed in schizophrenia. Importantly, this phase delay abnormality was substantially larger than the gamma power and phase synchrony abnormalities that have been the focus of prior 40-Hz ASSR studies in schizophrenia. PLA provides a unique neurobiological measure of gamma band abnormalities in schizophrenia, likely reflecting a distinct pathophysiological mechanism from those underlying PLF and power abnormalities.

T13. PROGRESSIVE SPONTANEOUS AND SYNCHRONY GAMMA-BAND OSCILLATION DEFICITS IN FIRST EPISODE SCHIZOPHRENIA

BackgroundDeficits in the gamma-band (30–100 Hz) auditory steady-state response (ASSR) and progressive volumetric decreases in the primary auditory cortex have been detected shortly after the onset of schizophrenia (SZ), and may be associated with symptoms such as auditory hallucinations. Disruption of gamma-band oscillation has received considerable interest, as the basic mechanisms underlying these oscillations are understood and are conserved across species. Despite the importance of abnormal gamma-band oscillations in SZ, it remains unclear whether the gamma-band ASSR deficit shows progressive change over time during the early stages of the disease. Moreover, animal models based on NMDA receptor hypofunction demonstrate an increase in spontaneous gamma power, which has been reported in chronic SZ (Hirano et al., JAMA Psychiatry 2015), yet it still remains unclear in first-episode schizophrenia (FESZ). Hence, a longitudinal electroencephalogram study of the spontaneous and synchrony gamma-band oscillation in FESZ is important to better understand the pathophysiology and trajectory of early-stage schizophrenia.MethodsSubjects were 23 FESZ (14 treated and 9 untreated with antipsychotics), and 39 matched healthy controls (HC). Dipole source localization of dense electrode EEG data was used to examine oscillatory activities in auditory cortices during auditory steady-state stimulation (20/30/40-Hz rates). ICA was used to remove artifacts. Phase locking factor (PLF) and induced power (not phase-locked) were calculated from artifact-free single trial source estimates. Clinical symptoms were assessed by SAPS and SANS. Subjects were recruited as part of the Boston CIDAR Center (www.bostoncidar.org). Test sessions (Time-1/Time-2) were 11.9 months apart.ResultsCompared to HC, FESZ showed reduced 40-Hz ASSR PLF (synchrony gamma) and increased induced gamma power (spontaneous gamma) during continuous auditory stimuli at time-1. Longitudinally, FESZ showed overall progressive reductions in 40-Hz ASSR PLF and progressive increases in induced gamma power, especially within the left auditory cortex. These progressive deficits were not related to antipsychotic medication. Progressive increase of induced gamma power was correlated with increased positive symptoms.DiscussionWe found coincide disruptions of auditory gamma-band oscillation, which showed progressive increase in spontaneous gamma (cortical excitability) and progressive decrease in synchrony gamma (cortical synchrony failure) during continuous auditory stimuli in FESZ. These two apparently distinctive circuit progressive abnormalities already occurred in the very early stage of the disease. We propose that assessing ASSR-PLF and spontaneous gamma in FESZ may provide a sensitive translatable biomarker for the integrity of neural networks that are fundamentally altered in the very early stage of SZ.

Auditory steady-state responses in primary and non-primary regions of the auditory cortex in neonatal ventral hippocampal lesion rats.

Auditory steady-state responses (ASSRs) represent the electrophysiological activity of the auditory nervous system in response to a periodic acoustic stimulus. Spectrogram analysis can reveal the frequency and phase information entrained in ASSRs. Clinically, the ASSR is used to detect abnormalities in electroencephalographs obtained from schizophrenia patients, who show reduced power and phase locking of ASSRs. The neonatal ventral hippocampal lesion (NVHL) rat is a widely used model to investigate the neurodevelopmental mechanisms of schizophrenia. It has been established that NVHL rats exhibit several schizophrenia-like behavioral and molecular abnormalities. However, no clear abnormalities in ASSRs have been reported to date. The present study compared ASSRs of adult NVHL and sham-operated rats. We inserted microelectrodes into the primary auditory cortex (A1) or posterior auditory field (PAF) and recorded the local field potential (LFP) in response to 40- and 80-Hz click train stimuli. Spectrogram analysis was performed to obtain the mean trial power (MTP) and phase-locking factor (PLF) of the click train-evoked LFPs. We found that in the control animals, A1 showed a stronger MTP and PLF of ASSR than PAF, and NVHL operation mainly impaired the ASSR in PAF. Analysis of spike activity also indicated that NVHL operation extended the duration of tone-evoked responses in PAF neurons. Our results reveal, for the first time, that NVHL may distinctly influence the neural activities of primary and non-primary fields of the auditory cortex.

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

Background/Aims: The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-<smlcap>D</smlcap>-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. Methods: Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. Results: Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. Conclusions: Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders.

Striosomal dysfunction affects behavioral adaptation but not impulsivity-Evidence from X-linked dystonia-parkinsonism.

Executive functions including behavioral adaptation and impulse control are commonly impaired in movement disorders caused by striatal pathology. However, as yet it is unclear what aspects of behavioral abnormalities are related to pathology in which striatal subcomponent, that is, the matrix and the striosomes. We therefore studied cognitive control in X-linked dystonia-parkinsonism, a model disease of striosomal degeneration, using behavioral paradigms and EEG. We studied genetically confirmed X-linked dystonia-parkinsonism patients (N = 21) in their early disease stages and healthy matched controls. Error-related behavioral adaptation was tested in a flanker task and response inhibition in a Go/Nogo paradigm during EEG. We focused on error-related negativity during error processing and the Nogo-N2 and Nogo-P3 in the response inhibition task. Source localization analyses were calculated. In addition, total wavelet power and phase-locking factor reflecting neural synchronization processes in time and frequency across trials were calculated. Error processing and behavioral adaptation predominantly engaging the anterior cingulate cortex was markedly impaired in X-linked dystonia-parkinsonism. This was reflected in abnormal reaction times correlating with error-related negativity amplitudes, error related theta band activity, and the phase-locking factor. Also, abnormal error processing correlated with dystonia severity but not with parkinsonism. Response inhibition and corresponding EEG activity were normal. This dissociable pattern of cognitive deficits most likely reflects predominant dysfunction of the striosomal compartment and its connections to the anterior cingulate cortex in X-linked dystonia-parkinsonism. The results underscore the importance of striosomes for cognitive function in humans and suggest that striosomes are relays of error-related behavioral adaptation but not inhibitory control. © 2017 International Parkinson and Movement Disorder Society.

Abnormal auditory synchronization in stuttering: A magnetoencephalographic study

In a previous magnetoencephalographic study, we showed both functional and structural reorganization of the right auditory cortex and impaired left auditory cortex function in people who stutter (PWS). In the present work, we reevaluated the same dataset to further investigate how the right and left auditory cortices interact to compensate for stuttering. We evaluated bilateral N100m latencies as well as indices of local and inter-hemispheric phase synchronization of the auditory cortices. The left N100m latency was significantly prolonged relative to the right N100m latency in PWS, while healthy control participants did not show any inter-hemispheric differences in latency. A phase-locking factor (PLF) analysis, which indicates the degree of local phase synchronization, demonstrated enhanced alpha-band synchrony in the right auditory area of PWS. A phase-locking value (PLV) analysis of inter-hemispheric synchronization demonstrated significant elevations in the beta band between the right and left auditory cortices in PWS. In addition, right PLF and PLVs were positively correlated with stuttering frequency in PWS. Taken together, our data suggest that increased right hemispheric local phase synchronization and increased inter-hemispheric phase synchronization are electrophysiological correlates of a compensatory mechanism for impaired left auditory processing in PWS.

Perceptual Temporal Asymmetry Associated with Distinct ON and OFF Responses to Time-Varying Sounds with Rising versus Falling Intensity: A Magnetoencephalography Study.

This magnetoencephalography (MEG) study investigated evoked ON and OFF responses to ramped and damped sounds in normal-hearing human adults. Two pairs of stimuli that differed in spectral complexity were used in a passive listening task; each pair contained identical acoustical properties except for the intensity envelope. Behavioral duration judgment was conducted in separate sessions, which replicated the perceptual bias in favour of the ramped sounds and the effect of spectral complexity on perceived duration asymmetry. MEG results showed similar cortical sites for the ON and OFF responses. There was a dominant ON response with stronger phase-locking factor (PLF) in the alpha (8–14 Hz) and theta (4–8 Hz) bands for the damped sounds. In contrast, the OFF response for sounds with rising intensity was associated with stronger PLF in the gamma band (30–70 Hz). Exploratory correlation analysis showed that the OFF response in the left auditory cortex was a good predictor of the perceived temporal asymmetry for the spectrally simpler pair. The results indicate distinct asymmetry in ON and OFF responses and neural oscillation patterns associated with the dynamic intensity changes, which provides important preliminary data for future studies to examine how the auditory system develops such an asymmetry as a function of age and learning experience and whether the absence of asymmetry or abnormal ON and OFF responses can be taken as a biomarker for certain neurological conditions associated with auditory processing deficits.

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors.

Schizophrenia patients exhibit dysfunctional gamma oscillations in response to simple auditory stimuli or more complex cognitive tasks, a phenomenon explained by reduced NMDA transmission within inhibitory/excitatory cortical networks. Indeed, a simple steady-state auditory click stimulation paradigm at gamma frequency (~40 Hz) has been reproducibly shown to reduce entrainment as measured by electroencephalography (EEG) in patients. However, some investigators have reported increased phase locking factor (PLF) and power in response to 40 Hz auditory stimulus in patients. Interestingly, preclinical literature also reflects this contradiction. We investigated whether a graded deficiency in NMDA transmission can account for such disparate findings by administering subanesthetic ketamine (1-30 mg/kg, i.v.) or vehicle to conscious rats (n=12) and testing their EEG entrainment to 40 Hz click stimuli at various time points (~7-62 min after treatment). In separate cohorts, we examined in vivo NMDA channel occupancy and tissue exposure to contextualize ketamine effects. We report a robust inverse relationship between PLF and NMDA occupancy 7 min after dosing. Moreover, ketamine could produce inhibition or disinhibition of the 40 Hz response in a temporally dynamic manner. These results provide for the first time empirical data to understand how cortical NMDA transmission deficit may lead to opposite modulation of the auditory steady-state response (ASSR). Importantly, our findings posit that 40 Hz ASSR is a pharmacodynamic biomarker for cortical NMDA function that is also robustly translatable. Besides schizophrenia, such a functional biomarker may be of value to neuropsychiatric disorders like bipolar and autism spectrum where 40 Hz ASSR deficits have been documented.

Detecting neuromagnetic synchrony in the presence of noise

BackgroundSynchrony between neuroelectric oscillations in distant brain areas is currently used as an indicator of functional connectivity between the involved neural substrates. Coherence measures, which quantify synchrony, are affected by concurrent brain activities, commonly subsumed as noise. New methodUsing Monte-Carlo simulation, we analysed the properties of circular statistics and how those are affected by noise. We considered three different models of neuroelectric signal generation, which are an additive model, phase-reset, and reciprocal phase-interaction. Using the receiver-operating characteristic method, we compared the performances of currently implemented algorithms for coherence detection such as phase-coherence or phase-locking factor, magnitude-squared coherence, and phase-lagging index, all based on circular statistics, and a more general approach to synchrony, using measures of mutual information. We compared inter-trial coherence as a method for signal detection with coherence between multiple sources as measure of source interaction and connectivity. ResultsCharts of performance characteristics showed that the choice of methods depend on the underlying signal generation model. Detection of coherence requires in general a higher signal-to-noise ratio than detection of the signal itself, and again, the difference in performance depends strongly on the underlying model of signal generation. Comparison with existing methodsPrevious comparisons of the performances of different algorithms for signal detection and coherence have not considered systematically the underlying neural generation mechanisms. ConclusionDetection of coherence generated by additive signals or a phase-reset requires largely higher signal-to-noise ratio compared to signal detection. Only in case of true phase interaction, signal detection and coherence measures are similarly sensitive.

Attentional Load Effects on Beta Oscillations in Healthy and Schizophrenic Individuals.

Attentional deficits are prominent among the cognitive disturbances found in schizophrenia. Given that schizophrenia is also characterized by abnormalities in high-frequency oscillations, we investigated whether attentional function in schizophrenia is related to abnormalities in high-frequency oscillations in a visual discrimination task in which attentional load was manipulated. Sixteen healthy control subjects (HC) and 23 chronic schizophrenia patients (SZ) discriminated between target discs (p = 0.2) and standard discs (p = 0.8). Attentional load was manipulated by varying the size difference between the target and standard discs across blocks: large (Easy condition), medium (Medium), and small (Difficult). The electroencephalogram was recorded and the oscillations evoked by the standard stimuli were analyzed using the Morlet wavelet transform. Subjects’ performance decreased as attentional load increased, but HC and SZ did not differ. Attentional load increased β phase-locking factor at frontal, parietal, and occipital electrode sites in HC but not SZ. In SZ, however, there was a correlation between the β attentional load effect and overall d′, indicating that high-performing SZ had relatively normal β attentional load effects. These results show that variations in attentional load are associated with β oscillations and provide a link between attentional dysfunction and β-generating neural circuitry in schizophrenia.

Phencyclidine Disrupts the Auditory Steady State Response in Rats.

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule.

Spontaneous Gamma Activity in Schizophrenia.

A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30-100 Hz) gamma power was increased in patients with SZ compared with controls during steady-state stimulation (6.579 [3.783] vs 3.984 [1.843]; F1,46 = 9.128 [P = .004]; d = 0.87) but not during rest (0.006 [0.003] vs 0.005 [0.002]; F1,34 = 1.067 [P = .309]; d = 0.35). Induced gamma power in the left hemisphere of the patients with SZ during the 40-Hz stimulation was positively correlated with auditory hallucination symptoms (tangential, ρ = 0.587 [P = .031]; radial, ρ = 0.593 [P = .024]) and negatively correlated with the ASSR phase-locking factor (baseline: ρ = -0.572 [P = .024]; ASSR: ρ = -0.568 [P = .032]). Spontaneous gamma activity is increased during auditory steady-state stimulation in SZ, reflecting a disruption in the normal balance of excitation and inhibition. This phenomenon interacts with evoked oscillations, possibly contributing to the gamma ASSR deficit found in SZ. The similarity of increased spontaneous gamma power in SZ to the findings of increased spontaneous gamma power in animal models of NMDAR hypofunction suggests that spontaneous gamma power could serve as a biomarker for the integrity of NMDARs on parvalbumin-expressing inhibitory interneurons in humans and in animal models of neuropsychiatric disorders.

EEG findings of reduced neural synchronization during visual integration in schizophrenia.

Schizophrenia patients exhibit well-documented visual processing deficits. One area of disruption is visual integration, the ability to form global objects from local elements. However, most studies of visual integration in schizophrenia have been conducted in the context of an active attention task, which may influence the findings. In this study we examined visual integration using electroencephalography (EEG) in a passive task to elucidate neural mechanisms associated with poor visual integration. Forty-six schizophrenia patients and 30 healthy controls had EEG recorded while passively viewing figures comprised of real, illusory, or no contours. We examined visual P100, N100, and P200 event-related potential (ERP) components, as well as neural synchronization in the gamma (30-60 Hz) band assessed by the EEG phase locking factor (PLF). The N100 was significantly larger to illusory vs. no contour, and illusory vs. real contour stimuli while the P200 was larger only to real vs. illusory stimuli; there were no significant interactions with group. Compared to controls, patients failed to show increased phase locking to illusory versus no contours between 40-60 Hz. Also, controls, but not patients, had larger PLF between 30-40 Hz when viewing real vs. illusory contours. Finally, the positive symptom factor of the BPRS was negatively correlated with PLF values between 40-60 Hz to illusory stimuli, and with PLF between 30-40 Hz to real contour stimuli. These results suggest that the pattern of results across visual processing conditions is similar in patients and controls. However, patients have deficits in neural synchronization in the gamma range during basic processing of illusory contours when attentional demand is limited.

EEG gamma-band activity during audiovisual speech comprehension in different noise environments.

The presence of cross-modal stochastic resonance in different noise environments has been proved in previous behavioral and event-related potential studies, while it was still unclear whether the gamma-band oscillation study was another evidence of cross-modal stochastic resonance. The multisensory gain of gamma-band activity between the audiovisual (AV) and auditory-only conditions in different noise environments was analyzed. Videos of face motion articulating words concordant with different levels of pink noise were used as stimuli. Signal-to-noise ratios (SNRs) of 0, -4, -8, -12 and -16dB were selected to measure the speech recognition accuracy and EEG activity for 20 healthy subjects. The power and phase of EEG gamma-band oscillations increased in a time window of 50-90ms. The multisensory gains of evoked and total activity, as well as phase-locking factor, were greatest at the -12dB SNR, which were consistent with the behavioral result. The multisensory gain of gamma-band activity showed an inverted U-shaped curve as a function of SNR. This finding confirmed the presence of cross-modal stochastic resonance. In addition, there was a significant correlation between evoked activity and phase-locking factor of gamma-band at five different SNRs. Gamma-band oscillation was believed to play a role in the rapid processing and information linkage strengthening of AV modalities in the early stage of cognitive processes.