Brian J. Roach

Event-Related EEG Time-Frequency Analysis: An Overview of Measures and An Analysis of Early Gamma Band Phase Locking in Schizophrenia

An increasing number of schizophrenia studies have been examining electroencephalography (EEG) data using time-frequency analysis, documenting illness-related abnormalities in neuronal oscillations and their synchronization, particularly in the gamma band. In this article, we review common methods of spectral decomposition of EEG, time-frequency analyses, types of measures that separately quantify magnitude and phase information from the EEG, and the influence of parameter choices on the analysis results. We then compare the degree of phase locking (ie, phase-locking factor) of the gamma band (36-50 Hz) response evoked about 50 milliseconds following the presentation of standard tones in 22 healthy controls and 21 medicated patients with schizophrenia. These tones were presented as part of an auditory oddball task performed by subjects while EEG was recorded from their scalps. The results showed prominent gamma band phase locking at frontal electrodes between 20 and 60 milliseconds following tone onset in healthy controls that was significantly reduced in patients with schizophrenia (P = .03). The finding suggests that the early-evoked gamma band response to auditory stimuli is deficiently synchronized in schizophrenia. We discuss the results in terms of pathophysiological mechanisms compromising event-related gamma phase synchrony in schizophrenia and further attempt to reconcile this finding with prior studies that failed to find this effect.

Synch before you speak: Auditory hallucinations in schizophrenia.

OBJECTIVE Synchronization of neural activity preceding self-generated actions may reflect the operation of the forward model, which acts to dampen sensations resulting from those actions. If this is true, pre-action synchrony should be related to subsequent sensory suppression. Deficits in this mechanism may be characteristic of schizophrenia and related to positive symptoms, such as auditory hallucinations. If so, schizophrenia patients should have reduced neural synchrony preceding movements, especially patients with severe hallucinations. METHOD In 24 patients with schizophrenia or schizoaffective disorder and 25 healthy comparison subjects, the authors related prespeech neural synchrony to subsequent auditory cortical responsiveness to the spoken sound, compared prespeech neural synchrony in schizophrenia patients and healthy comparison subjects, and related prespeech neural synchrony to auditory hallucination severity in patients. To assess neural synchrony, phase coherence of single-trial EEG preceding talking was calculated at a single site across repeated trials. To assess auditory cortical suppression, the N1 event-related brain potentials to speech sound onset during talking and listening were compared. RESULTS In healthy comparison subjects, prespeech neural synchrony was related to subsequent suppression of responsiveness to the spoken sound, as reflected in reduction of N1 during talking relative to listening. There was greater prespeech synchrony in comparison subjects than in patients, especially those with severe auditory hallucinations. CONCLUSIONS These data suggest that EEG synchrony preceding speech reflects the action of a forward model system, which dampens auditory responsiveness to self-generated speech and is deficient in patients who hallucinate.

Out-of-Synch and Out-of-Sorts: Dysfunction of Motor-Sensory Communication in Schizophrenia

BACKGROUND Phase synchronization of neural activity preceding a motor act may reflect an efference copy of the motor plan and its expected sensory consequences (corollary discharge), which is sent to sensory cortex to herald the arrival of self-generated sensations and dampen the resulting sensory experience. We performed time-frequency decomposition of response-locked electroencephalogram (EEG) to examine phase synchronization of oscillations across trials (phase-locking factor [PLF]) to self-paced button presses. If prepress PLF reflects the activity in motor cortex, it should be contralateralized. If it reflects the action of the efference copy, it should be related to subsequent sensory suppression. If efference copy/corollary discharge mechanisms are abnormal in schizophrenia, it should be reduced in patients with schizophrenia. METHODS Electroencephalogram was collected while 23 patients (20 schizophrenia; 3 schizoaffective) and 25 age-matched control subjects pressed a button, at will, every 1 to 2 sec. Phase-locking factor preceding and following button presses was calculated from single-trial EEG; averaging single trials yielded response-locked event-related potentials (ERPs) to the tactile response associated with button pressing. RESULTS Consistent with its hypothesized reflection of efference copy/corollary discharge signals, prepress gamma band neural synchrony was 1) maximal over the contralateral sensory-motor cortex in healthy subjects, 2) correlated with the ipsilateralized somatosensory ERP amplitude evoked by the press, and 3) reduced in patients. Prepress neural synchrony in the beta band was also reduced in patients, especially those with avolition/apathy. CONCLUSIONS These data are consistent with dysfunction of forward model circuitry in schizophrenia and suggest that the specific motor-sensory system affected is selectively linked to symptoms involving that system.

Automatic Auditory Processing Deficits in Schizophrenia and Clinical High-Risk Patients: Forecasting Psychosis Risk with Mismatch Negativity

BACKGROUND Only about one third of patients at high risk for psychosis based on current clinical criteria convert to a psychotic disorder within a 2.5-year follow-up period. Targeting clinical high-risk (CHR) individuals for preventive interventions could expose many to unnecessary treatments, underscoring the need to enhance predictive accuracy with nonclinical measures. Candidate measures include event-related potential components with established sensitivity to schizophrenia. Here, we examined the mismatch negativity (MMN) component of the event-related potential elicited automatically by auditory deviance in CHR and early illness schizophrenia (ESZ) patients. We also examined whether MMN predicted subsequent conversion to psychosis in CHR patients. METHODS Mismatch negativity to auditory deviants (duration, frequency, and duration + frequency double deviant) was assessed in 44 healthy control subjects, 19 ESZ, and 38 CHR patients. Within CHR patients, 15 converters to psychosis were compared with 16 nonconverters with at least 12 months of clinical follow-up. Hierarchical Cox regression examined the ability of MMN to predict time to psychosis onset in CHR patients. RESULTS Irrespective of deviant type, MMN was significantly reduced in ESZ and CHR patients relative to healthy control subjects and in CHR converters relative to nonconverters. Mismatch negativity did not significantly differentiate ESZ and CHR patients. The duration + frequency double deviant MMN, but not the single deviant MMNs, significantly predicted the time to psychosis onset in CHR patients. CONCLUSIONS Neurophysiological mechanisms underlying automatic processing of auditory deviance, as reflected by the duration + frequency double deviant MMN, are compromised before psychosis onset and can enhance the prediction of psychosis risk among CHR patients.

The dependence of P300 amplitude on gamma synchrony breaks down in schizophrenia

INTRODUCTION Auditory P300 amplitude reduction in schizophrenia is canonical and may be explained by poor synchronization or reduced power of the underlying neural activity. We asked if patients have reduced synchrony and power, and whether together with P300 amplitude, they make unique or overlapping contributions to the discrimination between patients and controls. We also asked whether people who have large P300s have higher power and greater synchrony of neural activity, and if the relationships between P300 and power and synchrony are different in patients and healthy controls. METHODS We recorded EEG data from 22 controls and 21 patients with schizophrenia (DSM-IV) while they performed an auditory target detection task. We used wavelet analyses of the single trial data to estimate total power and synchrony of delta, theta, alpha, beta, and gamma activity in a 50ms window around the peak of the P300 to the target. We measured P300 amplitude from the average of the single trials, in a 50ms window around its peak. RESULTS AND CONCLUSIONS P300 amplitude and delta and theta synchrony were reduced in patients; delta power and synchrony better distinguished between groups than P300 amplitude. In healthy controls, but not patients, gamma synchrony predicted P300 amplitude. In patients, P300 and gamma synchrony are affected by independent factors; the relationship between them is attenuated by an additional pathophysiological process.

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball’ P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high’ in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing.

Glutamatergic Modulation of Auditory Information Processing in the Human Brain

BACKGROUND Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans. METHODS This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day. RESULTS Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive. CONCLUSIONS NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.

Visual Hallucinations Are Associated With Hyperconnectivity Between the Amygdala and Visual Cortex in People With a Diagnosis of Schizophrenia

INTRODUCTION While auditory verbal hallucinations (AH) are a cardinal symptom of schizophrenia, people with a diagnosis of schizophrenia (SZ) may also experience visual hallucinations (VH). In a retrospective analysis of a large sample of SZ and healthy controls (HC) studied as part of the functional magnetic resonance imaging (fMRI) Biomedical Informatics Research Network (FBIRN), we asked if SZ who endorsed experiencing VH during clinical interviews had greater connectivity between visual cortex and limbic structures than SZ who did not endorse experiencing VH. METHODS We analyzed resting state fMRI data from 162 SZ and 178 age- and gender-matched HC. SZ were sorted into groups according to clinical ratings on AH and VH: SZ with VH (VH-SZ; n = 45), SZ with AH but no VH (AH-SZ; n = 50), and SZ with neither AH nor VH (NoH-SZ; n = 67). Our primary analysis was seed based, extracting connectivity between visual cortex and the amygdala (because of its role in fear and negative emotion) and visual cortex and the hippocampus (because of its role in memory). RESULTS Compared with the other groups, VH-SZ showed hyperconnectivity between the amygdala and visual cortex, specifically BA18, with no differences in connectivity among the other groups. In a voxel-wise, whole brain analysis comparing VH-SZ with AH-SZ, the amygdala was hyperconnected to left temporal pole and inferior frontal gyrus in VH-SZ, likely due to their more severe thought broadcasting. CONCLUSIONS VH-SZ have hyperconnectivity between subcortical areas subserving emotion and cortical areas subserving higher order visual processing, providing biological support for distressing VH in schizophrenia.

Impaired Visual Cortical Plasticity in Schizophrenia

BACKGROUND Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ. METHODS Electroencephalographic data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual long-term potentiation paradigm. Visual evoked potentials were elicited by standard visual stimuli (∼.83 Hz, 2-minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS) (∼8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. Visual evoked potentials were subjected to principal components analysis. Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 msec (C1) and at 146 msec (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups. RESULTS High-frequency stimulation produced sustained potentiation of visual C1 and N1b in HCs but not in SZs. The HCs and SZs had comparable HFS-driven electroencephalographic visual steady state responses. However, greater visual steady state responses to the HFS predicted greater N1b potentiation in HCs but not in SZs. Schizophrenia patients with greater N1b potentiation decreased their reaction times to target stimuli. CONCLUSIONS Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in N-methyl-D-aspartate receptor function.

Error detection failures in schizophrenia: ERPs and FMRI.

Self-monitoring of actions, critical for guiding goal-directed behavior, is deficient in schizophrenia. Defective error-monitoring may reflect more general self-monitoring deficiencies. Prior studies have shown that the error-related negativity (ERN) component of the event-related potential (ERP) is smaller in patients with schizophrenia. Other studies using functional magnetic resonance imaging (FMRI) have shown the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC), both critical for error detection, to be less responsive to errors in patients with schizophrenia. In the present study, both ERP and FMRI data were collected while 11 patients with schizophrenia and 10 healthy controls performed a Go-NoGo task requiring a button press to Xs (p=.88) while withholding responses to Ks (p=.12). We measured the ERN and ACC and DLPFC activations to false alarms. The task elicited a robust ERN and modest activations in ACC and DLPFC to false alarms. As expected, ERN was larger in controls than patients. However, ACC and DLPFC activations were not greater in controls than patients. Surprisingly, DLPFC was more activated by errors in patients than controls. ERPs may be superior to fMRI for assessing error processing abnormalities in schizophrenia because (1) ERNs can be measured precisely without needing to control for the multiple comparisons of FMRI, and (2) ERPs have the temporal precision to detect transient activity necessary for error detection and on-the-fly behavioral adjustments.