Spectral decomposition of resting state electroencephalogram reveals unique theta/alpha activity in schizophrenia.

Resting state electroencephalographic (EEG) activity in schizophrenia (SZ) is frequently characterised by increased power at slow frequencies and/or a reduction of peak alpha frequency. Here we investigated the nature of these effects. As most studies to date have been limited by reliance on a priori frequency bands which impose an assumed structure on the data, we performed a data-driven analysis of resting EEG recorded in SZ patients and healthy controls (HC). The sample consisted of 39 chronic SZ and 36 matched HC. The EEG was recorded with a dense electrode array. Power spectral densities were decomposed via Varimax-rotated principal component analysis (PCA) over all participants and for each group separately. Spectral PCA was repeated at the cortical level on cortical current source density computed from standardised low resolution brain electromagnetic tomography. There was a trend for power in the theta/alpha range to be increased in SZ compared to HC, and peak alpha frequency was significantly reduced in SZ. PCA revealed that this frequency shift was because of the presence of a spectral component in the theta/alpha range (6-9 Hz) that was unique to SZ. The source distribution of the SZ > HC theta/alpha effect involved mainly prefrontal and parahippocampal areas. Abnormal low frequency resting EEG activity in SZ was accounted for by a unique theta/alpha oscillation. Other reports have described a similar phenomenon suggesting that the neural circuits oscillating in this range are relevant to SZ pathophysiology.

Neurophysiological evidence of motor preparation in inner speech and the effect of content predictability.

Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor. In three experiments, we compared the contingent negative variation elicited in a cue paradigm in an active vs. passive condition. In Experiment 1, participants produced an inner phoneme, at which an audible phoneme whose identity was unpredictable was concurrently presented. We found that while passive listening elicited a late contingent negative variation, inner speech production generated a more negative late contingent negative variation. In Experiment 2, the same pattern of results was found when participants were instead asked to overtly vocalize the phoneme. In Experiment 3, the identity of the audible phoneme was made predictable by establishing probabilistic expectations. We observed a smaller late contingent negative variation in the inner speech condition when the identity of the audible phoneme was predictable, but not in the passive condition. These findings suggest that inner speech is associated with motor preparatory activity that may also represent the predicted action-effects of covert actions.

Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients' blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients' group with mitochondrial dysfunction "Psy-D", having high miR-137 and low COX6A2 levels in exosomes, and (b) a "Psy-ND" subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia.

Increases in broadband cortical electroencephalogram (EEG) power in the gamma band (30-80 Hz) range have been observed in schizophrenia patients and in mouse models of schizophrenia. They are also seen in humans and animals treated with the psychotomimetic agent ketamine. However, the mechanisms which can result in increased broadband gamma power and the pathophysiological implications for cognition and behavior are poorly understood. Here we report that tonic optogenetic manipulation of an ascending arousal system bidirectionally tunes cortical broadband gamma power, allowing on-demand tests of the effect on cortical processing and behavior. Constant, low wattage optogenetic stimulation of basal forebrain (BF) neurons containing the calcium-binding protein parvalbumin (PV) increased broadband gamma frequency power, increased locomotor activity, and impaired novel object recognition. Concomitantly, task-associated gamma band oscillations induced by trains of auditory stimuli, or exposure to novel objects, were impaired, reminiscent of findings in schizophrenia patients. Conversely, tonic optogenetic inhibition of BF-PV neurons partially rescued the elevated broadband gamma power elicited by subanesthetic doses of ketamine. These results support the idea that increased cortical broadband gamma activity leads to impairments in cognition and behavior, and identify BF-PV activity as a modulator of this activity. As such, BF-PV neurons may represent a novel target for pharmacotherapy in disorders such as schizophrenia which involve aberrant increases in cortical broadband gamma activity.

Neuronal imbalance of excitation and inhibition in schizophrenia: a scoping review of gamma-band ASSR findings.

Recent empirical findings suggest that altered neural synchronization, which is hypothesized to be associated with an imbalance of excitatory (E) and inhibitory (I) neuronal activities, may underlie a core pathophysiological mechanism in patients with schizophrenia. The auditory steady-state response (ASSR) examined by electroencephalography (EEG) and magnetoencephalography (MEG) has been proposed as a potential biomarker for evaluating altered neural synchronization in schizophrenia. For this review, we performed a comprehensive literature search for papers published between 1999 and 2021 examining ASSRs in patients with schizophrenia. Almost all EEG-ASSR studies reported gamma-band ASSR reductions, especially to 40-Hz stimuli both in power and/or phase synchronization in chronic and first-episode schizophrenia. In addition, similar to EEG-ASSR findings, MEG-ASSR deficits to 80-Hz stimuli (high gamma) have been reported in patients with schizophrenia. Moreover, the 40-Hz ASSR is likely to be a predictor of the onset of schizophrenia. Notably, increased spontaneous (or ongoing) broadband (30-100 Hz) gamma power has been reported during ASSR tasks, which resembles the increased spontaneous gamma activity reported in animal models of E/I imbalance. Further research on ASSRs and evoked and spontaneous gamma oscillations is expected to elucidate the pathophysiology of schizophrenia with translational implications.

Longitudinal evaluation of visual P300 amplitude in clinical high-risk subjects: An event-related potential study.

AIM: We previously reported abnormal P300 and N200 in a visual oddball task, and progressive P300 amplitude reduction at 1-year follow-up in patients with first-episode schizophrenia. P300 reduction as well as intact P1/N1 were also observed in clinical high-risk subjects (CHR), but whether or not these components change over time is unknown. This study evaluates, longitudinally, the visual P300, as well as P1, N1, and N200, in CHR. METHODS: Visual event-related potentials (ERP) were recorded twice, once at baseline and once at 1-year follow-up in CHR (n = 19) and healthy comparison subjects (HC; n = 28). Participants silently counted infrequent target stimuli ('x') among standard stimuli ('y') presented on the screen while the 64-channel electroencephalogram was recorded. RESULTS: No CHR converted to psychosis from baseline to 1-year follow-up in this study. Visual P300 amplitude was reduced and the latency was delayed significantly in CHR at both time points compared with HC. Furthermore, CHR subjects who had more positive symptoms showed more amplitude reduction at both time points. P1, N1, and N200 did not differ between groups. CONCLUSION: Visual P300 amplitude was found to be reduced in CHR individuals compared with HC. We note that this finding is in subjects who did not convert to psychosis at 1-year follow-up. The association between visual P300 amplitude and symptoms suggests that for CHR who often experience clinical symptoms and seek medical care, visual P300 may be an important index that reflects the pathophysiological impairment underlying such clinical states.

Inner speech is accompanied by a temporally-precise and content-specific corollary discharge.

When we move our articulator organs to produce overt speech, the brain generates a corollary discharge that acts to suppress the neural and perceptual responses to our speech sounds. Recent research suggests that inner speech - the silent production of words in one's mind - is also accompanied by a corollary discharge. Here, we show that this corollary discharge contains information about the temporal and physical properties of inner speech. In two experiments, participants produced an inner phoneme at a precisely-defined moment in time. An audible phoneme was presented 300 ms before, concurrently with, or 300 ms after participants produced the inner phoneme. We found that producing the inner phoneme attenuated the N1 component of the event-related potential - an index of auditory cortex processing - but only when the inner and audible phonemes occurred concurrently and matched on content. If the audible phoneme was presented before or after the production of the inner phoneme, or if the inner phoneme did not match the content of the audible phoneme, there was no attenuation of the N1. These results suggest that inner speech is accompanied by a temporally-precise and content-specific corollary discharge. We conclude that these results support the notion of a functional equivalence between the neural processes that underlie the production of inner and overt speech, and may provide a platform for identifying inner speech abnormalities in disorders in which they have been putatively associated, such as schizophrenia.

Frontal P3 event-related potential is related to brain glutamine/glutamate ratio measured in vivo.

BACKGROUND: The auditory P3 event-related potential (ERP) is thought to index cognitive processing relevant to attention and working memory processes. Drug challenge studies suggest that glutamate neurotransmission plays an important role in modulating P3 ERP. However, while direct links between glutamate activity and P3 ERP response in humans are suspected, mechanistic details remain largely unknown. We investigated here the relationships between P3 ERP and indices of glutamatergic processing measured in vivo with proton magnetic resonance spectroscopy ((1)H MRS). We hypothesized that a higher index of glutamatergic processing (glutamine/glutamate ratio; abbreviated Gln/Glu) in the anterior cingulate (ACC) and in the parietal-occipital (POC) cortices would associate with larger frontal P3a and parietal P3b amplitudes, respectively. METHODS: Frontal P3a (Fz) and parietal P3b (Pz) were collected from 32 healthy participants who performed an auditory oddball task. Resting glutamate (Glu), glutamine (Gln), and Gln/Glu (an index of glutamatergic processing) measures were obtained on a 4T MR scanner using J-resolved MR spectroscopy. Linear regression and partial correlations were used for statistical analysis. RESULTS: Significant positive correlations were found between frontal P3a amplitude and ACC Gln/Glu ratio (partial R=0.57; P=0.001) and between frontal P3a amplitude and ACC Gln concentration (partial R=0.43; P=0.02). Relationships between parietal P3b and the glutamate indices in the POC were not significant. CONCLUSIONS: These results indicate a specific connection between an index of glutamate neurotransmitter function in ACC and frontal P3 ERP, providing a novel insight into the neurochemistry underlying scalp recorded EEG response. Abnormalities in glutamate neurotransmission have been observed in schizophrenia and other psychiatric conditions and may underlie illness related deficits of P3 ERP.

Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report.

Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P = 1.27 × 10(-9) ). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude.

The contribution of gamma bursting to spontaneous gamma activity in schizophrenia.

Increased spontaneous gamma (30-100 Hz) activity (SGA) has been reported in the auditory cortex in schizophrenia. This phenomenon has been correlated with psychotic symptoms such as auditory hallucinations and could reflect the dysfunction of NMDA receptors on parvalbumin-expressing inhibitory interneurons. Previous findings are from time-averaged spectra, so it is unknown whether increased spontaneous gamma occurs at a constant level, or rather in bursts. To better understand the dynamical nature of spontaneous gamma activity in schizophrenia, here we examined the contribution of gamma bursting and the slope of the EEG spectrum to this phenomenon. The main results from this data set were previously reported. Participants were 24 healthy control participants (HC) and 24 matched participants with schizophrenia (SZ). The data were from EEG recordings during auditory steady-state stimulation, which were localized to bilateral pairs of dipoles in auditory cortex. Time-frequency analysis was performed using Morlet wavelets. Oscillation bursts in the gamma range were defined as periods during which power exceeded 2 standard deviations above the trial-wide average value for at least one cycle. We extracted the burst parameters power, count, and area, as well as non-burst trial power and spectral slope. Gamma burst power and non-burst trial power were greater in SZ than HC, but burst count and area did not differ. Spectral slope was less negative in SZ than HC. Regression modeling found that gamma burst power alone best predicted SGA for both HC and SZ (> = 90% of variance), while spectral slope made a small contribution and non-burst trial power did not influence SGA. Increased SGA in the auditory cortex in schizophrenia is accounted for by increased power within gamma bursts, rather than a tonic increase in gamma-range activity, or a shift in spectral slope. Further research will be necessary to determine if these measures reflect different network mechanisms. We propose that increased gamma burst power is the main component of increased SGA in SZ and could reflect abnormally increased plasticity in cortical circuits due to enhanced plasticity of synapses on parvalbumin-expressing inhibitory interneurons. Thus, increased gamma burst power may be involved in producing psychotic symptoms and cognitive dysfunction.

Phase Delay of the 40†Hz Auditory Steady-State Response Localizes to Left Auditory Cortex in Schizophrenia.

Background. The auditory steady state response (ASSR) is generated in bilateral auditory cortex and is the most used electroencephalographic (EEG) or magnetoencephalographic measure of gamma band abnormalities in schizophrenia. While the finding of reduced 40-Hz ASSR power and phase consistency in schizophrenia have been replicated many times, the 40-Hz ASSR phase locking angle (PLA), which assesses oscillation latency or phase delay, has rarely been examined. Furthermore, whether 40-Hz ASSR phase delay in schizophrenia is lateralized or common to left and right auditory cortical generators is unknown. Methods. Previously analyzed EEG data recorded from 24 schizophrenia patients and 24 healthy controls presented with 20-, 30-, and 40-Hz click trains to elicit ASSRs were re-analyzed to assess PLA in source space. Dipole moments in the right and left hemisphere were used to assess both frequency and hemisphere specificity of ASSR phase delay in schizophrenia. Results. Schizophrenia patients exhibited significantly reduced (ie, phase delayed) 40-Hz PLA in the left, but not the right, hemisphere, but their 20- and 30-Hz PLA values were normal. This left-lateralized 40-Hz phase delay was unrelated to symptoms or to previously reported left-lateralized PLF reductions in the schizophrenia patients. Conclusions. Consistent with sensor-based studies, the 40-Hz ASSR source-localized to left, but not right, auditory cortex was phase delayed in schizophrenia. Consistent with prior studies showing left temporal lobe volume deficits in schizophrenia, our findings suggest sluggish entrainment to 40-Hz auditory stimulation specific to left auditory cortex that are distinct from well-established deficits in gamma ASSR power and phase synchrony.

Predicting inter-hemispheric transfer time from the diffusion properties of the corpus callosum in healthy individuals and schizophrenia patients: a combined ERP and DTI study.

BACKGROUND: Several theories of schizophrenia have emphasized the role of aberrant neural timing in the etiology of the disease, possibly as a consequence of conduction delays caused by structural damage to the white-matter fasciculi. Consistent with this theory, increased inter-hemispheric transmission times (IHTTs) to unilaterally-presented visual stimuli have been reported in patients with schizophrenia. The present study investigated whether or not these IHTT abnormalities could be underpinned by structural damage to the visual fibers of the corpus callosum. METHODS: Thirty three schizophrenia patients and 22 matched controls underwent Event Related Potential (ERP) recording, and a subset of 19 patients and 16 controls also underwent 3T Diffusion-Tensor Imaging (DTI). Unilateral visual stimuli (squares, 2×2 degrees) were presented 6 degrees lateral to either side of a central fixation point. IHTTs (ipsilateral minus contralateral latencies) were calculated for the P1 and N1 components at parietal-occipital sites in current source density-transformed ERPs. The visual fibers of the corpus callosum were extracted with streamline tractography and the diffusion metrics of Fractional Anisotropy (FA) and Mode calculated. RESULTS: While both subject groups exhibited highly significant IHTTs across a range of posterior electrode pairs, and significantly shorter IHTTs from left-to-right hemisphere than vice versa, no significant groupwise differences in IHTT were observed. However, participants' IHTTs were linearly related to their FA and Mode, with longer IHTTs being associated with lower FA and more prolate diffusion ellipsoids. CONCLUSIONS: These results suggest that IHTTs are estimable from DTI measures of white matter integrity. In light of the range of diffusion abnormalities that have been reported in patients with schizophrenia, particularly in frontal fasciculi, these results support the conjecture that schizophrenia is associated with abnormalities in neural timing.

The genetic and environmental influences of event-related gamma oscillations on bipolar disorder.

OBJECTIVES: Gamma oscillations have been proposed to play an important role in neural information coding. There have been a limited number of electrophysiology studies in evoked gamma band responses (GBRs) in bipolar disorder (BPD). It is also unclear whether GBR deficits, if present, are potential endophenotypes for BPD as little is known about the heritability of GBRs. The present study aimed to examine whether GBRs derived from two auditory tasks, the oddball task and the dual-click paradigm, are potential BPD endophenotypes. METHODS: A total of 308 subjects were included in this study: 198 healthy controls, 59 BPD patients (22 monozygotic BPD twins and 37 BPD patients from 31 families), and 51 unaffected relatives. The evoked gamma responses were calculated using a Morlet wavelet transformation. Structural equation modelling was applied to obtain the genetic (heritability) and environment estimates in each GBR variable and their (genetic) overlap with BPD. RESULTS: The heritability estimates of GBR to standard stimuli were 0.51 and 0.35 to target stimuli in the oddball task. However, neither response type was impaired in BPD patients or their unaffected relatives. The heritability estimates of GBR to S1 stimuli were 0.54 and 0.50 to S2 stimuli in the dual-click paradigm. BPD patients had reduced gamma power and suppression to S1 stimuli but their unaffected relatives did not. CONCLUSIONS: Evoked GBRs are heritable traits. However, GBR deficits are not observed in clinically unaffected relatives nor associated with BPD. Gamma responses do not appear to satisfy criteria for being BPD endophenotypes.

Language-Related Neurophysiological Deficits in Schizophrenia.

Schizophrenia is a severe psychiatric disorder that affects all aspects of one's life with several cognitive and social dysfunctions. However, there is still no objective and universal index for diagnosis and treatment of this disease. Many researchers have studied language processing in schizophrenia since most of the patients show symptoms related to language processing, such as thought disorder, auditory verbal hallucinations, or delusions. Electroencephalography (EEG) and magnetoencephalography (MEG) with millisecond order high temporal resolution, have been applied to reveal the abnormalities in language processing in schizophrenia. The aims of this review are (a) to provide an overview of recent findings in language processing in schizophrenia with EEG and MEG using neurophysiological indices, providing insights into underlying language related pathophysiological deficits in this disease and (b) to emphasize the advantage of EEG and MEG in research on language processing in schizophrenia.

Altered P3a Modulations to Emotional Faces in Male Patients With Chronic Schizophrenia.

Existing evidence suggests that patients with schizophrenia may have a deficit in processing facial expressions. However, the neural basis of this processing deficit remains unclear. A total of 20 men diagnosed with chronic schizophrenia and 13 age- and sex-matched controls participated in the study. We investigated visual N170 and P3a components evoked in response to fearful, happy, and sad faces during an emotion discrimination task. Compared with control subjects, patients showed significantly smaller N170 amplitudes bilaterally (P = .04). We found no significant main effect of emotion of the presented faces (fearful, happy, or sad) on N170 amplitude. Patients showed significantly smaller P3a amplitudes in response to fearful (P = .01) and happy (P = .02) faces, but no significant between-group differences were observed for sad faces (P = .22). Moreover, we found no significant P3a modulation effect in response to emotional faces in patients with schizophrenia. Our results suggest that altered P3a modulations to emotional faces may be associated with emotion recognition deficits in patients with schizophrenia.

A roadmap for development of neuro-oscillations as translational biomarkers for treatment development in neuropsychopharmacology.

New treatment development for psychiatric disorders depends critically upon the development of physiological measures that can accurately translate between preclinical animal models and clinical human studies. Such measures can be used both as stratification biomarkers to define pathophysiologically homogeneous patient populations and as target engagement biomarkers to verify similarity of effects across preclinical and clinical intervention. Traditional "time-domain" event-related potentials (ERP) have been used translationally to date but are limited by the significant differences in timing and distribution across rodent, monkey and human studies. By contrast, neuro-oscillatory responses, analyzed within the "time-frequency" domain, are relatively preserved across species permitting more precise translational comparisons. Moreover, neuro-oscillatory responses are increasingly being mapped to local circuit mechanisms and may be useful for investigating effects of both pharmacological and neuromodulatory interventions on excitatory/inhibitory balance. The present paper provides a roadmap for development of neuro-oscillatory responses as translational biomarkers in neuropsychiatric treatment development.

Auditory Cortex Volume and Gamma Oscillation Abnormalities in Schizophrenia.

We investigated whether the gray matter volume of primary auditory cortex (Heschl's gyrus [HG]) was associated with abnormal patterns of auditory γ activity in schizophrenia, namely impaired γ synchronization in the 40-Hz auditory steady-state response (ASSR) and increased spontaneous broadband γ power. (The γ data were previously reported in Hirano et al, JAMA Psychiatry, 2015;72:813-821). Participants were 24 healthy controls (HC) and 23 individuals with chronic schizophrenia (SZ). The ASSR was obtained from the electroencephalogram to click train stimulation at 20, 30, and 40 Hz rates. Dipole source localization of the ASSR was used to provide a spatial filter of auditory cortex activity, from which ASSR evoked power and phase locking factor (PLF), and induced γ power were computed. HG gray matter volume was derived from structural magnetic resonance imaging at 3 T with manually traced regions of interest. As expected, HG gray matter volume was reduced in SZ compared with HC. In SZ, left hemisphere ASSR PLF and induced γ power during the 40-Hz stimulation condition were positively and negatively correlated with left HG gray matter volume, respectively. These results provide evidence that cortical gray matter structure, possibly resulting from reduced synaptic connectivity at the microcircuit level, is related to impaired γ synchronization and increased spontaneous γ activity in schizophrenia.

Left auditory cortex gamma synchronization and auditory hallucination symptoms in schizophrenia.

BACKGROUND: Oscillatory electroencephalogram (EEG) abnormalities may reflect neural circuit dysfunction in neuropsychiatric disorders. Previously we have found positive correlations between the phase synchronization of beta and gamma oscillations and hallucination symptoms in schizophrenia patients. These findings suggest that the propensity for hallucinations is associated with an increased tendency for neural circuits in sensory cortex to enter states of oscillatory synchrony. Here we tested this hypothesis by examining whether the 40 Hz auditory steady-state response (ASSR) generated in the left primary auditory cortex is positively correlated with auditory hallucination symptoms in schizophrenia. We also examined whether the 40 Hz ASSR deficit in schizophrenia was associated with cross-frequency interactions. Sixteen healthy control subjects (HC) and 18 chronic schizophrenia patients (SZ) listened to 40 Hz binaural click trains. The EEG was recorded from 60 electrodes and average-referenced offline. A 5-dipole model was fit from the HC grand average ASSR, with 2 pairs of superior temporal dipoles and a deep midline dipole. Time-frequency decomposition was performed on the scalp EEG and source data. RESULTS: Phase locking factor (PLF) and evoked power were reduced in SZ at fronto-central electrodes, replicating prior findings. PLF was reduced in SZ for non-homologous right and left hemisphere sources. Left hemisphere source PLF in SZ was positively correlated with auditory hallucination symptoms, and was modulated by delta phase. Furthermore, the correlations between source evoked power and PLF found in HC was reduced in SZ for the LH sources. CONCLUSION: These findings suggest that differential neural circuit abnormalities may be present in the left and right auditory cortices in schizophrenia. In addition, they provide further support for the hypothesis that hallucinations are related to cortical hyperexcitability, which is manifested by an increased propensity for high-frequency synchronization in modality-specific cortical areas.

Abnormal pitch mismatch negativity in individuals with schizotypal personality disorder.

BACKGROUND: The goal of the study was to examine mismatch negativity (MMN) in schizotypal personality disorder (SPD) individuals. Abnormal MMN has been a consistent finding in chronic schizophrenia and there also have been reports of reduced duration MMN in first episode schizophrenia patients [Umbricht, D., Krljes, S., Mismatch negativity in schizophrenia: a meta-analysis. Schizophrenia Research (2005); 76(1):1-23], with some studies finding no pitch MMN amplitude differences [Salisbury, D.F., Shenton, M.E., Griggs, C.B., Bonner-Jackson, A., McCarley, R.W., Mismatch negativity n chronic schizophrenia and first-episode schizophrenia. Archives of General Psychiatry (2002); 59(8):686-694.], while others reporting a modest reduction [Umbricht, D.S., Bates, J.A., Lieberman, J.A., Kane, J.M., Javitt, D.C., Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biological Psychiatry (2006); 59(8):762-772], in recent onset schizophrenia patients. To our knowledge no reports exist of MMN in SPD individuals. METHODS: Twenty six normal (14 females) control and 23 SPD (12 females) individuals were tested using the pitch MMN paradigm. Normal control (NC) and SPD individuals were recruited from the general population and assessed using DSM-IV. SPD individuals were included if they met 5 or more criteria for SPD disorder. The subjects listened to 2000 frequent 1 kHz pure tones and 100 rare 1.2 kHz pure tones while reading a magazine article. MMN was measured from a difference waveform within the latency window of 175-276 ms. RESULTS: Reduced MMN amplitude was found in SPD relative to NC subjects (p<0.045). CONCLUSIONS: These results point to potential differences between SPD and schizophrenia, where no reduction in MMN was found in most studies of first episode patients.

Progressive reduction of auditory evoked gamma in first episode schizophrenia but not clinical high risk individuals.

The early auditory-evoked gamma band response (EAGBR) may serve as an index of the integrity of fast recurrent inhibition or synaptic connectivity in the auditory cortex, where abnormalities in individuals with schizophrenia have been consistently found. The EAGBR has been rarely investigated in first episode schizophrenia patients (FESZ) and individuals at clinical high risk (CHR) for schizophrenia, and never been compared directly between these populations nor evaluated longitudinally. Here we examined the EAGBR in FESZ, CHR, and matched healthy controls (HC) at baseline and 1-year follow-up assessments to determine whether the EAGBR was affected in these clinical groups, and whether any EAGBR abnormalities changed over time. The electroencephalogram was recorded with a dense electrode array while subjects (18 FESZ, 18 CHR, and 40 HC) performed an auditory oddball task. Event-related spectral measures (phase locking factor [PLF] and evoked power) were computed on Morlet-wavelet-transformed single epochs from the standard trials. At baseline, EAGBR PLF and evoked power did not differ between groups. FESZ showed progressive reductions of PLF and evoked power from baseline to follow-up, and deficits in PLF at follow-up compared to HC. EAGBR peak frequency also increased at temporal sites in FESZ from baseline to follow-up. Longitudinal effects on the EAGBR were not found in CHR or HC, nor did these groups differ at follow-up. In conclusion, we detected neurophysiological changes of auditory cortex function in FESZ during a one-year period, which were not observed in CHR. These findings are discussed within the context of neurodevelopmental models of schizophrenia.