Diagnostic specificity and familiality of early versus late evoked potentials to auditory paired stimuli across the schizophrenia-bipolar psychosis spectrum.

Disrupted sensory processing is a core feature of psychotic disorders. Auditory paired stimuli (PS) evoke a complex neural response, but it is uncertain which aspects reflect shared and/or distinct liability for the most common severe psychoses, schizophrenia (SZ) and psychotic bipolar disorder (BDP). Evoked time-voltage/time-frequency domain responses quantified with EEG during a typical PS paradigm (S1-S2) were compared among proband groups (SZ [n = 232], BDP [181]), their relatives (SZrel [259], BDPrel [220]), and healthy participants (H [228]). Early S1-evoked responses were reduced in SZ and BDP, while later/S2 abnormalities showed SZ/SZrel and BDP/BDPrel specificity. Relatives' effects were absent/small despite significant familiality of the entire auditorineural response. This pattern suggests general and divergent biological pathways associated with psychosis, yet may reflect complications with conditioning solely on clinical phenomenology.

Spatiotemporal and frequency domain analysis of auditory paired stimuli processing in schizophrenia and bipolar disorder with psychosis.

Individuals with schizophrenia (SZ) or bipolar disorder with psychosis (BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography (EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated prestimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among participants with both SZ and BPP. Conversely, (iii) N1s in those with SZ to S1 were reduced compared to healthy volunteers and those with BPP, whereas (iv) beta range oscillations 200-300 ms following S2 were accentuated in those with BPP but not those with SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses.

Target probability affects the likelihood that a P300 will be generated in response to a target stimulus, but not its amplitude.

The ensemble-averaged P300 amplitude is affected by global and local target probability and interstimulus interval. We hypothesize that the local target probability-induced amplitude changes arise from a failure to consistently produce a P300 rather than producing lower amplitude responses. Single-trial analysis was conducted on auditory P300 data from 13 healthy subjects to determine the absence or presence of a P300 component for each target response separately. Selective, normalized averages were computed for each local target probability. Target stimuli preceded by one or two nontargets led to significantly more trials lacking a P300 than the other local target probability categories. The amplitudes of the responsive trials did not differ between the local target probability categories. This suggests that local target probability affects the consistency with which a subject responds to target stimuli, but not the P300 amplitude.

Generators of the intracranial P50 response in auditory sensory gating.

Clarification of the cortical mechanisms underlying auditory sensory gating may advance our understanding of brain dysfunctions associated with schizophrenia. To this end, data from nine epilepsy patients who participated in an auditory paired-click paradigm during pre-surgical evaluation and had grids of electrodes covering temporal and frontal lobe were analyzed. A distributed source localization approach was applied to the intracranial P50 response and the Gating Difference Wave obtained by subtracting the response to the second stimuli from the response to the first stimuli. Source reconstruction of the P50 showed that the main generators of the response were localized in the temporal lobes. The analysis also suggested that the maximum neuronal activity contributing to the amplitude reduction in the P50 time range (phenomenon of auditory sensory gating) is localized at the frontal lobe. Present findings suggest that while the temporal lobe is the main generator of the P50 component, the frontal lobe seems to be a substantial contributor to the process of sensory gating as observed from scalp recordings.

Genetic and environmental influences on sensory gating of mid-latency auditory evoked responses: a twin study.

A deficit in sensory gating measured by the suppression of P50 auditory event-related potential (ERP) has been implicated in the biological bases of schizophrenia and some other psychiatric disorders and proposed as a candidate endophenotype for genetic studies. More recently, it has been shown that gating deficits in schizophrenics extend to ERP components reflecting early attentive processing (the N1/P2 complex). However, evidence for heritability of sensory gating in the general population is very limited. Heritability of P50, N1, and P2 amplitudes and gating was estimated in 54 monozygotic and 55 dizygotic twin pairs using a dual-click auditory paradigm. Genetic model-fitting analysis showed high heritability of peak amplitudes of P50, N1, and P2 waves. Genetic influences on P50 gating (S2/S1) were modest, while heritability of N1 and P2 gating was high and significant. The alternative gating measure (S1-S2 difference) showed significant heritability for all three ERP components. Weak genetic influences on P50 gating ratio can be related to its poor test-retest reliability demonstrated in previous studies. These results suggest that gating measures derived from the N1/P2 wave complex may be useful endophenotypes for population-based genetic studies of the sensory gating function and its impairments in psychopathology.

Habituation of auditory evoked potentials in intracranial and extracranial recordings.

Effects of stimulus repetition are investigated in short-term habituation experiments. In these experiments, trains of stimuli are applied with longer intervals of no stimulation between the trains. In scalp recordings, an amplitude and latency decrease of the auditory N100 is usually observed at the beginning of the train. This contrasts to a recent finding with intracranial recordings, exhibiting an effect on N100 amplitude, but not on its latency. In the current study, P50 and N100 were simultaneously recorded intra- and extracranially in epilepsy patients. The amplitudes of P50 and N100 decreased in both recordings, whereas the P50 latency was not significantly affected. A latency decrease was revealed for the extracranially recorded N100, but not for the intracranial N100. This dissociation between the intracranial and scalp recordings might be explained by a different sensitivity of the two measurements for N100 generators.

gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.

BACKGROUND: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/2C) receptors, were studied in 23 healthy male subjects. METHODS: Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after. RESULTS: Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol. CONCLUSIONS: Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.

Risk factors for experiencing psychosis during cocaine use: a preliminary report.

UNLABELLED: Cocaine induced psychosis (CIP) is a common, but not universal side effect of cocaine abuse. Factors underlying the development and severity of CIP remain poorly understood. This study tests the hypothesis that earlier age of initiation of regular use may increase the likelihood of developing CIP, or the severity of CIP symptoms. METHODS: Cocaine use history and severity of CIP (if any) were assessed with the Cocaine Experience Questionnaire in 51 abstinent (3 weeks-1 year) cocaine dependent individuals. Subjects were divided into those with high and low CIP severity, and into those with early age of initiation of regular cocaine use, and later age of initiation. Various cutoffs between early and late age of initiation were used, ranging from 15 to 22 years. RESULTS: From ages 17 through 20, controlling for cumulative duration of use, severity scores were significantly higher for the early initiation group than for the later initiation group (p values ranged from 0.031 to 0.036). Cumulative duration of use, but not age of initiation, significantly predicted initial development of CIP (p=0.044). CONCLUSIONS: The data suggest that early age of initiation of regular cocaine use occurring during vulnerable periods of brain development, may lead to increased severity of CIP.

Subdural recordings of the mismatch negativity (MMN) in patients with focal epilepsy.

Mismatch negativity (MMN) is elicited by discernible changes in an otherwise regular stream of auditory stimulation and reflects a pre-attentive detection mechanism. In the current study, auditory evoked potentials were recorded intracranially and electrode contacts sensitive for stimulus deviance were selected in order to further elucidate the contribution of different brain areas to MMN generation. Data were obtained from patients with frontal and temporal lobe epilepsy undergoing a presurgical evaluation by subdural and depth electrodes. In 13 of 29 patients under investigation an intracranial MMN could be observed, while in four other patients a response recovery of the N100 was revealed, mimicking an MMN. Most electrodes with an MMN signal were located in or close to the superior temporal lobe. In two patients an MMN was observed at electrode contacts over the lateral inferior frontal cortex and in one patient at a frontal interhemispheric electrode strip, giving evidence for a participation of the frontal gyrus in MMN generation. Current findings have, however, to be interpreted with caution owing to the placement and limited extension of the used electrode arrays.

Cortical excitability in cocaine-dependent patients: a replication and extension of TMS findings.

Cortical excitability can be assessed by transcranial magnetic stimulation (TMS). Previously we observed that TMS motor threshold (MT) was elevated in abstinent cocaine-dependent subjects. In the current study we aimed at replicating our initial finding, exploring other TMS-based measures of excitability, and examining association with personality characteristics. Nineteen cocaine-dependent and 12 healthy control subjects were examined. Resting and activated motor thresholds (RMT and AMT) and duration of the cortical silent period (CSP) were examined. The Cocaine Experience Questionnaire (CEQ) was administered to assess cocaine-induced psychotic symptoms. The relationship between Minnesota Multiphasic Personality Inventory (MMPI) scales and cortical excitability measures was also examined. AMT was significantly elevated in cocaine-dependent subjects on both hemispheres. RMT was also significantly elevated on the right hemisphere. No CSP changes were noted. Patients with cocaine-induced paranoia had longer CSPs on the right hemisphere compared to subjects reporting no paranoid experiences. The patients displayed significantly elevated scores on several MMPI scales, though the scale scores did not correlate with cortical excitability measures. These data support our initial finding of decreased cortical excitability in abstinent cocaine-dependent subjects. We interpret this finding as a compensatory mechanism against the stimulating and epileptogenic effects of cocaine.

Short-term habituation of the intracranially recorded auditory evoked potentials P50 and N100.

At an interstimulus interval (ISI) of 500-ms stimulus repetition leads to a strong decrease in cortical response. The functional foundation of this response suppression (or sensory gating) is yet not fully understood. Experiments on short-term habituation using the same stimulus material as sensory gating experiments and same ISI might help to elucidate the mechanisms behind the P50 suppression. Event-related potentials were recorded intracranially in epileptic patients undergoing presurgical evaluation with subdural and depth electrodes. Stimulus material consisted of trains of six clicks, with the last stimulus deviating in pitch and duration. P50 and N100 were calculated for each stimulus in the train separately and compared by analysis of variance (ANOVA). A highly significant amplitude reduction was found from the 1st to 2nd stimulus for both P50 and N100. From the 2nd to 5th stimulus no further amplitude decrease was observable. The deviating 6th stimulus led to a response recovery of both components, but the P50 elicited by the 6th stimulus was still smaller than the P50 of the 1st stimulus. Current results indicate that the P50 suppression as investigated in sensory gating experiments seems to be completed after the 2nd stimulus.

Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism.

OBJECTIVE: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. METHOD: Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under double-blind conditions. The healthy individuals with at least one first-degree relative and another first- or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any first- or second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels. RESULTS: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. CONCLUSIONS: These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism.

Morphological and latency abnormalities of the mid-latency auditory evoked responses in schizophrenia: a preliminary report.

INTRODUCTION: Evoked potential (EP) amplitude and latency abnormalities have been extensively examined in schizophrenia. Morphological abnormalities of the mid-latency auditory evoked responses (MLAERs; P50, N100, P200), on the other hand, received very little attention. METHODS: Based on a priori defined set of morphological criteria, the morphology and latency of the MLAERs were blindly compared between stable outpatients with schizophrenia (N=27) and age- and gender-matched healthy control subjects (N=22). The morphology of the MLAERs was considered abnormal if one or more of the components fell outside the expected latency range, if one or more of the components were missing, or if a later occurring component was smaller in amplitude than an earlier occurring one. RESULTS: Of the 27 schizophrenia subjects, 20 had waveforms that were deemed atypical, while only 8 from the control group were classified as atypical (chi(2)=5.52, p<0.02). The latencies of the P50 and N100 components, identified based on morphology, were significantly prolonged in schizophrenia patients. CONCLUSIONS: These preliminary data suggest that morphological abnormalities of the MLAERs in schizophrenia patients are significant and should be taken into consideration when examining the MLAERs of this patient population.

Sensory gating deficits during the mid-latency phase of information processing in medicated schizophrenia patients.

Sensory gating during preattentive phases of information processing has been extensively examined. Sensory gating processes that occur during subsequent phases of information processing have not been fully examined. The relationship between P50 sensory gating and schizophrenia symptoms remains underspecified and the clinical correlates of N100 and P200 gating are yet to be examined. Sensory gating indices derived from the mid-latency auditory evoked responses during preattentive (P50) and attentive (N100, P200) phases of information processing were collected from schizophrenia patients who were stable and mainly being treated with atypical antipsychotic medications (n=23) and age- and gender-matched healthy control subjects (n=23). Schizophrenia patients had demonstrable habituation or sensory gating difficulties throughout the mid-latency range of information processing. Moreover, we found no correlations between P50-derived sensory gating indices and the amplitude or latency of the more attention-related P300 evoked response. A number of N100 and P200 gating measures correlated with P300 variables. Finally, we found no correlations between sensory gating indices and schizophrenia symptoms clusters. These results suggest that sensory gating is a pervasive abnormality in schizophrenia patients that is not limited to the preattentive phase of information processing. Furthermore, the data suggest that N100 and P200 gating indices may influence subsequent information processing.

Contribution of different EEG frequencies to auditory evoked potential abnormalities in schizophrenia.

OBJECTIVE: We have shown previously [Clin Neurophysiol 2003;114:79] that phase reorganization of the ongoing electroencephalogram (EEG) plays an important role in the generation of auditory evoked potential (EP) components with a latency between 50 and 200 ms. In the present study, we investigate whether schizophrenia patients suffer from phase synchronization deficits as compared to normal subjects. METHODS: The auditory EPs from 20 normal subjects and 19 schizophrenia patients were analyzed. EPs were obtained using a double stimulus paradigm, in which two identical tone bursts (S1 and S2) were delivered with an average inter-stimulus interval of 500 ms and an inter-pair interval of 8 s. The Piecewise Prony Method (PPM) was used to decompose single trial auditory evoked potentials into different frequency bands. Pre- and post-stimulus phase histograms were compared for each frequency band to determine the degree of phase synchronization produced by auditory stimulation in the two populations. RESULTS: The S1 stimulus produced significantly less (P < 0.05) phase synchronization in schizophrenia patients than in normal subjects in the 2-12 Hz frequency range. Far fewer and smaller inter-population phase synchronization differences were seen for the S2 stimulus. Both populations showed more phase synchronization for S1 than S2. A significant correlation (P < 0.01) between N100 amplitude and phase synchronization 100 ms post S1 was observed for the normal population but not for the schizophrenia group. The correlation between P200 amplitude and phase synchronization 200 ms post S1 was significant for the normal group (P < 0.01) and the schizophrenia group (P < 0.03). CONCLUSIONS: Schizophrenia patients have a phase synchronization deficiency, as compared to a normal control group, especially for the first stimulus, in the 2-12 Hz frequency range. This deficiency explains the lower EP amplitudes and may be a significant factor contributing to reduced sensory gating reported in schizophrenic subjects. SIGNIFICANCE: The research presented here contributes to the understanding of the mechanism underlying sensory gating in health and gating deficiencies in schizophrenia.

Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.

Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.

Electrophysiological aberrations in borderline personality disorder: state of the evidence.

Electrophysiological technology is noninvasive and relatively inexpensive. In order to assess the usefulness of this technology in probing the pathophysiology of borderline personality disorder (BPD), we reviewed the literature in which an electrophysiological modality was used to examine BPD. Twenty-two articles were identified, from which diagnostic criteria and data on comorbidity and control groups were extracted. Although the majority of studies pointed to a high prevalence of electrophysiological aberrations in patients, very few studies had adequate control groups and adequate evaluation of comorbidity. We conclude that although the existing literature reflects a preliminary stage of the field, it suggests that electrophysiological investigations may be useful in investigating BPD.