Timm Rosburg

Reduced auditory evoked potential component N100 in schizophrenia--a critical review.

The role of a reduced N100 (or N1) component of the auditory event related potential as a potential trait marker of schizophrenia is critically discussed in this review. We suggest that the extent of the N100 amplitude reduction in schizophrenia depends on experimental and subject factors, as well as on clinical variables: N100 is more consistently reduced in studies using interstimulus intervals (ISIs) >1 s than in studies using shorter ISIs. An increase of the N100 amplitude by allocation of attention is often lacking in schizophrenia patients. A reduction of the N100 amplitude is nevertheless also observed when such an allocation is not required, proposing that both endogenous and exogenous constituents of the N100 are affected by schizophrenia. N100 is more consistently reduced in medicated than unmedicated patients, but a reduction of the N100 amplitude as a consequence of antipsychotic medication was shown in only two of seven studies. In line with that, the association between the N100 reduction and degree of psychopathology of patients appears to be weak overall. A reduced N100 amplitude is found in first degree relatives of schizophrenia patients, but the risk of developing schizophrenia is not reflected in the N100 amplitude reduction.

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.

Effect of ketamine on the neuromagnetic mismatch field in healthy humans

Mismatch negativity (MMN) is a component of the auditory evoked event-related potentials (ERP) that assesses automatic sound change detection and is disturbed in schizophrenic patients. Animal experimental evidence has linked the generation of MMN to the N-methyl-D-aspartate (NMDA) receptor. We investigated the neuromagnetic mismatch field (MMF) in healthy volunteers before and after intravenous application of a subanesthetic dose of the NMDA receptor antagonist ketamine (0.3 mg/kg). Ketamine had a significant influence on latency and dipole moment of the MMF, whereas the N100m latency of the standard tone was not prolonged and its dipole moment remained stable. Our results suggest that ketamine interferes with aspects of preattentive information processing and is in line with the view that disturbed NMDA receptor function may mediate the deficient auditory mismatch response in patients with schizophrenia.

Impaired sensory processing in male patients with schizophrenia—a magnetoencephalographic study of auditory mismatch detection

The generation of mismatch negativity (MMN) as a component of auditory evoked event-related brain potentials has been reported previously to be severely disturbed in patients with schizophrenia. In the present study, we extended these findings to magnetoencephalography and investigated the neuromagnetic mismatch field (MMNm) in 15 male schizophrenic inpatients as compared to 16 healthy male volunteers. A standard tone of 1000 Hz and three different types of mismatch (1050-Hz tone, 5000-Hz tone, tone omission) were employed within the same paradigm, each mismatch occurring with a 10% pseudorandom probability. After correction for eye artifacts, the mean global field power of the mismatch reaction was calculated. Mismatch generation in patients with schizophrenia proved to be significantly impaired for all three conditions. This result confirms the theory of impaired auditory information processing in patients with schizophrenia at the level of the primary auditory cortex. Deficient generation of MMNm probably represents an impaired generation and/or faster decay of the sensory memory trace on the basis of disturbed sensory processing in male patients with schizophrenia.

Left hemispheric dipole locations of the neuromagnetic mismatch negativity to frequency, intensity and duration deviants.

The aim of the current study was to differentiate the sources of neuromagnetic mismatch negativity (MMNm) to deviants of different features. For this purpose, the MMNm of twenty-one healthy subjects (seven males) were recorded left-hemispherically. Subjects were stimulated monaurally in an oddball paradigm with standard tones of 1000 Hz and three different kinds of mismatch tones (frequency, duration and intensity deviants). Data analysis revealed mean MMNm dipole locations anterior, inferior and more medial than the N100m dipoles. The mean difference between the N100m and MMNm dipoles was in the range of up to 6 mm in one dimension. The dipole locations of all three kinds of deviants differed significantly from each other. The MMNm dipoles of both frequency and duration deviants were found to be significantly inferior to the corresponding source of intensity deviants, while the MMNm dipoles of duration and frequency deviants significantly differed in anterior-posterior direction. This differentiation between sources emphasizes the importance of feature analysis in MMN(m) generation.

Increased calcium-independent phospholipase A2 activity in first but not in multiepisode chronic schizophrenia

BACKGROUND Increased activity of calcium independent phospholipase A2 (iPLA2) has repeatedly been found in the serum of unmedicated first-episode schizophrenia patients and assumed to reflect a pertubation of phospholipid metabolism. Previous studies in chronic schizophrenia were less conclusive. To explore whether iPLA2 changes are stage dependent, we investigated serum iPLA2 activity in various stages of schizophrenia. METHODS iPLA2 activity was assessed in the serum of 30 first-episode and 23 multiepisode schizophrenia patients and 53 healthy control subjects matched for age and gender. A fluorimetric assay was applied using the PLA2 specific substrate NBDC6-HPC, thin-layer chromatography of reaction products, and digital image scanning for signal detection. RESULTS Group comparison between first-episode and multiepisode patients and corresponding control groups revealed significantly increased iPLA2 activity only in first-episode patients. Enzyme activity in first-episode patients was also markedly increased, compared with chronic patients. iPLA2 changes observed were irrespective of neuroleptic medication, age, or gender. CONCLUSIONS Our results suggest increased lipid turnover in the acute early phase of schizophrenia that is less obvious in chronic stages. Future longitudinal studies involving iPLA2 activity and phosphorous magnetic resonance spectroscopy need to address the relation between perturbed brain lipid metabolism and iPLA2 increment in the course of schizophrenia.

Phase-locking within human mediotemporal lobe predicts memory formation.

Lesion and imaging studies have demonstrated that encoding of declarative memories, i.e. consciously accessible events and facts, is supported by processes within the rhinal cortex and the hippocampus, two substructures of the mediotemporal lobe (MTL). Successful memory formation has, for instance, been shown to be accompanied by the rhinal N400 component, followed by a hippocampal positivity, as well as by transient rhinal-hippocampal phase synchronization. However, it has been an open question, which mediotemporal electroencephalogram (EEG) measures predict memory formation most accurately. Therefore, we analyzed and compared the association of different mediotemporal EEG measures with successful memory formation. EEG characteristics were extracted from intracranial rhinal and hippocampal depth recordings in 31 epilepsy patients performing a continuous word recognition paradigm. Classical event-related potential measures, rhinal-hippocampal synchronization, as well as inter-trial phase-locking and power changes within rhinal cortex and hippocampus were evaluated. We found that inter-trial phase-locking is superior to other EEG measures in predicting subsequent memory. This means that memory formation is related to the precise timing of EEG phases within the MTL with respect to stimulus onset. In particular, early rhinal and hippocampal phase-locking in the alpha/beta range reaching its maximum already between 100 and 300 ms after stimulus onset appears to be a precursor of successful memory formation. Our data suggest that early mediotemporal phase adjustments constitute a relevant mechanism underlying declarative memory encoding.

Sensory gating in the human hippocampal and rhinal regions

OBJECTIVE The objective of this work was to ascertain if sensory gating can be demonstrated within the human medial temporal lobe. METHODS Eight patients with intractable epilepsy with depth electrodes implanted in the medial temporal lobe for pre-surgery evaluation underwent evoked response recording to auditory paired-stimuli (S1-S2). Each of the eight subjects had a diagnosis of left medial temporal lobe epilepsy (MTLE). RESULTS Data from the non-focal right hippocampi revealed a large negative response on S1 (starting at about 190 ms and lasting for approximately 300 ms from stimulus onset). Rhinal region recordings revealed a positive response (starting at about 240 ms with a rapid incline, followed by a long-lasting decline). A significant attenuation of both responses to S2 stimuli was observed. CONCLUSIONS Data are suggestive of an involvement of the human medial temporal lobe in the processing of simple auditory information which occurs in a time frame later than the neocortical auditory evoked components. The exact role of these anatomical structures in the sensory gating process remains to be defined. SIGNIFICANCE This study provides the first evidence of an activation of the rhinal cortex after simple auditory stimulation and provides new evidence that the activation of the medial temporal lobe structures occurs at a later stage than that of the neocortex.

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.

The effect of face inversion on intracranial and scalp recordings of event-related potentials

The face inversion effect (FIE) refers to a disproportionate disruption of the processing of face information by inverting faces. We investigated the FIE in epilepsy patients by simultaneous intracranial and scalp recordings of event-related potentials (ERPs). In scalp recordings, a typical FIE on ERPs was observed with increased latencies and amplitudes of the positive counterpart of the occipito-temporal N170, namely, the vertex positive potential (VPP), in response to inverted faces. Similar amplitude and latency increases were revealed for the intracranial N200 recorded over face-sensitive and non-face-sensitive areas in the lateral occipital cortex, but not in the ventral temporal cortex. Peak latencies did not differ between the scalp VPP and intracranial N200. Findings indicate that the lateral occipital cortex but not the ventral temporal cortex contributes primarily to the FIE observed in scalp recordings.