Abnormality of thought and emotion in schizophrenic patients is widely hypothesized to be caused by functional dissociation between brain processes. Analyses of the typically small groups of schizophrenic patients yielded different neurophysiological findings, because small patient groups are likely to comprise different schizophrenia subtypes. We wanted to see whether there are identical deteriorated cortical functional EEG connectivities in different patient groups. Multichannel no-task resting eyes-closed EEG from three small groups of acutely ill, first episode productive schizophrenic patients before start of medication (from three centers: Bern N = 9; Osaka N = 9; Berlin N = 12) and their controls was analyzed. Using LORETA (low resolution brain electromagnetic tomography), we computed intracortical source model-based lagged functional connectivity (not biased by volume conduction effects) between 19 cortical regions of interest (ROIs). The connectivities were compared between controls and patients of each group. The results across groups were combined using conjunction analysis. Six aberrant cortical functional connectivities were identical in the three patient groups as determined by conjunction analysis. Four of these occurred in the facilitating EEG alpha 1 frequency band; they were decreased in the patients. Another two of these occurred in the inhibiting EEG delta frequency band; they were increased in the patients. Thus, all six reduced the functional interactions between the concerned brain regions. The principal spatial orientation of the six aberrant cortical functional connectivities was sagittal; five of them involved both hemispheres. The study shows that, common across schizophrenia subtypes in the three patient groups, a core set of functional connections between the preprocessing functions in posterior brain areas and the evaluation and behavior control functions in anterior brain areas is compromised. The results also support the concept of functional dissociation in schizophrenia.

In young, first-episode, productive, medication-naive patients with schizophrenia, EEG microstates (building blocks of mentation) tend to be shortened. Koenig et al. [Koenig, T., Lehmann, D., Merlo, M., Kochi, K., Hell, D., Koukkou, M., 1999. A deviant EEG brain microstate in acute, neuroleptic-naive schizophrenics at rest. European Archives of Psychiatry and Clinical Neuroscience 249, 205-211] suggested that shortening concerned specific microstate classes. Sequence rules (microstate concatenations, syntax) conceivably might also be affected. In 27 patients of the above type and 27 controls, from three centers, multichannel resting EEG was analyzed into microstates using k-means clustering of momentary potential topographies into four microstate classes (A-D). In patients, microstates were shortened in classes B and D (from 80 to 70 ms and from 94 to 82 ms, respectively), occurred more frequently in classes A and C, and covered more time in A and less in B. Topography differed only in class B where LORETA tomography predominantly showed stronger left and anterior activity in patients. Microstate concatenation (syntax) generally were disturbed in patients; specifically, the class sequence A-->C-->D-->A predominated in controls, but was reversed in patients (A-->D-->C-->A). In schizophrenia, information processing in certain classes of mental operations might deviate because of precocious termination. The intermittent occurrence might account for Bleuler's "double bookkeeping." The disturbed microstate syntax opens a novel physiological comparison of mental operations between patients and controls.

Multikanal-Spontan-EEG kann durch k-means-Clustering in Abschnitte mit quasi-stationärer Potenzial-Topographie zerlegt werden, in „Mikrozustände“ im Bereich von 100 ms. Verschiedene Mikrozustände inkorporieren verschiedene Modi der Informationsverarbeitung. Multikanal-EEG (~37s/Person) von 27 akut ersterkrankten und noch nicht behandelten jungen Schizophrenen und von 27 gematchen Gesunden (von 3 Zentren) wurde in Mikrozustände zerlegt, die 4 Klassen (A–D) bildeten. Die über Personen gemittelten bevorzugten Richtungen der Aufeinanderfolge der Klassen wurden zwischen Patienten und Gesunden statistisch verglichen: ANCOVA (2 Personengruppen x 6 Richtungs-Bevorzugungen, Zentren als Kovariate) zeigte eine signifikante Interaktion Personengruppe x Richtungs-Bevorzugungen. Posthoc-Tests klärten, dass 2 der 6 Verkettungen zwischen den 4 Klassen signifikant verschiedene Richtungen hatten: Die bevorzugte Folge war C-A-D bei den Patienten, jedoch umgekehrt D-A-C bei den Gesunden. Die signifikant geänderte Syntax der hirnelektrischen Mikrozustände der Schizophrenen öffnet einen neuen Blickwinkel auf die Hirnmechanismen, welche die Denkstörungen der Patienten implementieren. Da die physiologischen Abweichungen vielfach wiederholt und intermittierend im Subsekundenbereich geschehen, könnten sie gut die instantanen Perspektive-Änderungen der Patienten (Bleuler's „doppelte Buchführung“) erklären.

Current concepts of cognitive control suggest that the anterior cingulate cortex (ACC) is involved in performance monitoring. This idea is supported by the finding that increased ACC activity is found in situations in which errors are likely to occur, even if none are actually made. In addition, recent results suggest that increased ACC activity is negatively correlated with reaction time. We have now compared the error rates and the ACC activity of healthy subjects with short (n=19) vs. long reaction times (n=17) in an auditory choice reaction paradigm and analysed the current density differences in the ACC in the time range of the N1 component with low resolution electromagnetic tomography. Subjects with short reaction times showed significantly more ACC activation (Brodmann Area 24) and an increased error rate. This finding suggests that increased ACC activity is associated with a gain in reaction speed at the expense of correctness and is discussed in the context of current concepts about the role of the ACC in cognitive functions.

The GABA B receptor 1 gene is mapped to chromosome 6p21.3 within the HLA class I region close to the HLA‐F gene. Susceptibility loci for epilepsy and schizophrenia have been mapped in this region. Based on pharmacological evidence, it has been suggested that GABA B receptors may play a crucial role in the synchronization of EEG oscillations, which in turn can be abnormal in neuropsychiatric disorders. In the present study, the hypothesis was tested, whether three exonic variants of the gene encoding the human GABA B receptor (GABA B R1) modify cortical synchronization measured as scalp‐recorded EEG‐coherence. Two principal components of EEG coherence (frontal coherence, parietotemporal coherence) were investigated in 104 healthy subjects during three conditions: resting EEG, activated EEG, and event‐related EEG. No significant associations were found between the frontal coherence component and any polymorphism or between the parietotemporal coherence component and the exon 1a1 polymorphism. However, parietotemporal coherence showed statistically highly significant associations across all three experimental conditions with exon 7 and trend associations with exon 11. The results provide evidence that the translated polymorphism of exon 7 may be functionally meaningful and impact cortical EEG oscillations. Since variations of EEG coherence have been described for several neuropsychiatric disorders, the present association should be tested in clinical samples using EEG coherence as an intermediate phenotype. © 2003 Wiley‐Liss, Inc.

Attention deficits have been consistently described in schizophrenia. Functional neuroimaging and electrophysiological studies have focused on anterior cingulate cortex (ACC) dysfunction as a possible mediator. However, recent basic research has suggested that the effect of attention is also observed as a relative amplification of activity in modality-associated cortical areas. In the present study, the question was addressed whether an amplification deficit is seen in the auditory cortex of schizophrenic patients during an attention-requiring choice reaction task. Twenty-one drug-free schizophrenic patients and 21 age- and sex-matched healthy controls were studied (32-channel EEG). The underlying generators of the event-related N1 component were separated in neuroanatomic space using a minimum-norm (LORETA) and a multiple dipole (BESA) approach. Both methods revealed activation in the primary auditory cortex (peak latency approximately 100 ms) and in the area of the ACC (peak latency approximately 130 ms). In addition, the adapted multiple dipole model also showed a temporal-radial source activation in nonprimary auditory areas (peak latency approximately 140 ms). In schizophrenic patients, significant activation deficits were found in the ACC as well as in the left nonprimary auditory areas that differentially correlated with negative and positive symptoms. The results suggest that (1) the source in the nonprimary auditory cortex is detected only with a multiple dipole approach and (2) that the N1 generators in the ACC and in the nonprimary auditory cortex are dysfunctional in schizophrenia. This would be in line with the notion that attention deficits in schizophrenia involve an extended cortical network.

This study was performed in order to address the question whether the newly introduced technique of low-resolution electromagnetic tomography (LORETA) is able to detect hypofrontality in schizophrenic patients. We investigated resting EEGs of 19 unmedicated schizophrenics and 20 normal subjects. For comparison, we also investigated 19 subjects with schizotypal personality and 30 unmedicated depressive patients. A significant increase of delta activity was found in schizophrenic patients over the whole cortex, most strongly in the anterior cingulate gyrus and temporal lobe (fusiform gyrus). Both schizotypal subjects and depressive subjects showed significantly less delta, theta and beta activity in the anterior cingulum, a decrease of alpha1 activity in the right temporal lobe and a decrease of alpha2 activity in the left temporal lobe. The results suggest general cortical hypoactivation, most pronounced in the anterior cingulate and temporal lobe in schizophrenics, whereas there is evidence for a complex, frequency-dependent spatial pattern of hyperactivation in schizotypal subjects and depressive patients. The results are discussed within a neurophysiological and methodological framework.

This study compared the intensity dependence of the auditory evoked N1 and N1m components in 10 healthy subjects. The evoked responses were recorded simultaneously at 33 channels for the auditory evoked potentials (AEP) and with a 37-channel magnetometer for the auditory evoked fields (AEF). They were satisfactorily modeled by a tangential and a radial dipole per hemisphere for the N1 component and a tangential dipole in the left hemisphere for the N1m component. The tangential dipoles showed different dipole characteristics. The amplitude of the AEP rose significantly with increasing stimulus intensity whereas the amplitudes of the AEF tended to plateau between the highest intensities. The magnetic dipole shifted to the surface of the skull with higher stimulus intensity whereas the electric tangential dipole moved to the center of the skull. The latencies decreased with increasing stimulus intensity.

The aim of the present study is to analyze how well physiological measures of sleepiness derived from pupillography and the Multiple Sleep Latency Test correlate with a subjective measure, the Stanford Sleepiness Scale (SSS) score. The results are based on data from 12 healthy participants, who underwent these tests every 2 hr from 7:00 a.m. until 11:00 p.m. Sleep latencies were correlated with four different variables derived from pupillography and the SSS score. The results indicate that the physiologically based variables correspond very well. This is reflected by similar patterns of time-of-day variations, a good agreement at the group level, and correlations at the individual level, whereas the SSS shows a quite different pattern of variation. The two physiological measures of sleepiness seem to reflect the same aspect of the level of tonic central nervous activation, which is not correlated with the subjective feeling of sleepiness.

There is good evidence from neuroanatomic postmortem and functional imaging studies that dysfunction of the anterior cingulate cortex plays a prominent role in the pathophysiology of schizophrenia. So far, no electrophysiological localization study has been performed to investigate this deficit. We investigated 18 drug-free schizophrenic patients and 25 normal subjects with an auditory choice reaction task and measured event-related activity with 19 electrodes. Estimation of the current source density distribution in Talairach space was performed with low-resolution electromagnetic tomography (LORETA). In normals, we could differentiate between an early event-related potential peak of the N1 (90-100 ms) and a later N1 peak (120-130 ms). Subsequent current-density LORETA analysis in Talairach space showed increased activity in the auditory cortex area during the first N1 peak and increased activity in the anterior cingulate gyrus during the second N1 peak. No activation difference was observed in the auditory cortex between normals and patients with schizophrenia. However, schizophrenics showed significantly less anterior cingulate gyrus activation and slowed reaction times. Our results confirm previous findings of an electrical source in the anterior cingulate and an anterior cingulate dysfunction in schizophrenics. Our data also suggest that anterior cingulate function in schizophrenics is disturbed at a relatively early time point in the information-processing stream (100-140 ms poststimulus).

The SIESTA project had two major goals: developing new tools for analyzing computer-based sleep recordings and creating a reference database for sleep-related features. Basically, both goals have been reached, although validation and fine tuning of the sleep analyzer is still on-going. Investigations on the Web interface will be finished soon and a documentation of the database (including a CD-ROM with all test forms and all clinical, psychometric and actigraphic data as well as all R&K-scorings) will be published. Besides its scientific impact, the SIESTA project also emphasizes two other important aspects: the need of national and international cooperation between different experts and disciplines and the importance of standardized methods in scientific and clinical research.

A literature review has been done on interrater reliability of sleep stage scoring according to the Rechtschaffen and Kales rules both between two and more than two raters. These results have been compared with the interrater reliability between visual scorings and semiautomatic as well as fully automated scorings. For single night scorings the interrater reliability varies between 61% and 96% while at the group level the agreement between visual scorings varies between 85% and 95% with an average of approximately 89%. The Interrater reliability between visual and automatic scoring at a group level varies between 70% and 95% with an average of about 83%. The interrater reliability of sleep stage scorings varies with the number and the experience of the scorers, the choice of the 100% reference (if two or more human experts are involved), the number of stages that are distinguished, the sample (healthy subjects vs. patients with sleep disturbances), the age of the subjects and the choice of the statistical method to estimate the interrater reliability. Based on the review of interrater reliability data methodological considerations on the measurement of interrater reliability are presented and discussed. For variables measured on different scales (quantitative sleep parameters measured on a metric scale vs. sleep stages as qualitative variables measured on a nominal scale) different approaches to estimate interrater reliability are used. For sleep parameters measured on a metric scale the advantages and disadvantages of correlation statistics on one hand and approaches to test group differences on the other are discussed. Among the approaches of correlation analysis, intra-class correlation should be the method of choice and with regard to approaches that test group differences the paired nature of the data has to be considered. Only a combination of both statistical approaches yields a comprehensive impression on the interrater reliability of the scoring results. For sleep stages, which represent nominal scaled qualitative data, agreement is commonly expressed as a percentage. Although this is a simple measure which is readily understood, it is not an adequate index of agreement since it makes no allowance for agreement between scorers that might be attributed just to chance. This disadvantage is overcome by the kappa statistics (by Cohen for two scorers and by Fleiss for more than two scorers), which expresses the difference between observed and chance agreement in relation to maximum possible excess of observed over chance agreement. Kappa usually varies between 0 (agreement is equal to chance) and 1 (complete agreement between scorers). Values <0, which are rarely observed, indicate that there is a systematic deviation in agreement.

Recent publications on the formation of sleep theories and theories on the importance of individual sleep stages are reviewed.It seems evident that sleep is regulated by two processes as documented in the theories of Borbely. The light-darkness-triggered 24 1/2-25h rhythm process C induced by the suprachiasmatic nuclei, and the homoeostatic process 5, induced by the work/wake time and the kind of activity done during waking. in addition, there is the 90-min REM/NREM cycle during day and night, according to Hobson caused by changing firing rates in the peri-brachial pons.While processes S and Care plausible for the theory of restorative functions of sleep, for the REM/NREM cycle no satisfactory theory is available. The restorative functions of sleep include muscle resting, decreased thalamic activity as well as periodic process C-dependent and process S-dependent production of hormones and proteins.The 90-min cycle of REM/NREM sleep is most likely necessary for memory consolidation, error correction and nerve fibre sprouting. However, there are no detailed theories available as to when and where exactly and through which mechanisms during sleep this would happen. Many publications as reviewed by Sejnowski and Destexhe describe the neurophysiological and biochemical mechanisms during SWS and REM; however, these findings do not result in a holistic theory about the importance or the mechanisms of REM/NREM cycle integrated into the 2-process model of Borbely.

It was the aim of the present study 1) to investigate how many cortical activity maxima of scalp-recorded P300 are detected by Low Resolution Electromagentic Tomography (LORETA) when analyses are performed with high time-resolution, 2) to see if the resulting LORETA-solution is in accordance with intracortical recordings as reported by others and 3) to compare the given pattern of cortical activation maxima in the P300-timeframe between schizophrenic patients and normal controls. Current density analysis was performed in 3-D Talairach space with high time resolution i.e. in 6 ms steps. This was done during an auditory choice reaction paradigm separately for normal subjects and schizophrenic patients with subsequent group comparisons. In normal subjects, a sequence of at least seven cortical activation maxima was found between 240-420ms poststimulus: the prefrontal cortex, anterior or medial cingulum, posterior cingulum, parietal cortex, temporal lobe, prefrontal cortex, medial or anterior cingulum. Within the given limits of spatial resolution, this sequential maxima distribution largely met the expectations from reports on intracranial recordings and functional neuroimaging studies. However, localization accuracy was higher near the central midline than at lateral aspects of the brain. Schizophrenic patients less activated their cortex in a widespread area mainly in the left hemisphere including the prefrontal cortex, posterior cingulum and the temporal lobe. From these analyses and comparsions with intracranial recordings as reported by others, it is concluded that LORETA correctly localizes P300-related cortical activity maxima on the basis of 19 electrodes except for lateral cortical aspects which is most likely an edge-phenomenon. The data further suggest that the P300-deficit in schizophrenics involves an extended cortical network of the left hemisphere at several steps in time during the information processing stream.

Background: A study was performed to analyze time-of-day variations of different indicators of attention and their interrelations.Methods: After a sufficiently long all-night sleep 12 healthy non-sleep-deprived subjects ran through a test battery (Stanford Sleepiness Scale, Visual Analogue Scale, Critical Flicker Fusion Test [CFF], Visualization Test Number Facility Test, Reaction Time, Pupillometry, and modified Multiple Sleep Latency Test) every 2 hours from 7:00 AM until 11:00 PM, Time-of-day variations were tested nonparametrically with Friedman's test for repeated measurements. Principal component factor analysis (of individually standardized values) was used to identify variable complexes with the same pattern of time-of-day variation.Results: Statistically significant time-of-day variations were found for all variables, except for Fusion Frequency in CFF and Reaction Time. In factor analysis the physiologic parameters (pupillometric variables and sleep latencies) load on one factor, whereas the self-assessment scales, the Visualization Test, Number Facilty Test, and CFF load on the second factor, The variables that load primarily on factor I show peak levels of alertness immediately after getting up (at 7:00 AM) and again at 9:00 PM. Those variables that load primarily on factor 2 indicate a peak level of alertness around noon (11:00 AM-3:00 PM).Conclusions: Different aspects of attention follow different time-of-day variations. It is discussed that these findings cart be attributed to underlying circadian and homeostatic factors. (C) 2000 Society of Biological Psychiatry.

Lithium is potentially toxic to the central nervous system. Clinical lithium neurotoxicity may appear at any time during therapy and may go unrecognized. Failure to appreciate this fact leads to delays in diagnosis and treatment, placing the patient at risk of permanent neurological damage or death. In spite of a largely clinical diagnosis of lithium intoxication, the EEG provides an objective criterion of intoxication. We report a case of lithium intoxication with neurotoxic symptoms associated with marked EEG changes despite moderate lithium serum levels. In contrast to the interindividually varying EEG changes under uncomplicated lithium therapy, pathological EEG findings are the rule in the case of intoxication. Several reports evince a closer relationship between neurotoxic symptoms with EEG changes than with serum levels of lithium. This is of clinical interest with respect to intoxication under therapeutic lithium serum levels, since the EEG is the only examination indicating an intoxication. In patients with intoxication, the phenomenon of long-lasting EEG changes after discontinuation of lithium is discussed with respect to neuronal storing of lithium and persisting neurological disturbances.

Objective: This study was performed in order to clarify the mechanisms which underlie the reduced signal-to-noise of event-related potentials in schizophrenic patients. Specifically, we wanted to find out, whether it is reduced activation and/or synchronization (phase-locking) in specific frequency bands of the ongoing EEG which is related to the decreased signal amplitude and signal-to-noise ratio in schizophrenics.Methods: We investigated 41 unmedicated schizophrenics (10 of them drug-naı̈ve) and compared them with healthy control subjects (n=233) as well as unmedicated subjects with schizotypal personality (n=21), who were considered to be high-risk subjects for schizophrenia, and unmedicated depressive patients (n=71). We measured event-related activity during an acoustical choice reaction paradigm and calculated the signal-to-noise ratio, signal power and noise for a time interval of 50–200 ms after stimulus presentation. Signal-to-noise ratio was calculated from the power of the averaged trials (signal power) divided by the mean power of the single trials minus the power of the average (noise power). Also, we performed a frequency analysis of the pre- and poststimulus EEG based on a factor analytical approach. Group comparisons were performed with ANCOVA.Results: As expected, a decreased signal-to-noise ratio of evoked activity was found in the schizophrenic and a non-significant trend in the schizotypal subjects and the depressive patients. We were able to show that the observed decrease is due to a reduced signal power and an increase of absolute noise power. Frequency analysis of the evoked activity revealed that normals, schizophrenics schizotypal subjects and depressive patients increased theta/delta activity between pre- and poststimulus interval to a similar extend. However, this theta/delta-augmentation does not correlate with signal power in schizophrenics. Also, normals and depressive subjects augment coherence between both temporal lobes during information processing, which is not found in schizophrenics and schizotypal subjects. In contrast, these two groups augment frontal lobe coherence, which goes along with an increase of noise.Conclusions: Reduced stimulus-induced phase-locking and bitemporal coherence of cortically evoked activity but not a failure to activate the cortex may be responsible for the observed low signal-to-noise ratio during information processing in schizophrenics. Accordingly, schizophrenics increase noise after stimulus presentation instead of building up a signal. This is discussed in the framework of the theory of stochastic resonance.

We determined whether schizophrenic patients can be reliably classified with electrophysiological tools. We developed a fully computerized classifier based on 5 minutes of EEG recording during an acoustical choice reaction time task (AMDP-module IV). We included factorized variables from the frequency domain and evoked potentials (N100/P200-complex) from central and frontal electrodes, which were preprocessed in a sample of 150 normal subjects prior to classification. We applied discriminant analyses to the electrophysiological data from depressive, schizophrenic and schizotypal subjects, most of them being unmedicated or drug-naïve. The classifier was developed on a training set (33 schizophrenics, 49 normals) and tested on an independent sample (32 schizophrenics, 49 normals). A simple three-variable classifier was found to classify schizophrencis and normals in 77% of those tested correctly. Diagnostic specificity of the classifier proved to be low as the inclusion of depressive patients (n=60) significantly decreased classification power. It was demonstrated that atypical but not typical neuroleptic drugs may influence the classification results. Correctly classified schizophrenics showed significantly more negative symptoms and slower reaction times than those schizophrenics who were misclassified as normals. In contrast, these misclassified schizophrenics showed a non-significant trend for more positive symptoms and shorter reaction times. As the correctly classified schizophrenics showed increased frontally pronounced delta-activity and decreased signal power of the N100/P200 amplitude, it was concluded that these schizophrenics show dysfunction of the frontal lobe. It is proposed that this new classifier can be useful for clinical and research applications when subtyping of schizophrenics with detection of frontal dysfunction as the aim.