W.M. Herrmann

Reduced Event-Related Current Density in the Anterior Cingulate Cortex in Schizophrenia

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).

Schizophrenia: reduced signal-to-noise ratio and impaired phase-locking during information processing.

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-naïve) 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.

Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia.

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.

Artifact processing in computerized analysis of sleep EEG - a review.

Quantitative analysis of sleep EEG data can provide valuable additional information in sleep research. However, analysis of data contaminated by artifacts can lead to spurious results. Thus, the first step in realizing an automatic sleep analysis system is the implementation of a reliable and valid artifact processing strategy. This strategy should include: (1) high-quality recording techniques in order to minimize the occurrence of avoidable artifacts (e.g. technical artifacts); (2) artifact minimization procedures in order to minimize the loss of data by estimating the contribution of different artifacts in the EEG recordings, thus allowing the calculation of the ‘corrected’ EEG (e.g. ocular and ECG interference), and finally (3) artifact identification procedures in order to define epochs contaminated by remaining artifacts (e.g. movement and muscle artifacts). Therefore, after a short description of the types of artifacts in the sleep EEG and some typical examples obtained in different sleep stages, artifact minimization and identification procedures will be reviewed.

P300 and LORETA : comparison of normal subjects and schizophrenic patients

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.

A new concept for melatonin deficit: on pineal calcification and melatonin excretion.

Even though exogenous melatonin has proven to influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin replacement therapy. In this manuscript, we present a new concept towards a definition of a melatonin deficit. The purpose of the study was to introduce a marker for an intra-individual decrease in melatonin production. Therefore, we developed a method to quantify the degree of pineal calcification (DOC) using cranial computed tomography. Combining pineal DOC with the organss size, we estimated the uncalcified pineal gland volume. This estimation was positively and significantly associated with 6-sulfatoxymelatonin (aMT6s), collected over 24 hours in urine, in 26 subjects. Data yielded evidence that the decline in aMT6s excretion with age can be sufficiently explained by an increased pineal calcification. These results suggest that DOC might be useful as an indicator of an intra-individual, decreased capability of the pineal gland to produce melatonin. DOC might prove to be a response-marker for melatonin replacement therapy and a vulnerability marker of the circadian timing system.

A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease.

Two doses of idebenone were studied in a prospective, randomized, double-blind, placebo-controlled multicentre study in patients suffering from dementia of the Alzheimer type (DAT) of mild to moderate degree. Diagnosis was based on DSM-III-R (primary degenerative dementia) and NINCDS-ADRDA criteria (probable Alzheimers disease). A total of 300 patients were randomized to either placebo, idebenone 30 mg t.i.d. or 90 mg t.i.d. (n = 100, each) and treated for 6 months. The primary outcome measure was the total score of the Alzheimers Disease Assessment Scale (ADAS-Total) at month 6. Secondary outcome measures were the ADAS cognitive (ADAS-Cog) and noncognitive scores (ADAS-Noncog), the clinical global response (CGI-Improvement), the MMSE, the Digit Symbol Substitution test (DSS) and several scales for the assessment of daily activities (the self- and observer-rating scales NAA and NAB of the Nuremberg Age Inventory NAI and Greenes Assessment). Safety parameters were adverse events, vital signs, ECG and clinical laboratory parameters. Clinical and psychometric evaluations were performed at baseline, and after 1, 3 and 6 months of treatment. After month 6 idebenone 90 mg t.i.d. showed statistically significant improvement in the primary efficacy variable ADAS-Total and in ADAS-Cog. An analysis of therapy responders performed for 3 outcome measures (CGI-global improvement, ADAS-Cog, ADAS-Noncog), selected to represent different domains of assessment, revealed significant superiority of idebenone 90 mg t.i.d. with respect to placebo in each of the 3 variables and in the concordance of responses across the 3 measures. Exploratory results for a subgroup of patients (ADAS-Total > or = 20) showed dose-related superiority of idebenone additionally on ADAS-Noncog and the CGI-Improvement scale. Safety results were inconspicuous for all assessments. The study results demonstrate the efficacy and safety of idebenone in the treatment of DAT patients.

Time-of-day variations of indicators of attention: performance, physiologic parameters, and self-assessment of sleepiness

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 Friedmans 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 Faculty Test, and CFF load on the second factor. The variables that load primarily on factor 1 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 can be attributed to underlying circadian and homeostatic factors.

Cortical hypoactivation during resting EEG in schizophrenics but not in depressives and schizotypal subjects as revealed by low resolution electromagnetic tomography (LORETA)

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.

Cortical activation, signal-to-noise ratio and stochastic resonance during information processing in man

OBJECTIVES The goal of this study was to determine the relation between EEG, event-related potentials and information processing as measured by an acoustical choice reaction time task. In particular, we wanted to find out to what extent reaction-time performance is related to the pre-stimulus EEG activity (frequency domain) and the magnitude of signal power as well as noise power (stimulus-uncorrelated activity) after the tones (time domain). MATERIALS AND METHODS For parametrization, EEG-activity was factorized across pre-defined frequency bands and 19 electrode positions, applying spectral power and coherence analysis. Signal power was estimated by calculating the mean power of the evoked single sweeps. Noise power was computed by subtracting the latter minus the power of the average evoked potential. We investigated 254 healthy subjects who had to perform an acoustical choice reaction task during running EEG. RESULTS In the frequency domain, it was found that high frontally pronounced delta-power in the pre-stimulus EEG correlates with fast reaction-time performance, which was regarded as the expression of a readiness potential in the frequency domain, reflecting increased cortical activation. In the time domain, fast reaction times were found to be correlated with the amplitude of the event-related potential N100 as well as with the signal power and signal-to-noise ratio of the evoked activity. This result pointed to the frequently described relation between evoked signals and information processing. In accordance with the theory of stochastic resonance, we also found a positive correlation between the magnitude of noise power after the stimulus and reaction-time performance. Besides, noise power was found to be positively correlated with pre-stimulus cortical activation (mainly in the delta and alphal frequency band), whereas no relation was found between pre-stimulus EEG and the signal power of the event-related activity, except for a weak relation to the alpha2 power. CONCLUSION Our findings support the notion that information processing is not only dependent on signal strength but also on a certain amount of basic noise, reflecting the overall energy state of the brain.