Electrophysiological subtypes of psychotic states.

OBJECTIVE: This research sought neurobiological features common to psychotic states displayed by patients with different clinical diagnoses. METHOD: Cluster analysis with quantitative electroencephalographic (QEEG) variables was used to subtype drug-naïve, non-medicated, and medicated schizophrenic, depressed and alcoholic patients with psychotic symptoms, from the USA and Germany. QEEG source localization brain images were computed for each cluster. RESULTS: Psychotic patients with schizophrenia, depression and alcoholism, and drug- naïve schizophrenic patients, were distributed among six clusters. QEEG images revealed one set of brain regions differentially upregulated in each cluster and another group of structures downregulated in the same way in every cluster. CONCLUSION: Subtypes previously found among 94 schizophrenic patients were replicated in a sample of 390 non-schizophrenic as well as schizophrenic psychotics, and displayed common neurobiological abnormalities. Collaborative longitudinal studies using these economical methods might improve differential understanding and treatment of patients based upon these features rather than clinical symptoms.

Comparison of the amplitude/intensity function of the auditory evoked N1m and N1 components.

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.

Genetic programming approach for the optimal selection of combinations of neuronal networks to classify sleep stages by QUISI.

The usefulness of a new way to optimize the cooperation of trained neural networks for automatic one-channel sleep stage analysis using genetic programming and performance evaluation by including the interrater reliability are the focus of our paper. The one-channel sleep classification could be significantly improved by the optimization. The software tool HENNE, with its genetic programming compartment was developed for this purpose. The tool has proved to be useful for searching for optima in difficult goal surfaces. To contribute to the general discussion about the benefit of the automatic one-channel sleep analysis on the basis of the frontal site, we tried to evaluate our results before the background of the interrater variability. Comparing the kappa statistics of different independent studies with our results, we concluded that there are no dramatic differences as a rule and that QUISI is a useful device as a presleep laboratory and ambulatory diagnostic tool.

Time-of-day variations in different measures of sleepiness (MSLT, pupillography, and SSS) and their interrelations.

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.

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.

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).

Is the EEG helpful in diagnosing and monitoring lithium intoxication? A case report and review of the literature.

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.

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 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 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.

Frontal dysfunction in schizophrenia--a new electrophysiological classifier for research and clinical applications.

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-naive. 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 schizophrenics 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.

Cyclandelate in the treatment of patients with mild to moderate primary degenerative dementia of the Alzheimer type or vascular dementia: experience from a placebo controlled multi-center study.

A 24-week, double-blind, multi-center, randomised parallel group study compared the efficacy and safety of 800 mg bid cyclandelate with placebo in patients with mild to moderate dementia of primary degenerative or vascular origin. A total of 196 patients entered the study, 147 patients completed treatment in adherence with the protocol. Primary outcome measures were the cognitive score of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the subscale Instrumental Activities of Daily Living of the Nurses' Observation Scale for Geriatric Patients (NOSGER-IADL) and the Clinical Global Impressions of Change (CGI-C). Safety assessments included adverse events, vital signs, ECG and clinical laboratory parameters. The primary efficacy results based on a multi-level responder analysis including ADAS-Cog, NOSGER-IADL and CGI-C failed to demonstrate statistical superiority of cyclandelate in comparison to placebo. The direction of changes favored cyclandelate in each of the variables, but the differences to placebo were small and varied considerably between patients and centers. Retrospective exploratory analyses suggested that efficacy of cyclandelate might be dependent on the severity of the disease. The treatment effects in favor of cyclandelate were statistically significant in the subgroup of moderately impaired patients (MMSE at baseline <18) for ADAS-Cog (delta = -4.0 points, p = 0.015) and CGI-C (delta = -0.4 points, p = 0.043) but not for NOSGER-IADL (delta = -1.6 points, p = 0.059). When patients were stepwise selected for the severity of the disease according to ADAS-Cog at baseline (>15, >20, >25 points), statistical significance was reached for ADAS-Cog and NOSGER-IADL beginning with the step ADAS-Cog >20 points: delta ADAS-Cog = -3.9 points, p = 0.044; delta NOSGER-IADL = -1.0, p = 0.023. The treatment differences increased further with the step ADAS-Cog >25 points: delta ADAS-Cog = -7.0 points, p = 0.008; delta NOSGER-IADL = -1.7, p = 0.003. Treatment differences in CGI-C increased marginally with the stepwise selection but did not reach statistical significance. The drug was safe and well tolerated.

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.

Sleep-wake cycle, sleep-related disturbances, and sleep disorders: a chronobiological approach.

There is convincing evidence that the functions of sleep include restoration of brain energy storage and memory consolidation. The circadian timing system (CTS) is involved in the daily variation of almost any physiological and psychological variable evaluated thus far. Disturbances of the CTS can be clinically observed by their influence on the sleep-wake cycle, hormones, body temperature, and locomotor activity. This article reviews the basic mechanisms of circadian rhythm sleep disturbances, names the applicable diagnostic tools and specific therapeutic strategies, and thereby hints at the impact of circadian rhythm sleep disturbance on psychiatric disorders, especially disorders of affect and cognition. In light of the preventive, diagnostic, and therapeutic tools now available, a new round of chronobiological studies in psychiatry seems justified, promising, and necessary.

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.

Pharmacokinetics of thymosin alpha1 after subcutaneous injection of three different formulations in healthy volunteers.

OBJECTIVE: Thymosin alpha1, an immunomodulatory endogenous peptide, has been shown to be effective in the treatment of chronic hepatitis B and C. In this study, single- and 5-day multiple-dose pharmacokinetics were characterized in nine Caucasian volunteers after subcutaneous administration of 900 microg/m2 thymosin alpha1. METHODS: Using a randomized, 3-way crossover design three available drug formulations were compared: Zadaxin (SciClone), Timosina (Sclavo), and Thymosin alpha1 (Tal-HLR; Hoffmann La Roche). AUC, Cmax, t(max), t(1/2), Cl/f, and the volume of distribution, V(Z)/f, were derived by model-independent methods. RESULTS: Endogenous serum concentrations were below the limit of quantification (0.10 microg/l) of the enzyme-linked immunosorbent assay method in most subjects. Thymosin alpha1 was well absorbed with a mean t(max) between 1-2 hours from all galenic formulations. Cmax concentrations of 30 to 80 microg/l and AUC(0-infinity) from 95 to 267 microg x h/l did not differ between single- and multiple-dose administration of all drugs. This apparent lack of accumulation was supported by the short elimination half-life of less than 3 hours. As indicated by a V(Z)/f in the range of 30-40 l, thymosin alpha1 appears to distribute within the extracellular volume. AUC and Cmax were similar for Zadaxin and T alpha1-HLR, but higher after administration of Timosina. CONCLUSION: Thymosin alpha1 kinetics from this study are comparable to those previously obtained in Japanese volunteers or cancer patients, but may be influenced by the drug formulation used.

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 organs's 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.

Electrophysiology in neuropsychiatric research: a network perspective.

A growing number of anatomic and physiologic studies have shown that parallel sensory and motor information processing occurs in multiple cortical areas. These findings challenge the traditional model of brain processing, which states that the brain is a collection of physically discrete processing modules that pass information to each other by neuronal impulses in a stepwise manner. New concepts based on neural network models suggest that the brain is a dynamically shifting collection of interpenetrating, distributed, and transient neural networks. Neither of these models is necessarily mutually exclusive, but each gives different perspectives on the brain that might be complementary. Each model has its own research methodology, with functional magnetic resonance imaging supporting notions of modular processing, and electrophysiology (eg, electroencephalography) emphasizing the network model. These two technologies might be combined fruitfully in the near future to provide us with a better understanding of the brain. However, this common enterprise can succeed only when the inherent limitations and advantages of both models and technologies are known. After a general introduction about electrophysiology as a research tool and its relation to the network model, several practical examples are given on the generation of pathophysiologic models and disease classification, intermediate phenotyping for genetic investigations, and pharmacodynamic modeling. Finally, proposals are made about how to integrate electrophysiology and neuroimaging methods.

On pineal calcification and its relation to subjective sleep perception: a hypothesis-driven pilot study.

We classified the degree of pineal calcification (DOC) into seven groups using cranial Computer Tomography (cCT) and then correlated pineal DOC to chronic subjective sleep-related disturbances as measured by a sleep questionnaire in 36 patients. Analysed by logistic regression models, age and sex were not, but higher pineal DOC was significantly associated with the presence of daytime tiredness (OR = 4.15, 95% CI: 1.63, 10.54) and sleep disturbance (OR = 1.74, 95% CI: 1.10, 2.74). This study provides initial confirmation of the hypothesis that the increasing degree of pineal calcification (DOC) might indicate a decrease of melatonin production, which consecutively might lead to a disturbed circadian rhythmicity in the sleep-wake cycle, with the principal symptom being daytime tiredness.

Quantitative EEG (QEEG) predicts relapse in patients with chronic alcoholism and points to a frontally pronounced cerebral disturbance.

The capability of predicting relapse in chronic alcoholism using quantitative EEG was investigated. For this purpose, 78 in-patients with alcoholism underwent EEG recordings (eyes closed) 7 days after the beginning of detoxification. Additionally, other clinical evaluations were carried out. After discharge from hospital, patients were regularly re-evaluated for the duration of 3 months in order to determine whether they relapsed or abstained from alcohol during this time. For classification of the two diagnostic subgroups (relapsers vs. abstainers), multivariate discriminant analysis as well as artificial neural network technology has been applied. Correct classification of patients' EEGs was achieved in 83-85% and thus outperformed classification with clinical variables considerably. Furthermore, artificial neural networks (ANN) improved classification results when compared with discriminant analysis. It was found that, in comparison to abstainers, relapsers had EEGs that were more desynchronized over frontal areas, which was interpreted as a functional disturbance of the prefrontal cortex.

[Antihypertensive action of various talinolol dosages after four week's treatment in comparison with placebo]. / Antihypertensive Wirksamkeit verschiedener Talinolol-Dosierungen nach vierwöchiger Behandlung im Vergleich zu Plazebo.

The dose dependence of the antihypertensive effect of the beta 1 selective blocker talinolol (CAS 57460-41-0, Cordanum) was investigated in 97 essential hypertensive patients (mild to moderate) using the ambulatory blood pressure monitoring (ABPM) in a single-centre, double-blind, randomized parallel-group study. After 4 weeks of treatment a comparison was made between the once daily administered doses of 50, 100 and 200 mg as well as with placebo. The primary parameter was the mean diastolic blood pressure between 8.00 and 22.00 (dTMW). Furthermore, the duration of action of the once daily administration of 200 mg talinolol was compared with the twice daily application of 100 mg each. With regard to dTMW an increasing antihypertensive effect was determined for the dosage step from 50 mg to 100 mg talinolol/d. No further increase in the blood pressure lowering effect was observed with 200 mg talinolol/d. The highest frequency of therapy responders was found in the 100 mg group with 72.2%. Moreover it could be demonstrated, that within the dosage range of 1 x 100-200 mg Talinolol/d a significant and 24 h lasting reduction of blood pressure and pulse rate was achieved, including the early morning period. There were no differences between the blood pressure profile of the 200 mg group and the 2 x 100 mg group at the end of the 4 weeks treatment. All talinolol dosages investigated in this study were proved to be safe and well tolerated. The observed complaints classified as adverse drug reactions represented typical side effects of beta-blockers of mild to moderate intensity. It can be concluded from the results that the once daily intake of talinolol in the dosage range of 100-200 mg/d shows a reliable efficacy in the treatment of essential hypertension accompanied by a noncritical safety profile.