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.

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.

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.

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.

The long-term tolerability of bencyclane ('Fludilat') in patients with peripheral occlusive disease: a 48-week prospective double-blind controlled study versus placebo.

In a controlled, multi-centre, double-blind trial, 75 patients with Stage II peripheral occlusive disease (Fontaine IIa) were treated with either 200 mg bencyclane twice daily or placebo over a period of 12 months. Undesired drug effects and concomitant phenomena were documented, and efficacy was evaluated. Bencyclane caused a slight, clinically negligible decrease in blood pressure. The pulse rate remained mostly unchanged, ECG and laboratory parameters showed no changes which would indicate a specific effect of the test substance. In the context of the generally low incidence of concomitant effects, patients in the bencyclane group mentioned symptoms such as insomnia, depressive mood, sweating and reduced motoricity more often than those in the placebo group. These symptoms are regarded as signs of the central nervous actions of the drug. The parameters used to assess the efficacy, i.e. the pain-free walking distance estimated by the patients and the physician's global judgment based on Ratschow's test, the palpability of the pedal pulse, the walking range and the patients' subjective statements about the incidence of chill, formication, and pain in the legs, showed a constant and statistically significant superiority of bencyclane over placebo.

The future of computer-assisted investigation of the polysomnogram: sleep microstructure.

Previous attempts at automated analysis of sleep were mainly directed towards imitating the Rechtschaffen and Kales rules (RKR) in order to save scoring time and further objectify the procedure. RKR, however, do not take into consideration the sleep microstructure of REM, stage 2, and SWS. While the microstructure of stage 2 has been analyzed in the past decade, the microstructure of REM and SWS are virtually unknown. In stage 2 the amount and distribution of spindles, K complexes, and arousal reactions have been studied. At least two types of spindles (12/s and 14/s) with different dynamics and locations have been identified. Two different shapes for K complexes have been described: one related to external sensory stimuli with similarities to evoked potentials and another one more related to sinusoidal slow wave activity seen in SWS. These two different K complex shapes have different distributions and, obviously, different functions. The authors also suggest that one should differentiate between arousal reactions and true arousals. Recent investigations suggest two types of delta waves in SWS. The more sinusoidal 1-3/s delta waves with a frontal maximum are already seen with lower amplitude in late stage 2 and increase their amplitude and incidence towards stage 3 and Stage 4. The other delta-wave type is slower (< 1/s), polymorphic, and has varying amounts of theta and higher frequency waves superimposed. During REM sleep it seems to be important to separate phases with rapid eye movements from those with none (REM sine REM), and count the amount and distribution of sawtooth activity. Background activity during REM and REM sine REM, as well as intra- and interhemispheric coherence should be analyzed separately. Only if the microstructure of the sleep EEG can be analyzed automatically using newer techniques such as transformation into wavelets and pattern classification with neuronal networks, and only if we learn more about the importance of microstructure elements, can automated sleep analysis go beyond the limited information obtained from scoring according to RKR.

Effect of lithium on the dynamics of electroencephalographic vigilance in healthy subjects.

Eleven healthy male volunteers had EEG recordings before lithium, after 10 days of lithium administration and 2 weeks after discontinuation of lithium. As postulated from previous investigations the typical lithium effect on the dynamics of electroencephalographic vigilance proved to consist of: (1) a decrease of non-alpha segments, i.e., an increase of alpha continuity or an enhancement of alpha activity; (2) an increase of the anterior/posterior ratio of absolute alpha power (AQ); (3) a decrease of the dynamic variability of this alpha anteriorization (CV-AQ). In addition the decrease of dynamic variability of alpha anteriorization was found to be associated with an increase in the amplitude of P1/N1 components of auditory evoked potentials.

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.

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.

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.

Pharmaco-electroencephalographic and clinical effects of the cholinergic substance--acetyl-L-carnitine--in patients with organic brain syndrome.

In two double-blind, placebo-controlled clinical studies of the nootropic compound acetyl-L-carnitine on the electroencephalogram (EEG) and impaired brain functions of elderly outpatients with mild to moderate cognitive decline of the organic brain syndrome, statistically significant effects could be detected after eight weeks (on the EEG), and after 12 weeks of treatment (on the physician's clinical global impression and the patient-rated level of activities of daily living). Side-effects of acetyl-L-carnitine were generally minor and overall rare. Longer treatment periods and further specifications with regard to the aetiopathology and degree of cognitive impairment are recommended for further clinical studies of this promising compound.

Some examples for the possibilities and limitations of pharmacoelectroencephalography as a method in clinical pharmacology.

Pharmacoelectroencephalography is a new methodology using clinical pharmacological research designs and the method of electroencephalography, and its parametrisation by computer analysis. Pharmacoelectroencephalography is considered to be the most sensitive method for describing drug effects on the human CNS on a functional electrophysiological level. There is an unrevoked hypothesis that all drugs effecting the CNS do reflect those effects in well designed, well conducted and well analysed pharmacoelectroencephalographical studies. On the other hand, if a systematic pharmacoelectroencephalographical study does not verify an effect, then, according to this hypothesis, the drug does not have functional effects on the CNS. The EEG however, is not a direct indicator of toxic effects on the central nervous system. Therefore, from lack of pharmacoelectroencephalographical effects it cannot be concluded that a drug has no toxic effects on the CNS. Pharmacoelectroencephalography has been used to show the efficacy of drugs on a functional CNS level, to establish dose- and time relationships of CNS active drugs, and to suggest dosage levels for therapeutic use and time intervals for their application. Furthermore, with pharmacoelectroencephalography a drug's influence on vigilance and vigilance regulation can be described, and substances can - within certain limits - be screened for their eventual psychotropic properties. It will be demonstrated that pharmacoelectroencephalography provides a sensitive and very useful method for clinical pharmacology, without which the development of new drugs is nowadays almost impossible. However, there are strict limitations for the use of this method and the interpretation of its results: The EEG is not sufficiently validated externally. It is an experimental model based on the electrical activity of the awake brain. The meaning of the changes in this activity is almost completely unknown. Although it has been possible to classify a high number of psychotropic drugs into a predetermined five drug class system on the basic of their EEG effects (19) and although certain drugs have been found whose psychotropic properties were predicted from the EEG (26), it is not possible to describe a drug's psychotropic properties by means of the EEG. The EEG indicates CNS effects, but not necessarily psychotropic properties, even though useful information can be obtained at very early stages in a drug's development, about its influence on vigilance and the organization of the brain's electrical activity.

Are nootropics a separate class of drugs? A differentiation in various models.

Psychostimulants, analeptics, and nootropics are three classes of drugs that have been used with varying success in the treatment of impaired brain functions. They all produce an excitatory and disinhibitory effect on the CNS but can be distinguished through their characteristic properties. Psychostimulants are drugs that lead to a general, but nonphysiological activation, which is followed by a phase of inhibition. Analeptics are drugs that stimulate the CNS, in particular the respiratory and circulatory centers, and which in high doses lead to convulsions. Nootropics are drugs that (in impaired brain functions) lead to a physiological activation of adaptation.

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.

Preventive treatment of migraine headache with a new isoergolenyl derivative.

In the present double-blind clinical trial an isoergolenyl derivative with periphal antiserotonin, central dopaminergic activity and alpha-increasing effect on the human EEG, lisuride hydrogen maleate, was tested against placebo in a six-month trial involving 240 patients. Lisuride in long-term administration significantly reduces the frequency of migraine attacks in comparison to placebo. Its advantages are good tolerance and minimal side-effects. It is therefore concluded that lisuride is a suitable and effective drug for the prevention of migraine.

Pilot controlled double-blind study of the hypnotic effects of zolpidem in patients with chronic 'learned' insomnia: psychometric and polysomnographic evaluation.

In a pilot double-blind trial in 21 patients with learned or idiopathic insomnia (DSM-IIIR), patients received placebo for 1 week (nights 1-7), either active (zolpidem, 10 mg) or placebo treatment for 2 weeks (nights 8-21) and then placebo for a further week (nights 22-28). Variables to measure efficacy, rebound and withdrawal were assessed daily from day 1 to day 28. Polysomnographic recordings together with sleep cycle analysis were performed on nights 7, 21 and 28. Patients treated with 10 mg zolpidem for 2 weeks had significantly improved sleep efficiency at the end of the randomised double-blind phase compared with the placebo group. Fractionated sleep-cycle analysis showed an increase in slow-wave sleep during the first 2-hour cycle after sleep onset. During the withdrawal placebo week, most of the main sleep variables remained relatively stable in the zolpidem group (nights 22-28), and deteriorated further in the placebo group. At the end of the withdrawal phase, there was a statistically significant difference between groups, in favour of the zolpidem treatment, in sleep efficiency, total sleep time, absolute and percentage of time awake, and percentage of REM sleep. REM sleep, which was normal in both groups at baseline, decreased significantly in the placebo group between nights 22 and 28 (during the withdrawal placebo week) compared with the zolpidem treatment group, and the number of periods of time awake increased. Minor subjective complaints were recorded under zolpidem and were comparable with those under placebo. Zolpidem seemed to improve some important sleep variables, when assessed both objectively and subjectively. The sleep cycle analysis suggested a possible shift of slow-wave sleep to an earlier period of the night, with a more physiological sleep structure. There was no evidence for withdrawal or rebound after stopping the 2 weeks of zolpidem treatment, but rather signs that the effect of zolpidem outlasted active treatment. The present pilot study justifies a prospective confirmatory comparison of zolpidem with benzodiazepines in an adequate number of patients and withdrawal after 6-8 weeks of treatment.