In silico fragment-based drug design using a PASS approach.

Fragment-based drug design integrates different methods to create novel ligands using fragment libraries focused on particular biological activities. Experimental approaches to the preparation of fragment libraries have some drawbacks caused by the need for target crystallization (X-ray and nuclear magnetic resonance) and careful immobilization (surface plasmon resonance). Molecular modelling (docking) requires accurate data on protein-ligand interactions, which are difficult to obtain for some proteins. The main drawbacks of QSAR application are associated with the need to collect large homogeneous datasets of chemical structures with experimentally determined self-consistent quantitative values (potency). We propose a ligand-based approach to the selection of fragments with positive contribution to biological activity, developed on the basis of the PASS algorithm. The robustness of the PASS algorithm for heterogeneous datasets has been shown earlier. PASS estimates qualitative (yes/no) prediction of biological activity spectra for over 4000 biological activities and, therefore, provides the basis for the preparation of a fragment library corresponding to multiple criteria. The algorithm for fragment selection has been validated using the fractions of intermolecular interactions calculated for known inhibitors of nine enzymes extracted from the Protein Data Bank database. The statistical significance of differences between fractions of intermolecular interactions corresponds, for several enzymes, to the estimated positive and negative contribution of fragments in enzyme inhibition.

Computer-aided prediction of QT-prolongation.

Drug-induced cardiac arrhythmia is acknowledged as a serious obstacle in successful development of new drugs. Several methods for in silico prediction of acquired long QT syndrome (LQTS) caused by the pharmacological blockade of human hERG K+ channels are discussed in literature. We propose to use the computer program PASS, which estimates the probabilities of about 3000 biological activities, not only for prediction of hERG blockade and QT-prolongation but also for the analysis of indirect mechanisms of these actions. After addition in the PASS training set of 163 compounds with data on QT-Prolongation and re-training, it was shown that accuracy of prediction was 87.1% and 81.8% for hERG blockade and QT-prolongation, respectively. Using computer program PharmaExpert we found that in the predicted biological activity spectra there was a certain correlation between the hERG blockade and some other molecular mechanisms of action. Possible role of 1-phosphatidylinositol-4-phospate 5-kinase, dimethylargininase and progesterone 11 alpha-monooxygenase inhibition in hERG blockade was discussed.

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.

Topology of EEG coherence changes may reflect differential neural network activation in cold and pain perception.

Pain perception in the brain can be analyzed by neuroimaging (PET, fMRI) and electrophysiological parameter mapping (EEG, ERP/MEG, MEF). These studies have generally been focused on the localization of cerebral activation. Whether pain can be conceptualized as localized function or best be understood by distributed function is important to the theory of human pain processing in the brain. Here, we report that cold and pain perception in the brain is characterized by webs of EEG coherence changes which may reflect coupling or de-coupling of different cortical areas during cold and pain processing. EEG was recorded during cold and pain perception (right hand immersion in 15 degrees C cool-water vs. 0.3 degrees C ice-water for 3 min.) with eyes opened. Subjects rated the cold perception at 2.3 (cool to cold, but no pain) and the pain perception at 6.7 (moderate-strong pain) in a 1-10 scale. The obtained EEG spectral parameters were compared with the corresponding parameters of the resting baseline using paired Wilcoxon tests in the sense of statistical filters to depict those differences which differ clearly from changes by chance. The results were presented in probability maps. The EEG results indicated highly differential coherence networks between cold and pain perception. The cold perception was characterized as decreased coherence in the theta band mainly between frontal electrodes and increased interhemispheric coherence in the alpha range mainly between central and frontal positions. During pain perception almost no coherence changes in the theta band were observed, but great coherence increase in the delta band between central, parietal and frontal electrodes. The network of coherence changes in the alpha band showed strong involvement of electrode C3 concerning coherence increases with frontal positions. In the beta-1 band coherence increase within the left hemisphere was much more pronounced during pain than during cold. The differential characteristics of EEG coherence changes based on neural networks and their spatial organization in the neocortex indicate the distributed brain processing between cold and pain perception in man. This study may contribute to our understanding of the large scale neural networks in cognition based on neurophysiological binding hypothesis and network connections of neural ensembles.

The possible meaning of the upper and lower alpha frequency ranges for cognitive and creative tasks.

This study is aimed at verifying the functional independence of two frequency bands within the alpha range. It is based on experiments that examined the role of these two hands with regard to the amount of local electrogenesis (amplitude) and the cooperation of brain areas (coherence) in mental tasks concerning: (1) visual perception and imagery; (2) listening to and composing music; (3) verbal and visual creativity; and (4) aspects of mood. In all experiments EEG were recorded for at least 1 min during each task, separated one from another by at rest periods of at least equal lengths. EEG electrodes were pasted according to the 10/20 system (averaged ear lobes as reference). After FFT power was calculated for all 19 electrodes, coherence was estimated for all possible electrode pairs (i.e. 171). This was done for six frequency ranges between 1.5 and 31.5 Hz, the alpha range having been divided into two (7.5-9 Hz and 9.5-12.5 Hz). The spectral parameters obtained during each task were compared with those of the merged EEG at rest, significant changes (P < or = 0.01-P < or = 0.05) were entered into schematic maps of the brain. Generally, fewer differences were found for amplitude than for coherence. In all four tasks concerning visual perception the clearest differences were found in single person studies. But also in group studies more or less distinct differences were found between alpha 1 and 2. Also in the series with music the two alpha bands did not behave uniformly, nor were uniform features found in the two series of musically trained and untrained subjects. Distinct discrepancies were also found in a verbal and visual imagery task. With respect to mood, only elevated mood was correlated with a decrease of coherence in alpha 2 and an increase of amplitude in alpha 1. This study though hinting at a different functional significance of these two alpha bands, however, does not allow to draw any conclusions as to their distinct functional meanings. Generally, the long-term coherence changes observed under these different mental tasks support the idea that part of information processing in the brain is reflected by the EEG. Structural peculiarities and microelectrode recordings of the cortex support this conclusion.

The reflection of cognitive tasks in EEG and MRI and a method of its visualization.

Up until recently, neurology was dominated by localisatory thinking. Language and other so-called "centers" were considered to be centers of command controlling the respective functions. Today, there is general agreement that, instead, for every brain function numerous brain regions must act together. For the exploration of these manifold topographic cooperations produced by cognitive tasks, coherence of long-term EEG periods proved to be a proficient parameter for the representation of functionally essential connections. Because of the unequivocal meaningfulness of absolute coherence values, instead, only the signs of significant differences between coherence values during cognitive tasks and periods of EEG at rest before and after the task were considered for all possible electrode pairings and charted on schematic maps of the brain. In addition, the signs of significant changes of amplitude were entered. This procedure was performed for each of 6 frequency bands and for the 19 electrodes of the 10/20 system, thus yielding 171 possible plus or minus values for coherence and 19 for amplitude, respectively. The positions of the electrodes were marked by an MRI contrast medium. After the EEG, MRI examination was performed. The MRI data were segmented and the cortex was mapped onto a plane using a method similar to cartography. The exact electrode positions are registered from a similarly obtained map of the scalp and the electrode position pattern is used as basis for the coherence graphs. A detailed map of the cortex based on the segmented MRI data with the electrode positions marked is provided as a reference enabling allocation of the electrodes to the cortical structures. The usefulness of this procedure is demonstrated with a single subject by means of different cognitive tasks including musical thinking.

EEG aspects of mentally playing an instrument.

This pilot study examines the possibility to detect activities of SMA by means of EEG coherence analysis in a female professional violoncellist. The proband was asked, for 5 min each, to listen to a piece of music (she knew by heart), to imagine playing this piece and to imagine playing scales. The experiment was repeated after 5 days. Consistent significant coherence changes with respect to the averaged EEG at rest were plotted as probability maps. For each of these three tasks different coherence patterns emerged. Among the electrodes next to SMA, Fz was most involved while playing scales, less while imagining playing the same piece and still less while just listening to it.

Calculation of event-related coherence--a new method to study short-lasting coupling between brain areas.

This article deals with the estimation of event-related coherence (ERCoh) and its application to the planning and execution of self-paced index finger movement. ERCoh estimation complements the event-related desynchronization (ERD) measurements of rhythms within the alpha band. ERCoh yields information of the functional relationships between different brain areas as a function of time. The time resolution is 125 msec. Before movement onset a contralateral ERCoh increase was found between premotor and motor areas. This coherence increase was accompanied by an ERCoh decrease in parallel to the ERD over the contralateral centro-temporal areas. During movement, the ERD became bilaterally symmetrical. Simultaneously, interhemispheric coherence between contralateral and ipsilateral sensori-motor areas increased.

Brain electrical mechanisms of bilingual speech management: an initial investigation.

This exploratory study deals with EEG changes in 3 professional interpreters while mentally interpreting from their mother language into foreign languages and vice versa. EEGs were recorded while interpreting and compared with the periods at rest between these periods of interpreting. Significant (P < 0.05) changes of coherence between all pairs of electrodes with respect to the averaged EEG at rest were computed for 5 frequency bands between 4 and 32 Hz. The verbal tasks were control-compared with comparable coherence measures for mental arithmetic and listening to music. Interindividual differences predominated, but certain common characteristics of the EEG measures were also found. The temporal regions were most involved in interpreting and particularly in the uppermost beta band (24-32 Hz). More coherence increases--particularly in the right hemisphere--were found while interpreting into the foreign than into the native language. Coherence changes were found to accumulate in certain regions of the scalp as pivots or focal areas which apparently have functional significance for the task in question as nodal points of information exchange and/or transfer. Such pivots were found in T3 more than in T4 (in the right-handers) and vice versa in a left-hander. Theta and alpha bands behaved differently and did not show such clear-cut differences. The results during mental arithmetic and listening to music were different from the ones while interpreting. The results give support to the conception of the cortex as a network serving the greatest possible divergence and convergence of signals.