NeuMonD: a tool for the development of new indicators of anaesthetic effect.

Electroencephalogram (EEG) signals and auditory evoked potentials (AEPs) have been suggested as a measure of depth of anaesthesia, because they reflect activity of the main target organ of anaesthesia, the brain. The online signal processing module NeuMonD is part of a PC-based development platform for monitoring "depth" of anaesthesia using EEG and AEP data. NeuMonD allows collection of signals from different clinical monitors, and calculation and simultaneous visualisation of several potentially useful parameters indicating "depth" of anaesthesia using different signal processing methods. The main advantage of NeuMonD is the possibility of early evaluation of the performance of parameters or indicators by the anaesthetist in the clinical environment which may accelerate the process of developing new, multiparametric indicators of anaesthetic "depth".     

Optimal (‘Wiener’) digital filtering of auditory evoked potentials: use of coherence estimates

Auditory evoked potentials (AEPs) to 40 Hz clicks and amplitude-modulated 500 Hz tones in human subjects were digitally filtered using an optimal (‘Wiener’) filter uniquely determined for each AEP. Use of coherence functions to compute coefficients appropriate for filtering grand average AEPs or subsets such as split-half averages is described. Wiener-filtered AEPs correlated better than unfiltered AEPs with split-half replicates and with references AEPs (obtained with long data collection periods). Visual detection thresholds were lower (more sensitive) for the Wiener-filtered AEPs, but not as low as objectively determined thresholds using coherence values.     

Changes in components of the auditory long-latency evoked potentials at different stages of the slow-wave sleep

In accordance with the present views, during sleep, analysis of external stimuli continues at the subconscious level, because the need to estimate the biological significance of external stimuli in order to maintain a flexible contact of a sleeping subject with the environment persists during sleep. It is known that new components of the auditory evoked potentials (AEP) appear as sleep deepens. However, the common procedure of analysis of event-related potentials averaged for a group of subjects has some drawbacks because of the interindividual variability of the event-related potentials. Therefore, an additional analysis of the interindividual variability of the AEP shape and component structure can simplify the detection of individual components of group-averaged AEP at different stages of the slow-wave sleep. The AEPs were recorded in healthy volunteers (n = 26) during falling asleep in the evening from eight EEG derivations (F3, F4, C3, C4, P3, P4, O1, O2) in reference to a linked mastoid electrode. Computer-generated sound stimuli (50 ms-pulses with the frequency of 1000 Hz, 60 dB HL) were presented binaurally through earphones with interstimulus intervals of 20-40 s. Selective summation of AEPs for all the subjects was performed for each stage of the slow-wave sleep individually for each of the eight derivations. It was shown that the account made for interindividual variability of the AEP shape facilitated the identification of individual components of the group-averaged AEP typical of wakefulness (P1, N1, P300) and those which appeared during sleep onset and at different stages of the slow-wave sleep (P2, N350, P450, N550, N900).     

Changes in EEG power, acoustic evoked potentials and heart rate after mildly arousing non-acoustic priming stimuli in carp (Cyprinus carpio).

1. Changes in EEG power spectrum of carp to a priming non-acoustic stimulus followed by acoustic clicks were compared to those due to acoustic clicks delivered alone. Recordings were made from the telencephalon, midbrain and medulla. Acoustic evoked potentials (AEPs) to the clicks were also recorded. 2. EEG power changes to non-acoustic stimuli occurred over the whole 1-40 Hz frequency range and were regionally specific and consistent. 3. The changes in the EEG midfrequency 12-24 Hz power spectrum to non-acoustic stimuli were significantly correlated with changes in the AEP to subsequent clicks. An elevated medullary AEP amplitude and reduced duration were correlated with increased medullary EEG power and increased midbrain AEP duration. 4. Telencephalic EEG power changes were inversely related to changes in medullary and midbrain AEP amplitude.     

EMD-based EEG signal enhancement for auditory evoked potential recovery under high stimulus-rate paradigm

Short inter-stimulus interval (ISI) is one inherent characteristic of the high stimulus-rate (HSR) paradigms for studying auditory evoked potentials (AEPs). At short ISIs, the AEPs to adjacent stimuli overlap. To resolve the AEP to a specific stimulus requires an inverse process of overlapping. Inverse filtering (also called as deconvolution) has been commonly employed to achieve this goal. However, the resulted signal may be severely distorted as inverse filtering can substantially amplify such undesired components as noises and artifacts in the raw EEG recordings. In practice, even if care be taken to obtain quality EEGs, noises and artifacts are unavoidable. It is thus critical to remove or at least supress these undesired components for studies using HSR paradigms. In this paper, we propose a systematic approach to EEG signal enhancement based on empirical mode decomposition (EMD) and threshold filtering/rejection. Using synthetic and real data, we test the effectiveness of our approach. Results for both types of data consistently demonstrate that our methods can significantly improve the quality of recovered AEPs, according to visual inspection and SNRs estimated using two metrics.     

Novel Families of Archaeo-Eukaryotic Primases Associated with Mobile Genetic Elements of Bacteria and Archaea

Cellular organisms in different domains of life employ structurally unrelated, non-homologous DNA primases for synthesis of a primer for DNA replication. Archaea and eukaryotes encode enzymes of the archaeo-eukaryotic primase (AEP) superfamily, whereas bacteria uniformly use primases of the DnaG family. However, AEP genes are widespread in bacterial genomes raising questions regarding their provenance and function. Here, using an archaeal primase–polymerase PolpTN2 encoded by pTN2 plasmid as a seed for sequence similarity searches, we recovered over 800 AEP homologs from bacteria belonging to 12 highly diverse phyla. These sequences formed a supergroup, PrimPol-PV1, and could be classified into five novel AEP families which are characterized by a conserved motif containing an arginine residue likely to be involved in nucleotide binding. Functional assays confirm the essentiality of this motif for catalytic activity of the PolpTN2 primase–polymerase. Further analyses showed that bacterial AEPs display a range of domain organizations and uncovered several candidates for novel families of helicases. Furthermore, sequence and structure comparisons suggest that PriCT-1 and PriCT-2 domains frequently fused to the AEP domains are related to each other as well as to the non-catalytic, large subunit of archaeal and eukaryotic primases, and to the recently discovered PriX subunit of archaeal primases. Finally, genomic neighborhood analysis indicates that the identified AEPs encoded in bacterial genomes are nearly exclusively associated with highly diverse integrated mobile genetic elements, including integrative conjugative plasmids and prophages.     

Hearing sensation levels of emitted biosonar clicks in an echolocating Atlantic bottlenose dolphin

Emitted biosonar clicks and auditory evoked potential (AEP) responses triggered by the clicks were synchronously recorded during echolocation in an Atlantic bottlenose dolphin (Tursiops truncatus) trained to wear suction-cup EEG electrodes and to detect targets by echolocation. Three targets with target strengths of -34, -28, and -22 dB were used at distances of 2 to 6.5 m for each target. The AEP responses were sorted according to the corresponding emitted click source levels in 5-dB bins and averaged within each bin to extract biosonar click-related AEPs from noise. The AEP amplitudes were measured peak-to-peak and plotted as a function of click source levels for each target type, distance, and target-present or target-absent condition. Hearing sensation levels of the biosonar clicks were evaluated by comparing the functions of the biosonar click-related AEP amplitude-versus-click source level to a function of external (in free field) click-related AEP amplitude-versus-click sound pressure level. The results indicated that the dolphin's hearing sensation levels to her own biosonar clicks were equal to that of external clicks with sound pressure levels 16 to 36 dB lower than the biosonar click source levels, varying with target type, distance, and condition. These data may be assumed to indicate that the bottlenose dolphin possesses effective protection mechanisms to isolate the self-produced intense biosonar beam from the animal's ears during echolocation.     

Objective detection of 40 Hz auditory evoked potentials: phase coherence vs. magnitude-squared coherence

The relative performance of phase coherence (PC) and magnitude-squared coherence (MSC) for detection of steady-state evoked potentials was studied using 40 Hz auditory evoked potentials (AEPs) in 10 normal human subjects. In addition, simulation experiments were carried out to determine the effects of signal amplitude and phase variability on detection performance. All simulations showed MSC performance to be better than PC performance, with further improvements when MSC was supplemented with weighted averaging. However, human 40 Hz AEP data showed essentially identical detection performance for PC and MSC, with or without weighted averaging. These data support a “phase aggregation” model (at least near threshold) over the more usual model in which an AEP signal is added to a stationary noise. Human data collected under “no-stimulus” conditions agree well with theoretical distributions for both PC and MSC. For equal test time, long analysis periods (with less averaging) yielded equal performance to short analysis periods (with more averaging), for both PC and MSC.     

EEG parameters and their combination as indicators of depth of anaesthesia.

EEG parameters for assessment of depth of anaesthesia are typically based on different signal processing methods, such as spectral and complexity analysis. In the present study, the parameters investigated (WSMF, qWSMF, approximate entropy and Lempel-Ziv complexity) do not correlate monotonically to depth of anaesthesia. To obtain this correlation, parameters are combined based on fuzzy inference, whereby each parameter only operates in a specific range. Fuzzy inference seems to be a suitable approach, as the indicator designed separates wakefulness from unconsciousness as well as the best single parameter does and correlates to the depth of anaesthesia.     

The macrocyclizing protease butelase 1 remains autocatalytic and reveals the structural basis for ligase activity

Plant asparaginyl endopeptidases (AEPs) are expressed as inactive zymogens that perform maturation of seed storage protein upon cleavage‐dependent autoactivation in the low‐pH environment of storage vacuoles. The AEPs have attracted attention for their macrocyclization reactions, and have been classified as cleavage or ligation specialists. However, we have recently shown that the ability of AEPs to produce either cyclic or acyclic products can be altered by mutations to the active site region, and that several AEPs are capable of macrocyclization given favorable pH conditions. One AEP extracted from Clitoria ternatea seeds (butelase 1) is classified as a ligase rather than a protease, presenting an opportunity to test for loss of cleavage activity. Here, making recombinant butelase 1 and rescuing an Arabidopsis thaliana mutant lacking AEP, we show that butelase 1 retains cleavage functions in vitro and in vivo. The in vivo rescue was incomplete, consistent with some trade‐off for butelase 1 specialization toward macrocyclization. Its crystal structure showed an active site with only subtle differences from cleaving AEPs, suggesting the many differences in its peptide‐binding region are the source of its efficient macrocyclization. All considered, it seems that either butelase 1 has not fully specialized or a requirement for autocatalytic cleavage is an evolutionary constraint upon macrocyclizing AEPs.     

Changes in early acoustic-evoked potentials by mildly arousing priming stimuli in carp (Cyprinus carpio).

1. Averaged acoustic-evoked potential (AEPs) in the medulla and midbrain were recorded, as were changes in heart rate, indicating arousal, to a previous non-acoustic priming stimulus. 2. Useful AEP measures were amplitude of the early biphasic wave (less than 10 msec) in medulla and amplitude and duration of this wave in midbrain. 3. There was a negative regression of heart rate and medullary AEP amplitude especially evident for a 2 sec light stimulus. Decreased AEP amplitude in both regions was induced by water movement and an increase in midbrain AEP duration by the tactile stimulus. 4. Arousal effects even on these early AEP measures are specific to the form of arousing stimulus.     

Otoacoustic emissions,auditory evoked potentials and self-reported gender in people affected by disorders of sex development (DSD)

Both otoacoustic emissions (OAEs) and auditory evoked potentials (AEPs) are sexually dimorphic, and both are believed to be influenced by prenatal androgen exposure. OAEs and AEPs were collected from people affected by 1 of 3 categories of disorders of sex development (DSD) — (1) women with complete androgen insensitivity syndrome (CAIS); (2) women with congenital adrenal hyperplasia (CAH); and (3) individuals with 46,XY DSD including prenatal androgen exposure who developed a male gender despite initial rearing as females (men with DSD). Gender identity (GI) and role (GR) were measured both retrospectively and at the time of study participation, using standardized questionnaires. The main objective of this study was to determine if patterns of OAEs and AEPs correlate with gender in people affected by DSD and in controls. A second objective was to assess if OAE and AEP patterns differed according to degrees of prenatal androgen exposure across groups. Control males, men with DSD, and women with CAH produced fewer spontaneous OAEs (SOAEs) – the male-typical pattern – than control females and women with CAIS. Additionally, the number of SOAEs produced correlated with gender development across all groups tested. Although some sex differences in AEPs were observed between control males and females, AEP measures did not correlate with gender development, nor did they vary according to degrees of prenatal androgen exposure, among people with DSD. Thus, OAEs, but not AEPs, may prove useful as bioassays for assessing early brain exposure to androgens and predicting gender development in people with DSD.     

Cortical evoked potentials as indicators of auditory-visual cross-modal association in young adults

Auditory evoked potentials (AEPs) were studied from scalp locations Cz and Oz on 37 adults aged 20-22 years during sensori-sensorial association of a weak sound (S) and a strong flash of light (L). After sound alone repetition (habituation), S-L association modified AEP: first, it caused a generalized orienting response expressed as increasing of Cz and Oz amplitude AEPs. Then, this pattern gave way to an activation limited to the Oz lead: the increase of amplitude was then concomitant with shortened latencies when compared to sound-alone-habituated responses. Inter-individual differences were observed since these occipital modifications were recorded only on 26 subjects. The other 11 subjects did not exhibit any occipital modifications following S-L association. For them, the main modification was a strong decrease of Cz AEP induced by S-L association. These two groups also differed in their capacity to ignore irrelevant stimuli which is higher in the first group (AEP amplitude habituation with sound-alone repetition) than in the second one (no AEP habituation).     

Automated EEG preprocessing during anaesthesia: new aspects using artificial neural networks.

The computer-aided detection of artefacts became an essential task with increasing automation of quantitative electroencephalogram (EEG) analysis during anaesthesiological applications. The different algorithms published so far required individual manual adjustment or have been based on limited decision criteria. In this study, we developed an artificial neural networks-(ANN-)aided method for automated detection of artefacts and EEG suppression periods. 72 hr EEG recorded before, during and after anaesthesia with propofol have been evaluated. Selected parameterized patterns of 0.25 s length were used to train the ANN (22 input, 8 hidden and 4 output neurons) with error back propagation. The detection performance of the ANN-aided method was tested with processing epochs between 1 to10 s. Related to examiner EEG evaluation, the average detection performance of the method was 72% sensitivity and 80% specificity for artefacts and 90% sensitivity and 92% specificity for EEG suppression. The improvement in signal-to-noise ratio with automated artefact processing was 1.39 times for the spectral edge frequency 95 (SEF95) and 1.89 times for the approximate entropy (ApEn). We conclude that ANN-aided preprocessing provide an useful tool for automated EEG evaluation in anaesthesiological applications.     

The Narcotrend Index: classification algorithm, correlation with propofol effect-site concentrations, and comparison with spectral parameters.

A reliable assessment of the depth of hypnosis during sedation and general anaesthesia using the EEG is a subject of current interest. The Narcotrend Index implemented in the latest version 4.0 of the EEG monitor Narcotrend provides an automatic classification of the EEG on a scale ranging from 100 (awake) to 0 (very deep hypnosis, EEG suppression). The classification algorithms implemented in the EEG monitor Narcotrend are described. In a study the correlation of the propofol effect-site concentration with the Narcotrend Index and with the traditional spectral parameters total power, relative power in the standard frequency bands delta, theta, alpha, and beta, median frequency, 95% spectral edge frequency, burst-compensated spectral edge frequency, and spectral entropy was investigated. The Narcotrend Index had the highest average correlation with the propofol effect-site concentration and the smallest variability of the individual correlation values. Moreover, the Narcotrend Index was the only parameter which showed a monophasic trend over the whole investigated time period. The Narcotrend monitor can make a significant contribution to the improvement of the quality of anaesthesia by adjusting the dosage of hypnotics to individual patient needs.     

Activation of duration-sensitive auditory cortical fields in humans

The influence of stimulus duration on auditory evoked potentials (AEPs) was examined for tones varying randomly in duration, location, and frequency in an auditory selective attention task. Stimulus duration effects were isolated as duration difference waves by subtracting AEPs to short duration tones from AEPs to longer duration tones of identical location, frequency and rise time. This analysis revealed that AEP components generally increased in amplitude and decreased in latency with increments in signal duration, with evidence of longer temporal integration times for lower frequency tones. Different temporal integration functions were seen for different N1 subcomponents. The results suggest that different auditory cortical areas have different temporal integration times, and that these functions vary as a function of tone frequency.     

Sustained potential shifts,alterations in acoustic evoked potential amplitude and bradycardiac responses to the onset of illumination in the goldfish (Carassius auratus)

Sustained potential shift's (SPSs) and changes in acoustic evoked potential (AEP) amplitudes were recorded from medullary and mid-brain regions in restrained goldfish (Carassius auratus) in response to the onset of illumination against a sensory background restricted to repetitive (1/s) acoustic stimulation. At the tectal surface, a long duration negative SPS, significant 5–10 s after the onset of illumination, was recorded with a maximum negativity of ca. 145 V. Changes in acoustic responsiveness were also most apparent in the mid-brain where attenuations in AEP amplitude of ca. 15% were recorded.In general, AEPs exhibited attenuated amplitudes in response to the onset of illumination, perhaps reflecting attentional rather than arousal processes, arousal generally being associated with heightened sensory responsiveness. Changes in the amplitude of the medullary AEPs were directly related to the magnitude of bradycardiac responses such that lesser attenuations of the medullary AEP were associated with greater magnitude bradycardiac responses, suggesting a possible interaction of attentional and arousal processes.In response to repeated onset of illumination, SPSs tended towards increasing positivity (increasing in positivity at the medullary surface; decreasing in negativity at the tectal surface). The attenuation of AEPs recorded from the medulla and mid-brain habituated in response to stimulus repetition.Changes in amplitude of AEPs (AEP) recorded from the telencephalon and the torus semicircularis region of the mid-brain were correlated with locally recorded SPSs. At the telencephalon, this correlation was inverse; enhanced AEP amplitudes being associated with SPS negativity, attenuated AEP amplitudes with SPS positivity. In the torus semicircularis, experiential changes in SPS and AEP were directly correlated. As the SPS is considered to reflect glial redistribution of [K⁺]_e (Roitbak 1983), glia may contribute to changes in measures of sensory responsivity, such as the AEP, during changes in behavioural state.Abbreviations AEP Acoustic Evoked Potential - AEP Event-related change in amplitude of AEP following onset of illumination - SPS Sustained Potential Shift - [K⁺]_e Extracellular concentration of K⁺     

Single-trial latency variability does not contribute to fast habituation of the long-latency averaged auditory evoked potential in the albino rat

Fas habituation (FH) is defined as a general reduction in long-latency, vertex-recorded, averaged auditory evoked potential (AEP) amplitude that occurs in response to the second of a pair of acoustic stimuli. Our laboratory has been studying FH in a variety of human populations with different paradigms and has interpreted it to be a measure of neural attentional mechanism(s) and/or resource allocation related to the processing of cognitive information. We have also reported an analogous phenomenon in the rat. In the present investigation, we examined the relationship between FH (viz., averaged AEP component amplitude decrement) and the single-trial latency variability of the AEP peaks comprising that component. Specifically, AEPs were obtained to 60 paired-tone stimuli from unanesthetized and restrained albino rats previously implanted with chronic skull electrodes. Using a template-matching algorithm similar to that used by Michalewski et al. (Electroenceph. clin. Neurophysiol., 1986, 65:59–71), the latency variability for each animal was computed for the N1 and P2 peaks of the single-trial AEPs that were used to compose the averaged wave form. Findings indicated that (a) there was no difference in single-trial latency variability for these peaks either within or across tones, and (b) there was no relationship between single-trial latency variability for either the N1 or the P2 peaks and the overall peak-to-peak amplitude (N1-P2) of the averaged wave form in response to the second tone. Thus, FH of the N1-P2 (i.e. Peak 2) amplitude in the rat is not due to an increase in latency variability across tones.     

Anaesthesia Monitoring by Recurrence Quantification Analysis of EEG Data

Appropriate monitoring of the depth of anaesthesia is crucial to prevent deleterious effects of insufficient anaesthesia on surgical patients. Since cardiovascular parameters and motor response testing may fail to display awareness during surgery, attempts are made to utilise alterations in brain activity as reliable markers of the anaesthetic state. Here we present a novel, promising approach for anaesthesia monitoring, basing on recurrence quantification analysis (RQA) of EEG recordings. This nonlinear time series analysis technique separates consciousness from unconsciousness during both remifentanil/sevoflurane and remifentanil/propofol anaesthesia with an overall prediction probability of more than 85%, when applied to spontaneous one-channel EEG activity in surgical patients.     

Vasopressin and electrophysiological signs of attention in man

Seventeen pairs of monozygotic twins, females and males, were tested in a dichotic listening task, containing several types of pips: standard and deviating target pips, which the subject either attended to, or not. Averaged auditory evoked potentials (AEPs) to the pips provided measures of different attentional processes. Furthermore, EEG power spectra, heart rate and blood pressure and behavioral performance were measured. Subjects received treatments (20 I.U. lysine-vasopressin vs. placebo) intranasally 48, 24, and 1 hour prior to the experimental sessions according to a co-twin control design. Whereas measures of voluntary selective attention remained unchanged by lysine-vasopressin (LVP) the peptide primarily affected an attentional mechanism responding in an automatic fashion to stimulus deviance. This effect was indicated by a substantial negative shift of the AEP amplitudes following deviating stimuli within the latency range of the N2/P2 components (about 200 msec post-stimulus). The effect seemed to be unrelated to modulations of cortical arousal after LVP.