Marc Jobert

Topographical Analysis of Sleep Spindle Activity

There is evidence for two types of sleep spindle activity, one with a frequency of about 12 cycles/s (cps) and the other of about 14 cps. Visual examination indicates that both spindle types occur independently, whereby the 12-cps spindles are more pronounced in the frontal and the 14-cps spindles in the parietal region. The purpose of this paper is to provide more information about the exact topography of these patterns. First the occurrence of distinct signals in anterior and posterior brain regions was verified using pattern recognition techniques based on matched filtering. Thus the existence of two distinct sources of activity located in the frontal and parietal region of the brain, respectively, was demonstrated using EEG frequency mapping. Evaluation of sleep recordings showed high stability both in the frequency and location of the presumed spindle generators across sleep. Pharmacological effects of lormetazepam and zopiclone on both spindle types were investigated. Both substances enhanced the sleep spindle activity recorded from the frontal and parietal electrodes, but this increase was more pronounced in the parietal brain region.

Guidelines for the Recording and Evaluation of Pharmaco-EEG Data in Man: The International Pharmaco-EEG Society (IPEG)

The International Pharmaco-EEG Society (IPEG) presents updated guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-EEG data in man. Since the publication of the first pharmaco-EEG guidelines in 1982, technical and data processing methods have advanced steadily, thus enhancing data quality and expanding the palette of tools available to investigate the action of drugs on the central nervous system (CNS), determine the pharmacokinetic and pharmacodynamic properties of novel therapeutics and evaluate the CNS penetration or toxicity of compounds. However, a review of the literature reveals inconsistent operating procedures from one study to another. While this fact does not invalidate results per se, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. Moreover, this shortcoming hampers reliable comparisons between outcomes of studies from different laboratories and hence also prevents pooling of data which is a requirement for sufficiently powering the validation of novel analytical algorithms and EEG-based biomarkers. The present updated guidelines reflect the consensus of a global panel of EEG experts and are intended to assist investigators using pharmaco-EEG in clinical research, by providing clear and concise recommendations and thereby enabling standardisation of methodology and facilitating comparability of data across laboratories.

Wavelets-a new tool in sleep biosignal analysis.

SUMMARY  The wavelet transform is a relatively new approach to data processing which has been applied in different areas such as signal, speech and image processing. In the last decade, many papers have been published on wavelet theory and its applications. The wavelet transform provides an elegant alternative to the classical Fourier or Gabor transforms unifying numerous signal processing techniques in a common framework. The purpose of the present paper is to provide an overview of the applicability of the wavelet transform to EEG signal analysis. In the first part of the paper the mathematical background is summarized. In the second part, applications to the sleep EEG field are presented and discussed. The results of these illustrations demonstrate the usefulness of the wavelet transform to solve various problems including signal parametrization, pattern recognition and biosignal representation.

The diurnal distribution of sleep propensity: experimental data about the interaction of the propensities for slow‐wave sleep and REM sleep

The aim of the present study was to assess the diurnal variation of sleep propensity by evaluating the temporal distribution of sleep onset latency (SOL) and REM‐ and slow‐wave sleep (SWS) parameters in systematically scheduled daytime naps for 12 young males. To reduce the effect of prior SWS on subsequent REM sleep, a double‐nap technique was used, i.e. two adjacent naps A and B, which were separated by a 10‐min break. Nap duration was adjusted in such a way that nap A allowed 30 min of sleep and nap B one complete NREM–REM cycle. EEG slow wave activity (SWA, power density from 0.5–4 Hz) was estimated from nap A and REM sleep parameters from nap B. The time span between 08.00 hours and 24.00 hours was covered by nine double‐naps at 2 h intervals. The order of the nap sessions was systematically varied within and across subjects. For each subject, the time between successive double‐nap recordings was at least three days. SOL was shortest in the time interval 12.00 hours to 16.00 hours and significantly longer between 20.00 hours and 24.00 hours. REM sleep duration and the percentage of sleep onset REM episodes decreased continuously from 08.00 hours to the interval 18.00–20.00 hours and increased thereafter, with a time course inversely related to the one of body temperature, which was also measured continuously. SWA showed a steady, threefold increase from 08.00 hours to 24.00 hours. The study offers new data on the diurnal variation of sleep propensity which seems to be a composite function of the drives for SWS and REM sleep.

Pattern Recognition by Matched Filtering: An Analysis of Sleep Spindle and K-Complex Density under the Influence of Lormetazepam and Zopiclone

The evaluation of sleep EEG patterns is mostly accomplished by visual analysis. With modern personal computers however, it is possible to perform signal detection within a reasonable length of time automatically. This paper presents a method for signal processing based on matched filtering. This allows the detection of sleep spindles and K-complexes in a sleep EEG recording with a high degree of accuracy. First the technique is described, and the results of a validation study based on the comparison of visual evaluations and computer analysis are presented. Thereafter, results of an application study are presented. Sleep spindle and K-complex density under the influence of lormetazepam and zopiclone were examined. Under both medications sleep spindle density increased while K-complex density decreased. Computation of Pearsons correlation coefficients demonstrated that the interindividual sleep spindle and K-complex variations under both treatments are highly correlated. The data suggest that lormetazepam and zopiclone, although chemically different, have a similar mode of action and display comparable effects on the sleep EEG.

Effect of Two Antidepressant Drugs on REM Sleep and EMG Activity during Sleep

In a placebo-controlled study, the effects on sleep of single and repeated doses of imipramine and dexnafenodone, an antidepressant drug under development, were investigated in young, healthy volunteers. In contrast to placebo, both drugs suppressed REM sleep substantially after acute and repeated administration. As a consequence, REM sleep latencies increased under active treatment to mean values which were about two to four times larger than baseline values. Since the active inhibition of the muscle tone is a distinct feature of REM sleep, we studied the influence of the two antidepressant drugs on this variable. By means of computerised EMG analysis, tonic and transient EMG activity were computed for total recording time and for the different sleep stages. While tonic EMG activity during sleep was increased with both drugs, transient EMG events remained unaffected. Computerised analysis of the microstructure of sleep is an effective tool for studying the effect of antidepressant drugs on sleep.

ECG Activity in the Sleep of Insomniac Patients under the Influence of Lormetazepam and Zopiclone

The influence of the benzodiazepine hypnotic lormetazepam (1 mg) and the cyclopyrrolone hypnotic zopiclone (7.5 mg) on heart rate activity was studied in 16 elderly insomniacs in a placebo-controlled, randomised, 3-fold crossover trial. After digital preprocessing of the ECG, QRS complexes were automatically recognised by a detection technique based on adaptative thresholds. Both R-R periodicity and heart rate variability were analysed as a function of sleep stages and time of night. Under placebo, heart rate decreased significantly from the first to the second half of the night. The relationship between sleep stages and heart rate remained constant under both hypnotics. Although the two substances significantly modified the distribution of sleep stages, no relevant changes in ECG activity were observed when the proportion of the different sleep stages was taken into consideration.

Methodological Considerations for the Evaluation of EEG Mapping Data: A Practical Example Based on a Placebo/Diazepam Crossover Trial

Quantitative EEG is a sensitive method for measuring pharmacological effects on the central nervous system. Nowadays, computers enable EEG data to be stored and spectral parameters to be computed for signals obtained from a large number of electrode locations. However, the statistical analysis of such vast amounts of EEG data is complicated due to the limited number of subjects usually involved in pharmacological studies. In the present study, data from a trial aimed at comparing diazepam and placebo were used to investigate different properties of EEG mapping data and to compare different methods of data analysis. Both the topography and the temporal changes of EEG activity were investigated using descriptive data analysis, which is based on an inspection of patterns of pd values (descriptive p values) assessed for all pair-wise tests for differences in time or treatment. An empirical measure (tri-mean) for the computation of group maps is suggested, allowing a better description of group effects with skewed data of small samples size. Finally, both the investigation of maps based on principal component analysis and the notion of distance between maps are discussed and applied to the analysis of the data collected under diazepam treatment, exemplifying the evaluation of pharmacodynamic drug effects.

On the Choice of Recording Duration in Pharmaco-EEG Studies

Quantitative EEG is a sensitive method used to assess the effects of pharmacological substances on the central nervous system (CNS) activity. A standard technique is to measure the EEG under vigilance-controlled and resting conditions for a short duration, for example 5 min. The aim of the present study was to investigate the stability of 5-min EEG recordings. While the time course of the EEG was fairly stable during the recording session under the vigilance-controlled condition, systematic trends became apparent under the resting condition. Pharmaco-sensitivity of the EEG and its reliability increased with the recording duration. Five minutes of EEG recording seem to be sufficient and well chosen to evaluate the influence of drugs on the EEG.

Advanced Analysis of Pharmaco-EEG Data in Humans.

Pharmaco-electroencephalography (EEG) is a non-invasive method used to assess the effects of pharmacological compounds on the central nervous system by processing the EEG signals which directly reveal the spontaneous synchronised postsynaptic neuronal activity of the cortex with high temporal resolution. The International Pharmaco-Encephalography Society (IPEG) has recently published guidelines, which were produced by a global panel of EEG experts, with the goal to increase the standardisation of pharmaco-EEG studies in human subjects and facilitate the comparability of data across laboratories, thus enabling data-pooling and meta-analyses. The recommended standard experimental procedure is to measure EEG activity under vigilance-controlled and resting conditions. The IPEG guidelines thoroughly present the technical details and therefore constitute a robust reference. The complementary aim of the present paper is to focus on practical aspects, pitfalls and precautions to be considered when processing pharmaco-EEG data by covering the following topics: (1) investigate the stability and reliability of 5-min EEG recordings under both vigilance-controlled and resting conditions; (2) assess the spontaneous time-dependent changes in spectral activity over time, and (3) apply the data-processing strategies suggested in the pharmaco-EEG guidelines and designed to optimally capture drug effects. For this purpose, the EEG data from a randomised, double-blind, crossover trial aimed at comparing the effect of diazepam (10 mg) and placebo in 16 healthy male volunteers is used to illustrate the discussion of the processing techniques and difficulties commonly faced when analysing pharmaco-EEG data.