Innovative treatment modalities for urinary incontinence: a European survey identifying experience and attitude of healthcare providers.

INTRODUCTION AND HYPOTHESIS: Urinary incontinence is a common condition in women, with a reported prevalence ranging from 25% to 51%. Of these women, an estimated 38% suffer from stress urinary incontinence (SUI). A European research consortium is investigating an innovative system based on information and communication technology for the conservative treatment of women with SUI. When introducing a new intervention, implementation barriers arise and need to be identified. Therefore, we investigated healthcare providers' experience with and attitude towards innovative care options. METHODS: We performed an online survey to assess (1) the characteristics and practice of healthcare providers, (2) current protocols for SUI, (3) current use of biofeedback, and (4) knowledge about serious gaming. The survey was sent to members of professional societies in Europe (EUGA), UK (BSUG) and The Netherlands (DPFS). RESULTS: Of 341 questionnaires analyzed (response rate between 18% and 30%), 64% of the respondents had access to a protocol for the treatment of SUI, and 31% used biofeedback when treating patients with SUI. However, 92% considered that biofeedback has a clear or probable added value, and 97% of those who did not use biofeedback would change their practice if research evidence supported its use. Finally, 89% of respondents indicated that they had no experience of serious gaming, but 92% considered that it could be useful. CONCLUSIONS: Although inexperienced, European urogynecologists and physical therapists welcome innovative treatment options for the conservative treatment of SUI such as portable wireless biofeedback and serious gaming. Scientific evidence is considered a prerequisite to incorporate such innovations into clinical practice.

Acute Sleep Deprivation Induces a Local Brain Transfer Information Increase in the Frontal Cortex in a Widespread Decrease Context.

Sleep deprivation (SD) has adverse effects on mental and physical health, affecting the cognitive abilities and emotional states. Specifically, cognitive functions and alertness are known to decrease after SD. The aim of this work was to identify the directional information transfer after SD on scalp EEG signals using transfer entropy (TE). Using a robust methodology based on EEG recordings of 18 volunteers deprived from sleep for 36 h, TE and spectral analysis were performed to characterize EEG data acquired every 2 h. Correlation between connectivity measures and subjective somnolence was assessed. In general, TE showed medium- and long-range significant decreases originated at the occipital areas and directed towards different regions, which could be interpreted as the transfer of predictive information from parieto-occipital activity to the rest of the head. Simultaneously, short-range increases were obtained for the frontal areas, following a consistent and robust time course with significant maps after 20 h of sleep deprivation. Changes during sleep deprivation in brain network were measured effectively by TE, which showed increased local connectivity and diminished global integration. TE is an objective measure that could be used as a potential measure of sleep pressure and somnolence with the additional property of directed relationships.

EEG connectivity patterns in response to gaming and learning-based cognitive stimulations in Rett syndrome.

BACKGROUND: Functional connectivity is scarcely studied in Rett syndrome (RTT). Explorations revealed associations between RTT's clinical, genetic profiles, and coherence measures, highlighting an unexplored frontier in understanding RTT's neural mechanisms and cognitive processes. AIMS: To evaluate the effects of diverse cognitive stimulations-learning-focused versus gaming-oriented-on electroencephalography brain connectivity in RTT. The comparison with resting states aimed to uncover potential biomarkers and insights into the neural processes associated with RTT. METHODS AND PROCEDURES: The study included 15 girls diagnosed with RTT. Throughout sessions lasting about 25 min, participants alternated between active and passive tasks, using an eyetracker device while their brain activity was recorded with a 20-channel EEG. Results revealed significant alterations during cognitive tasks, notably in delta, alpha and beta bands. Both tasks induced spectral pattern changes and connectivity shifts, hinting at enhanced neural processing. Hemispheric asymmetry decreased during tasks, suggesting more balanced neural processing. Linear and nonlinear connectivity alterations were observed in active tasks compared to resting state, while passive tasks showed no significant changes. CONCLUSIONS AND IMPLICATIONS: Results underscores the potential of cognitive stimulation for heightened cognitive abilities, promoting enhanced brain connectivity and information flow in Rett syndrome. These findings offer valuable markers for evaluating cognitive interventions and suggest gaming-related activities as effective tools for improving learning outcomes.

High-density surface EMG maps from upper-arm and forearm muscles.

BACKGROUND: sEMG signal has been widely used in different applications in kinesiology and rehabilitation as well as in the control of human-machine interfaces. In general, the signals are recorded with bipolar electrodes located in different muscles. However, such configuration may disregard some aspects of the spatial distribution of the potentials like location of innervation zones and the manifestation of inhomogineties in the control of the muscular fibers. On the other hand, the spatial distribution of motor unit action potentials has recently been assessed with activation maps obtained from High Density EMG signals (HD-EMG), these lasts recorded with arrays of closely spaced electrodes. The main objective of this work is to analyze patterns in the activation maps, associating them with four movement directions at the elbow joint and with different strengths of those tasks. Although the activation pattern can be assessed with bipolar electrodes, HD-EMG maps could enable the extraction of features that depend on the spatial distribution of the potentials and on the load-sharing between muscles, in order to have a better differentiation between tasks and effort levels. METHODS: An experimental protocol consisting of isometric contractions at three levels of effort during flexion, extension, supination and pronation at the elbow joint was designed and HD-EMG signals were recorded with 2D electrode arrays on different upper-limb muscles. Techniques for the identification and interpolation of artifacts are explained, as well as a method for the segmentation of the activation areas. In addition, variables related to the intensity and spatial distribution of the maps were obtained, as well as variables associated to signal power of traditional single bipolar recordings. Finally, statistical tests were applied in order to assess differences between information extracted from single bipolar signals or from HD-EMG maps and to analyze differences due to type of task and effort level. RESULTS: Significant differences were observed between EMG signal power obtained from single bipolar configuration and HD-EMG and better results regarding the identification of tasks and effort levels were obtained with the latter. Additionally, average maps for a population of 12 subjects were obtained and differences in the co-activation pattern of muscles were found not only from variables related to the intensity of the maps but also to their spatial distribution. CONCLUSIONS: Intensity and spatial distribution of HD-EMG maps could be useful in applications where the identification of movement intention and its strength is needed, for example in robotic-aided therapies or for devices like powered- prostheses or orthoses. Finally, additional data transformations or other features are necessary in order to improve the performance of tasks identification.

Influence of the number of trials on evoked motor cortical activity in EEG recordings.

Objective. Improvements in electroencephalography enable the study of the localization of active brain regions during motor tasks. Movement-related cortical potentials (MRCPs), and event-related desynchronization (ERD) and synchronization are the main motor-related cortical phenomena/neural correlates observed when a movement is elicited. When assessing neurological diseases, averaging techniques are commonly applied to characterize motor related processes better. In this case, a large number of trials is required to obtain a motor potential that is representative enough of the subject's condition. This study aimed to assess the effect of a limited number of trials on motor-related activity corresponding to different upper limb movements (elbow flexion/extension, pronation/supination and hand open/close).Approach. An open dataset consisting on 15 healthy subjects was used for the analysis. A Monte Carlo simulation approach was applied to analyse, in a robust way, different typical time- and frequency-domain features, topography, and low-resolution electromagnetic tomography.Main results. Grand average potentials, and topographic and tomographic maps showed few differences when using fewer trials, but shifts in the localization of motor-related activity were found for several individuals. MRCP and beta ERD features were more robust to a limited number of trials, yielding differences lower than 20% for cases with 50 trials or more. Strong correlations between features were obtained for subsets above 50 trials. However, the inter-subject variability increased as the number of trials decreased. The elbow flexion/extension movement showed a more robust performance for a limited number of trials, both in population and in individual-based analysis.Significance. Our findings suggested that 50 trials can be an appropriate number to obtain stable motor-related features in terms of differences in the averaged motor features, correlation, and changes in topography and tomography.

Improving the ripple classification in focal pediatric epilepsy: identifying pathological high-frequency oscillations by Gaussian mixture model clustering.

Objective. High-frequency oscillations (HFOs) have emerged as a promising clinical biomarker for presurgical evaluation in childhood epilepsy. HFOs are commonly classified in stereo-encephalography as ripples (80-200 Hz) and fast ripples (200-500 Hz). Ripples are less specific and not so directly associated with epileptogenic activity because of their physiological and pathological origin. The aim of this paper is to distinguish HFOs in the ripple band and to improve the evaluation of the epileptogenic zone (EZ).Approach. This study constitutes a novel modeling approach evaluated in ten patients from Sant Joan de Deu Pediatric Hospital (Barcelona, Spain), with clearly-defined seizure onset zones (SOZ) during presurgical evaluation. A subject-by-subject basis analysis is proposed: a probabilistic Gaussian mixture model (GMM) based on the combination of specific ripple features is applied for estimating physiological and pathological ripple subpopulations.Main Results. Clear pathological and physiological ripples are identified. Features differ considerably among patients showing within-subject variability, suggesting that individual models are more appropriate than a traditional whole-population approach. The difference in rates inside and outside the SOZ for pathological ripples is significantly higher than when considering all the ripples. These significant differences also appear in signal segments without epileptiform activity. Pathological ripple rates show a sharp decline from SOZ to non-SOZ contacts and a gradual decrease with distance.Significance. This novel individual GMM approach improves ripple classification and helps to refine the delineation of the EZ, as well as being appropriate to investigate the interaction of epileptogenic and propagation networks.

Drug effect on EEG connectivity assessed by linear and nonlinear couplings.

Quantitative analysis of human electroencephalogram (EEG) is a valuable method for evaluating psychopharmacological agents. Although the effects of different drug classes on EEG spectra are already known, interactions between brain locations remain unclear. In this work, cross mutual information function and appropriate surrogate data were applied to assess linear and nonlinear couplings between EEG signals. The main goal was to evaluate the pharmacological effects of alprazolam on brain connectivity during wakefulness in healthy volunteers using a cross-over, placebo-controlled design. Eighty-five pairs of EEG leads were selected for the analysis, and connectivity was evaluated inside anterior, central, and posterior zones of the scalp. Connectivity between these zones and interhemispheric connectivity were also measured. Results showed that alprazolam induced significant changes in EEG connectivity in terms of information transfer in comparison with placebo. Trends were opposite depending on the statistical characteristics: decreases in linear connectivity and increases in nonlinear couplings. These effects were generally spread over the entire scalp. Linear changes were negatively correlated, and nonlinear changes were positively correlated with drug plasma concentrations; the latter showed higher correlation coefficients. The use of both linear and nonlinear approaches revealed the importance of assessing changes in EEG connectivity as this can provide interesting information about psychopharmacological effects.

SGM: a novel time-frequency algorithm based on unsupervised learning improves high-frequency oscillation detection in epilepsy.

OBJECTIVE: We propose a novel automated method called the S-Transform Gaussian Mixture detection algorithm (SGM) to detect high-frequency oscillations (HFO) combining the strengths of different families of previously published detectors. APPROACH: This algorithm does not depend on parameter tuning on a subject (or database) basis, uses time-frequency characteristics, and relies on non-supervised classification to determine if the events standing out from the baseline activity are HFO or not. SGM consists of three steps: the first stage computes the signal baseline using the entropy of the autocorrelation; the second uses the S-Transform to obtain several time-frequency features (area, entropy, and time and frequency widths); and in the third stage Gaussian mixture models cluster time-frequency features to decide if events correspond to HFO-like activity. To validate the SGM algorithm we tested its performance in simulated and real environments. MAIN RESULTS: We assessed the algorithm on a publicly available simulated stereoelectroencephalographic (SEEG) database with varying signal-to-noise ratios (SNR), obtaining very good results for medium and high SNR signals. We further tested the SGM algorithm on real signals from patients with focal epilepsy, in which HFO detection was performed visually by experts, yielding a high agreement between experts and SGM. SIGNIFICANCE: The SGM algorithm displayed proper performance in simulated and real environments and therefore can be used for non-supervised detection of HFO. This non-supervised algorithm does not require previous labelling by experts or parameter adjustment depending on the subject or database considered. SGM is not a computationally intensive algorithm, making it suitable to detect and characterize HFO in long-term SEEG recordings.

Alterations in EEG connectivity in healthy young adults provide an indicator of sleep depth.

Current sleep analyses have used electroencephalography (EEG) to establish sleep intensity through linear and nonlinear measures. Slow wave activity (SWA) and entropy are the most commonly used markers of sleep depth. The purpose of this study is to evaluate changes in brain EEG connectivity during sleep in healthy subjects and compare them with SWA and entropy. Four different connectivity metrics: coherence (MSC), synchronization likelihood (SL), cross mutual information function (CMIF), and phase locking value (PLV), were computed focusing on their correlation with sleep depth. These measures provide different information and perspectives about functional connectivity. All connectivity measures revealed to have functional changes between the different sleep stages. The averaged CMIF seemed to be a more robust connectivity metric to measure sleep depth (correlations of 0.78 and 0.84 with SWA and entropy, respectively), translating greater linear and nonlinear interdependences between brain regions especially during slow wave sleep. Potential changes of brain connectivity were also assessed throughout the night. Connectivity measures indicated a reduction of functional connectivity in N2 as sleep progresses. The validation of connectivity indexes is necessary because they can reveal the interaction between different brain regions in physiological and pathological conditions and help understand the different functions of deep sleep in humans.

Automated detection of epileptic ripples in MEG using beamformer-based virtual sensors.

OBJECTIVE: In epilepsy, high-frequency oscillations (HFOs) are expressively linked to the seizure onset zone (SOZ). The detection of HFOs in the noninvasive signals from scalp electroencephalography (EEG) and magnetoencephalography (MEG) is still a challenging task. The aim of this study was to automate the detection of ripples in MEG signals by reducing the high-frequency noise using beamformer-based virtual sensors (VSs) and applying an automatic procedure for exploring the time-frequency content of the detected events. APPROACH: Two-hundred seconds of MEG signal and simultaneous iEEG were selected from nine patients with refractory epilepsy. A two-stage algorithm was implemented. Firstly, beamforming was applied to the whole head to delimitate the region of interest (ROI) within a coarse grid of MEG-VS. Secondly, a beamformer using a finer grid in the ROI was computed. The automatic detection of ripples was performed using the time-frequency response provided by the Stockwell transform. Performance was evaluated through comparisons with simultaneous iEEG signals. MAIN RESULTS: ROIs were located within the seizure-generating lobes in the nine subjects. Precision and sensitivity values were 79.18% and 68.88%, respectively, by considering iEEG-detected events as benchmarks. A higher number of ripples were detected inside the ROI compared to the same region in the contralateral lobe. SIGNIFICANCE: The evaluation of interictal ripples using non-invasive techniques can help in the delimitation of the epileptogenic zone and guide placement of intracranial electrodes. This is the first study that automatically detects ripples in MEG in the time domain located within the clinically expected epileptic area taking into account the time-frequency characteristics of the events through the whole signal spectrum. The algorithm was tested against intracranial recordings, the current gold standard. Further studies should explore this approach to enable the localization of noninvasively recorded HFOs to help during pre-surgical planning and to reduce the need for invasive diagnostics.

Influence of metallic artifact filtering on MEG signals for source localization during interictal epileptiform activity.

OBJECTIVE: Medical intractable epilepsy is a common condition that affects 40% of epileptic patients that generally have to undergo resective surgery. Magnetoencephalography (MEG) has been increasingly used to identify the epileptogenic foci through equivalent current dipole (ECD) modeling, one of the most accepted methods to obtain an accurate localization of interictal epileptiform discharges (IEDs). Modeling requires that MEG signals are adequately preprocessed to reduce interferences, a task that has been greatly improved by the use of blind source separation (BSS) methods. MEG recordings are highly sensitive to metallic interferences originated inside the head by implanted intracranial electrodes, dental prosthesis, etc and also coming from external sources such as pacemakers or vagal stimulators. To reduce these artifacts, a BSS-based fully automatic procedure was recently developed and validated, showing an effective reduction of metallic artifacts in simulated and real signals (Migliorelli et al 2015 J. Neural Eng. 12 046001). The main objective of this study was to evaluate its effects in the detection of IEDs and ECD modeling of patients with focal epilepsy and metallic interference. APPROACH: A comparison between the resulting positions of ECDs was performed: without removing metallic interference; rejecting only channels with large metallic artifacts; and after BSS-based reduction. Measures of dispersion and distance of ECDs were defined to analyze the results. MAIN RESULTS: The relationship between the artifact-to-signal ratio and ECD fitting showed that higher values of metallic interference produced highly scattered dipoles. Results revealed a significant reduction on dispersion using the BSS-based reduction procedure, yielding feasible locations of ECDs in contrast to the other two approaches. SIGNIFICANCE: The automatic BSS-based method can be applied to MEG datasets affected by metallic artifacts as a processing step to improve the localization of epileptic foci.

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aß42 Levels in Cognitively Normal Elderly.

STUDY OBJECTIVES: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Aß). We thus aimed to examine relationships between concentrations of Aß42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. METHODS: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Aß42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Aß42 groups to compare SWS bout length using survival analyses. RESULTS: A significant inverse correlation was found between CSF Aß42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Aß42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Aß42. CONCLUSIONS: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Aß42, suggesting that disturbed sleep might drive an increase in soluble brain Aß levels prior to amyloid deposition.

Automatic BSS-based filtering of metallic interference in MEG recordings: definition and validation using simulated signals.

OBJECTIVE: One of the principal drawbacks of magnetoencephalography (MEG) is its high sensitivity to metallic artifacts, which come from implanted intracranial electrodes and dental ferromagnetic prosthesis and produce a high distortion that masks cerebral activity. The aim of this study was to develop an automatic algorithm based on blind source separation (BSS) techniques to remove metallic artifacts from MEG signals. APPROACH: Three methods were evaluated: AMUSE, a second-order technique; and INFOMAX and FastICA, both based on high-order statistics. Simulated signals consisting of real artifact-free data mixed with real metallic artifacts were generated to objectively evaluate the effectiveness of BSS and the subsequent interference reduction. A completely automatic detection of metallic-related components was proposed, exploiting the known characteristics of the metallic interference: regularity and low frequency content. MAIN RESULTS: The automatic procedure was applied to the simulated datasets and the three methods exhibited different performances. Results indicated that AMUSE preserved and consequently recovered more brain activity than INFOMAX and FastICA. Normalized mean squared error for AMUSE decomposition remained below 2%, allowing an effective removal of artifactual components. SIGNIFICANCE: To date, the performance of automatic artifact reduction has not been evaluated in MEG recordings. The proposed methodology is based on an automatic algorithm that provides an effective interference removal. This approach can be applied to any MEG dataset affected by metallic artifacts as a processing step, allowing further analysis of unusable or poor quality data.

Auditory P3a and P3b neural generators in schizophrenia: An adaptive sLORETA P300 localization approach.

The present study investigates the neural substrates underlying cognitive processing in schizophrenia (Sz) patients. To this end, an auditory 3-stimulus oddball paradigm was used to identify P3a and P3b components, elicited by rare-distractor and rare-target tones, respectively. Event-related potentials (ERP) were recorded from 31 Sz patients and 38 healthy controls. The P3a and P3b brain-source generators were identified by time-averaging of low-resolution brain electromagnetic tomography (LORETA) current density images. In contrast with the commonly used fixed window of interest (WOI), we proposed to apply an adaptive WOI, which takes into account subjects' P300 latency variability. Our results showed different P3a and P3b source activation patterns in both groups. P3b sources included frontal, parietal and limbic lobes, whereas P3a response generators were localized over bilateral frontal and superior temporal regions. These areas have been related to the discrimination of auditory stimulus and to the inhibition (P3a) or the initiation (P3b) of motor response in a cognitive task. In addition, differences in source localization between Sz and control groups were observed. Sz patients showed lower P3b source activity in bilateral frontal structures and the cingulate. P3a generators were less widespread for Sz patients than for controls in right superior, medial and middle frontal gyrus. Our findings suggest that target and distractor processing involves distinct attentional subsystems, both being altered in Sz. Hence, the study of neuroelectric brain information can provide further insights to understand cognitive processes and underlying mechanisms in Sz.

Neurophysiological correlates in Mild Cognitive Impairment detected using group Independent Component Analysis.

Alzheimer's disease is the most prevalent cause of dementia. Mild Cognitive Impairment (MCI) is defined as a grey area between intact cognitive functioning and clinical dementia. Electroencephalography (EEG) has been used to identify biomarkers in dementia. Currently, there is a great interest in translating the study from raw signals to signal generators, trying to keep the relationship with neurophysiology. In the current study, EEG recordings during an encoding task were acquired in MCI subjects and healthy controls. Data was decomposed using group Independent Component Analysis (gICA) and the most neuronal components were analyzed using Phase Intertrial Coherence (PIC) and Phase shift Intertrial Coherence (PsIC). MCI subjects exhibited an increase of PIC in the theta band, while controls showed increase in PsIC in the alpha band. Correlation between PIC and PsIC and clinical scales were also found. Those findings indicate that the methodology proposed based in gICA can help to extract information from EEG recordings with neurophysiological meaning.

Reduction of metallic interference in MEG signals using AMUSE.

Magnetoencephalography is a technique that can noninvasively measure the brain signal. There are many advantages of using this technique rather than similar procedures such as the EEG for the evaluation of medical diseases. However, one of its main problems is its high sensitivity to sources causing metallic distortion of the signal, and the removal of this type of artifacts remains unsolved. In this study a technique for reducing metallic interference was presented. This algorithm was based on AMUSE, a second order blind source separation method, and a procedure for choosing the artifactual independent components was also presented. The results showed that the elimination of these artifacts would be possible by means of the application of this AMUSE-based interference reduction procedure.

Analysis of muscle coupling during isokinetic endurance contractions by means of nonlinear prediction.

Isokinetic exercises have been extensively used in order to analyze muscle imbalances and changes associated with fatigue. It is known that such changes are difficult to assess from EMG signals during dynamic contractions, especially, using linear signal processing tools. The aim of this work was to use nonlinear prediction in order to analyze muscle couplings and interactions in this context and to assess the load-sharing of different muscles during fatigue. Results show promising for detecting interaction strategies between muscles and even for the interaction between muscles and the output torque during endurance tests.

Coordination of respiratory muscles assessed by means of nonlinear forecasting of demodulated myographic signals.

Pulmonary diseases such as obstructive sleep apnea syndrome (OSAS) affect function of respiratory muscles. Individuals with OSAS suffer intermittent collapse of the upper airways during sleep due to unbalanced forces generated by the contraction of the diaphragm and upper airway dilator muscles. Respiratory rhythm and pattern generation can be described via nonlinear or coupled oscillators; therefore, the resulting activation of different respiratory muscles may be related to complex nonlinear interactions. The aims of this work were: to evaluate locally linear models for fitting and prediction of demodulated myographic signals from respiratory muscles; and to analyze quantitatively the influence of a pulmonary disease on this nonlinear forecasting related to low and moderate levels of respiratory effort. Electromyographic and mechanomyographic signals from three respiratory muscles (genioglossus, sternomastoid and diaphragm) were recorded in OSAS patients and controls while awake during an increased respiratory effort. Variables related to auto and cross prediction between muscles were calculated from the r(2) coefficient and the estimation of residuals, as functions of prediction horizon. In general, prediction improved linearly with higher levels of effort. A better prediction between muscle activities was obtained in OSAS patients when using genioglossus as the predictor signal. The prediction was significant for more than two respiratory cycles in OSAS patients compared to only a half cycle in controls. It could be concluded that nonlinear forecasting applied to genioglossus coupling with other muscles provides a promising assessment to monitor pulmonary diseases.

Connectivity analysis of EEG under drug therapy.

Analysis of human EEG constitutes a useful instrument for the evaluation of drug bioavailability at the brain. Linear and nonlinear techniques were applied to EEG signals for the assessment of brain connectivity after drug intake by coherence and cross mutual information, respectively. The main goal was to evaluate the pharmacological effect of different doses of alprazolam on the brain during wakefulness. Preliminary results reported in this work showed statistically significant differences in EEG channels coupling between the states corresponding to placebo and different drug doses. However, nonlinear variables correlated better with the expected within-doses and within-time effects.