Validation of a new approach for distinguishing anesthetized from awake state in patients using directed transfer function applied to raw EEG

Aim: In a previous study, we found that the state of wakefulness in patients undergoing general anesthesia with propofol can effectively be monitored with high temporal resolution using an automatic measure of connectivity based on the Directed Transfer Function (DTF) calculated from short segments of electroencephalography (EEG) time-series. The study described here was designed to test whether the same measure can be used to monitor the state of the patients also during sevoflurane anesthesia. Methods: Twenty-five channel EEG recordings were collected from 8 patients undergoing surgical anesthesia with sevoflurane. The EEG data were segmented into one second epochs and labeled as awake or anesthetized in accordance with the clinician's judgement, and the sensor space directed connectivity was quantified for every epoch using the DTF. The resulting DTF derived connectivity parameters were compared to corresponding parameters from our previous study using permutation statistics. A data driven classification algorithm was then employed to objectively classify the individual 1-second epochs as coming from awake or anesthetized state, using a leave-one-out cross-validation approach. The classifications were made for every epoch using the median DTF parameters across the five preceding 1-second EEG epochs. Results: The DTF derived connectivity parameters showed a significant difference between the awake and sevoflurane-induced general anesthesia at the group level (p<0.05). In contrast, the DTF parameters were not significantly different when comparing sevoflurane and propofol data neither in the awake nor in anesthetized state (p>0.05 for both comparisons). The classification algorithm reached a maximum accuracy of 96.8% (SE=0.63%). Optimizing the algorithm for simultaneously having high sensitivity and specificity in classification reduced the accuracy to 95.1% (SE=0.96%), with sensitivity of 98.4% (SE=0.80%) and specificity of 94.8% (SE=0.10%). Conclusion: These findings indicate that the DTF changes in a similar manner when humans undergo general anesthesia caused by two distinct anesthetic agents with different molecular mechanisms of action. This seems to support the idea that brain connectivity is related to the level of consciousness in humans, although further studies are needed to clarify whether our results may be contaminated by confounding factors.

[1]  M. Boly,et al.  Granger Causality Analysis of Steady-State Electroencephalographic Signals during Propofol-Induced Anaesthesia , 2012, PloS one.

[2]  Marcello Massimini,et al.  Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients , 2012, Brain : a journal of neurology.

[3]  Marta I. Garrido,et al.  Brain Connectivity in Disorders of Consciousness , 2012, Brain Connect..

[4]  R. Dengler,et al.  Propofol Blocks Human Skeletal Muscle Sodium Channels in a Voltage-Dependent Manner , 2001, Anesthesia and analgesia.

[5]  M. Gemma,et al.  Linear transformation of the encoding mechanism for light intensity underlies the paradoxical enhancement of cortical visual responses by sevoflurane , 2017, The Journal of physiology.

[6]  A. Seth,et al.  Causal density and integrated information as measures of conscious level , 2011, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[7]  Katarzyna J. Blinowska,et al.  A new method of the description of the information flow in the brain structures , 1991, Biological Cybernetics.

[8]  UnCheol Lee,et al.  Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane , 2013, Anesthesiology.

[9]  G. Tononi,et al.  Breakdown of Cortical Effective Connectivity During Sleep , 2005, Science.

[10]  D. Simpson,et al.  Directional connectivity in the EEG is able to discriminate wakefulness from NREM sleep , 2017, Physiological measurement.

[11]  Frank Wells.  ACTION ON BARBITURATES , 1974 .

[12]  G. Tononi,et al.  Consciousness and Anesthesia , 2008, Science.

[13]  Emery N. Brown,et al.  Electroencephalogram signatures of loss and recovery of consciousness from propofol , 2013, Proceedings of the National Academy of Sciences.

[14]  M. Brazier,et al.  ACTION OF BARBITURATES ON THE CEREBRAL CORTEX: ELECTROENCEPHALOGRAPHIC STUDIES , 1945 .

[15]  B. Antkowiak,et al.  Different actions of general anesthetics on the firing patterns of neocortical neurons mediated by the GABA(A) receptor. , 1999, Anesthesiology.

[16]  B. Antkowiak,et al.  Molecular and neuronal substrates for general anaesthetics , 2004, Nature Reviews Neuroscience.

[17]  G. Tononi,et al.  Stratification of unresponsive patients by an independently validated index of brain complexity , 2016, Annals of neurology.

[18]  Karl J. Friston,et al.  Estimating Directed Connectivity from Cortical Recordings and Reconstructed Sources , 2015, Brain Topography.

[19]  R. Blair,et al.  An exact statistical method for comparing topographic maps, with any number of subjects and electrodes , 2005, Brain Topography.

[20]  A. Loomis,et al.  Cerebral states during sleep, as studied by human brain potentials , 1937 .

[21]  Armin Schubert,et al.  Pharmacologic and Physiologic Influences Affecting Sensory Evoked Potentials: Implications for Perioperative Monitoring , 2003, Anesthesiology.

[22]  S. Georgiadis,et al.  Directional Connectivity between Frontal and Posterior Brain Regions Is Altered with Increasing Concentrations of Propofol , 2014, PloS one.

[23]  P. Leese.  Comparison of the effects , 1992 .

[24]  P. Rossini,et al.  Changes in fronto‐posterior functional coupling at sleep onset in humans , 2004, Journal of sleep research.

[25]  T. Ledowski,et al.  Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane, sevoflurane, isoflurane or total i.v. anaesthesia. , 1998, British journal of anaesthesia.

[26]  G. Tononi,et al.  Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness , 2010, Proceedings of the National Academy of Sciences.

[27]  Marcello Massimini,et al.  A perturbational approach for evaluating the brain's capacity for consciousness. , 2009, Progress in brain research.

[28]  Arnaud Delorme,et al.  EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis , 2004, Journal of Neuroscience Methods.

[29]  G. Tononi,et al.  A Theoretically Based Index of Consciousness Independent of Sensory Processing and Behavior , 2013, Science Translational Medicine.

[30]  Clemens Brunner,et al.  Volume Conduction Influences Scalp-Based Connectivity Estimates , 2016, Front. Comput. Neurosci..

[31]  M. Boly,et al.  Complexity of Multi-Dimensional Spontaneous EEG Decreases during Propofol Induced General Anaesthesia , 2015, PloS one.

[32]  Katarzyna J. Blinowska,et al.  Review of the methods of determination of directed connectivity from multichannel data , 2011, Medical & Biological Engineering & Computing.

[33]  M. Kronbichler,et al.  Connectivity biomarkers can differentiate patients with different levels of consciousness , 2014, Clinical Neurophysiology.

[34]  G. A. Miller,et al.  Comparison of different cortical connectivity estimators for high‐resolution EEG recordings , 2007, Human brain mapping.

[35]  P. G. Larsson,et al.  Feasibility of Long-Term Continuous EEG Monitoring During the First Days of Life in Preterm Infants: An Automated Quantification of the EEG Activity , 2011, Pediatric Research.

[36]  M. Mehta,et al.  Spinal Cord Motoneuron Excitability during Isoflurane and Nitrous Oxide Anesthesia , 1997, Anesthesiology.

[37]  F. Martin,et al.  Comparison of the effects of sevoflurane and propofol on cortical somatosensory evoked potentials. , 2002, British journal of anaesthesia.

[38]  Katarzyna J. Blinowska,et al.  The Influence of Volume Conduction on DTF Estimate and the Problem of Its Mitigation , 2017, Front. Comput. Neurosci..

[39]  E R John,et al.  Quantitative EEG changes associated with loss and return of consciousness in healthy adult volunteers anaesthetized with propofol or sevoflurane. , 2001, British journal of anaesthesia.

[40]  I. Rampil,et al.  Anesthetic Depression of Spinal Motor Neurons May Contribute to Lack of Movement in Response to Noxious Stimuli , 1994, Anesthesiology.

[41]  D. Chernik,et al.  Validity and Reliability of the Observer's: Assessment of Alertness/Sedation Scale Study with Intravenous Midazolam , 1990, Journal of clinical psychopharmacology.

[42]  Laura Astolfi,et al.  Connectome : A MATLAB toolbox for mapping and imaging of brain , 2010 .

[43]  P. G. Larsson,et al.  Effective connectivity in long-term EEG monitoring in preterm infants , 2015, Clinical Neurophysiology.

[44]  Michael Eichler,et al.  On the Evaluation of Information Flow in Multivariate Systems by the Directed Transfer Function , 2006, Biological Cybernetics.

[45]  B. E. Juel,et al.  Distinguishing Anesthetized from Awake State in Patients: A New Approach Using One Second Segments of Raw EEG , 2018, Front. Hum. Neurosci..