Analysis of the Hindriks and van Putten model for propofol anesthesia: Limitations and extensions.

We present a detailed analysis of the Hindriks and van Putten thalamocortical mean-field model for propofol anesthesia [NeuroImage 60(23), 2012]. The Hindriks and van Putten (HvP) model predicts increases in delta and alpha power for moderate (up to 130%) prolongation of GABAA inhibitory response, corresponding to light anesthetic sedation. Our analysis reveals that, for deeper anesthetic effect, the model exhibits an unexpected abrupt jump in cortical activity from a low-firing state to an extremely high-firing stable state (∼250 spikes/s), and remains locked there even at GABAA prolongations as high as 300% which would be expected to induce full comatose suppression of all firing activity. We demonstrate that this unphysiological behavior can be completely suppressed with appropriate tuning of the parameters controlling the sigmoidal functions that map soma voltage to firing rate for the excitatory and inhibitory neural populations, coupled with elimination of the putative population-dependent anesthetic efficacies introduced in the HvP model. The modifications reported here constrain the anesthetized brain activity into a biologically plausible range in which the cortex now has access to a moderate-firing state ("awake") and a low-firing ("anesthetized") state such that the brain can transition from "awake" to "anesthetized" states at a critical level of drug concentration. The modified HvP model predicts a drug-effect hysteresis in which the drug concentration required for induction is larger than that at emergence. In addition, the revised model shows a decrease in the intensity and frequency of alpha-band fluctuations, transitioning to delta-band dominance, with deepening anesthesia. These predicted drug concentration-dependent changes in EEG dynamics are consistent with clinical reports.

Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications.

BACKGROUND: Postoperative delirium is associated with an increased risk of morbidity and mortality, especially in the elderly. Delirium in the postanaesthesia care unit (PACU) could predict adverse clinical outcomes. METHODS: We investigated a potential link between intraoperative EEG patterns and PACU delirium as well as an association of PACU delirium with perioperative outcomes, readmission and length of hospital stay. The risk factors for PACU delirium were also explored. Data were collected from 626 patients receiving general anaesthesia for procedures that would not interfere with frontal EEG recording. RESULTS: Of the 626 subjects enrolled, 125 tested positive for PACU delirium. Whilst age, renal failure, and pre-existing neurological disease were associated with PACU delirium in the univariable analysis, the multivariable analysis revealed the importance of information derived from the EEG, anaesthetic technique, anaesthesia duration, and history of stroke or neurodegenerative disease. The occurrence of EEG burst suppression during maintenance [odds ratio (OR)=1.86 (1.13-3.05)] and the type of EEG emergence trajectory may be predictive of PACU delirium. Specifically, EEG emergence trajectories lacking significant spindle power were strongly associated with PACU delirium, especially in cases that involved ketamine or nitrous oxide [OR=6.51 (3.00-14.12)]. Additionally, subjects with PACU delirium were at an increased risk for readmission [OR=2.17 (1.13-4.17)] and twice as likely to stay >6 days in the hospital. CONCLUSIONS: Specific EEG patterns were associated with PACU delirium. These findings provide valuable information regarding how the brain reacts to surgery and anaesthesia that may lead to strategies to predict PACU delirium and identify key areas of investigation for its prevention.

Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique.

BACKGROUND: The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept. METHODS: Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power-frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling. RESULTS: Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power-frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders. CONCLUSIONS: Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia. CLINICAL TRIAL REGISTRATION: NCT02248623.

Self-administered methoxyflurane for procedural analgesia: experience in a tertiary Australasian centre.

Methoxyflurane, an agent formerly used as a volatile anaesthetic but that has strong analgesic properties, will soon become available again in the UK and Europe in the form of a small hand-held inhaler. We describe our experience in the use of inhaled methoxyflurane for procedural analgesia within a large tertiary hospital. In a small pilot crossover study of patients undergoing burns-dressing procedures, self-administered methoxyflurane inhalation was preferred to ketamine-midazolam patient-controlled analgesia by five of eight patients. Patient and proceduralist outcomes and satisfaction were recorded from a subsequent case series of 173 minor surgical and radiological procedures in 123 patients performed using inhaled methoxyflurane. The procedures included change of dressing, minor debridement, colonoscopy and incision-and-drainage of abscess. There was a 97% success rate of methoxyflurane analgesia to facilitate these procedures. Limitations of methoxyflurane include maximal daily and weekly doses, and uncertainty regarding its safety in patients with pre-existing renal disease.

Randomized controlled trial of the effect of depth of anaesthesia on postoperative pain.

BACKGROUND: Our hypothesis was that deep anaesthesia, as estimated by a low target bispectral index (BIS) of 30-40, would result in less postoperative pain than that achieved at a conventional depth of anaesthesia. METHODS: We undertook a randomized double-blind controlled study at two tertiary teaching hospitals in New Zealand (2010-1) recruiting 135 adult patients ASA I-II presenting for non-emergent surgery under general anaesthesia requiring tracheal intubation. Anaesthesia was maintained with desflurane and a multimodal analgesia regimen comprising fentanyl infusion, i.v. paracetamol, and parecoxib. Patients were randomly assigned to either a low BIS (30-40) group or a high BIS (45-60) group. Desflurane concentrations were titrated to achieve these targets. Postoperative pain was assessed by: the pain on awakening (0-10, verbal rating scale, VRS(awake)) in the post-anaesthetic care unit; pain on activity at 20-24 h after operation (VRS(d1A)); and the rate of morphine patient-controlled analgesia (PCA) usage over the first 24 h. RESULTS: There was no statistically significant difference between the two groups for any of the pain scores. The median [inter-quartile range (IQR)] VRS(awake) was 4.0 (0-8) for the low and 4.0 (0-8) for the high BIS groups (P=0.56). The median (IQR) VRS(d1A) was 3.0 (1-5) for the low and 3.0 (1.5-4.5) for the high BIS groups (P=0.83). The median PCA morphine consumption in the low BIS group was 0.61 mg h(-1) (0.04-1.5) vs 0.43 mg h(-1) (0-1.59) in the high BIS group (P=0.98). CONCLUSIONS: We conclude that there is no clinically useful analgesic effect of a deep anaesthesia regimen.

Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.

BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Cross-frequency coupling during isoflurane anaesthesia as revealed by electroencephalographic harmonic wavelet bicoherence.

BACKGROUND: Fourier bicoherence has previously been applied to investigate phase coupling in the EEG in anaesthesia. However, there are significant theoretical limitations regarding its sensitivity in detecting transient episodes of inter-frequency coupling. Therefore, we used a recently developed wavelet bicoherence method to investigate the cross-frequency coupling in the EEG of patients under isoflurane anaesthesia; examining the relationship between the patterns of wavelet bicoherence and the isoflurane concentrations. METHODS: We analysed a set of previously published EEG data, obtained from 29 patients who underwent elective abdominal surgery under isoflurane anaesthesia. Artifact-free, 1 min EEG segments at different isoflurane concentrations were extracted from each subject and the wavelet bicoherence calculated for all pairs of frequencies from 0.5 to 20 Hz. RESULTS: Isoflurane caused two peaks in the α (6-13 Hz) and slow δ (<1 Hz) regions of the bicoherence matrix diagonal. Higher concentrations of isoflurane shifted the α peak to lower frequencies [11.3 (0.9) Hz at 0.3% to 7.1 (1.2) Hz at 1.5%], as has been previously observed in the power spectra. Outside the diagonal, we also found a significant α peak that was phase-coupled to the slow δ waves; higher concentrations of isoflurane shifted this peak to lower frequencies [10.8 (1.2) to 7.7 (0.7) Hz]. CONCLUSIONS: Isoflurane caused cross-frequency coupling between α and slow δ waves. Increasing isoflurane concentration slowed the α frequencies where the coupling had occurred. This phenomenon of α-δ coupling suggests that slow cortical oscillations organize the higher α band activity, which is consistent with other studies in natural sleep.

A mechanism for ultra-slow oscillations in the cortical default network.

When the brain is in its noncognitive "idling" state, functional MRI measurements reveal the activation of default cortical networks whose activity is suppressed during cognitive processing. This default or background mode is characterized by ultra-slow BOLD oscillations (∼0.05 Hz), signaling extremely slow cycling in cortical metabolic demand across distinct cortical regions. Here we describe a model of the cortex which predicts that slow cycling of cortical activity can arise naturally as a result of nonlinear interactions between temporal (Hopf) and spatial (Turing) instabilities. The Hopf instability is triggered by delays in the inhibitory postsynaptic response, while the Turing instability is precipitated by increases in the strength of the gap-junction coupling between interneurons. We comment on possible implications for slow dendritic computation and information processing.

The role of connexin36 gap junctions in modulating the hypnotic effects of isoflurane and propofol in mice.

Gap junction blockade is a possible mechanism by which general anaesthetic drugs cause unconsciousness. We measured the sensitivity of connexin36 knockout mice to the hypnotic effects of isoflurane and propofol. The experimental endpoint was recovery of the righting reflex of the anaesthetised animals during 0.2% step-reductions in isoflurane concentration, or following intraperitoneal injection of propofol (100 mg.kg(-1) ). Connexin36 knockout animals were more sensitive to the hypnotic effects of isoflurane than 'normal' wild-type animals. The half maximal effective concentration (EC50) for recovery of righting reflex was 0.37% for connexin36 knockout vs 0.49% for wild-type animals (p < 0.001). For propofol, connnexin36 knockout animals showed more rapid loss of righting reflex than wild-type animals (mean (SD) 2.8 (0.13) vs 3.8 (0.27) min); and young (< 60 days) connexin36 knockout animals remained anaesthetised for longer than young wild-type mice (47.2 (2.9) vs 30.5 (1.7) min; p < 0.00001). These findings suggest that the hypnotic effects of anaesthetic drugs may be moderately enhanced by gap junction blockade.

Changes in airway configuration with different head and neck positions using magnetic resonance imaging of normal airways: a new concept with possible clinical applications.

BACKGROUND: The sniffing position is often considered optimal for direct laryngoscopy. Another concept of airway configuration involving a laryngeal vestibule axis and two curves has also been suggested. We investigated whether this theory can be supported mathematically and if it supports the sniffing position as being optimal for direct laryngoscopy. METHODS: Magnetic resonance imaging scans were performed in 42 normal adult volunteers. The airway passage was divided into two curves-primary (oro-pharyngeal curve) and secondary (pharyngo-glotto-tracheal curve). Airway configuration was evaluated in the neutral, extension, head lift, and sniffing positions. The airway passage, point of inflection (where the two curves meet), its tangent, and the line of sight were plotted on each scan. RESULTS: The point of inflection lay within the laryngeal vestibule in all positions. The head lift and sniffing positions caused the tangent to the point of inflection to approximate the horizontal plane. The sniffing, extension, and head lift positions caused a reduction in the area between the line of sight and the airway curve compared with the neutral position. CONCLUSIONS: A two-curve theory is proposed as a basis for explaining airway configuration. The changes in these curves with head and neck positioning support the sniffing position as optimal for direct laryngoscopy. Application of this new concept to other forms of laryngoscopy should be investigated.

Modeling brain activation patterns for the default and cognitive states.

We argue that spatial patterns of cortical activation observed with EEG, MEG and fMRI might arise from spontaneous self-organisation of interacting populations of excitatory and inhibitory neurons. We examine the dynamical behavior of a mean-field cortical model that includes chemical and electrical (gap-junction) synapses, focusing on two limiting cases: the "slow-soma" limit with slow voltage feedback from soma to dendrite, and the "fast-soma" limit in which the feedback action of soma voltage onto dendrite reversal potentials is instantaneous. For slow soma-dendrite feedback, we find a low-frequency (approximately 1 Hz) dynamic Hopf instability, and a stationary Turing instability that catalyzes formation of patterned distributions of cortical firing-rate activity with pattern wavelength approximately 2 cm. Turing instability can only be triggered when gap-junction diffusion between inhibitory neurons is strong, but patterning is destroyed if the tonic level of subcortical excitation is raised sufficiently. Interaction between the Hopf and Turing instabilities may describe the non-cognitive background or "default" state of the brain, as observed by BOLD imaging. In the fast-soma limit, the model predicts a high-frequency Hopf (approximately 35 Hz) instability, and a traveling-wave gamma-band instability that manifests as a 2-D standing-wave pattern oscillating in place at approximately 30 Hz. Small levels of inhibitory diffusion enhance and broaden the definition of the gamma antinodal regions by suppressing higher-frequency spatial modes, but gamma emergence is not contingent on the presence of inhibitory gap junctions; higher levels of diffusion suppress gamma activity. Fast-soma instabilities are enhanced by increased subcortical stimulation. Prompt soma-dendrite feedback may be an essential component of the genesis and large-scale cortical synchrony of gamma activity observed at the point of cognition.

Spinodal decomposition in a mean-field model of the cortex: Emergence of hexagonally symmetric activation patterns.

Spinodal decomposition is a well-known pattern-forming mechanism in metallurgic alloys, semiconductor crystals, and colloidal gels. In metallurgy, if a heated sample of a homogeneous Zn-Al alloy is suddenly quenched below a critical temperature, then the sample can spontaneously precipitate into inhomogenous textures of Zn- and Al-rich regions with significantly altered material properties such as ductility and hardness. Here we report on our recent discovery that a two-dimensional model of the human cortex with inhibitory diffusion can, under particular homogeneous initial conditions, exhibit a form of nonconserved spinodal decomposition in which regions of the cortex self-organize into hexagonally distributed binary patches of activity and inactivity. Fine-scale patterns precipitate rapidly, and then the dynamics slows to render coarser-scale shapes which can ripen into a range of slowly evolving patterns including mazelike labyrinths, hexagonal islands and continents, nucleating "mitotic cells" which grow to a critical size then subdivide, and inverse nucleations in which quiescent islands are surrounded by a sea of activity. One interesting class of activity coalesces into a soliton-like narrow ribbon of depolarization that traverses the cortex at ∼4cm/s. We speculate that this may correspond to the thus far unexplained interictal waves of cortical activation that precede grand-mal seizure in an epileptic event. We note that spinodal decomposition is quite distinct from the Turing mechanism for symmetry breaking in cortex investigated in earlier work by the authors [Steyn-Ross et al., Phys. Rev. E 76, 011916 (2007)PLEEE81539-375510.1103/PhysRevE.76.011916].

Permutation entropy of the electroencephalogram: a measure of anaesthetic drug effect.

BACKGROUND: It would be useful to have an open-source electroencephalographic (EEG) index of gamma-amino-butyric acid (GABA)-ergic anaesthetic drug effect that is resistant to eye-blink artifact, responds rapidly to changes in EEG pattern, and can be linked to underlying neurophysiological and neuropharmacological mechanisms that control the conscious state. METHODS: The EEG waveform can be described as a sequence of ordinal patterns. The permutation entropy (PE) describes the relative occurrence of each of these patterns. It is high ( approximately 1.0) when the signal has predominantly high frequencies and low ( approximately 0.4) when the signal consists of only low frequencies. The response of the PE to various computer-generated EEG-like waveforms was assessed. A composite PE index (CPEI) was developed, which was the sum of two simple PEs and included a small measurement-noise threshold (0.5 microV). We also applied the CPEI to two small pilot EEG data sets from patients receiving sevoflurane (n=21) or propofol (n=9) anaesthesia. RESULTS: With minimal pre-processing or artifact rejection, the CPEI reliably tracked the anaesthetic-related EEG changes, namely loss of high frequencies, spindle-like waves, and delta waves. Using NONMEM, it was possible to construct adequate pharmacokinetic-pharmacodynamic models from the data. The CPEI was comparable with models derived using the bispectral index [BIS R(2)=0.88 (0.08) vs CPEI R(2)=0.91 (0.06) for the propofol data] and M-entropy indices [M-entropy R(2)=0.91 (0.06) vs CPEI R(2)=0.87 (0.09) for the sevoflurane data]. CONCLUSIONS: PE of the EEG shows promise as a simple measure of GABAergic anaesthetic drug effect.

Gap junctions mediate large-scale Turing structures in a mean-field cortex driven by subcortical noise.

One of the grand puzzles in neuroscience is establishing the link between cognition and the disparate patterns of spontaneous and task-induced brain activity that can be measured clinically using a wide range of detection modalities such as scalp electrodes and imaging tomography. High-level brain function is not a single-neuron property, yet emerges as a cooperative phenomenon of multiply-interacting populations of neurons. Therefore a fruitful modeling approach is to picture the cerebral cortex as a continuum characterized by parameters that have been averaged over a small volume of cortical tissue. Such mean-field cortical models have been used to investigate gross patterns of brain behavior such as anesthesia, the cycles of natural sleep, memory and erasure in slow-wave sleep, and epilepsy. There is persuasive and accumulating evidence that direct gap-junction connections between inhibitory neurons promote synchronous oscillatory behavior both locally and across distances of some centimeters, but, to date, continuum models have ignored gap-junction connectivity. In this paper we employ simple mean-field arguments to derive an expression for D2, the diffusive coupling strength arising from gap-junction connections between inhibitory neurons. Using recent neurophysiological measurements reported by Fukuda [J. Neurosci. 26, 3434 (2006)], we estimate an upper limit of D2 approximately 0.6cm2. We apply a linear stability analysis to a standard mean-field cortical model, augmented with gap-junction diffusion, and find this value for the diffusive coupling strength to be close to the critical value required to destabilize the homogeneous steady state. Computer simulations demonstrate that larger values of D2 cause the noise-driven model cortex to spontaneously crystalize into random mazelike Turing structures: centimeter-scale spatial patterns in which regions of high-firing activity are intermixed with regions of low-firing activity. These structures are consistent with the spatial variations in brain activity patterns detected with the BOLD (blood oxygen-level-dependent) signal detected with magnetic resonance imaging, and may provide a natural substrate for synchronous gamma-band rhythms observed across separated EEG (electroencephalogram) electrodes.

White-noise susceptibility and critical slowing in neurons near spiking threshold.

We present mathematical and simulation analyses of the below-threshold noisy response of two biophysically motivated models for excitable membrane due to H. R. Wilson: a squid axon ("resonator") and a human cortical neuron ("integrator"). When stimulated with a low-intensity white noise superimposed on a dc control current, both membrane types generate voltage fluctuations that exhibit critical slowing down--that is, the voltage responsiveness to noisy input currents grows in amplitude while slowing in frequency--as the membrane approaches spiking threshold from below. We define threshold unambiguously as that dc current that renders a zero real eigenvalue for the Jacobian matrix for the integrator neuron, and, for the resonator neuron, as the dc current that gives a complex eigenvalue pair whose real part is zero. Using a linear Ornstein-Uhlenbeck analysis, we give exact small-noise expressions for the variance, power spectrum, and correlation function of the voltage fluctuations, and we derive the scaling laws for the divergence of susceptibility and correlation times for approach to threshold. We compare these predictions with numerical simulations of the nonlinear stochastic equations, and demonstrate that, provided the white-noise perturbations are kept sufficiently small, the linearized theory works well. These predictions should be testable in the laboratory using a current-clamped cell configuration. If confirmed, then the proximity of a neuron to its spike-transition point can be judged by measuring its subthreshold susceptibility to white-noise stimulation. We postulate that such temporally correlated fluctuations could provide a means of subthreshold signaling via gap-junction connections with neighboring neurons.