Statistical modeling of behavioral dynamics during propofol-induced loss of consciousness.

BACKGROUND: Accurate quantitative analysis of the changes in responses to external stimuli is crucial for characterizing the timing of loss and recovery of consciousness induced by anesthetic drugs. We studied induction and emergence from unconsciousness achieved by administering a computer-controlled infusion of propofol to ten human volunteers. We evaluated loss and recovery of consciousness by having subjects execute every 4s two interleaved computer delivered behavioral tasks: responding to verbal stimuli (neutral words or the subject's name), or less salient stimuli of auditory clicks. NEW METHOD: We analyzed the data using state-space methods. For each stimulus type the observation model is a two-stage binomial model and the state model is two dimensional random walk in which one cognitive state governs the probability of responding and the second governs the probability of correctly responding given a response. We fit the model to the experimental data using Bayesian Monte Carlo methods. RESULTS: During induction subjects lost responsiveness to less salient clicks before losing responsiveness to the more salient verbal stimuli. During emergence subjects regained responsiveness to the more salient verbal stimuli before regaining responsiveness to the less salient clicks. COMPARISON WITH EXISTING METHOD(S): The current state-space model is an extension of previous model used to analyze learning and behavioral performance. In this study, the probability of responding on each trial is obtained separately from the probability of behavioral performance. CONCLUSIONS: Our analysis provides a principled quantitative approach for defining loss and recovery of consciousness in experimental studies of general anesthesia.

A transition in brain state during propofol-induced unconsciousness.

Rhythmic oscillations shape cortical dynamics during active behavior, sleep, and general anesthesia. Cross-frequency phase-amplitude coupling is a prominent feature of cortical oscillations, but its role in organizing conscious and unconscious brain states is poorly understood. Using high-density EEG and intracranial electrocorticography during gradual induction of propofol general anesthesia in humans, we discovered a rapid drug-induced transition between distinct states with opposite phase-amplitude coupling and different cortical source distributions. One state occurs during unconsciousness and may be similar to sleep slow oscillations. A second state occurs at the loss or recovery of consciousness and resembles an enhanced slow cortical potential. These results provide objective electrophysiological landmarks of distinct unconscious brain states, and could be used to help improve EEG-based monitoring for general anesthesia.

Electroencephalogram signatures of loss and recovery of consciousness from propofol.

Unconsciousness is a fundamental component of general anesthesia (GA), but anesthesiologists have no reliable ways to be certain that a patient is unconscious. To develop EEG signatures that track loss and recovery of consciousness under GA, we recorded high-density EEGs in humans during gradual induction of and emergence from unconsciousness with propofol. The subjects executed an auditory task at 4-s intervals consisting of interleaved verbal and click stimuli to identify loss and recovery of consciousness. During induction, subjects lost responsiveness to the less salient clicks before losing responsiveness to the more salient verbal stimuli; during emergence they recovered responsiveness to the verbal stimuli before recovering responsiveness to the clicks. The median frequency and bandwidth of the frontal EEG power tracked the probability of response to the verbal stimuli during the transitions in consciousness. Loss of consciousness was marked simultaneously by an increase in low-frequency EEG power (<1 Hz), the loss of spatially coherent occipital alpha oscillations (8-12 Hz), and the appearance of spatially coherent frontal alpha oscillations. These dynamics reversed with recovery of consciousness. The low-frequency phase modulated alpha amplitude in two distinct patterns. During profound unconsciousness, alpha amplitudes were maximal at low-frequency peaks, whereas during the transition into and out of unconsciousness, alpha amplitudes were maximal at low-frequency nadirs. This latter phase-amplitude relationship predicted recovery of consciousness. Our results provide insights into the mechanisms of propofol-induced unconsciousness, establish EEG signatures of this brain state that track transitions in consciousness precisely, and suggest strategies for monitoring the brain activity of patients receiving GA.

Assessing the effects of pharmacological agents on respiratory dynamics using time-series modeling.

Developing quantitative descriptions of how stimulant and depressant drugs affect the respiratory system is an important focus in medical research. Respiratory variables-respiratory rate, tidal volume, and end tidal carbon dioxide-have prominent temporal dynamics that make it inappropriate to use standard hypothesis-testing methods that assume independent observations to assess the effects of these pharmacological agents. We present a polynomial signal plus autoregressive noise model for analysis of continuously recorded respiratory variables. We use a cyclic descent algorithm to maximize the conditional log likelihood of the parameters and the corrected Akaike's information criterion to choose simultaneously the orders of the polynomial and the autoregressive models. In an analysis of respiratory rates recorded from anesthetized rats before and after administration of the respiratory stimulant methylphenidate, we use the model to construct within-animal z-tests of the drug effect that take account of the time-varying nature of the mean respiratory rate and the serial dependence in rate measurements. We correct for the effect of model lack-of-fit on our inferences by also computing bootstrap confidence intervals for the average difference in respiratory rate pre- and postmethylphenidate treatment. Our time-series modeling quantifies within each animal the substantial increase in mean respiratory rate and respiratory dynamics following methylphenidate administration. This paradigm can be readily adapted to analyze the dynamics of other respiratory variables before and after pharmacologic treatments.

Decomposition of neurological multivariate time series by state space modelling.

Decomposition of multivariate time series data into independent source components forms an important part of preprocessing and analysis of time-resolved data in neuroscience. We briefly review the available tools for this purpose, such as Factor Analysis (FA) and Independent Component Analysis (ICA), then we show how linear state space modelling, a methodology from statistical time series analysis, can be employed for the same purpose. State space modelling, a generalization of classical ARMA modelling, is well suited for exploiting the dynamical information encoded in the temporal ordering of time series data, while this information remains inaccessible to FA and most ICA algorithms. As a result, much more detailed decompositions become possible, and both components with sharp power spectrum, such as alpha components, sinusoidal artifacts, or sleep spindles, and with broad power spectrum, such as FMRI scanner artifacts or epileptic spiking components, can be separated, even in the absence of prior information. In addition, three generalizations are discussed, the first relaxing the independence assumption, the second introducing non-stationarity of the covariance of the noise driving the dynamics, and the third allowing for non-Gaussianity of the data through a non-linear observation function. Three application examples are presented, one electrocardigram time series and two electroencephalogram (EEG) time series. The two EEG examples, both from epilepsy patients, demonstrate the separation and removal of various artifacts, including hum noise and FMRI scanner artifacts, and the identification of sleep spindles, epileptic foci, and spiking components. Decompositions obtained by two ICA algorithms are shown for comparison.

Correcting for serial dependence in studies of respiratory dynamics.

Understanding the physiological impact of drug treatments on patients is important in assessing their performance and determining possible side effects. While this effect might be best determined in individual subjects, conventional methods assess treatment performance by averaging a physiological measure of interest before and after drug administration for n subjects. Summarizing large numbers of time-series observations in two means for each subject in this way results in significant information loss. Treatment effect can instead be analyzed in individual subjects. Because serial dependence of observations from the same animal must then be considered, methods that assume independence of observations, such as the t-test and z-test, cannot be used. We address this issue in the case of respiratory data collected from anesthetized rats that were injected with a dopamine agonist. In order to accurately assess treatment effect in time-series data, we begin by formulating a method of conditional likelihood maximization to estimate the parameters of a first-order autoregressive (AR) process. We show that treatment effect of a dopamine agonist can be determined while incorporating serial effect into the analysis. In addition, while maximum likelihood estimators of a large sample with independent observations may converge to an asymptotically normal distribution, this result of large sample theory may not hold when observations are serially dependent. In this case, a parametric bootstrap comparison can be used to approximate an appropriate measure of uncertainty.

Phase-based measures of cross-frequency coupling in brain electrical dynamics under general anesthesia.

The state of general anesthesia (GA) is associated with an increase in spectral power in scalp electroencephalogram (EEG) at frequencies below 40 Hz, including spectral peaks in the slow oscillation (SO, 0.1-1 Hz) and α (8-14 Hz) bands. Because conventional power spectral analyses are insensitive to possible cross-frequency coupling, the relationships among the oscillations at different frequencies remain largely unexplored. Quantifying such coupling is essential for improving clinical monitoring of anesthesia and understanding the neuroscience of this brain state. We tested the usefulness of two measures of cross-frequency coupling: the bispectrum-derived SynchFastSlow, which is sensitive to phase-phase coupling in different frequency bands, and modulogram analysis of coupling between SO phase and α rhythm amplitude. SynchFastSlow, a metric that is used in clinical depth-of-anesthesia monitors, showed a robust correlation with the loss of consciousness at the induction of propofol GA, but this could be largely explained by power spectral changes without considering cross-frequency coupling. Modulogram analysis revealed two distinct modes of cross-frequency coupling under GA. The waking and two distinct states under GA could be discriminated by projecting in a two-dimensional phase space defined by the SynchFastSlow and the preferred SO phase of α activity. Our results show that a stereotyped pattern of phase-amplitude coupling accompanies multiple stages of anesthetic-induced unconsciousness. These findings suggest that modulogram analysis can improve EEG based monitoring of brain state under GA.

Bayesian analysis of trinomial data in behavioral experiments and its application to human studies of general anesthesia.

Accurate quantification of loss of response to external stimuli is essential for understanding the mechanisms of loss of consciousness under general anesthesia. We present a new approach for quantifying three possible outcomes that are encountered in behavioral experiments during general anesthesia: correct responses, incorrect responses and no response. We use a state-space model with two state variables representing a probability of response and a conditional probability of correct response. We show applications of this approach to an example of responses to auditory stimuli at varying levels of propofol anesthesia ranging from light sedation to deep anesthesia in human subjects. The posterior probability densities of model parameters and the response probability are computed within a Bayesian framework using Markov Chain Monte Carlo methods.

Robust time-varying multivariate coherence estimation: application to electroencephalogram recordings during general anesthesia.

Coherence analysis characterizes frequency-dependent covariance between signals, and is useful for multivariate oscillatory data often encountered in neuroscience. The global coherence provides a summary of coherent behavior in high-dimensional multivariate data by quantifying the concentration of variance in the first mode of an eigenvalue decomposition of the cross-spectral matrix. Practical application of this useful method is sensitive to noise, and can confound coherent activity in disparate neural populations or spatial locations that have a similar frequency structure. In this paper we describe two methodological enhancements to the global coherence procedure that increase robustness of the technique to noise, and that allow characterization of how power within specific coherent modes change through time.

Asymmetric control mechanisms of bimanual coordination: an application of directed connectivity analysis to kinematic and functional MRI data.

Mirror-symmetrical bimanual movement is more stable than parallel bimanual movement. This is well established at the kinematic level. We used functional MRI (fMRI) to evaluate the neural substrates of the stability of mirror-symmetrical bimanual movement. Right-handed participants (n=17) rotated disks with their index fingers bimanually, both in mirror-symmetrical and asymmetrical parallel modes. We applied the Akaike causality model to both kinematic and fMRI time-series data. We hypothesized that kinematic stability is represented by the extent of neural "cross-talk": as the fraction of signals that are common to controlling both hands increases, the stability also increases. The standard deviation of the phase difference for the mirror mode was significantly smaller than that for the parallel mode, confirming that the former was more stable. We used the noise-contribution ratio (NCR), which was computed using a multivariate autoregressive model with latent variables, as a direct measure of the cross-talk between both the two hands and the bilateral primary motor cortices (M1s). The mode-by-direction interaction of the NCR was significant in both the kinematic and fMRI data. Furthermore, in both sets of data, the NCR from the right hand (left M1) to the left (right M1) was more prominent than vice versa during the mirror-symmetrical mode, whereas no difference was observed during parallel movement or rest. The asymmetric interhemispheric interaction from the left M1 to the right M1 during symmetric bimanual movement might represent cortical-level cross-talk, which contributes to the stability of symmetric bimanual movements.

Akaike causality in state space. Instantaneous causality between visual cortex in fMRI time series.

We present a new approach of explaining instantaneous causality in multivariate fMRI time series by a state space model. A given single time series can be divided into two noise-driven processes, a common process shared among multivariate time series and a specific process refining the common process. By assuming that noises are independent, a causality map is drawn using Akaike noise contribution ratio theory. The method is illustrated by an application to fMRI data recorded under visual stimulation.

Modelling non-stationary variance in EEG time series by state space GARCH model.

We present a new approach to modelling non-stationarity in EEG time series by a generalized state space approach. A given time series can be decomposed into a set of noise-driven processes, each corresponding to a different frequency band. Non-stationarity is modelled by allowing the variances of the driving noises to change with time, depending on the state prediction error within the state space model. The method is illustrated by an application to EEG data recorded during the onset of anaesthesia.