Electroencephalographic recordings (EEG) present an opportunity to monitor changes
in human brain electrical activity during changing states of consciousness like sleep
or general anesthesia. Frontal EEG recordings during surgical interventions with anesthetic-induced
unconsciousness help to estimate the patients' level of (un)consciousness.
EEG-based monitoring of the level of consciousness: commercial devices
The classical way to extract information from the recorded EEG relevant for assessment
of the level of anesthesia is the application of algorithms that evaluate changes
in the oscillatory behavior of the EEG that is mainly derived from frontal EEG montages
placed on the patients' forehead. These calculations are most often performed in the
frequency domain, i.e., after transformation of the signal, e.g., by the Fourier Transform.
The most prominent commercial system, the bispectral index (BIS, Medtronic, Dublin,
Ireland) evaluates changes in the log ratio of the 30 to 47 Hz and 11 to 20 Hz EEG
band power (BetaRatio) as well as a ratio of the sum of bispectrum peaks in the 0.5
to 47 Hz and the 40 to 47 Hz range (SynchFastSlow) (Rampil, 1998). The bispectrum
presents a higher order spectrum that evaluates the phase correlation of different
frequency components and is able to identify nonlinear signal properties (Rampil,
1998). The BetaRatio subparameter outperforms SynchFastSlow and BIS in separating
consciousness from unconsciousness (Schneider et al., 2004). SynchFastSlow dominates
BIS calculation during surgical levels of anesthesia (Rampil, 1998). State and Response
entropy (GE Healthcare, Chicago, IL) evaluate changes in the shape of the power spectrum
(Viertio-Oja et al., 2004). Other devices like the CSI (Danmeter, Odense, Denmark),
IoC (Morpheus Medical, Barcelona, Spain), or qCON (Quantium Medical, Mataro, Spain)
use ratios of EEG band power (Jensen et al., 2006, 2014; Revuelta et al., 2008). The
IoC also processes information from the EEG after transformation to a time series
of symbols (Revuelta et al., 2008). The Narcotrend (Narcotrend, Hannover, Germany)
utilizes information from the spectral domain as well from autoregressive modeling
in the time domain (Kreuer and Wilhelm, 2006). The PSI from the SEDLine monitor (Masimo,
Irvine, CA) processes spectral power from different frequency bands as well as interhemispheric
power gradients and synchrony (Prichep et al., 2004). The Brain Anesthesia Response
(BAR) monitor (Cortical Dynamics Ltd., North Perth, Australia) takes a different approach.
It generates its index by modeling EEG dynamics (Liley et al., 2010b). These devices
have in common, that combining the subparameters is performed by a proprietary algorithm,
and hence the contribution of each parameter to the index is not known. In general,
these indices track the suppression of high frequency EEG activity and the activation
of low frequent oscillations, as triggered by many common anesthetics (Brown et al.,
2010). By using spectral power, or parameters derived from it, as key parameters,
the monitoring systems may dismiss signal information content by neglecting the phase
component of the signals' frequency and only exploiting information from the amplitude
spectrum (Callegaro, 2012). Further, the devices susceptibility to muscle activity
(Messner et al., 2003; Schuller et al., 2015), especially by including high EEG frequencies
as well as the time delay, necessary for index calculation (Pilge et al., 2006; Zanner
et al., 2009; Kreuzer et al., 2012) may present a limiting factor in performance to
reliably track the anesthetic state.
EEG-based consciousness monitoring in research: time-domain analytical approaches
More recent approaches to extract information from the EEG at different levels of
anesthesia use nonlinear parameters that reflect signal information content, complexity,
and/or predictability. These approaches seem capable to extract non-linear information
from the signal as investigated with surrogate techniques, while linear measures like
spectral entropy or the Hurst exponent did not detect these non-linearities (Jordan
et al., 2009; Anier et al., 2010). In EEG and anesthesia research the most prominent
players are approximate entropy (ApEn) (Pincus, 1991; Bruhn et al., 2000) and permutation
entropy (PeEn) (Bandt and Pompe, 2002; Jordan et al., 2008; Olofsen et al., 2008)
for single channel analysis and cross approximate entropy (Pincus Steven et al., 1996;
Hudetz, 2002; Kreuzer et al., 2010), (symbolic) transfer entropy (Schreiber, 2000;
Imas et al., 2005; Staniek and Lehnertz, 2008; Jordan et al., 2013), or order recurrence
plots (Groth, 2006) for bivariate analysis. These measures are applied to the EEG
time domain, usually after band-pass filtering of the EEG to a wide frequency range
with a low pass filter set to around 25 to 30 Hz to limit EEG signal contamination
by electromyographic activity (EMG). Frontal EMG activity can occur in the entire
frequency range but seems to peak between 25 and 30 Hz (Goncharova et al., 2003).
The mentioned entropy measures usually define consecutive amplitude values or their
ranks as pieces of information, called motifs. The EEG is then represented as series
of motifs. The user can define the length m of a motif (the number of amplitude values
it is generated from), a time lag parameter τ (to consider only each τth amplitude
value to define a motif of length m), and a shift k (to shift k amplitude values from
the first amplitude value of the previous motif to start generation of the next motif
of length m with lag τ). Figure 1 presents the impact of k and τ on motif generation.
Figure 1
In order to generate a motif as used for the nonlinear, entropy based approaches,
motive length m, time delay τ, and shift k have to be defined. The parameter k defines
the shift. For a k = 1, the first motif of length m = 3 starts at data point i, and
the second at i+k = 2 and so on (red). For a k of 2, the first motif would start at
data point i, and the second at i+k = 3, and so on (yellow). The parameter τ defines
how many data points are left out to generate the motif. E.g., for a τ = 1 and m =
3, the data points i, i+1, and i+2 are used to generate the motif (light blue). For
a τ = 1, the data points i, i+2, and i+4 are used (pink).
The transfer entropies that quantify directed information flow include another parameter
δ (Staniek and Lehnertz, 2008) to define transfer lags or transmission time of the
motif of information between the two channels. The time lag parameters δ may evaluate
changes in signal information roughly associated with a certain frequency range. When
compared to spectral approaches and commercial monitors, the univariate measures ApEn
and PeEn showed higher performance in distinguishing EEG recorded during consciousness
from EEG recorded during unconsciousness and to reflect different levels of general
anesthesia (Bruhn et al., 2000; Jordan et al., 2008; Liang et al., 2015). A newly
proposed, multimodal index, integrates PeEn to separate consciousness from unconsciousness
and ApEn to scale different levels of anesthesia (Schneider et al., 2014). The use
of the bivariate transfer entropies revealed a loss of cortical feedback connectivity
as a key mechanism of anesthetic-induced unconsciousness that is universal for most
anesthetics (Ku et al., 2011; Jordan et al., 2013; Lee et al., 2013; Ranft et al.,
2016). Interestingly the parameter settings were targeted toward the EEG beta frequency
range. This frequency range may play an important role in synchronizing different
cortical regions (von Stein and Sarnthein, 2000; Bassett et al., 2009; Hipp et al.,
2011). So although these nonlinear parameters are applied to a wide frequency range,
their intrinsic setting defines the information to be extracted from the signal.
Different entropies evaluate different properties
These findings are a strong claim to include nonlinear analysis techniques in commercial
“depth of anesthesia” monitoring as well as to extend the EEG electrode layout to
at least one electrode placed in parietal or occipital regions to be able to monitor
the loss of cortical feedback activity. Further, there is something to be mentioned
regarding “entropy analysis” in anesthesiology. Often, for instance at conferences
there is just a discussion about “entropy” analysis without defining what method really
has been used. These measures, even if they share the term “entropy” analyze different
signal features. A very prominent example is the spectral entropy, a measure evaluating
the change in shape of the power spectrum (Viertio-Oja et al., 2004). It evaluates
the changes in the frequency domain, so it cannot be compared to analytical techniques
in the time domain. Another example is the difference between ApEn and PeEn. The ordinal
PeEn evaluates the probability distribution of amplitude rank patterns in the signal,
while ApEn evaluates the probability of similar absolute amplitude patterns detected
in the signal remain similar if they are extended by one more amplitude value. In
order to define similarity of two absolute amplitude values, the algorithm contains
a tolerance that acts like a low pass filter on the signal, while the formation of
rank pattern in the PeEn is more like a high pass that removes slow underlying trends
in amplitude from the signal. Figure 2 presents a graphical example of the described
differences. As mentioned earlier, ApEn and PeEn have different strengths. ApEn seems
strong in scaling different levels of unconsciousness, while PeEn presents a strong
parameter to separate consciousness from unconsciousness (Schneider et al., 2014).
Figure 2
Left: in order to calculate the spectral entropy as for example used in the GE Entropy
Module, the EEG power spectrum is calculated from the recording. The spectral entropy
value reflects the shape of the power spectrum. The more uniformly distributed the
power is among the frequencies, the higher is the spectral entropy value. Right: permutation
entropy (PeEn, top) and approximate entropy (ApEn, bottom) in contrast are directly
derived from the EEG time series. For the ordinal PeEn motifs of length m are represented
as a series of ranks, with the lowest amplitude value being equal to rank 0 and the
highest amplitude value being equal to rank m−1.
Hence, the EEG time series is converted to a series of rank patterns. The more uniform
the probability distribution of the m! possible rank patterns, the higher is PeEn.
ApEn evaluates the predictability of a time series by evaluating the occurrence of
similar patterns of length m. Similar means that the maximum difference of the EEG
amplitude values is smaller than a tolerance r. The concept of ApEn is to evaluate
the probability, that if a similar pattern of length m was detected, the patterns
extended to m+1 will be similar as well. The higher this probability, the lower ApEn
will be.
Proposed relationships between EEG frequency and communication
Although the nonlinear approaches seem to reflect the level of consciousness in a
superior way, there is a strong point in favor of continuing to use spectral analyses,
together with the aforementioned approaches to optimize monitoring. It is the assumption
that (frontal) EEG oscillations of certain frequencies seem to correlate with interactions
of the monitored cortical area with other cortical or subcortical areas. In general,
the EEG mainly reflects cortical activity (Fisch and Spehlmann, 1999), but this cortical
activity also carries information from subcortical regions. Frontal EEG theta power
for instance seems associated with working memory (Klimesch et al., 1994; Summerfield
and Mangels, 2005). The prominent alpha peak that develops in the EEG power spectrum
during general anesthesia is potentially caused by synchronous activity in the thalamocortical
loop (John and Prichep, 2005; Ching et al., 2010). But this thalamocortical relationship
and the contribution of each region to alpha EEG is controversially discussed, as
nicely reviewed by Liley and coworkers. The thalamus may not present the principal
source because thalamocortical projections are sparse, the amplitude of thalamocortical
excitatory postsynaptic potentials is small, the corticocortical activity is more
coherent than thalamocortical activity, the isolated cortex is able to generate rhythmic
oscillations, and drugs may modulate alpha oscillations in cortex and thalamus in
a different way (Liley et al., 2010a). As mentioned earlier, activity in EEG beta-band
may play a role in synchronizing cortical regions (von Stein et al., 1999; John and
Prichep, 2005; Bassett et al., 2009; Hipp et al., 2011). Hence changes in these frequency
bands' spectral power may help to understand anesthetic-induced changes in brain activity
among different regions and possibly target different components of general anesthesia.
These relationships between EEG frequency and the brain's communication structure
may help future research to improve EEG based patient monitoring in anesthesia with
a new focus on adding an “anesthesia quality” component to monitoring, i.e., to associate
EEG recorded during anesthesia maintenance and emergence with adverse outcomes like
pain or delirium following anesthesia.
Correlation of intraoperative EEG markers and adverse outcomes
The current monitoring systems as well as the presented results using nonlinear approaches
to EEG-based monitoring focus on a reliable separation of different hypnotic levels
that range from “fully awake” to “(burst) suppression.” Hence, these monitoring systems/approaches
may be able to prevent too deep levels of general anesthesia. Prevention of too deep
anesthesia may help to reduce delirious outcomes (Chan et al., 2013). But there is
no algorithm component that specifically deals with the detection of intraoperative
EEG markers that may be associated with postoperative adverse outcomes. There seems
increasing evidence that investigation of EEG alpha-band activity may present a good
start to research intraoperative EEG and its association with post-anesthetic adverse
outcomes, at least for the commonly used propofol and inhaled ethers. For anesthesia
emergence, results suggest that returning from anesthesia-induced unconsciousness
may be more complex than anesthesia induction. The patients' EEG can follow different
emergence trajectories that put patients at higher or lower risk when it comes to
adverse outcomes in the postoperative care unit. Patients that abruptly transition
from spectral EEG patterns of unconsciousness to spectral “wake” EEG seem more vulnerable
to express pain and delirium in the postoperative care unit than patients that show
episodes of non-slow wave anesthesia during emergence (Chander et al., 2014; Hight
et al., 2014; Garcia et al., 2016; Kreuzer et al., 2017). During anesthesia maintenance
patients most often develop a so called alpha peak in frontal EEG for the most common
anesthetics propofol and sevoflurane that seems to reflect reverberations in the thalamocortical
loop at least in part caused by hyperpolarization of the thalamus (Akeju et al., 2014b).
Evaluation of spectral alpha peak properties may help to estimate “anesthesia quality.”
Strong surgical stimulation can cause a reduction of the peak (Kochs et al., 1994)
and may even lead to disappearance of the peak. Because of the possible association
of alpha oscillations with the thalamus, this reduction may be caused by desynchronization
of thalamocortical activity that may represent arousal (McCormick and Bal, 1997).
Patients that are not expressing strong alpha power during anesthesia or react to
surgical stimulation in a stronger fashion may be at higher risk of delirium in postoperative
care unit (PACU-D, unpublished data). Although PACU-D is a transient phenomenon current
results highlight the association with postoperative long-term complications (Card
et al., 2015; Garcia et al., 2016). Hence, avoiding or detecting PACU-D as early as
possible may help to decrease the risk of developing long-term adverse outcomes. Information
from the EEG alpha range may help to identify this subset of patients at risk. The
correlation of lower alpha power and PACU-D may reflect a patient population with
a “frailer” brain that is not able to maintain a state of stable thalamocortical synchronization.
So it would definitely make sense to additionally monitor the patients' EEG reaction
following surgical stimuli, adding a nociception component to EEG-based monitoring.
There is (almost) no EEG based (combined hypnosis and) analgesia/nociception monitoring
Hagihira et al. showed that bicoherence peaks around 10 Hz and around 20 Hz, that
are typical for gas anesthesia, decrease with noxious stimulation if no opioid is
given (Hagihira et al., 2004). But these observations have not been used for current
monitors of nociception. These devices use processed EEG like the BIS as subparameters
(Ellerkmann et al., 2013; Castro et al., 2016), a wide range of spectral band power
(Jensen et al., 2014), or non EEG information from heart rate variability (Ledowski
et al., 2013), modeled drug and opioid concentrations (Luginbühl et al., 2010), or
the polysynaptic spinal withdrawal reflex (Von Dincklage et al., 2012). One exception
is the BAR. It uses two measures, cortical state and cortical input that are designed
to reflect the hypnotic and analgesic component of anesthesia (Liley et al., 2010b).
The Cortical Dynamics website claims that BAR detect the effects of a range of analgesic
agents and hence lead the way toward a combined EEG-based analgesia and anesthesia
monitoring.
Besides the susceptibility of the intraoperative EEG alpha peak to stimulation, age
also influences EEG power. There is a negative absolute alpha power and total frontal
EEG power to age relationship (Klimesch, 1997; Purdon et al., 2015) and age presents
a risk factor for the development of delirious outcomes (Deiner and Silverstein, 2009)
after general anesthesia. Cortical thinning seems to occur with age (Fjell et al.,
2009). Consequently the number of (pyramidal) neurons and the number of synapses decreases
as well (Teplan, 2002). The decrease in volume and neurons may present a reason for
the observed reduction on total EEG power. As a consequence, the brain's communication
may become more fragile and less robust to influences like surgical stimuli. All these
associations indicate the usefulness to pay attention to what is happening to EEG
alpha oscillations during general anesthesia maintenance and emergence. Previous research
and commercial applications for monitoring anesthesia have not specifically focused
on this EEG frequency range, as mentioned earlier. The addition of information extracted
from the EEG alpha range may help to include a factor predictive for adverse outcomes
to “depth of anesthesia” monitoring. All the findings regarding adverse outcomes base
on frequency domain analyses. Additional information from nonlinear analytical approaches
in the time domain may help to optimize and improve intraoperative monitoring to identify
patients at risk for adverse outcomes in the future. While this article mainly deals
with the EEG alpha range, probably numerous other markers in other EEG frequencies
from frontal and non-frontal electrode locations exist that may help to optimize monitoring.
Further the described findings are probably not valid for certain drugs like (S-)ketamine
or dexmeditomitine that affect EEG activity in completely different ways than sevoflurane
or propofol (Maksimow et al., 2006; Akeju et al., 2014a).
I think that around 20 years after the introduction of EEG based anesthesia monitoring
to the operating room and ongoing optimization of analytical algorithms, the inclusion
to consider the well-being of the patient in the postoperative period seems the logical
next step. Recent and future findings from the correlation of intraoperative EEG (alpha)
activity may help to introduce a new generation of anesthesia monitoring. It may present
the transition from EEG-based “depth of anesthesia” to “quality of anesthesia” monitoring.
Author contributions
The author confirms being the sole contributor of this work and approved it for publication.
Conflict of interest statement
The author declares that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.