䡵 SPECIAL ARTICLE
Anesthesiology 2005; 102:447–71
The Anesthetic Cascade
A Theory of How Anesthesia Suppresses Consciousness
E. Roy John, Ph.D.,* Leslie S. Prichep, Ph.D.*
ADEQUATE surgical anesthesia must achieve three goals:
immobility, amnesia, and absence of awareness. After
the evidence of anesthetic lipophilicity was presented by
Meyer1 and Overton,2 it was widely assumed that all
these actions were accomplished at some unitary site.2 A
body of evidence has now accumulated demonstrating
that for many anesthetic agents, the dose required to
suppress consciousness exceeds the amnestic dose but
is substantially less then that required for surgical immo-
bility during noxious stimuli.3,4 This suggests that these
three dimensions may be mediated by different regions
of the central nervous system. As has been pointed out
by Rampil,5 the variability among anesthetics of the
ratios of concentrations needed to suppress conscious-
ness, to block memory, and to achieve surgical immobil-
ity further invalidate the unitary hypothesis.
A comprehensive explanation of the mechanism by
which anesthetics cause loss of consciousness (LOC) has
not yet been developed. Abundant in vitro and in vivo
evidence has been provided of effects of anesthetics on
a wide variety of molecular and cellular processes. Cam-
pagna et al.6 have recently provided a review of current
understanding of the molecular mechanisms of anesthe-
sia, summarizing evidence showing that inhaled anes-
thetics achieve immobilization by depressing the spinal
cord, whereas amnesic actions are mediated within the
brain. They document research indicating that subtle
differences in the clinical actions of inhaled anesthetics
may be attributed to distinct actions on a number of
critical molecular targets. Although this evidence makes
it clear that neuronal actions and interactions at many
different levels and in many different brain tissues are
altered or disrupted by anesthetic drugs, it does not
explain why these different more or less discrete effects
have the common global effect of causing LOC, which
we define as suppression of awareness. This article at-
tempts to provide such an explanation in terms of the
* Professor.
Received from the Department of Psychiatry, Brain Research Laboratories,
New York University School of Medicine, New York, New York, and the Nathan
S. Kline Psychiatric Research Institute, Orangeburg, New York. Submitted for
publication May 10, 2004. Accepted for publication September 28, 2004. Some
of the work cited was supported by grant Nos. APR 76-24662 and DAR 78-18772
from the National Science Foundation, Arlington, Virginia; grant No. MH 32577
from the National Institute of Aging, Bethesda, Maryland; and Physiometrix, Inc.,
North Billerica, Massachusetts.
Address reprint requests to Dr. John: Brain Research Laboratories, Old Belle-
vue Administration Building, 8th Floor, 462 First Avenue, New York, New York
10016. Address electronic mail to: johnr01@endeavor.med.nyu.edu. Individual
article reprints may be purchased through the Journal Web site,
www.anesthesiology.org.
Anesthesiology, V 102, No 2, Feb 2005
© 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
alteration of neurophysiologic processes that are essen-
tial for the mediation of consciousness. Before undertak-
ing that effort, it is appropriate to provide a brief over-
view of the results of research in related fields.
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Proposed Mechanisms of General Anesthesia
Action of Anesthetics to Produce Immobility
During the past 15 yr, major progress was made to
establish that anesthetics achieve immobilization largely
by actions on the spinal cord. These investigations were
guided by demonstrations that the thalamus and cortex
are more sensitive to anesthetics than the spinal cord7
and that transmission is blocked and spinal motor neu-
rons are depressed by inhaled anesthetics.8,9 Rampil and
Laster10 provided supporting evidence further implicat-
ing action at the level of the spinal cord by their dem-
onstration that movement responses to noxious stimula-
tion could occur despite an electroencephalogram made
essentially isopotential by isoflurane, after removal of
cortex and thalamus,11 and after hypothermic transec-
tion of the spinal cord.12 Concordant evidence was pro-
vided by the findings that neither freezing the cerebral
hemispheres13 nor causing forebrain ischemia14 nor us-
ing brain-preferential anesthetic procedures15 blocked
movement. This body of evidence supports the conclu-
sion that immobility may be achieved by action at the
level of the spinal cord.5 However, the blockade of
ascending somatosensory transmission by spinal anes-
thesia alters the excitability of reticulothalamocortical
arousal mechanisms, reflecting the interactions between
the different levels of the nervous system.16 –18
Much subsequent research focused on ligand- and ion-
gated channels, examining whether specific receptors
mediated immobility. Numerous neurotransmitters or
ionic sites of action are plausible candidates for such
effects. Genetic engineering provides animals with spe-
cific modifications that allow discrete testing of particu-
lar candidates for producing immobility. After a review
of the extensive literature on the results of interfering
with ion channels, Sonner et al.19 concluded that no
action on a single receptor can explain how inhaled
anesthetics achieve immobility and concurrent actions
on many receptors are implausible. Their evidence indi-
cates that among the candidates not yet convincingly ruled
out are glycine receptors, serotonin type 2 (5-HT2A) recep-
tors, sodium channels, and N-methyl-D-aspartate (NMDA)
receptors, whereas potassium channels, ␣2 adrenorecep-
447
448
tors, and ␣-amino-3-hydroxy-5-methyl-4-isoxa-zole prop-
ionic acid (AMPA), ␥-aminobutyric acid (GABA), opioid,
serotonin type 3 (5-HT3), or acetylcholine receptors are
probably irrelevant.
Action of Anesthetics to Produce Amnesia
There is adequate reason to believe that the amnestic
effects of anesthetics are mediated by some processes
other than those that block awareness. Abundant find-
ings unequivocally demonstrate that memory can be
blocked at levels of anesthetic that do not suppress
awareness. As cited previously, for many anesthetics the
dose to suppress consciousness significantly exceeds
that required to prevent memory storage.3 Gajraj et al.20
used repeated arousals from periods of unconsciousness
produced by target-controlled propofol infusion during
hip or knee replacement under spinal anesthesia in 12
patients. The auditory evoked potential (AEP) index, a
measure derived from the midlatency auditory evoked
response (MLAER), increased sharply at each awakening,
thereby indicating recovery of the MLAER. The MLAER is
depressed with loss of consciousness and recovers on
return of consciousness (ROC; see AEP monitors in sec-
tion entitled Electrophysiologic Monitors of the Effects
of Anesthetics). However, at the end of the procedures,
none of the more than 120 such awakenings was re-
called by these patients.
As well as anesthetics, a class of “nonimmobilizing”
agents predicted to have anesthetic action by virtue of
their lipid solubility can suppress learning and produce
amnesia without causing LOC or surgical immobili-
ty.21,22 Dutton et al.23 studied one of these agents to
ascertain whether these effects might result from block-
ade of perception of external stimuli required for learn-
ing to take place. They studied alterations of the vertex-
recorded MLAER in rats during inhalation of isoflurane,
desflurane, or nitrous oxide that produced sedation, as
well as inhalation of the nonimmobilizer compound 2N
that failed to produce sedation. All the volatile anesthet-
ics increased the latency and depressed the amplitude of
particular components of the MLAER recorded at the
vertex. These components arise from the medial genic-
ulate in the thalamus and the primary auditory cortex.
Because compound 2N did not significantly alter either
of these indices, it was concluded that the site at which
2N interfered with learning was not a component gen-
erator of the MLAER vertex response. This finding impli-
cates some anatomical substrate later in the processing
stream than the primary auditory cortex.
In a series of elegant studies using quantitative electro-
encephalographic as well as positron emission tomo-
graphic (PET) evaluation of alterations of brain activity,
correlated with blockade of memory during conscious
sedation, Veselis et al.,24 –28 presented evidence leading
to the same conclusion, showing that the effects of
anesthetics on episodic memory are related to actions
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
primarily on the dorsolateral prefrontal cortex. The an-
terior cingulate, medialis dorsalis nucleus in the thala-
mus, and parietal association areas may also be affected.
We know of no studies in humans that have probed the
extent to which the effects of these agents on memory
may involve the communications of various neocortical
regions with each other, as reflected in studies of coher-
ence. Effects on interactions with the limbic system
must also be evaluated, possibly awaiting technically
difficult and demanding studies that require use of func-
tional magnetic resonance imaging or intracerebral elec-
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trodes. Finally, the studies of the sort thus far cited have
only evaluated episodic but not implicit memory that is not
manifested as explicit recall but is usually demonstrable
only using associative or priming paradigms. A substantial
literature indicates that implicit memory formation is pos-
sible even though consciousness is not present.
Action of Anesthetics to Suppress Consciousness
The evidence thus far summarized supports the con-
clusions that anesthetics act on different regions of the
nervous system to produce immobilization, amnesia, and
absence of awareness, and that immobilization very
likely is mediated by effects on the spinal cord while
amnesia is probably mediated by effects on the dorsolat-
eral prefrontal cortex. This theoretical article is focused
on the most significant, perhaps more intriguing, and
less well-understood problem of how anesthetics act to
suppress consciousness, which we define as the absence
of awareness. Although our primary concern is the at-
tempt to explain the neurophysiologic processes by
which this remarkable property is mediated, the current
status of understanding of the underlying molecular
mechanisms will first be summarized.
Molecular Mechanisms of Anesthesia
A number of neurochemical/neuropharmacologic the-
ories of how anesthetics suppress consciousness have
been proposed. This approach seeks to identify specific
receptors and molecular sites for anesthetic action, with
the goal of identifying the processes within the brain at the
neuronal level that are critical for anesthesia. With the
Meyer-Overton demonstration of correlation between an-
esthetic action and solubility of anesthetic drugs in fat-like
solvents, attention was directed toward membranes as
likely sites of drug action. Initially, many concluded that
general anesthetics acted by extensively disrupting the
lipid portions of neuronal membranes. It was thought that
nonpolar amino acid side groups become buried within
protein interiors in the process of protein folding and that
polar interactions with solvent water would be avoided in
such hydrophobic pockets. The lipid-like characteristics of
these pockets would dissolve anesthetics, which might
bind in them.
As experimental evidence contradicted the hypothesis
of lipophilicity, the work of Franks and Lieb29 shifted
ANESTHETIC SUPPRESSION OF AWARENESS
attention from lipids to proteins as anesthetic targets.
Many subsequent studies on the effects of anesthetics in
the central nervous system focused on nerve mem-
branes, ion channels and their regulatory mechanisms,
and especially on synaptic transmission. Franks and
Lieb30 proposed that at the molecular level, anesthetics
almost certainly act by binding directly to proteins rather
than by perturbing lipid layers in cell membranes. They
concluded that although at high enough levels general
anesthetics might act nonspecifically on a wide variety of
neuronal sites, at clinical concentrations they are much
more selective and might act by binding to only a small
number of targets in the central nervous system. These
were considered likely to be postsynaptic ligand-gated ion
channels, because voltage-gated ion channels are very re-
sistant to clinical concentrations of general anesthetics.
Some agents seem to be effective at both inhibitory and
excitatory synapses, and both inhibition of excitatory syn-
apses and potentiation of inhibitory synapses may be in-
volved in anesthetic effects. Although some agents might
act at excitatory synapses (such as ketamine at NMDA
receptors), others suggested that anesthetic potentiation of
inhibitory synaptic receptors (primarily GABA) best
matches the pharmacologic profile of a wide variety of
general anesthetic agents. General anesthetics potentiate
GABA by increasing flow of Cl ions in open channels, and
it has been suggested that anesthetics act at the GABA
receptors at the lipid–protein interface.31,32 Franks and
Lieb33 later suggested that inhalation anesthetics act by
inactivating proteins that are transmitter-gated receptors
for GABA, serotonin and acetylcholine, and possibly gluta-
mate receptors. Urban and Friederich34 believed that the
evidence demonstrates that both voltage-gated and ligand-
gated ion channels may be affected by clinically relevant
concentrations of general anesthetics.
Theoretical Explanations of Anesthetic Action
A number of explanations of a more theoretical nature
have been proposed to account for the effects of anes-
thetics on consciousness. In a conceptually different
approach to this problem, Flohr35 proposed that the
conditions for consciousness to appear can be defined
by a specific computational structure that gives rise to
functional states that are identical with states of con-
sciousness. Such functional states are higher-order rep-
resentations by which an information processing system
represents its own inner state. Flohr reviewed the long
philosophical tradition of this proposition and proposed
that higher-order representations are instantiated by
complex, rapidly formed cell assemblies that depend
critically on the function of the NMDA synapse. The
NMDA synapse is both voltage and transmitter depen-
dent. This group argued that the NMDA receptor serves
as a Hebbian coincidence detector, modulating the syn-
aptic efficacy as a function of amount of use, and the
activation state of the cortical NMDA synapses deter-
Anesthesiology, V 102, No 2, Feb 2005
449
mines the size and complexity of representational struc-
tures that can be built up. If the receptor were disabled,
the representations could not be produced, which they
considered equivalent to LOC. They proposed that the
common mode of anesthetic action is the disruption of
NMDA-dependent computational processes. They as-
serted that inhibition of such processes is the necessary
and sufficient condition for agents to have anesthetic
properties, reviewing the extensive literature showing
that many substances antagonize or modulate membrane
functions relevant to activation of the NMDA receptor
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channel complex. An excellent review of research on how
different classes of inhaled anesthetics act on specific mo-
lecular targets and ion channels to affect neural networks
has recently been provided by Campagna et al.6
Challenging the view that consciousness arises as the
result of discrete interactions via synaptic connections
in specific interconnected neural networks, which are
blocked by anesthetics, some have attempted to explain
the molecular basis of anesthetic action using concepts
from quantum physics. Hameroff36 has suggested that
nonpolar amino acid side groups are interiorized by
folding of target proteins, creating hydrophobic pockets
to which anesthetics probably bind. This retards elec-
tron mobility required for protein dynamics and may
thereby potentiate the activity of inhibitory and inhibit
the action of excitatory receptors, especially in thalamo-
cortical projections. However, he questioned whether
the mere presence of anesthetic molecules in hydropho-
bic pockets would be sufficient to explain anesthesia. He
has presented a quantum-theoretical model proposing
that consciousness arises from the coherent superposi-
tion of states described by wave functions, generated by
endogenous van der Waal London forces in hydrophobic
pockets of certain brain proteins, collapsing when an
objective threshold of entropy is reached. Anesthetics
are proposed to act by preventing quantum states in
such pockets.
In more recent work, Woolf and Hameroff37 have
proposed that rudimentary visual consciousness de-
pends on quantum computation in microtubules in the
cytoplasmic interiors of cortical pyramidal dendrites in-
terconnected by gap junctions, forming a horizontal syn-
cytium or “hyperneuron” spanning visual cortical areas.
These interactions are critically dependent on cholin-
ergic action on pyramidal cell dendrites and on ␥-ami-
nobutyric acid–mediated (GABAergic) interneurons in-
terconnected by electrotonic gap–junction connections.
They suggest that it is at this level that the anesthetic
action interferes. Jibu38 has attempted to explain the
action of anesthetics within the framework of con-
densed matter physics. A new phase of condensation of
massive photons (called tunneling photons) in the per-
imembranous region is proposed to control the lateral
diffusion of molecules in the nerve cell membrane, de-
termining the molecular biologic functioning of the cell
450
by modulating chemical reactions. Jibu proposes that
anesthetic molecules trespassing into the perimembra-
nous region break the order of this condensation and
thereby disrupt cell functions that require maintenance
of ordered chemical reactions. Although such proposals
remain theoretically controversial and without experi-
mental support, they are mentioned here for complete-
ness and to illustrate that theories of the molecular
mechanisms of anesthesia still cover a wide range.
As is evident from consideration of this body of re-
search and contemporary theoretical speculations, anes-
thetics may act on a variety of neurotransmission pro-
cesses, and the effects are anatomically widespread
throughout the brain. Ion channel proteins do not func-
tion by themselves but are integrated with other pro-
teins into a membrane patch, patches are integrated into
a nerve cell, nerve cells are integrated into networks,
and local networks are integrated into functional units. It
is not sufficient for a theory of anesthesia to be based on
demonstration of some primary effects of an anesthetic
drug on neuron membranes or receptors or on some
particular molecular or cellular site of action. Evidence
on that level of discourse cannot explain why such
actions result in the disappearance of consciousness.
As Mashour39 has pointed out, perceptual processing
is accomplished by relatively discrete and functionally
specialized neural ensembles that are anatomically dis-
persed. Abundant evidence suggests that synchroniza-
tion within and among these regions may play a critical
role in integrating such dispersed information into a
unified perception. Cognitive binding at all levels plays a
crucial role in the generation of conscious experience. A
deeper understanding of how anesthetics disrupt con-
sciousness might require examination of whether they
interfere with this binding process at some critical lev-
els. In view of the hierarchical organization of the central
nervous system and the cascade of consequences of
action at any level, it seems evident that to judge the
relevance of any particular effects at any level of obser-
vation, whether molecular, ion channel, membrane, cel-
lular, or network, we must identify the neuronal net-
works underlying the interlocking constituents of
general anesthesia and how these components interact
with one another. The primary goal of this article is to
describe these networks and explain how their interac-
tion produces perception and awareness.
Electrophysiologic Monitors of the Effects of
Anesthetics
One approach to understanding the critical mecha-
nisms by which general anesthetics suppress awareness
is to seek for invariant changes in the human brain as
patients lose and regain consciousness under the effects
of a variety of anesthetic agents. Such information is
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
increasingly available from a variety of electrophysi-
ologic instruments that have been developed to enable
continuous intraoperative quantification of the depth of
anesthesia, independent of any particular agent. Numer-
ous studies support the belief that variables extracted by
computer analysis from the electroencephalogram and
the AEP are well correlated with changes in conscious-
ness. Although they are based on quite different tech-
niques, the methods have in common their reliance on
electrophysiologic assessment of brain activity, reflect-
ing effects that are anatomically widespread throughout
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the brain. This evidence clearly establishes that several
dimensions of brain electrical activity sensitively and
reliably reflect effects of the administration of a wide
variety of agents that result in LOC. This article combines
what is known about processes underlying these various
aspects of brain electrical activity with some recent
findings in cellular neurophysiology to conceptualize
how anesthetics suppress awareness.
The instruments currently being used to monitor the
depth of hypnosis fall into two categories. One class of
such devices quantifies electroencephalographic vari-
ables extracted from the spontaneous electrical activity
of the resting brain, quantitative electroencephalo-
graphic monitors. Some other monitoring approaches
measure the AEPs elicited by stimulation (AEP monitors).
Quantitative Electroencephalographic Monitors
Based on visual inspection of electroencephalographic
tracings, early studies found that anesthesia induction was
accompanied by an increase of fast, high-frequency oscilla-
tions of voltage waves in frontal regions, spreading to more
posterior regions with increased sedation and LOC. Con-
versely, slow low-frequency waves appeared in posterior
regions and migrated forward. This topographic pattern of
frontal predominance or “anteriorization” of quantitative
electroencephalographic power with LOC during anesthe-
sia was first reported in monkeys40 and has since been
consistently replicated in humans.
Early attempts to use brain electrical activity in patients
to evaluate the depth of anesthesia relied on global
features extracted from the power spectrum provided
by the fast Fourier transform. This transform describes
any brief waveshape that is represented as a series of
numerical values at successive time points, such as a
digitized segment of a quantitative electroencephalo-
graphic tracing, QEEG (t), as the sum of a number of
sinusoidal waveforms across the frequency range from
low to high frequencies. The amount or “amplitude” of
each frequency fi contained in the original tracing is
represented by a coefficient, ai, of the corresponding
term in the time series, so that
QEEG (t) ⫽ a1f1 ⫹ a2f2 ⫹ a3f3 · · · ⫹ an⫺1fn⫺1n ⫹ anfn.
The waveshape of the original tracing can be accu-
rately reconstructed by addition of the set of waveforms
ANESTHETIC SUPPRESSION OF AWARENESS
fi in this “expansion,” multiplying each oscillation by the
corresponding coefficient ai. A precise and concise rep-
resentation of the original tracing is therefore provided
by the set of amplitude coefficients a1 to an. It has
become conventional to square each term in this repre-
sentation, thereby converting amplitude to power, thus
obtaining the “power spectrum.”
In attempts to summarize the most relevant informa-
tion about a particular quantitative electroencephalo-
graphic sample that was provided by this analysis, mea-
sures have been devised, such as the median frequency or
the spectral edge frequency, which respectively define
those frequencies below which one finds 50% or 95% of
the quantitative electroencephalographic power. Such
measures have been related to clinical signs or compared to
analgesic endpoints (see review elsewhere).41 The use of
these relatively crude features is based on the hypothesis
that with increasing depth of anesthesia, the distribution of
power in the quantitative electroencephalogram steadily
shifts toward lower frequencies. Median frequency can be
conceptualized as akin to the center of mass of the area of
the curve outlining the power spectrum. Such methods
attempt to summarize the information in the whole spec-
trum by a single number representing only that point in the
spectrum that satisfies an algebraic definition. However, a
great variety of more comprehensive descriptors of the
electrical activity of the brain can be constructed by math-
ematically combining quantitative features extracted from
an array of electrodes using such spectral analysis methods.
The quantitative electroencephalogram measures cur-
rently being used in commercial monitors to estimate
the depth of anesthesia include the following.
Bispectral Index. The Bispectral Index® (BIS®) mon-
itor (Aspect Medical, Newton, MA) relies on spectral
analysis of the electroencephalogram recorded from one
or two electrode positions on the forehead. The constit-
uent measures contributing to the BIS value are derived
from this analysis and include power in selected fre-
quency bands and certain elements of the “bispectrum,”
which represent the covariance of power in particular
low frequencies with the power at particular high fre-
quencies. This monitor combines a variety of such de-
scriptors of the quantitative electroencephalogram into a
multivariate number, the BIS, using a proprietary algo-
rithm.42 This number is then scaled to range between 0
and 100. High correlations between this number and the
state of consciousness have been reported in numerous
studies.43– 45 The performance of BIS has been evaluated
as the input to a closed-loop system for propofol admin-
istration that was considered to be clinically acceptable
in a comparison with standard practice– controlled
administration.46
Patient State Index. The Patient State Analyzer, PSA®
monitor (Physiometrix, Inc, N. Billerica, MA) computes a
different multivariate quantitative electroencephalo-
graphic index called the Patient State Index to assess
Anesthesiology, V 102, No 2, Feb 2005
451
the depth of anesthesia.47,48 The initial version of this
instrument analyzed the quantitative electroencephalo-
gram from four brain regions in an anterior/posterior
array, and a later version uses a number of electrodes on
the forehead. Extracted features describe not only the
local quantitative electroencephalographic power spec-
trum at each electrode but also some dynamic relations
among these regions, such as power gradient and coher-
ence. These features are combined into a proprietary
discriminant function to assess the probability that the
patient is “awake,” a number scaled to range from 0 to
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100. Significant relations of the Patient State Index with
“level of consciousness” and sensitivity to change in
state have been demonstrated.47– 49
Narcotrend® Index. The dimensionless Narcotrend®
index (NCI; MonitorTechnik, Bad Bramstedt, Germany)
is a new index based on quantitative electroencephalo-
graphic pattern recognition,50 classifying the raw elec-
troencephalographic epochs into six different stages
from A (awake) to F (increasing burst suppression to
electrical silence), rescaled into an index from 100
(awake) to 0 (electrical silence). This instrument derives
from previous studies on automatic sleep staging of the
electroencephalogram into five stages, with an added
sixth stage of isopotential electroencephalography.51 Af-
ter artifact rejection, electroencephalographic segments
are classified based on similarity to analyses of proto-
typic waveshapes in the time and frequency domain,
results are entered into a discriminant analysis, probabil-
ities of similarity are calculated, and the result is ex-
pressed as the index from 0 to 100.
Electroencephalographic Entropy Monitors. En-
tropy, as a physical concept, is related to the amount of
“disorder” in a system52 and, in an information theoret-
ical context, describes the irregularity, complexity, or
unpredictability of a signal.53 Entropy can be computed
in the time domain, the frequency domain, or both. The
S/5® Entropy Module (Datex-Ohmeda, Helsinki, Finland)
computes the approximate entropy of the power spec-
trum to quantify the depth of anesthesia.54,55 This
method treats the quantitative electroencephalographic
power spectrum obtained before induction of anesthesia
essentially as the “ground state” of the organized signal
system represented by the quantitative electroencepha-
logram and quantifies the shift from that state as negative
entropy, or disorganization. Entropy measures have also
been utilized to evaluate LOC induced by anesthetic as a
phase transition.56
AEP Monitors
Evoked potentials (EPs) are a series of oscillations in
the brain electrical activity that are “time-locked” to the
presentation of a stimulus, i.e., the successive peaks in
these oscillations appear at particular latencies after stim-
ulus onset. EP waveshapes elicited by different stimulus
modalities have been well studied, and the most proba-
452
ble neural generators whose activation corresponds to
peaks at distinctive latencies have been identified. The
latency of each peak in the EP waveshape reflects the
time required for the neuronal encoded information
about the stimulus to be transmitted to successive struc-
tures in the sensory pathway. As long as an individual
subject remains in a stable state, transmission velocities
are constant and latencies remain stable. Changes in
latencies of EP components along a neural pathway
caused by anesthetic therefore can potentially provide a
sensitive indicator of anesthetic effects on the excitabil-
ity of the corresponding brain structures. The EP mea-
sures in current use to monitor anesthesia include the
following.
MLAER. The AEP can be divided into several domains
as a function of latency. The brainstem auditory evoked
response extends from 0 to approximately 6 ms and is
composed of a wave with five peaks, reflecting transmis-
sion in the lateral lemniscal pathway from the acoustic
nerve to the inferior colliculus. The next domain in the
AEP is the midlatency response or MLAER that extends
from approximately 6 to 60 ms, reflecting transmission
through the medial geniculate body in the thalamus to
the primary auditory cortex.57 The remaining compo-
nents of the AEP are considered to be long-latency re-
sponses and are comprised of several latency regions
that reflect increasingly complex cognitive processes
engaging cortical association areas, the frontal cortex, and
the hippocampus. It has long been known that the wave-
shape of the auditory evoked response simplifies and be-
comes smaller with increasing depth of anesthesia.
Although the brainstem auditory evoked response is
essentially resistant to anesthetic effects and the long-
latency responses are too variable to facilitate reliable
and rapid evaluation, the MLAER has received substantial
attention as a possible monitor of the depth of anesthe-
sia. The MLAER has been shown to reflect reliably the
level of anesthesia with a wide variety of anesthetic
agents58 – 61 and to detect awareness.62 Methods have
been devised to quantify the morphology of this region
of the auditory EP, using features extracted from the
MLAER61,63– 66 and incorporated into anesthesia moni-
tors. One such measure, referred to as the Auditory
Index, is implemented in an instrument called the Alaris
AEP® Monitor (Danmeter, Inc., Odense, Denmark). This
measure represents the morphology of the MLAER by
calculating the total length of the curve describing the
EP waveshape as if it were a string. The longer the string
is, the lighter the anesthesia level is, and the shorter the
string is, the deeper the level of anesthesia is.
Forty-hertz Auditory Steady State Evoked Re-
sponse. Another method to use auditory evoked re-
sponses to evaluate anesthetic depth has been proposed,
which is based on the 40-Hz steady state auditory evoked
response (ASSR).67 The ASSR arises mainly from the pri-
mary auditory cortex,68,69 with a lesser contribution from
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E. R. JOHN AND L. S. PRICHEP
subcortical generators in the thalamus or midbrain.70,71
This method takes advantage of the fact that the responses
of the brain to auditory stimuli become “entrained” as the
repetition rate of the stimulation is increased. Essentially,
the later components of the MLAER elicited by each stim-
ulus become superimposed on the early peaks of the re-
sponse to the subsequent auditory input. Thus, the ASSR
provides a simple index of the ability of the brain to re-
spond to rapid stimulation as it is impaired by anesthesia,
which can be quantified by using spectral analysis with the
fast Fourier transform to compute the power at the stimu-
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lus repetition rate.72,73
Comparisons among Electrophysiologic Indices
As might be expected, investigations of the relative
sensitivity and specificity of the detection of the absence
and return of awareness, ease, and reliability of these
different methods are already in progress. Gajraj et al.20
compared the performance of the BIS, the AEP index,
the spectral edge frequency, and the mean frequency
during repeated transitions from consciousness to un-
consciousness. Sleigh et al.74 compared the BIS, spectral
edge, and approximate entropy. Vanluchene et al.75
compared spectral entropy to the BIS and processed
MLAER. Bonhomme et al.76 compared the ASSR and the
BIS, and Struys et al.77 compared the BIS and MLAER.
Kreuer et al.78 compared the Narcotrend® and BIS indi-
ces during propofol sedation. Schmidt et al.79 compared
the Narcotrend®, the BIS, and the classic quantitative
electroencephalographic variables: spectral edge fre-
quency, median frequency, and relative power in the
four quantitative electroencephalographic frequency
bands, ␦, ␪, ␣, and ␤. A detailed evaluation of the relative
virtues of various indices is beyond the scope of this
article. These studies are cited only to point out that the
concern is no longer whether such electrophysiologic
descriptors have validity but rather the relative sensitiv-
ity and specificity of different measures and to provide
readers interested in such comparisons with ready ac-
cess to relevant reports.
Autonomic and Electromyographic Indices of
Anesthetic Depth
Some researchers have investigated the feasibility of
anesthesia monitors using heart rate variability and re-
spiratory sinus arrhythmia80 and electromyography of
the frontal and orbicularis muscles, or the Facial Electro-
myographic Index.81 These measures are also electro-
physiologic and are mentioned in the interest of com-
pleteness. Although these indicators display sensitivity
to anesthetics, they will not be further discussed in this
article, which is devoted to more direct measures of
brain electrical activity.
ANESTHETIC SUPPRESSION OF AWARENESS
Theoretical Implications of the Capability for
Electrophysiologic Monitoring of Depth of Anesthesia
The proposition that aspects of the quantitative elec-
troencephalogram and the EP reflect the depth of anes-
thesia has become well accepted. Quantitative electro-
encephalographic and AEP monitors to extract and
quantify mathematical electrophysiologic descriptors
have been incorporated into a wide variety of instru-
ments and are increasingly being used routinely by many
anesthesiologists as adjuncts to standard procedures for
the evaluation of intraoperative depth of anesthesia. Nu-
merous reports have been published confirming that
selected measures of brain electrical activity change in a
reliable way with the administration of a wide variety of
agents that cause LOC. The magnitude of such changes
can be used to ascertain whether the depth of anesthesia
is sufficient to allow intubation and to permit surgical
procedures to begin. Reversal of these changes gives a
reliable indication that the patient is returning to a con-
scious and responsive state.
Reliable correlations between specified quantitative
electroencephalographic and AEP parameters and clini-
cal signs demonstrate that certain aspects of brain elec-
trical activity are sensitive to the level of consciousness.
These clinical monitors rely on the stability and sensitiv-
ity of brain electrical activity but differ with respect to
the particular quantitative electroencephalographic
rhythms or EP waveshapes selected for monitoring, the
scalp regions from which recordings are collected, the
precise nature of the features objectively extracted from
the raw data, and the invariance or lack thereof that has
been demonstrated for the effects of various anesthetic
agents on the measure. They have in common that they
provide practical clinical evidence that consciousness is
a neurobiologic phenomenon that can be objectively
quantified so that depth of anesthesia can be analyzed
reliably using electrophysiologic variables. Although
such derived measures correlate well with drug concen-
trations or clinical state, they provide relatively little
insight into the underlying physiology of anesthesia or
the brain mechanisms mediating consciousness.
They differ in that they focus on different aspects of
brain electrophysiology. To try to infer the basis of
anesthetic action from such condensed descriptors is
reminiscent of the four blindfolded individuals in the
folk tale who were trying to describe an elephant by
each touching one of his four legs. However, by consid-
ering the neuroanatomical and neurochemical system
which is the origin of the electrical activity being mea-
sured, and by comprehensively analyzing the set of neu-
rophysiologic changes in processes generated by this
system that take place in common when anesthetics
suppress consciousness, much can be inferred about the
brain mechanisms of anesthesia and perhaps about the
processes that sustain consciousness. The intent of this
article is to examine the neurophysiologic processes that
Anesthesiology, V 102, No 2, Feb 2005
453
underlie the quantitative electroencephalographic and
EP measures that display reliable and sensitive alterations
during anesthesia and to combine that information with
a number of recent research findings to construct a
neurophysiologic theory of anesthesia.
Neurophysiologic Bases of Contemporary
Quantitative Electroencephalographic and EP
Monitors of Depth of Anesthesia
Stability of the Quantitative
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Electroencephalographic Power Spectrum
Recordings from the surface of the scalp have long
been known to demonstrate rhythmic voltage oscilla-
tions derived from the electrical activity of the subjacent
neuronal populations.82 Such fluctuations of voltage in
brain electrical activity, whether recorded from the
scalp as the electroencephalogram or EP waves or as
intracerebral local field potentials, reflect the nonran-
dom synchronization of postsynaptic potentials in enor-
mous numbers of neurons. The various quantitative elec-
troencephalographic and EP monitoring techniques rely
on the fact that the spontaneous electrical activity, re-
corded from the scalp of a healthy person resting with
closed eyes, is dynamically regulated by interactions
within a homeostatic system that are mediated by many
different neurotransmitters. The existence of such a ho-
meostatic system is established by evidence that the
power spectrum of the quantitative electroencephalo-
gram can be predicted for repeated samples of adequate
length, recorded from healthy, normally functioning in-
dividuals while at rest with closed eyes. The same power
spectrum will be obtained reproducibly from a set of
artifact-free samples of adequate length obtained shortly
after each other, provided that the state of the brain does
not change. The homeostatic regulatory system is dis-
cussed in the section entitled Homeostatic Regulation of
Brain Electrical Activity.
Such instruments inherently depend on establishing a
multivariate signal space of features extracted from the
quantitative electroencephalogram, in which a reference
region around the origin or “baseline” is defined as
awake and functioning normally. This baseline is deter-
mined by statistically scaling and combining measures
extracted from the patient and compared to some large
reference database. The BIS, GABA, and other quantita-
tive electroencephalographic indices may be conceptu-
alized as the estimated length of a vector describing the
distance between the momentary brain measure taken
from a patient and the origin of the signal space in which
they are contained. These indices differ with respect to
the actual extracted measures chosen to be combined
measures and also in that some use actual values of the
extracted features, such as microvolts or phase angle or
percent change, whereas others rescale to reflect the
probability of the observation relative to the baseline.
454
Fig. 1. The stability of the electroencephalographic power spec-
trum is shown by this developmental surface for log spectra at
the O1 region, obtained from 211 healthy subjects aged 5–97 yr.
The vertical axis is log power, and the horizontal axis is fre-
quency from 0.39 to 19 Hz. From Valdes P, Valdes M, Carballo
JA, Alvarez A, Diaz GF, Biscay R, Perez MC, Szava S, Virues T,
Quesada ME: QEEG in a public health system. Brain Topogr
1992; 4:259 – 66. Used with permission.
Specificity and Sensitivity of Variables Extracted
from the Electroencephalogram by Computer
(Quantitative Electroencephalography)
After a sufficient sample of artifact-free data has been
collected, using validated automatic editing algorithms
to remove contaminated signals that do not arise from
brain electrical activity, quantitative electroencephalog-
raphy uses computer analysis to describe the power
spectrum in each scalp region. The many measures that
can be calculated using spectral analysis include the total
power and the amount in each of several frequency
bands of the local activity in each region (absolute
power), the percentage of power in a region that lies
within each of these bands (relative power), and the
relations among regions within or between the two
hemispheres in total and within each band (coherence
and symmetry). For such quantitative electroencephalo-
graphic analyses, the quantitative electroencephalogram
is conventionally divided into frequency bands, approx-
imately defined as ␦ (0.5– 4 Hz), ␪ (4 – 8 Hz), low ␣ (8 –10
Hz), high ␣ (10 –12 Hz), ␤ (12–25 Hz), and ␥ (25–50 Hz).
Neurometric Quantitative Electroencephalography
There are a variety of methods for quantitative electro-
encephalographic analysis. The quantitative electroen-
cephalographic analysis method we have used in the
studies reported here is called neurometrics. This term
refers to using certain mathematical procedures de-
scribed below, for probabilistically scaling and combin-
ing measures derived from an individual and compared
to a particular set of normative equations that describe
the resting state.
Figure 1 illustrates average power spectra, extracted from
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
the quantitative electroencephalogram recorded from the
scalp over the left occipital cortical areas (10/20 electrode
position O1) and obtained from a large group of healthy,
normally functioning individuals at ages ranging from 5 to
97 yr of age. Similarly, regular evolution with age has been
shown for power spectra from quantitative electroen-
cephalograms recorded at every position of the Interna-
tional 10/20 Electrode Placement System.
These sets of quantitative electroencephalographic
spectra have been described by algebraic equations in
which the major variable is the age of the subject, mul-
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tiplied by a different set of constant coefficients for every
cortical region. These age-regression equations provide
the mean value and SD of the distribution of many
different variables extracted from the power spectrum
of the quantitative electroencephalogram recorded from
any scalp electrode position. The accuracy with which
such developmental equations predict the composition
of the quantitative electroencephalogram in healthy in-
dividuals has been widely investigated and confirmed in
a large number of research studies. These precise de-
scriptions are independent of the ethnic or cultural back-
ground of the subject, confirmed in many countries
around the world.83 Neurometric quantitative electroen-
cephalography has excellent test–retest replicability
within an individual and has been demonstrated to have
extremely high specificity as well as extremely high
sensitivity to a wide variety of cognitive, developmental,
neurologic, and psychiatric disorders.84,85 Because it is
also exquisitely sensitive to changes of state, it offers an
ideal method to examine the effects on the brain of
agents that alter consciousness, such as pharmacologic
agents and anesthetics.
After extraction of quantitative electroencephalo-
graphic variables from any recording, they are preferably
subjected to a mathematical transformation to achieve
gaussianity of the normative distributions.86,87 Trans-
forming a set of measures sampled in a reference popu-
lation into gaussian distributions, sometimes referred to
as normal distributions, legitimizes the rescaling of
each such measure to a standard or Z score, such that
Z ⫽ 共M ⫺ S兲/sd,
where M ⫽ mean value of the measure in the popula-
tion, S ⫽ the value obtained from an individual subject,
and sd ⫽ the SD of the reference sample.
Z transformation rescales a variable into units of SDs
from the mean value of the reference distribution. Be-
cause the transformation to gaussianity has forced 100%
of the reference distribution to correspond to the famil-
iar bell curve, calculation of the Z score for an obtained
measurement defines the percentage of the reference
population that lies more SDs away from the mean than
the observation in question. Integration of the remaining
area establishes the probability, P, that the observation
could be obtained in the reference population by chance
ANESTHETIC SUPPRESSION OF AWARENESS 455

Fig. 2. Schematic block diagram of inter-

actions among brain regions hypothe-
sized to constitute the homeostatic sys-
tem that generates and regulates the
electroencephalographic power spec-
trum. Complex dependence on ionic cur-
rents that cause development of a se-
quence of hyperpolarizations followed
by depolarizations can cause some neu-
rons in thalamocortical circuits to be-
have as neuronal pacemakers in re-
sponse to network interactions. Under
certain conditions, these cells have an
intrinsic propensity to enter oscillatory
modes of activity in the 7.5- to 12.5-Hz

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range, generating prominent rhythms in
the ␣ frequency range, 7–14 Hz. ␥-Ami-
nobutyric acid–mediated influences of
nucleus reticularis can hyperpolarize cell
membranes of these thalamic neurons,
slowing the ␣ rhythm toward the ␪ range
(3.5–7.5 Hz), and the cortex can initiate
such action, closing thalamic gates to di-
minish or exclude sensory throughput.
This mechanism can serve as a focus of attention and may also be involved in sleep. Input of sensory stimulation to the brainstem
reticular formation, sometimes referred to as the ascending reticular activating system, can oppose such inhibition by the release
of acetylcholine, which serves to antagonize ␥-aminobutyric acid and to depolarize the membranes of the oscillators, increasing the
frequency of the ␣ rhythm. Theta activity (3.5–7.5 Hz) is generated by the limbic system and is propagated to the cortex vias the
anterior cingulate and medialis dorsalis. Delta activity (0.5–3.5 Hz) is generated in the cortex when cortical neurons are deprived of
input, and ␤ activity (12.5–25 Hz) largely reflects intracortical transactions. Gamma activity (25–50 Hz) reflects corticocortical and
corticothalamocortical transactions particularly important in perceptual processes, which generate a reverberating ␥ loop. This is
further explained in figure 3.

alone and can be found using any set of statistical tables.
For example, P ⫽ 0.35 if Z ⫽ 1.0, 0.10 if Z ⫽ 1.64, 0.05
if Z ⫽ 1.96, 0.01 if Z ⫽ 2.56, 0.001 if Z ⫽ 3.20, and so
forth. Thus, use of these methods for quantitative elec-
troencephalographic analysis allows electroencephalo-
graphic recordings to be evaluated statistically by trans-
forming each quantitative variable from its initial
physical dimensions (voltage, covariance, latency, and
others) into the metric of probability. The probability of
a mean Z score for a group of n individuals can be
assessed by multiplying the mean Z value by the square
root of n and estimating the probability of n1/2 Z.
A further advantage of the transformation of univariate
quantitative electroencephalographic measurements
into Z scores is that variables in the common metric of
probability can be legitimately combined into multivari-
ate descriptors of brain state, and differences among
such brain states can be further evaluated by multivariate
discriminant functions or other similarly powerful objec-
tive methods. Such analyses have shown quantitative
electroencephalographic evaluations to have high spec-
ificity, with false-positive findings at the chance level,
and also to have high sensitivity to a wide variety of
cognitive, neurologic, and psychiatric disorders.83,86,87
Specificity and Sensitivity of the Evoked Potential
The EP monitoring techniques rely on the fact that
each peak in an EP waveshape reflects the excitation of
huge numbers of neurons within successive levels of the
transmission pathways from sensory receptors to the
cortex. The waveshapes of EPs from any region elicited
by multimodal sensory stimuli are also predictable88 and
sensitive.89,90 The latency of each EP peak is determined
by conduction time and the amplitude by the excitability
of these neuroanatomical structures, and both of these
parameters are similarly regulated. As a result, the mor-
phology and scalp distributions of auditory, visual, and
somatosensory evoked potentials in the resting, normal
individual are well known and are used widely in clinical
neurology to assess the integrity of sensory pathways.91
Homeostatic Regulation of Brain Electrical Activity
The neuroanatomical structure of the homeostatic sys-
tem regulating the quantitative electroencephalographic
power spectrum is depicted in the much simplified sche-
matic diagram in figure 2. The system shown here is
adapted from a more complete diagram constructed by
Hughes and John,92 which also indicates the putative neu-
rotransmitters mediating some of the indicated neural in-
teractions. In this figure, dotted arrows indicate primary
multimodal sensory inputs; solid arrows indicate excitatory
relations; and heavy, dashed arrows indicate inhibitory
interactions.
This complex neuroanatomical homeostatic system,
probably genetically determined, regulates baseline lev-
els of (1) local synchrony,93 (2) global interactions
among regions,94 and (3) periodic sampling of the signal
space.95 A critical role in the regulation of brain rhythms
is played by the interaction between brainstem, limbic
system, thalamus, and cortex. The spontaneous electro-
encephalogram is conventionally considered to consist
of rhythmic oscillations in several broad frequency

Anesthesiology, V 102, No 2, Feb 2005

456
bands, referred to as ␦, ␪, ␣, ␤, and ␥ activity. The
following processes are believed to generate these dis-
tinctive rhythms.
␣ Activity. The sensory receptors encode information
about the environment. Multimodal sensory inputs (dot-
ted arrows) go to sensory specific relay nuclei in the
thalamus, serving as gates between the receptors and the
cortex. Pacemaker neurons distributed throughout tha-
lamic regions oscillate in the frequency range of the ␣
rhythm (8 –12 Hz, with a mean frequency of approxi-
mately 10 Hz), regulating and synchronizing the excit-
ability of the cells in the thalamocortical pathways. This
modulation is further distributed throughout the cortex
by cortico– cortical interactions. Small spatially distrib-
uted cortical areas seem to act as epicenters from which
␣ activity spreads through cortical neuronal networks by
interneuronal connections, generating the ␣ rhythm that
dominates the resting quantitative electroencephalo-
graphic power spectrum seen in recordings from many
scalp regions. This rhythm is often at different mean
frequencies and phase in these dispersed regions.
To clarify this explanation, a brief discussion of the
structure of the thalamic neural networks is necessary. A
much more detailed explanation has been provided by
Steriade96 and by Lopes da Silva.97 In the thalamic relay
nuclei, some types of neurons display rhythmic oscilla-
tions in the frequency range of 6 –10 Hz. This oscillatory
behavior seems to be an intrinsic property of these
neurons. Alpha activity arises from the interaction be-
tween populations of these neurons in the thalamus and
in certain areas of the cortex. In the thalamic nuclei
where this activity can be recorded, three main types of
neurons interact: thalamocortical relay (TCR) nuclei
whose axons project to the cortex, reticular nucleus (RE)
neurons that interact synaptically with the TCR cells and
contribute GABAergic inhibitory feedback control, and lo-
cal intrinsic neurons. The TCR neurons display two distinct
modes: either functioning as relay cells that depolarize and
produce spikes in response to an adequate input volley
from sensory pathways or as oscillatory cells that produce
rhythmic bursts of high-frequency spikes repeated in a
rhythmic oscillatory pattern. The mode of activity is deter-
mined by the resting membrane potential of the TCR neu-
ron and the strength of its synaptic interactions with the
sensory inputs and the RE neurons. Hyperpolarization of
the TCR neurons by the RE neurons blocks transmission by
TCR neurons of sensory input to the cortex and enhances
slow rhythmic oscillations.
Essentially in the center of the brainstem, mesial to the
lemniscal auditory and somatosensory pathways, lies the
brainstem reticular formation. All afferent sensory path-
ways send collaterals into this region. Based on a series
of lesion and stimulation experiments, it has been
known for many years that bilateral transection of this
system led to long-lasting coma. Further, electrical stim-
uli delivered to this region would awaken a sleeping
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
animal and desynchronize the electroencephalogram in
widespread regions of the cortex.98 From such early
observations, this system was denoted as the ascending
reticular activating system (ARAS). Cholinergic influ-
ences of the ARAS, as a consequence of sensory stimu-
lation, diminish the efficacy of the GABAergic RE neu-
rons, resulting in removal of their hyperpolarizing
influences and facilitating throughput to the cortex. A
concomitant of strong activation by the ARAS is cortical
“arousal,” desynchronization of the ␣ oscillators, with
the appearance of faster rhythms in the ␤ frequency
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range (12–25 Hz). Evidence that such arousal could also
be accomplished by stimulation of the intralaminar nu-
clei of the thalamus has led some to modify this view,
referring to an “extended reticular–thalamic activating
system.”99 It has been proposed that normal conscious
functioning requires a circulating flow of activation
among the ARAS, the intralaminar nuclei, and the cortex.
Activity within a subcortical reticular–intralaminar nu-
cleus–RE system is proposed to be necessary for the
state of consciousness, whereas interaction of this sys-
tem with cortex is envisaged to provide the perceptual
content of consciousness.100,101
␪ Activity. By GABAergic action, RE neurons of nucleus
reticularis, a thin shell of cells surrounding much of the
thalamus, can inhibit these thalamic pacemaker neurons
(thick dashed arrows), slowing their rhythms. Unless op-
posed, these inhibitory influences of the nucleus reticularis
can act to hyperpolarize the pacemakers and diminish
sensory throughput from the TCR neurons to the cortical
receiving areas, slowing the mean frequency of the oscilla-
tors and shifting the ␣ rhythm toward ␪ (4 – 8 Hz).
Mesolimbic ␪ Activity. In parallel with these pro-
cesses, a mesolimbic system receives multimodal inputs,
from the ARAS in the brainstem and collaterals of afferent
sensory pathways as well as via the inferotemporal cortex,
and distributes this activity to a system comprised of the
entorhinal cortex, hippocampus, amygdala, septum (pha-
sically inhibited by the hippocampus-thick dotted arrows),
and anterior cingulate cortex. Representations of relevant
past experience, stored in this system, are activated by
associative linkages. This readout from the “endogenous
system” is transmitted via the non–sensory-specific, in-
tralaminar, diffuse projection nuclei and nucleus medialis
dorsalis, and by the anterior cingulate gyrus, to the axoden-
dritic synapses of pyramidal neurons in upper cortical lay-
ers (layer 1). This nonsensory specific input produces the
late secondary positive peaks that appear after the primary
component of the EP at latencies that depend on the
sensory modality. Strong activation of this system can gen-
erate widespread ␪ rhythms. A distinctive output from this
system is often observed as “frontal midline ␪” during
performance of cognitive tasks such as delayed matching
or mental arithmetic.
␦ Activity. Extreme depression of thalamic gates re-
leases some cortical cells from the influences of sensory
ANESTHETIC SUPPRESSION OF AWARENESS
specific input that, together with diminished activation
of the cortex by the ARAS, results in the production of a
very slow rhythm called ␦ activity (0.5– 4 Hz). Note that
the cortex can inhibit the ARAS by descending pathways
via the striatum (heavy dotted arrows).
␤ Activity. The ARAS receives inputs via collaterals
(double dotted arrows) of afferent activity from the sen-
sory pathways. Activation of this system by incoming
stimuli causes the brainstem reticular formation to in-
hibit the nucleus reticularis, opposing the GABAergic
inhibitory action of nucleus reticularis by acetylcholine
and releases its inhibitory actions on the thalamus. The
frequency of the thalamic oscillators is increased into the
10- to 12-Hz region. Thalamic gates are opened so that
afferent inputs from the “exogenous system” are trans-
mitted from the sensory specific thalamic nuclei via the
projection pathways to axosomatic synapses of pyrami-
dal neurons in lower layers of the cortex (layer 5).
Information about complex, multimodal environmental
events is fractionated, and “fragments of sensation” are
distributed across the cortex into cell assemblies of fea-
ture extractors. Cortical activity is desynchronized in
some regions thus activated, sometimes referred to as
event-related desynchronization, and corticocortical in-
teractions generate the ␤ rhythm (12–25 Hz). This sen-
sory-specific input also produces the primary or early
positive components of the EP recorded from the scalp.
␥ Activity. Information about current complex envi-
ronmental stimuli and relevant previous experience, aris-
ing from the anatomically distinct exogenous and endog-
enous systems, converges on synapses in layers 1 and 5
of the anatomically extensive sheets of cortical pyrami-
dal neurons. Experiments using direct electrical stimula-
tion of pyramidal neurons with micropipettes,102 as well
as studies in brain slices combining direct electrical
stimulation of specific and nonspecific thalamic nuclei
with visualization of cortical responses using voltage
sensitive dyes,103 have directly demonstrated that the
pyramidal neurons act as comparators, detecting tempo-
ral coincidence of inputs to layer 1 and layer 5 synapses.
Direct stimulation of the soma of the pyramidal neuron
or stimulation of a specific thalamic relay nucleus (ven-
trobasal) caused a moderate activation in layer 5 of the
corresponding sensory cortex. Direct stimulation of the
apical synapse or stimulation of nonspecific nucleus of
the diffuse projection system (centralis lateralis) caused
a moderate activation in cortical layer 1. When both
somatic and apical synapses or ventrobasal plus centralis
lateralis were stimulated concurrently, that is when ex-
ogenous and endogenous inputs were coincident, corti-
cothalamic discharges were markedly enhanced, and
activity at the ␥ frequency back-propagated to the cortical
regions where coincidence had occurred. This feedback
from the corticothalamic volley binds the distributed frag-
ments and causes coherent corticothalamocortical loops to
reverberate at the frequency of the ␥ rhythm (25–50 Hz).
Anesthesiology, V 102, No 2, Feb 2005
457
Such reverberation has been proposed by Thompson and
Varela,104 Rodriguez et al.,105 and Llinas et al.103 to play an
essential role in perception.
These neurophysiologic interactions that regulate
brain electrical activity are mediated by a wide variety of
neurotransmitters. Brain functions are critically depen-
dent on the availability of these substances and the
processes that control their synthesis and metabolism, a
complex topic beyond the scope of this article. The
monitoring strategies implemented in quantitative elec-
troencephalographic and EP anesthesia monitors are
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based on detecting electrophysiologic correlates of dis-
ruptions of this homeostatic regulation by different an-
esthetic agents, which exert their effects at various
points of the system. Some of these distinctive effects are
illustrated in this article.
Dependence of Perception on Intact Coincidence
Detection
Based on animal experiments, John106,107 proposed
that perception depended on the coincidence at the
cortical level between exogenous, sensory-specific input
of information about the environment and endogenous,
non–sensory-specific readout from a representational
system encoding memories of the relevant past. Confir-
mation in human subjects of this hypothesis was first
provided by Libet.108 In awake neurosurgical patients,
Libet stimulated the cortex electrically to coincide with the
time of arrival of the non–sensory-specific, secondary com-
ponent of the EP waveshape, usually present in the re-
sponse of the somatosensory cortex that was evoked by a
mild electrical shock to the wrist, and found that such
time-locked brain stimulation could block subjective aware-
ness of the wrist shock. Similar findings during brain sur-
gery were reported shortly thereafter by Hassler,109 who
recorded the cortical evoked responses to mild wrist
shock, electrical shock to the sensory specific ventrobasal
nucleus, and electrical shock to the non–sensory-specific
nucleus centralis lateralis. The waveshape of the cortical
response evoked by wrist shock consisted of an early com-
ponent like the response to ventrobasal nucleus alone plus
a later component like that to centralis lateralis alone.
Hassler then showed that the perception by a patient of
wrist shock could be blocked by later stimulation of cent-
ralis lateralis in the thalamus, appropriately delayed to dis-
rupt the late cortical response.
Based on intracerebral recordings, several authors
have reported that a brief period of ␥ activity with zero
phase lag appears coherently between prefrontal cortex
and parietal cortex of human subjects during perfor-
mance of perceptual tasks.110,111 Varela104 has proposed
that such spatially extensive, phase-locked ␥ oscillations
may be the physiologic concomitant of perception. Co-
incidence detection may serve to convert fragmented
sensory attributes of the complex stimuli to fragments of
percepts, thus identified and encoded in distributed fea-
458
Fig. 3. Model of the hypothetical system proposed to construct
fragments of perception from dispersed neural ensembles,
whose activity has been nonrandomly enhanced by coinci-
dence detection, and binding these fragments together into a
unified reverberating system that comprises the perceptual
content of consciousness. Blue arrows indicate input to the
axosomatic synapses of pyramidal neurons, located in layer 5
of the cortex. Gold arrows depict input from the endogenous
system to axodendritic synapses on the apical dendrites of the
pyramidal neurons, located in layer 1 of the cortex. Green
arrows depict the corticothalamic ␥ discharge resulting from
coincidence detection between these two inputs, with back-
propagation culminating in thalamocorticothalamic reverbera-
tion. Sustained reverberations of these thalamocortical loops
are hypothesized to result in a resonance that binds together
the fragments of perception dispersed throughout the cortex,
into a unified perception, which becomes the content of con-
sciousness.
ture detecting cell ensembles. Coherent corticothalamic
discharge of dispersed synchronized populations of corti-
cal pyramidal neurons, and the resulting back-propagation
from those neurons whose thalamocortical exogenous and
endogenous projections resulted in coincidence detec-
tion, may bind these fragments together into a unified
resonating system, which is the perceptual content of
consciousness.103,112–114 Such perception has been re-
ferred to by some as the “remembered present.”115 A
model of this process is shown in figure 3.
The blue arrows in figure 3 depict afferent input to the
exogenous system, propagating from the eyes and ears
to the primary relay nuclei in the thalamus and thence to
the axosomatic synapses of pyramidal neurons, in layer 5
of the auditory and visual cortices. Collaterals from these
exogenous inputs go to the endogenous system via the
reticular formation and the mesolimbic system, activat-
ing episodic memories by associative mechanisms. The
gold arrows in the figure depict the readouts of the
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
multimodal aspects of these relevant memories, which
are projected via the non–sensory-specific nuclei of the
diffuse projection system to the apical dendrites of the
pyramidal neurons, in layer 1 of the multimodal sensory
cortices. Coincidence between the inputs from the ex-
ogenous and the endogenous systems, converging on
selected neurons in the sensory cortices, causes a coher-
ent corticothalamic volley to impinge on the thalamic
cells from which the ascending coincident influences
arose. This volley causes a back-propagation and a
thalamocortical–thalamic reverberation in the ␥ fre-
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quency range, depicted by the green arrows. Persistence
of this reverberation engages the prefrontal cortex, and
these simultaneous reverberating, coherent circuits be-
come phase locked and resonant, binding the unimodal
elements of sensation into a multimodal conscious per-
ception. As has been pointed out by Mashour,39 as the
functions of binding dispersed elements of sensation
into a unified perception provide the framework for
integrating multiple simultaneous processes into a uni-
fied conscious experience, so might a paradigm of un-
binding provide a framework for understanding the ac-
tions that underlie anesthesia.
Effects of Anesthetics on Brain Activity
Effects on Power Spectra. In figure 4A are shown the
positions of the 19-electrode array located at positions
defined according to a convention standardized for clin-
ical electroencephalography, the International 10/20
Electrode Placement System. As in many of the head
maps illustrated later in this article, the head is displayed
as if seen from above, with the face at the top.
In figure 4B is a recording made from such an array,
recorded from an awake subject resting with closed
eyes. This recording is contaminated by some artifactual
potentials generated by movements of the eyeballs and
the head, but an artifact-free segment can be seen be-
tween the arrows in the central region of this time
period. To perform reliable intraoperative electrophysi-
ologic monitoring based on accurate quantitative elec-
troencephalographic measurements, such devices must
include algorithms for automatic detection and removal
of all artifactual contamination.
Figure 5 illustrates the prototypic effects of anesthesia
on quantitative electroencephalographic samples before
and after LOC, induced by infusion of propofol. After
computation of the absolute power spectra, the amount
of power at each frequency has been Z-transformed, and
the results are depicted as Z spectra. The Z spectra are
illustrated for every frequency at every electrode posi-
tion of the 10/20 System, labeled according to the usual
convention and shown above each graph. The two hor-
izontal lines are at Z ⫽ ⫾2 SDs, the interval that repre-
sents the 0.05 probability level of significant departure
from the reference distribution. The vertical lines in
each small graph are at the strongest peak in the power
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Fig. 4. (A) In the 10/20 convention, odd
numbers refer to placements over the left
hemisphere, even numbers refer to
placements over to the right hemisphere,
and Z refers to midline locations. Upper-
case letters indicate underlying brain re-
gions: C ⴝ central; F ⴝ frontal; Fp ⴝ fron-
topolar; O ⴝ occipital; P ⴝ parietal; T ⴝ
temporal. (B) Sample of electroencepha-
lographic recording. Each tracing comes
from 1 of the 19 electrodes in the 10/20
array, positioned according to the labels
at the left side of each trace. An artifact-
free segment lies in the region above the
two arrowheads on the bottom line.

spectra, and the number corresponding to the Z score
for that frequency is indicated to the right of the elec-
trode identification.
Figure 5A depicts the Z spectra recorded from a typical
patient at baseline, with a maximum deviation at approx-
imately 12 Hz, perhaps reflecting the effect of a mild
sedative premedication. Figure 5B depicts the mean Z
spectra for a group of 15 patients shortly after LOC due
to infusion of propofol, with a maximum deviation at
approximately 1–3 Hz in every lead. In figure 5A, all
preinduction baseline Z-spectral values lie between ⫺0.1
and 1.7, within the 95% confidence interval of the nor-
mal range in each graph (i.e., Z ⫽ ⫾2.). After LOC, the Z
scores at the frequency of 2 Hz lie between 3.6 and 6.8,
far outside the normal range.
Note that in figures 5–7, all Z scores were calculated
relative to the reference distributions of the same mea-
sures extracted from quantitative electroencephalo-
graphic recordings obtained from baseline recordings
from 164 resting patients, before premedication. Note
also that the significance of mean Z scores, averaged
across a group of n individuals, can be estimated by
multiplying the average Z value by the square root of the
sample size.
Effects on Selected Quantitative Electroencepha-
lographic Variables. Marked effects of anesthetic
agents on a wide variety of quantitative electroencepha-
lographic variables can be detected in all scalp elec-
trodes during induction of anesthesia and maintenance
at surgical plane with many different agents. Represen-
tative quantitative electroencephalographic effects of
such agents are depicted on group averaged interpolated
topographic Z score maps in figure 6. The Z scores were
calculated relative to the distribution of these quantita-

Anesthesiology, V 102, No 2, Feb 2005

460
sample of n subjects, the calculated Z score should be multiplied by the square root of n. For example, if an average Z score of 1.0
were obtained across a sample of 164 subjects, the statistical significance would be as if the score were approximately 12.8. (A)
Preinduction: Very-narrow-band (0.39-Hz bins) power Z spectra of the electroencephalographic data recorded from one typical
premedicated patient, at rest but alert with eyes closed. (B) Group average (n ⴝ 15) Z transformation of the very-narrow-band
electroencephalographic power spectra recorded just after loss of consciousness (LOC) with infusion of propofol.
tive electroencephalographic variables in this popula-
tion of 164 patients before the onset of induction.
Each map depicts interpolated mean Z scores of the
indicated feature from 164 patients, averaged across all
anesthetic protocols used for induction and surgical
maintenance. Statistical significance for all maps in figure
6 is encoded by using a single color palette. Different
scaling is necessary to avoid saturation of the color encod-
ing the actual statistical significance because the magnitude
of anesthetic effects varied on different variables. The ap-
propriate scaling constant for each variable is provided by
the numbers in the rows marked ⫾ Z, under rows 2 and 4
of the mean Z score maps. Each number specifies the Z
values to be assigned to the positive and negative extrema
of the color palettes used for the corresponding variable in
the preceding two rows of head maps. Recall that statistical
significance of a mean Z score is estimated by multiplying
the mean value by the square root of the sample size, or
12.8 with n ⫽ 164.
The six columns of maps depict (1) absolute power in
the ␪ band, (2) absolute power in the ␣ band, (3) absolute
power in the ␥ band, (4) interhemispheric coherence be-
tween symmetrical positions over the two hemispheres in
the ␦ band, (5) interhemispheric coherence in the ␤ band,
and (6) interhemispheric coherence in the ␥ band.
The first four rows of maps depict row 1, induction
(while counting on the operating table at the onset of
induction); row 2, LOC (immediately after cessation of
counting with loss of lash reflex); row 3, surgical plane
(during maintenance at surgical plane just before onset
of weaning); and row 4, ROC (immediately on return of
response to loud verbal command). The last two rows
encode the F value obtained using analysis of variance to
compare row 5, induction versus LOC, and row 6, sur-
gical plane to ROC. The numbers below each map in
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
Fig. 5. This figure presents a graph de-
picting narrow-band (0.39-Hz frequency
intervals) Z spectra for each electrode in
the 10/20 System, using standard nomen-
clature above the curves to identify each
location. All Z scores used in figures in
this article were calculated relative to the
reference distributions of the same mea-
sures extracted from electroencephalo-
graphic recordings obtained from 164
resting patients, before premedication.
The two horizontal bars in each graph
indicate the Z values that are 2 SDs above
and below the mean values of the norma-
tive distributions for each frequency. The
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number next to the electrode identifier
above each graph is the Z value corre-
sponding to the location of the vertical
cursor located at the position corre-
sponding to the most deviant value in the
graph. In estimating the confidence level
of Z scores averaged across data from a
row 5 and row 6 indicated the value to be assigned to F,
encoded by the horizontal color bar, 0 to *.
Note that the maps in row 1 already show a significant
shift of these variables from the baseline, which would
otherwise be encoded as the dull hues close to black on
the color bar. These changes reflect the slowly increas-
ing effects of the administration of the inducing agents,
altering brain state with increasing sedation but still
compatible with the patient systematically counting
backward aloud, a cognitive activity that itself is accom-
panied by shifts from the resting baseline. The dramatic
changes between rows 1 and 2 occur very abruptly with
cessation of counting and the disappearance of the lash
reflex. Note that many of the changes brought about
with LOC caused by the set of inducing agents, seen in
row 2, remain substantially unchanged during mainte-
nance at surgical plane by quite a different set of sub-
stances, as seen in row 3. Finally, some but not all of
these effects reverse with ROC, as some of the maps in
row 4 again become similar to those in row 1, during
induction.
The states and agents represented in figure 6 include
induction with methohexital, etomidate, or propofol and
maintenance with total intravenous concentration, gases
(desflurane, isoflurane, or sevoflurane), or nitrous/narcotic.
The mapped features were selected from a much larger set
to illustrate the great variety of quantitative electroencepha-
lographic variables that change invariantly and reversibly
with the LOC and ROC under the influence of agents
commonly used during surgical anesthesia.
These data show clearly that monitors of the depth of
anesthesia using quantitative electroencephalographic
variables have a rich panoply of effects on which to base
their assessment of the depth of anesthesia. The task of
development of anesthesia monitoring algorithms is to
ANESTHETIC SUPPRESSION OF AWARENESS
Fig. 6. (A) Mean values of Z scores for selected quantitative
electroencephalographic features are shown, averaged across
164 patients at different anesthetic states, established with a
wide variety of agents to achieve induction and maintain surgi-
cal anesthesia. The interpolated topographic maps depict the
19-electrode array of the 10/20 System, looking down on the
head, with the anterior regions at the top. The number under
each column of maps defines the Z score that corresponds to
the corresponding color on the horizontal palette. Induction ⴝ
on the operating table, counting at the onset of induction; LOC
ⴝ immediately after loss of consciousness, with loss of respon-
sivity and disappearance of lash reflex due to induction using
either thiopental, etomidate, or propofol in approximately
equal groups within the sample; surgical plane (SP) ⴝ approx-
imately midway during the procedures, with anesthesia under
standard procedures primarily maintained by propofol, gas
(isoflurane, desflurane, or sevoflurane), or nitrous/narcotic in
approximately equal groups within the sample. Note the re-
markable similarity of electroencephalographic effects of the
different agents used for induction versus maintenance. ROC ⴝ
immediately after return of consciousness, when patient first
opens eyes on loud command. (B) The results of analyses of
variance between (induction vs. LOC) and (SP vs. ROC) are
presented in the two rows of maps of the corresponding F
values, indicating that the changes illustrated are highly signif-
icant. All Z scores were calculated relative to the reference
distributions of the same measures extracted from electroen-
cephalographic recordings obtained from 164 resting patients,
before premedication. From John et al.121; used with
permission.
select the most robust set of variables from among these
many candidates that are both necessary and sufficient to
provide the most accurate and sensitive assessments of
patient state across the widest range of chemical agents,
with the most rapid and reliable detection of the changes
relevant for the optimal clinical management of each
case.
Anesthesiology, V 102, No 2, Feb 2005
461
Effects on Quantitative Electroencephalographic
Coherence. Coherence provides a measure of the func-
tional interaction or coupling between two brain regions.
Administration of anesthetic agents causes marked changes
in coherence, which are of particular interest because of
the hypothetical role of coherence in binding that has been
proposed in the theoretical formulation presented above in
the discussion illustrated by figure 3.
Figure 7 presents the results of more extensive com-
putations of coherence as well as power that were car-
ried out on the 164 patients whose Quantitative electro-
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encephalographic data were partially presented above.
All data shown in figure 7 represent mean Z scores
relative to the distribution of the resting baseline values
in the 164 patients before onset of induction; the signif-
icance of these mean Z scores can be estimated by
multiplying the average Z value by 12.8.
Figure 7A illustrates that the frontal lead F3 and the
occipital lead O1 demonstrate an increase in power and
a relative change in the power gradient at LOC in all
frequency bands except ␥, showing enhanced anterior-
ization, i.e., the increase in mean Z scores for ␦, ␣, and ␤
activity is greater for the frontal than for the occipital
lead. Changes in ␪ power essentially paralleled ␦ and are
not illustrated. These power changes gradually diminish
during emergence.
Figure 7B shows that coherence of ␥, but not of ␦, ␣,
or ␤, between F3 and O1 increases during the mental
task of counting backward during induction. Shortly
after LOC, coherence in all bands decreases significantly
and remains diminished during maintenance at surgical
plane. As emergence begins, although there is no
marked increase in power, coherence of ␤ and ␥ returns
to the levels seen while counting during induction.
These data suggest that anterior and posterior brain
regions become functionally uncoupled with the LOC
caused by the action of anesthetics and remain uncou-
pled during surgical maintenance. Consciousness re-
turns, as evidenced by the opening of eyes on a loud
command, as coupling between prefrontal cortex and
sensory regions is restored to previous levels in ␤ and ␥
frequencies. The most striking coherence changes as
emergence progresses are in ␥, for which sharp in-
creases in coherence begin to appear several minutes
before opening of the eyes. While similar uncoupling
occurs in all frequency bands, recoupling of ␦ and ␣
occurs only several minutes after responsive conscious-
ness is restored. These findings are particularly interest-
ing in view of some of the reports cited above, in the
discussion of the role of coincidence detection in bind-
ing, of prefrontal–parietal phase-locked ␥ coherence dur-
ing performance of perceptual tasks.
We interpret these data to suggest that anesthesia
interrupts and consciousness restores the cortico-
thalamocortical reverberation resulting from detection
by the pyramidal neurons of coincidence between the
462
exogenous report of sensory specific inputs and the
endogenous readout of episodic memories, endowing
the sensations with meaning. Whether this correlation is
unique to ␥ coherence or is also a property of coherent
activity in the ␤ range awaits inquiries specifically de-
signed to answer that question.
Effects on MLAER. In figure 8A is depicted the nor-
mal waveshape of the auditory evoked response and the
neuroanatomical structures presumed to generate the
successive components. These include the brainstem
auditory evoked response, with peaks I (acoustic nerve),
II (cochlear nucleus), III (superior olivary complex), IV
(trapezoid body), and V (inferior colliculus) and the early
cortical or midlatency evoked response, with peaks No
and Po (medial geniculate), Na, Pa, and Nb (early re-
sponses of primary auditory cortex), and P1 (also some-
times referred to as Pb), and later components are be-
lieved to reflect activity in association areas and frontal
cortex. In figure 8B are shown group averaged MLAERs,
obtained in surgical procedures using total intravenous
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
Fig. 7. Mean changes in Z scores for ab-
solute power of electroencephalogram
from left mesial prefrontal and occipital
(leads F3 and O1) and coherence between
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those two leads (F3O1), computed for the
␦, ␣, ␤, and ␥ frequency bands, at sequen-
tial stages between induction and return
of consciousness, averaged across 164 in-
dividuals in procedures using different
agents, as in the previous figure. All Z
scores were calculated relative to the ref-
erence distributions of the same mea-
sures extracted from electroencephalo-
gram recordings obtained from 164
resting patients, before premedication.
(A) Absolute power F3 and O1. (B) Coher-
ence F3O1. Induc ⴝ counting during in-
duction; LOC ⴝ immediately after loss of
consciousness; Maint ⴝ surgical plane;
ROC-1 ⴝ 5 min before ROC; ROC ⴝ im-
mediately after patient opens eyes on
loud command.
anesthetic (n ⫽ 19), isoflurane (n ⫽ 17), desflurane (n ⫽
6), and nitrous/narcotic (n ⫽ 20). Note the lengthening
of the Pa–Nb–Pb interval with LOC caused by each of
these agents and the diminished amplitude and longer
latency of subsequent components. Note that the prein-
duction Pa–Pb interval is approximately 25 ms, which is
the period of a 40-Hz oscillation (␥). In figure 8C are
depicted the set of power spectra computed from a
simulated series of EP templates; these simulated wave-
shapes were morphed using the MLAER waveshapes
from preoperative baseline to loss of consciousness re-
corded during induction with desflurane, as shown in
the middle panel. Note the gradual disappearance of the
40-Hz component from the resulting spectra. These re-
sults suggest that perhaps the change in the MLAER
waveshape reflects blockade of a 40-Hz thalamocortical
back-propagation.
Effects on the 40-Hz Steady State Evoked Re-
sponse. As noted above, the 40-Hz SSEP has been ex-
plored as a possible index of anesthesia. The 40-Hz SSEP
ANESTHETIC SUPPRESSION OF AWARENESS 463

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Fig. 8. Changes in midlatency auditory
evoked response with loss of conscious-
ness. (A) The sites in the auditory path-
ways usually attributed as neuroanatomi-
cal generators of components of auditory
evoked potentials. (B) Changes in the
midlatency auditory evoked response re-
corded from vertex (Cz) versus mastoid,
during standard administration of anes-
thesia with various agents (L. Gugino,
Ph.D., M.D.; L. S. Prichep, Ph.D.; and E. R.
John, Ph.D., unpublished observations,
May 2001). (C) Power spectra of the midla-
tency auditory evoked response morphed
from the awake state to loss of conscious-
ness. DES ⴝ desflurane; ISO ⴝ isoflurane;
N/N ⴝ nitrous/narcotic; TIVA ⴝ total intra-
venous anesthetic.

waveshape is a rhythmic oscillation at 40 Hz, reflecting
the entrainment of the small early components of the
MLAER by the much larger components of the subse-
quent cortical auditory responses to a series of closely
spaced auditory stimuli. Many anesthetics disrupt the
40-Hz SSEP, seen as the progressive diminution of ampli-
tude with increasing amount of anesthetic agent.
This effect is illustrated in figure 9, showing the
changes in ASSR with stepwise titration of the amount of
anesthetic, concomitant with clinical assessments of the
depth of anesthesia using the Observer’s Assessment of
Anesthesia and Sedation scale. Group grand averages
(n ⫽ 15) were constructed by averaging 40-Hz auditory
steady state evoked potential averages recorded from the
19 electrodes of the International 10/20 System, ob-
tained from volunteer subjects during stepwise titration

Anesthesiology, V 102, No 2, Feb 2005

464 E. R. JOHN AND L. S. PRICHEP

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Fig. 9. Group grand averages (n ⴝ 15) constructed by averaging 40-Hz auditory ASSRs recorded from the 19-electrode arrays of the
International 10/20 System referenced to linked earlobes, as if looking down on the head with the frontal electrodes at the top,
obtained from 15 volunteer subjects during stepwise titration of anesthesia using propofol. (Left column) PRE ⴝ on operating room
table, awaiting induction; LOC ⴝ immediately after loss of consciousness at 0.4 minimum alveolar concentration (MAC), with
cessation of counting and loss of lash reflex; 1.0 ⴝ after 15 min at 1.0 MAC, descending from 0.4 MAC. (Right column) 1.4 ⴝ after
15 min at 1.4 MAC, descending from 1.0 MAC; 0.4 ⴝ after 15 min at 0.4 MAC, ascending from 1.4 MAC; ROC ⴝ immediately after
opening eyes to a loud command.

of anesthesia using propofol. Each array is depicted as if imum alveolar concentration (MAC) equivalent, but LOC
viewed from above, with the face or nose at the top and and ROC were established using the usual clinical crite-
the left side of the subject on the left. The numbers at ria. The three arrays in the left column, from top to
the top left of each array refer to the approximate min- bottom, depict the steady state evoked potential at in-

Anesthesiology, V 102, No 2, Feb 2005

ANESTHETIC SUPPRESSION OF AWARENESS
creasing depths of anesthesia, pre, descending LOC (ap-
proximately 0.4 MAC), and 1.0 MAC, and the three
arrays in the right column depict the steady state evoked
potential at 1.4 MAC, 0.4 MAC, and ROC, defined by
opening of the eyes in response to a loud command.
Functional Brain Imaging Studies of Anesthesia:
Regional Cerebral Metabolic Rate, Regional
Cerebral Blood Flow, and Quantitative
Electroencephalographic Source Localization
To round out this overview of the effects of anesthetics
on the brain, it is useful to examine recent findings
obtained in functional brain imaging studies.
Effects on Regional Cerebral Metabolic Rate. Us-
ing evidence from PET scans to visualize changes in
brain regional cerebral metabolic rate (rCMR) during
general anesthesia with halothane and isoflurane, as re-
flected by uptake of radioactively labeled (F18) 2-deoxy-
glucose, Alkire et al.116 addressed two questions: (1) Did
the regional effects of halothane and isoflurane, exam-
ined with this method, show commonalities of action on
brain metabolism that help to understand the mecha-
nism by which these agents produce unconsciousness,
and (2) will the common effects of these two substances
be suppression of thalamocortical activity? Subjects
were 11 healthy volunteers who each underwent two
separate PET scan procedures separated by at least 1
week. The baseline awake regional cerebral metabolic
rate of glucose was assessed in the first scan. The second
scan assessed metabolism during a period of uncon-
sciousness, established by unresponsiveness to verbal
commands, prodding, or shaking, induced either with
halothane (n ⫽ 5) or isoflurane (n ⫽ 6) general inhala-
tion anesthesia. The mean expired halothane and isoflu-
rane concentrations were 0.7 ⫾ 0.2 and 0.5 ⫾ 0.1%,
respectively.
For all subjects, general inhalational anesthesia in-
duced both a global reduction and specific regional re-
ductions of brain glucose metabolism. No brain regions
were found that increased their metabolism during an-
esthesia. The mean global or whole-brain rCMRglu was
reduced by 42% (⫾ 13%) during isoflurane and 40% (⫾
10%) during halothane anesthesia. Effects common to
both agents were observed and included a significant
reduction of rCMRglu in the cuneus, thalamus, midbrain
reticular formation, dorsolateral prefrontal cortex, me-
dial frontal gyrus, inferior temporal gyrus, cerebellum,
and occipital cortex.
The results were interpreted to arise from hyperpolar-
ization block of the TCR neurons in thalamic networks
and a transition from the state enabling thalamocortical
throughput of sensory information to an inactivated state
in which thalamocortical gates are essentially closed.
These thalamic networks are discussed above in the
section on the generation of ␣ rhythms. These authors
envisaged that anesthetics cause neuronal changes coin-
Anesthesiology, V 102, No 2, Feb 2005
465
cident with LOC by three possible mechanisms or a
combination thereof: (1) direct hyperpolarizing effects
on thalamic and cortical cell membrane potentials117; (2)
suppression of midbrain/pontine areas involved with
regulating arousal, removing excitatory inputs to the
thalamocorticothalamic loops by inhibiting glutamater-
gic and cholinergic neurotransmission118; (3) enhance-
ment of GABAergic synaptic neurotransmission mediat-
ing inhibitory circuitry within thalamocortical loops119;
and (4) that different anesthetics might use only one of
these proposed mechanisms, but some agents might use
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various combinations of these different mechanisms. No
matter which process is initiated by the agent, these
authors suggest that any substance or event that pushes
thalamocortical cells toward hyperpolarization, no mat-
ter what the mechanism, will cause LOC.
Their initial hypothesis, based on neuroanatomical and
neurophysiologic evidence, was that thalamic and mid-
brain reticular formation activity is needed to maintain
function in a specific set of neurons essential for con-
sciousness. They argue that these findings place the
most important site of anesthetic action not in the retic-
ular formation itself, but rather in the thalamic gated
regions regulated by the reticular arousal centers. They
proposed, consonant with the extended reticular–tha-
lamic activating system theory proposed by Newman
and Baars,99 that those regions that generate conscious-
ness might have been identified in their experiments.
Effects on Regional Cerebral Blood Flow. Changes
in regional cerebral blood flow (rCBF), determined using
H2O15 PET imaging, can be used to visualize changes in
brain oxygen utilization by neural circuitry, reflecting
the effects of centrally acting drugs. This method was
used by Veselis et al.25,26 to study the effects of infusions
of two different concentrations of midazolam on mem-
ory and rCBF in 14 healthy volunteers. Midazolam has an
agonistic action at the GABAA receptor complex and is
widely used clinically to accomplish temporary sedation
and amnesia. Subjects were randomly assigned to re-
ceive computer-assisted continuous midazolam infusion
intended to produce either a “low” or a “high” effect.
The initial effect site target concentrations were 7.5 ⫾
1.7 mg midazolam (serum concentration ⫽ 74 ⫾ 24
ng/ml) for the low-effect group and 9.7 ⫾ 1.3 mg (serum
concentration ⫽ 129 ⫾ 48 ng/ml) for the high-effect
group.
Subjects were then classified into low- and high-effect
groups based solely on analysis of the quantitative elec-
troencephalograms obtained during PET scanning.
These effects were identified using spectral analysis of
the quantitative electroencephalographic activity during
the PET imaging, depending on the presence or absence
of a clear peak at 14 Hz in the power spectrum arising
from spindle activity. Effects were localized using statis-
tical parametric mapping with respect to standard ste-
reotaxic coordinates. Relative changes in rCBF were
466
calculated after the absolute changes in global rCBF
were determined. Participants were asked to memorize a
list of 16 words presented verbally at baseline, before
onset of drug infusion, and during midazolam infusion.
The degree of memory loss was measured by the number
of words retained. Participants in both groups experi-
enced memory loss during midazolam administration.
From the 16-word list presented during infusion, the
mean numbers of words recognized at the end of the
study day were 5 ⫾ 4.5 (P ⬍ 0.002) and 1.6 ⫾ 1.7 (P ⬍
0.001) for the low-effect and high-effect groups,
respectively.
The rCBF changes in the low-effect group were a
subset of those observed in the high-effect group. Re-
gions where the decreased in rCBF reached significance
at the P ⬍ 0.001 level included the insula, the thalamus,
the cingulate cortex, multiple areas of the prefrontal
cortex, and the parietal and temporal association areas of
the cortex. Conversely, rCBF was increased in the occip-
ital areas. The authors concluded that midazolam seda-
tion alters normal function of brain regions associated
with arousal, attention, and memory.
Levels of midazolam as high or slightly higher than
were used in the high effect group in this study can be
expected to cause deep sedation and unresponsiveness,
with severe obtunding of consciousness. The depression
of the thalamus can be attributed to the agonistic en-
hancement of GABA action by nucleus reticularis on the
TCR neurons, which would block throughput to the
axosomatic synapses on the lower layers of the cortex.
The observed effects also indicate interference with the
outflow of the mesolimbic system to the prefrontal cor-
tex and other neocortical regions via the anterior cin-
gulate and the medialis dorsalis nucleus of the thalamus.
This would block input to the axodendritic synapses of
the pyramidal neurons in upper layers of the cortex. The
net effect would be to prevent coincidence detection by
the pyramidal neurons of converging inputs from the
exogenous and endogenous systems onto the cortex.
Because prefrontal–parietal interactions are involved in
focusing attention and cognitive processing, these ef-
fects are compatible with interference with attention
and memory retrieval. The apparent increased rCBF in
the occipital areas may in fact indicate that the occipital
areas were relatively unaffected by midazolam, in view
of the fact that the global rCBF decreased; that is, the
images depict relative values, not absolute values, i.e.,
percent of total.
Effects on Three-dimensional Quantitative Elec-
troencephalographic Source Localization. If one
knows that there are a number of specific voltages at
particular points in space, together with certain electri-
cal parameters of the space, it is possible to describe the
potential field that will be generated in space by that set
of voltage points, and the solution is unique. However,
the converse is not true, i.e., if one knows the distribu-
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
tion of potentials in space, or the field, especially if the
number of generators is more than one, there are essen-
tially an infinite variety of spatial distributions of voltage
sources that will generate the same field. The mathemat-
ical problem of locating within the brain the most prob-
able neuroanatomical sources of electroencephalogram
or EP surface potentials is referred to as the inverse
problem. Until recently, this problem was considered
mathematically insolvable. By making a number of rea-
sonable assumptions and imposing a number of reason-
able constraints, several methods have been developed
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recently for this purpose.
One three-dimensional electroencephalographic
source localization method that has been developed su-
perimposes the computed generators of electroencepha-
lographic voltages recorded from the scalp on images of
brain slices taken from a Probabilistic MRI Atlas con-
structed at Montreal Neurologic Institute (Montreal,
Quebec, Canada). This method is referred to as variable
resolution electromagnetic tomography (VARETA).120
The solutions place the “proportional” positions of scalp
electrodes in the International 10/20 System in registra-
tion with the “proportional” Probabilistic MRI Atlas to
coregister the calculated three-dimensional quantitative
electroencephalographic source locations with neuro-
anatomical images, providing a “virtual functional MRI”
in so-called Talairach space. Methods like VARETA solve
the formidable problem posed by the uncertainty of
mathematical solutions to the problem, if approached
with no constraints, by two major conceptual break-
throughs: (1) neuroradiologists have constructed
“masks” that identify those voxels within white matter
or cerebrospinal fluid space that can arbitrarily be ex-
cluded from candidacy as putative voltage sources, and
(2) regularization parameters define the amount of
“smoothness” that must be imposed on the solutions,
thereby arbitrarily restricting the permitted gradients
around voxels where sources are located. Numerous
studies have found images computed using these various
three-dimensional methods to localize sources of quan-
titative electroencephalographic abnormalities to be in
good correspondence with images of neuropathology
obtained using computed tomography, magnetic reso-
nance imaging, and PET imaging techniques. Further-
more, a large quantitative electroencephalographic nor-
mative database has been used to compute the expected
distribution in more than 3,500 brain voxels, which are
cubic volumes 7 mm on a side, of the sources of power
from 0.37 to 19 Hz. The statistical significance of devia-
tions from the expected source strength of any voxel at
any frequency can now be encoded in color, yielding
functional neuroanatomical images that can be inter-
preted like a neurometric quantitative electroencephalo-
graphic map.
ANESTHETIC SUPPRESSION OF AWARENESS 467

Fig. 10. The five rows of images depict

group average variable-resolution elec-
tromagnetic tomography Z images com-
puted from the quantitative electroen-
cephalographic activity at 3.5 Hz in five
different states. Row 1 (baseline): at rest
on the operating table before induction
begins; row 2 (Induct): while counting on
the operating table at the onset of induc-
tion, just before row 3 (LOC): immedi-
ately after cessation of counting with loss
of lash reflex; row 4 (SP): during mainte-
nance at surgical plane just before onset
of weaning; row 5 (ROC): immediately on
return of response to loud verbal com-

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mand. Each panel (the axial, sagittal, and
covonal views) represents the average of
15 patients in the corresponding state for
each agent except for the nitrous/nar-
cotic data in rows 4 and 5, which repre-
sent the average of only 10 cases. The
bars under row 3 present the statistical
significance of the colors assigned to ev-
ery voxel of images in the first three rows
above, whereas the bars under row 5 re-
late only to the images in rows 4 and 5.
Every voxel has been Z-transformed rel-
ative to the resting distribution of power at 3.5 Hz in the baseline data from 164 cases. Only voxels that are significant beyond the
P < 0.001 level are colored in these images, i.e., the image has been thresholded to depict only extremely significant changes.

We have used VARETA to visualize the neuroanatomi-
cal regions that are the probable sources of changes in
quantitative electroencephalographic activity that are in-
variant and reversible with the LOC and ROC indepen-
dent of the anesthetic agents used for induction or main-
tenance of the anesthetized state.121 While numerous
quantitative electroencephalographic changes take
place with anesthesia, as shown previously in figure 6,
significant increases of absolute power at 3.5 Hz are
perhaps the most reliable quantitative electroencephalo-
graphic changes that accompany LOC with anesthesia,
and activity at this frequency is indicative of significant
inhibition. Therefore, we chose to report findings at this
frequency using this method. Representative VARETA
images at 3.5 Hz are presented in figure 10.
Figure 10 shows average VARETA images of groups of
patients (n ⫽ 15 in each panel) in five stages verified by
standard clinical practice: (1) at rest on the operating
table before induction; (2) counting just before LOC,
during induction with three different agents; (3) just
after LOC; (4) just before ROC, during emergence from
maintenance at surgical plane using three different
agents; and (5) just after opening their eyes in response
to a loud verbal command using their name. All images
were based on the localization of quantitative electroen-
cephalographic power at 3.5 Hz, one of the frequencies
that displayed the most distinctive and consistent set of
changes (heterogeneity of variance across states, homo-
geneity within each state across all agents). The fre-
quency is at the margin between high ␦ and low ␪ and
can be considered to reflect significant inhibitory effects.
The statistical significance of the changes in each voxel
of these images is color coded relative to the mean value
and SD (voxel Z score) of the distribution of resting
power in that voxel at that frequency, calculated from
the corresponding distribution of values in 176 patients
in the preoperative resting state. Hues of red through
yellow indicate increases, and hues of blue through
turquoise indicate decreases from the mean value.
The results show 3.5-Hz power increased significantly
(indicating relative inhibition) in a set of regions including
the orbital prefrontal cortex, dorsolateral prefrontal cortex,
anterior cingulate gyrus, basal ganglia, amygdala, postcen-
tral gyrus, hippocampus, and thalamus. This set of struc-
tures is in good correspondence with those showing most
marked changes in the rCMR and rCBF studies discussed
above.26,116 The depression of the thalamus can reflect
inhibition by the GABA action of nucleus reticularis, itself
released from inhibition due to depression of the midbrain
reticular formation. Inhibition of the TCR neurons would
block throughput to the axosomatic synapses on the lower
layers of the cortex. The depression of amygdala, hip-
pocampus, basal ganglia, and anterior cingulate indicates
the suppression of mesolimbic system outflow to the pre-
frontal cortex and other neocortical regions. This would
block input to the axodendritic synapses of the pyramidal
neurons, in upper layers of the cortex.
Therefore, the results discussed in this section indicate
that three different functional imaging methods, evalu-
ating brain changes caused by a variety of different
anesthetic agents, detected a common effect. This effect
is prevention of coincidence detection by the pyramidal
neurons of converging inputs from the exogenous and
endogenous systems onto the cortex.

Anesthesiology, V 102, No 2, Feb 2005

468
A Neurophysiologic Theory of the Action of
Anesthetics to Suppress Awareness
Based on the evidence presented above, we propose
that the neurophysiologic effects that produce amnesia
and loss of awareness due to the action of anesthetics
occur in six steps:
Step 1: Depression of the brainstem reduces the influ-
ences of the ARAS on the thalamus and cortex.
Step 2: Depression of mesolimbic– dorsolateral pre-
frontal cortex interactions leads to blockade of memory
storage.
Step 3: Further depression of the ARAS releases its
inhibition of the nucleus reticularis of the thalamus,
resulting in closure of thalamic gates (especially in the
diffuse projection system) by hyperpolarizing GABA-me-
diated inhibitory action of the nucleus reticularis (␪ in-
crease), thereby blocking
Step 4: Thalamocorticothalamocortical reverberations
and perception (␥ decrease), so that
Step 5: Parietal–frontal transactions are uncoupled (␥
coherence decreases), blocking cognition, and
Step 6: Prefrontal cortex is depressed to reduce aware-
ness (increase of frontal ␦ and ␪).
These steps are described in figure 11.
Conclusion
Although one may consider these six steps as a hierar-
chical sequence, it must be kept in mind that reciprocal
pathways interconnect all of the neuroanatomical struc-
tures engaged in this cascade. There are many ways that
amnesia and blockade of awareness can be accom-
plished. Agents that cause depression of the ARAS in the
brainstem can reduce activating and arousal influences
Anesthesiology, V 102, No 2, Feb 2005
E. R. JOHN AND L. S. PRICHEP
Fig. 11. Schematic depiction of six stages
(dark black font) hypothesized to ex-
plain the effects of anesthetics that cause
loss of consciousness. Step 1: depression
of the ascending reticular activating sys-
tem causing a diminution of availability
of acetylcholine, initially resulting in
step 2: decreased reactivity of the limbic
system blocking interaction with the dor-
solateral prefrontal cortex and prevent-
ing recent memory transfer for storage,
followed by step 3: further decrease of
acetylcholine disinhibiting the blockade
of the ␥-aminobutyric acid–mediated in-
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hibition by nucleus reticularis, resulting
in closure of thalamic gates of thalamic
gates, and leading to step 4: blockade of
reverberations in corticothalamocortical
␥ loops and interruption of resonance,
causing step 5: uncoupling of parietal-
prefrontal cortical ␥ interactions, result-
ing in step 6: depression of prefrontal
cortex with loss of consciousness.
on the specific and nonspecific thalamic nuclei and the
cortex. Depression of the ARAS can also release complex
GABAergic inhibitory effects in the limbic system due to
diminution of ARAS inputs that produce cholinergic in-
hibition of GABA. There seems to be a level of such
agents that diminishes interactions of the mesolimbic
circuits, including the amygdala, hippocampus– cingu-
late cortex with the dorsolateral prefrontal cortex, to
block the storage of memory and achieve amnesia for
ongoing events. A somewhat greater depression of the
brainstem releases the nucleus reticularis from the inhib-
iting influence of the ARAS. This can lead to closure of
thalamic gates due to the inhibitory action of nucleus
reticularis, resulting in diminished cortical input. De-
creased thalamocortical input may result either by loss of
activation from the ARAS or by dynamic inhibition via
nucleus reticularis. Inhibition of either the cortex or the
non–sensory-specific, diffuse thalamic projection nuclei
blocks the corticothalamocortical reverberations hy-
pothesized to be critical for awareness. Depression of
the parietal cortex interrupt the prefrontal–parietal
transactions critical for perception. Inhibition of the
prefrontal cortex releases its modulation of nucleus re-
ticularis, resulting in defocusing of attention and reduc-
ing activation of the systems mediating speech and
movement. The level of vigilance can be lowered by
influences from the striatum or substantia nigra imposed
on the reticular formation, increasing the threshold for
arousal.
We have attempted to determine how abruptly the
brain state changes with LOC due to anesthesia. These
studies have been limited by the temporal resolution of
our equipment and the VARETA software currently avail-
able to us. Although they must be considered tentative
and preliminary, the results lead us to an estimate on the
ANESTHETIC SUPPRESSION OF AWARENESS
order of 10 –20 ms, for the change in state shown by the
quantitative electroencephalographic alterations on
LOC, as illustrated in figure 6, and in the underlying
dispersed system of anatomical regions, illustrated in
figure 10. It should be pointed out that such speed may
make more plausible and attractive the notion of LOC as
a “phase transition,” as proposed by Steyn-Ross et al.122
Even though these steps may occur almost instanta-
neously, we propose that steps 1– 6 are arranged in a
sequence that corresponds to their sequential activation
and thus constitute a “cascade.” For example, it may be
that the release of corticofugal inhibitory influences on
the thalamus, as ascending reticular activating influences
on the cortex (and perhaps inhibitory reticulohippocam-
pal influences) are blocked in step 1, contributes to the
behavioral excitation evident in delirium or stage II an-
esthesia. The blockade of memory by low doses of an-
esthetics shown by Veselis et al.24 may reflect blockade
of long-term potentiation in the hippocampus and the
depression of septal– hippocampal outflow to the pre-
frontal cortex as proposed in step 2. The closing of the
gates of the thalamic diffuse projection system in step 3
nonetheless allow primary sensory thalamocortical in-
puts to continue, as reflected by preservation of the
primary components of cortical evoked potentials in
anesthesia or coma. Synchronization of interactions
within cortical ensembles may generate some level of
local ␥ activity even though interaction with other cor-
tical regions is blocked. While uncoupling of corticocor-
tical transactions is proposed in step 5, the implication is
that neural processing of data encoding sensory frag-
ments may continue although the formation of complex
representations may not. Effects initiated at any level of
the system rapidly propagate both upward and down-
ward through the brain to modulate other parts of this
interactive network. There is no unique neuroanatomi-
cal structure at which action is both necessary and suf-
ficient for an agent to accomplish modulation of the
level of awareness. Similarly, there is no unique molec-
ular agent acting on a special cellular target that can
initiate this process. However, by slow induction of
anesthesia, it may be possible to demonstrate whether
steps 1– 6 listed above occur in the indicated sequence.
The actions of anesthetic agents to achieve immobiliza-
tion seem to require concentrations to be further in-
creased, beyond the blockade of these interactions that
is necessary to suppress awareness, to depress motor
neurons in the spinal cord.
Particular importance must be attributed to the intra-
operative observations of the effects of anesthetics on
coherence in the various frequency bands of the quan-
titative electroencephalographic power spectrum.
These effects arise from the rapid initiation of steps 4 – 6.
It may not be possible experimentally to demonstrate
separability of the processes postulated in these steps,
because of their interdependence. It has been proposed
Anesthesiology, V 102, No 2, Feb 2005
469
that the lower the frequency is, the more remote the
brain region is from which the influence arises,123,124
evidence like that summarized previously and more fully
elsewhere,112,113 indicates that neural synchronization is
present from extremely small to global scales and plays
a critical role in assembling dispersed information into a
seamless conscious experience. Using indwelling elec-
trodes in epileptic patients, intracerebral electroen-
cephalographic recordings reveal progressive suppres-
sion of ␥ activity in the hippocampus with increased
concentrations of sevoflurane,125 a finding buttressed by
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subsequent neurophysiologic studies in animals that
showed septal– hippocampal inactivation and suppres-
sion of ␥ activity by both volatile and nonvolatile anes-
thetics.126 We have elsewhere proposed that the process
that generates ␥ activity in the hippocampus is the initial
source of the endogenous input to the apical dendrites
of the coincidence detector depicted in figure 3.127 As
Mashour39 has emphasized in discussing and extending
our findings, such evidence supports the concept of
cognitive unbinding as a final common mechanism for
anesthesia, occurring at many different levels ranging
from convergence at the cellular level to interruption of
synchronization within an ensemble assembling dis-
persed fragments of information within a system to bind-
ing the state of many systems into conscious awareness,
and reversing the elements of brain interactions that
produce cognitive binding.
Some of the original data contained herein was collected in collaboration with
Lavern Gugino, Ph.D., M.D. (Associate Professor, Department of Anesthesia,
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachu-
setts), and analyzed in collaboration with Robert Isenhart, B.S. (Assistant Re-
search Scientist, Department of Psychiatry, New York University School, New
York, New York). Some of the analyses performed on data reported herein were
done in collaboration with Arnaud Jacquin, Ph.D. (Senior DSP Engineer, Everest
Biomedical Instruments, Chesterfield, Missouri).
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