We appreciate Professor Antkowiak’s thoughtful disagreement with the mechanism we propose for how anesthesia suppresses consciousness.1Professor Antkowiak concludes that “the anesthetic cascade” explains anesthesia by a bottom-up process, criticizes assumptions we did not make, and provides examples of anesthetic effects at various brain levels to rebut what he perceives as our unitary theory of anesthetic action. We contend that consciousness is produced by a resonance binding together a phase-locked ensemble of oscillations linking spatially dispersed thalamocortical loops. Anesthetic agents act by blocking this resonance, which is constructed by a neurophysiologic process engaging brainstem, thalamic, limbic, and cortical regions. To describe this as a bottom-up unitary process is a misperception.

Professor Antkowiak asserts that the “statement that anesthetic-induced sedation and amnesia are causally related to a decreased concentration of acetylcholine in the brain is not backed by experimental evidence”; however, we made no such assertion in our article. Rather, we summarized previous work suggesting: (1) that cholinergic influences from the ascending reticular activating system diminish hyperpolarizing influences of γ-aminobutyric acid–mediated reticular nucleus neurons and facilitate throughput to the cortex; (2) that a circulating flow of activation between the ascending reticular activating system, the intralaminar nuclei, and the cortex may be necessary for the state of consciousness; (3) that acetylcholine receptors are probably irrelevant to how inhaled anesthetics achieve immobility; (4) that interconnections by gap junctions are critically dependent on cholinergic action; and (5) that common regional effects of halothane and isoflurane were a significant reduction of regional cerebral glucose metabolic rate utilization in the cuneus, thalamus, midbrain reticular formation, dorsolateral prefrontal cortex, medial frontal gyrus, inferior temporal gyrus, cerebellum, and occipital cortex. This and other evidence was interpreted to indicate that loss of consciousness may be due to four possible mechanisms or a combination thereof: (1) direct hyperpolarizing effects on thalamic and cortical cell membrane potentials;2(2) suppression of midbrain/pontine areas involved with regulating arousal, removing excitatory inputs to the TC-CT loops by inhibiting glutamatergic and cholinergic neurotransmission;3(3) depression of cortical activity; or (4) complex γ-aminobutyric acid–mediated inhibitory effects in the limbic system.

Our article further reviewed physiologic evidence that perception depended on the coincidence at the cortical level between exogenous, sensory specific input of information about the environment and endogenous, nonsensory specific readout from a representational system encoding memories of the relevant past. We proposed a detailed mechanism whereby exogenous and endogenous fragments of percepts are linked by pyramidal neurons serving as coincidence detectors, resulting in spatially extensive γ oscillations. Coherent corticothalamic discharge of dispersed synchronized populations of cortical pyramidal neurons, and the resulting back-propagation from those neurons whose thalamocortical exogenous and endogenous projections resulted in coincidence detection, may bind these fragments together into a unified resonating system, which is the perceptual content of consciousness. We proposed that just as the functions of binding dispersed elements of sensation into a unified perception provide the framework for integrating multiple simultaneous processes into a unified conscious experience, so might a paradigm of unbinding provide a framework for understanding the actions that underlie anesthesia. We reviewed evidence that 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 dispersed fragments of information within a system to binding the state of many systems into conscious awareness, and reversing the elements of brain interactions that produce cognitive binding.

We proposed 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 influences of the ascending reticular activating system on the thalamus and cortex; step 2: depression of mesolimbic–dorsolateral prefrontal cortex interactions leads to blockade of memory storage; step 3: further depression of the ascending reticular activating system releases its inhibition of nucleus reticularis of the thalamus, resulting in closure of thalamic gates (especially in the diffuse projection system) by hyperpolarizing γ-aminobutyric acid–mediated inhibitory action of n. reticularis (θ increase), thereby blocking step 4: thalamo-cortical-thalamo-cortical reverberations and perception (γ decrease), so that step 5: parietal–frontal transactions are uncoupled (γ coherence decreases), blocking cognition, and step 6: prefrontal cortex is depressed to reduce awareness (increase of frontal δ and θ).

Steps 1–6 are arranged in a sequence that corresponds to their sequential activation and thus constitute a “cascade.” These steps are different stages of a process. The process can be initiated at any stage and ripple through the system. Our article pointed out very explicitly, “Although one may consider these six steps as a hierarchical sequence, it must be kept in mind that reciprocal pathways interconnect all of the neuroanatomical structures engaged in this cascade. There are many ways that amnesia and blockade of awareness can be accomplished.” We then enumerated many ways in which disruption may occur at any level in the process. Effects initiated at any level of the system rapidly propagate both upward and downward through the brain to modulate other parts of this interactive network. There is no unique neuroanatomical structure at which action is both necessary and sufficient for an agent to accomplish modulation of the level of awareness, because this depends on the integrity of the system as a whole.

We have no disagreement with the evidence that Professor Antkowiak presents, but in spite of the provocative title of his critique, we do not find it relevant to our central proposal: Anesthetics act by disrupting resonance among oscillations binding together processes at many levels of the brain.

Professor Hagihira et al.  state that blocking of T-C-T-C reverberations is not always included in the anesthetic cascade. They infer this based on their observation that peak bicoherence (pBIC) values, measured from the electroencephalogram recorded from a single electrode derivation (FP1-A1) in the frequency range from 2 < f < 15 Hz, increased in two regions: pBIC-high appeared in the 7- to 14-Hz frequency range, which is the frequency range of the spindle wave, and pBIC-low appeared around 4 Hz, the frequency of the δ wave (conventionally called θ). They cite evidence by other workers that indicates that spindle waves arise from thalamo-cortico-thalamic circuits and the δ rhythm is the intrinsic rhythm of thalamocortical neurons. On this basis, they assume that nonlinear modulation among the spindle waves and the δ waves in the thalamus account for their observations.

Inferences drawn from measures of bicoherence in low frequency ranges are not relevant to the discussion. Our theory proposes that anesthetic action disrupts resonance among phase-locked thalamocortical and corticocortical oscillations in the γ frequency range (around 40 Hz). We cite a body of evidence that such oscillations are generated by coincidence detection of congruent inputs to apical dendrites in layer 1 and basal dendrites in layer 4 of cortical pyramidal neurons. We also cite our own evidence based on direct computations of interactions among all 19 electrodes in the 10/20 system, not only on inferences drawn from only one lead. We found that cortical-cortical coherence of all electroencephalographic frequency bands including γ is disrupted on loss of consciousness, and such incoherence is sustained at surgical plane, but only in the γ band is coherence restored before return of consciousness. Finally, although we believe that blockade of thalamocortical reverberations plays a dominant role in the action of anesthetics, the cascade theory suggests that consciousness can be disrupted by actions at many levels.

Second, they point out that in our data, δ activity is greater at loss of consciousness than during maintenance or just before return of consciousness and argue that the physiologic state just after loss of consciousness would be the same as just before return of consciousness. They point out correctly that such large δ is seen when anesthesia is induced by bolus administration of intravenous anesthetic. Although this was the case in all of the cases reported in our study, our report documented the changes in θ rather than δ.

They are quite correct that speed of administration must be taken into account when investigating the correlation between level of consciousness and electroencephalographic changes. Contemporary quantitative electroencephalographic instruments widely used to monitor the depth of anesthesia, such as the Patient State Analyzer (PSA® monitor; Physiometrix, Inc., N. Billerica, MA) or Bispectral Index® monitor (Aspect Medical, Newton, MA), are based on multivariate algorithms that do not depend on any single measure, such as the presence or amplitude of δ activity.

*New York University School of Medicine, New York, New York, and Nathan S. Kline Psychiatric Research Institute, Orangeburg, New York. roy.john@med.nyu.edu

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