Vadakkan SpringerPlus (2015)4:485

DOI 10.1186/s40064-015-1283-1

RESEARCH Open Access

A pressure‑reversible cellular mechanism

of general anesthetics capable of altering a
possible mechanism for consciousness
Kunjumon I. Vadakkan*

Abstract 
Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mecha-
nism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral
of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during
mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid
membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane
functional LINKs by different mechanisms. These include direct membrane contact by excluding the inter-membrane
hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid
membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit
vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location.
Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal
sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes
enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the peri-
lymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and
finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the
membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane com-
position and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can
lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mecha-
nism of anesthetics presented here can operate along with the known specific actions of different anesthetics.
Keywords:  Consciousness, General anesthetics, Pressure reversal, Semblance hypothesis, Inter-membrane contact,
Membrane hemifusion, Partial hemifusion, Complete hemifusion, Membrane fusion, Neurodegeneration

Background 2005; Brown et al. 2011; Kopp et al. 2009). Even though
It is not yet known how different general anesthetics the concept of degeneracy whereby consciousness is
that function as gamma-aminobutyric acidA (GABAA) produced by many mechanisms was introduced (Århem
receptor agonists, alpha adrenergic receptor agonists, et  al. 2003), it is not known how and where they block
N-methyl-d-aspartic acid (NMDA) receptor antago- the neurobiological mechanism for consciousness. In
nists, dopamine receptor antagonists and opioid recep- this context, it is thought that the primary reason for
tor agonists operate to achieve the common function of not understanding the converging mechanism that leads
reversible loss of consciousness (Kennedy and Norman to loss of consciousness is the lack of knowledge about
the physiological process of consciousness (Århem et al.
2003; Beecher 1947). Once a framework for conscious-
*Correspondence: [Link]@[Link] ness becomes available from neurobiological mecha-
Division of Neurology, Department of Medicine, University of Toronto, nisms, it should be able to explain a common mechanism
Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A4‑08,
Toronto, ON M4N 3M5, Canada
of anesthetics. The lipophilic property of the anesthetics

© 2015 Vadakkan. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
([Link] which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
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Vadakkan SpringerPlus (2015)4:485 Page 2 of 17

provides a common platform since various receptors thought to be related to their hydrophobicity (Miller et al.
upon which different anesthetics act are located within 1972a, b). Since different anesthetics are known to act on
the lipid membranes. It is also known that the hydro- specific receptors on the lipid membrane (Brown et  al.
phobic anesthetic molecules incorporated within the 2011), specific actions of individual anesthetics can occur
membrane can change the conformation of the receptor both independently and along with a common mecha-
molecules and alter their function (Rosenberg et al. 1975; nism that leads to the state of unconsciousness. Only a
Miller and Pang 1976; Haydon et al. 1977; Trudell 1977; few proposals that explain a common general mechanism
Vanderkooi et al. 1977; Franks and Lieb 1978). However, for the action of all the general anesthetics at the cellular
it is not known how the observed alteration in the func- molecular level were made and are described below.
tions of different types of receptors is associated with the
common function of blocking consciousness. Lipid membrane and other hypotheses
Alternate mechanisms for anesthetic action were The membrane hypothesis is generally stated as the
also put forward (Halsey et  al. 1978; Mashour 2004; Mayer (1899) and Overton (1901) rule based on which
Hamaroff 2006). The observation that general anesthe- the potency of an anesthetic is increased in proportion
sia induced by different anesthetics can be reversed by to its partition coefficient (concentration ratio) between
the application of high amounts of either hydrostatic olive oil and water (hydrophobic solubility). An experi-
or gas phase pressure applied on the animals (Johnson mental demonstration of this showed a correlation coef-
and Flagler 1950; Johnson and Miller 1970; Lever et  al. ficient of 0.997 (Firestone et  al. 1986). This correlation
1971; Miller 1974; Halsey and Wardley-Smith 1975; among inhaled anesthetics with potencies ranging over
Kent et  al. 1977; Beaver et  al. 1977; Smith et  al. 1984; 100,000-folds has been viewed as one of the most pow-
Wann and Macdonald 1988; Daniels 2000; Chau et  al. erful correlations in biological systems (Halsey 1992).
2009) provides a challenge and an opportunity to deter- Investigations show that anesthetics dissolve in the
mine the unique common mechanism of anesthetics. A hydrophobic region of the membrane causing this region
theoretical framework for consciousness derived from to expand, which led to the critical volume hypothesis
a neurobiological mechanism that can also be extended (Miller et  al. 1972a, b). The membrane expansion by
to explain other higher brain functions and related find- anesthetics was confirmed on erythrocyte membranes
ings at different levels can be examined for a possible (Roth and Seeman 1972). Specific mechanisms related
mechanism of anesthetics. Different findings at differ- to the spontaneous curvature of lipid membranes were
ent levels—such as the lipophilic nature of anesthetics, also proposed (Gruner and Shyamsunder 1991; Lenaz
the converging function of several anesthetics disturb- et al. 1978). Modification of the lateral phase separation
ing the mechanism of consciousness, the reversal of the properties of the membranes with a resulting inability of
unconscious state back to the normal conscious state membrane proteins to change conformation or undergo
after withdrawal of anesthetics and the pressure rever- insertion into the lipid membrane were proposed
sal of anesthesia—provide a problem-set whose solution (Trudell 1977; Cantor 1997; Brown et al. 2011). Another
is likely to provide a unique mechanistic explanation. In proposal was the multi-site expansion hypothesis (Halsey
this regard, the previously explained framework of con- et al. 1978). Based on the binding of general anesthetics
sciousness (Vadakkan 2010) from the semblance hypoth- to the hydrophobic sites, several other hypotheses were
esis (Vadakkan 2013) is examined. also generated (Rosenberg et al. 1975; Haydon et al. 1977;
Vanderkooi 1977). In short, lipid membranes have been
General anesthetics at the central-point of the mechanism of action of differ-
The most commonly used measurement to estimate the ent anesthetics.
potency of an anesthetic in humans is the minimum The information-processing hypothesis of anesthetic
alveolar concentration (MAC) that prevents gross mus- mechanism (Flohr 1995) was based on the premise that
cular response to a surgical incision in 50 % of patients. glutamatergic NMDA receptors affect Hebbian plasticity.
At around 0.3–0.5 MAC, the ability to respond to verbal This was supported by the finding that anesthetics that
commands is lost in 50  % of patients, and the onset of are GABA receptor agonists can have an inhibitory effect
unconsciousness is reached. Above 1.0 MAC, immobility on the NMDA receptor-mediated actions. Even though
to noxious stimulus is achieved (Hentschke et  al. 2005). anesthetics are thought to disrupt higher-order cortical
The currently used general anesthetics are lipophilic in information integration (Hudetz 2012), a fully reversible
nature and are more readily able to cross the blood–brain mechanism of anesthesia during withdrawal of anes-
barrier. Anesthetic potency correlates with the solubil- thetics and by application of pressure has not yet been
ity of the anesthetic chemicals in lipids and has been discovered.
Vadakkan SpringerPlus (2015)4:485 Page 3 of 17

Basic structure of the nervous system Framework of consciousness from semblance

The sensory identity of the first-person internal sensa- formation
tion of various higher brain functions, to which only The semblance hypothesis was developed to explain the
the owner of the nervous system has access, requires a basic mechanism of the formation of first-person inter-
neuronal circuit mechanism explaining the induction of nal sensations of various higher brain functions to which
internal sensory elements. The circuitry with this func- only the owner of the nervous system has access. Contin-
tion is expected to be connected to the motor neurons uous quantal release of the neurotransmitter takes place
for behavioral motor activity. What cellular mechanism all the time from single vesicles in the presynaptic ter-
can impart internal sensory elements to the system? Con- minals to the synaptic cleft. In addition, the arrival of an
sciousness being generated autonomously within the sys- action potential at the presynaptic terminal triggers the
tem is dependent on the specific frequency of surface or release of a volley of neurotransmitter into the synaptic
extracellular recorded oscillatory patterns of potentials cleft. In both these conditions, the postsynaptic terminal
in the cortex. Therefore, mechanisms that induce inter- develops potentials as a result of the release of the neu-
nal sensations are related to one or more vector compo- rotransmitter from its presynaptic terminal. Activating
nents responsible for oscillating potentials. Therefore, it the postsynaptic terminal in the absence of the release
is necessary to fully understand both the synaptic con- of the neurotransmitter from the presynaptic terminal
nections between the vertically oriented neuronal orders was hypothesized to induce units of internal sensations
in the cortex that can provide the vertical component and generating semblance of the arrival of activity from the
potential mechanisms that can provide the horizontal presynaptic terminal.
component for the oscillating potentials. Potentials arriving at the postsynaptic terminal through
The nervous system has synaptically connected neu- a LINK (the word “link” is highlighted to emphasize its
rons with a widely varying number of input and output importance) from the neighboring postsynaptic terminal
terminals. The number of input terminals (postsynaptic can evoke units of internal sensations eliciting the sem-
terminals or postsynapses or dendritic spines) to a neu- blance of the arrival of activity from the presynaptic ter-
ron ranges from approximately 5600 (monkey visual) to minal. An inter-postsynaptic functional LINK is expected
60,000 (monkey motor) (Cragg 1967). A synapse is the to form between the abutted postsynaptic locations as
junction between an output terminal (presynaptic termi- a function of the simultaneous arrival of activity from
nal) and an input terminal. Excitatory neurons and their two different sensory inputs during associative learn-
connections are taken as the primary circuit elements ing between two stimuli (Fig. 1a). The reactivation of the
that are regulated by inhibitory interneurons. The inputs LINK occurs as a function of the arrival of activity from
arrive at the postsynapses in the form of excitatory post- the one of the associatively learned stimuli through the
synaptic potentials (EPSPs). Spikes of potentials are seen inter-postsynaptic functional LINK to the inter-LINKed
at different locations on the neuronal processes: den- postsynaptic terminal (Fig. 1b). Since lipid bilayers of dif-
drites (dendritic spikes or regenerative potentials), the ferent postsynaptic terminals (Fig.  1c) abut each other
axonal hillock (axonal spikes or action potentials) and with a negligible extracellular matrix volume, as visu-
the cell body (somatic spikes or neuronal firing). Action alized in electron microscopic pictures, an interaction
potential generated at the axonal hillock area of the neu- between their outer layers is expected to occur (Fig. 1d).
rons is essential for the propagation of activity to higher The sensory identity of the semblance of the second
neuronal orders. An excitatory neuron fires when nearly stimulus formed at a postsynaptic terminal by the reac-
40 EPSPs summate spatially (Palmer et al. 2014), or even tivation of the inter-postsynaptic functional LINK by the
less than 40 EPSPs summate temporally close to the axon arrival of activity from the first stimulus and how it can
hillock, indicating that large numbers of EPSPs in excess be derived are explained in Fig. 2.
or less than the threshold values are not used for eliciting Phenomenal properties of consciousness such as sub-
an action potential. Therefore, their evolutionary pres- jectivity and intentionality can be viewed only from a
ervation is not yet known. Similarly, the functional sig- first-person perspective (Velmans 1991). Consciousness
nificance of dendritic spikes is also not yet known. The is seen as a binding process by which different internal
contribution of EPSPs generated at the apical dendrites sensations evoked by an item are associated in the nerv-
towards somatic spikes is minimal, making it essential to ous system similar to that taking place during associa-
make an inquiry to understand their functional signifi- tive learning (Vadakkan 2010). Spontaneous potentials
cance. In these contexts, all the EPSPs generated at vari- induced during dendritic spikes and the continuous
ous locations are examined for whether they contribute arrival of background sensory stimuli from inside the
to the generation of internal sensory elements for higher body and environment can contribute to the surface or
brain functions. extracellular recorded oscillating potentials. During
Vadakkan SpringerPlus (2015)4:485 Page 4 of 17

Fig. 1  Formation and reactivation of inter-postsynaptic functional LINKs. a The illustration shows functional LINK formation between two
postsynaptic membranes (postsynapses or dendritic spines) B and D when they are simultaneously activated when two stimuli are associated.
The functional LINK is reversible, stabilizable and its formation is a function of the simultaneous activation of postsynapses B and D. A and C are
corresponding presynaptic terminals. b At a later time, when one of the stimuli arrives at postsynapse B through synapse A–B, functional LINK B–D
is re-activated, resulting in the activation of postsynaptic membrane D. This induces a unit of internal sensation of activity arriving from presynaptic
terminal C. The reactivation of the functional LINK is a function of arrival of activity at one of the postsynaptic terminals. c Two abutted synapses are
shown with their presynaptic and postsynaptic terminal membranes in lipid bilayers. Note that the postsynaptic membranes are separated by extra-
cellular matrix space. d The formed inter-postsynaptic functional LINK is shown in red. Both direct membrane contact by excluding inter-membrane
hydrophilic region and reversible partial membrane hemifusion are common mechanisms (Figure modified from Vadakkan 2010)

these, inter-LINKed postsynapses are reactivated and The dendritic spikes indicate that potentials are spon-
concurrently induce semblances at large number of post- taneously generated at several postsynaptic terminals.
synaptic terminals. The apical area in the cortical layer The resistive properties of the long thin spine necks
1 where apical tufts from all cortical neuronal orders result in large potentials at the spine heads (postsynap-
anchor is a potential area where inter-postsynaptic tic terminal). There are two findings that need a matching
LINKs are expected to be densely present. Local den- explanation. First, the postsynaptic terminals are abutted
dritic spikes observed in in  vitro experiments (Regehr to each other at the apical tuft area. The second one is
et  al. 1993; Polsky et  al. 2009) were recently shown to the presence of surface or extracellular recorded oscilla-
be present in in  vivo by different studies (Palmer et  al. tory potentials. Since the oscillating potentials require a
2012; Sheffield and Dombeck 2015; Cichon and Gan mechanism for their horizontal components, an innate
2015). The potentials from these dendritic spikes from mechanism whereby several postsynaptic terminals form
the apical tufts degrade significantly as they reach the islets of inter-LINKed postsynapses (Fig.  3) is expected
soma, making their contribution to somatic spike often to occur at areas of the cortex where postsynaptic termi-
insignificant. In this context, their evolutionary preser- nals of different neurons abut each other. The changes in
vation implies their yet-unknown functional role. In this the horizontal component can then be examined for the
context, the sensory elements imparted by spontaneous observed changes in the frequency of oscillations during
events like dendritic spikes can be equated to the sem- various conditions.
blances described in Fig.  2 and are examined for their Pulvinar, mediodorsal, intralaminar and midline nuclei
contribution to the internal sensation of consciousness. of the thalamus receive major inputs from cortical layers
Semblance induced at the postsynaptic terminal by its 5 and 6 and project back to the cerebral cortex to form
stimulation, in the absence of the arrival of activity from cortico-thalamo-cortical pathways (Guillery 1995; Sher-
its presynaptic terminal, can be viewed as a mechanism man and Guillery 2002; Theyel et al. 2010) that can regu-
evoking internal sensations. From a large number of find- late the oscillating potentials. In addition, the horizontal
ings that localized stimulation of the extracellular matrix spread of activity through horizontally located processes
space (ECM) at specific sensory cortices induces related of the layer 1 neurons, recurrent collaterals and inhibi-
sensory hallucinations (Selimbeyoglu and Parvizi 2010), tory interneurons (Palmer et  al. 2012) are potential fac-
it can be inferred that units of internal sensation can be tors that regulate oscillations of potentials. Awareness
induced by spontaneous activation of certain neuronal of the self and the environment requires the function-
processes. ing of the ascending reticular activating system (ARAS)
Vadakkan SpringerPlus (2015)4:485 Page 5 of 17

originating from the reticular formation (RF) in the

brain stem and relayed through the intralaminar nucleus
of the thalamus to the cerebral cortex (Kinomura et  al.
1996; Edlow et al. 2012; Yeo et al. 2013; Saalmann 2014).
In addition to the brain stem nuclei including the locus
coeruleus, dorsal raphe, median raphe, pedunculopon-
tine nucleus, and parabrachial nucleus, the ARAS also
includes non-specific thalamic nuclei, the hypothalamus
and the basal forebrain (Aston-Jones et  al. 2001; Parvizi
and Damasio 2003).
Continuous formation of semblances occurs during
dendritic spikes and other spontaneous activations of
the postsynaptic terminals (in the absence of the arrival
of activity at the presynaptic terminals). The composition
of all the background semblances induced in a modular
fashion at different cortices in the resting state leads to
the formation of C-semblance (the net semblance for
consciousness) responsible for consciousness (Fig.  4)
(Vadakkan 2010). Since lower forms of animals show
intentionality to carry out basic motor behaviors for
feeding and reproduction, which are essential for main-
taining the species, a robust circuit property is expected
to be present in all the nervous systems that induce
internal sensations for maintaining states equivalent to
awareness. Consciousness is strongly associated with the
specific frequency of the surface or extracellular recorded
oscillating potentials. The dendritic spikes that involve
a large number of synapses at one location are likely
Fig. 2  Reactivation of an inter-postsynaptic functional LINK that to activate postsynapses within islets of inter-LINKed
induces the formation of units of internal sensation. An action postsynapses providing the required horizontal compo-
potential arriving at presynaptic terminal A activates synapse A–B and
reactivates inter-postsynaptic functional LINK between postsynapses
nent for oscillating potentials for C-semblance. Synaptic
B and D. When postsynapse D is activated in the absence of arrival transmission between the vertically oriented neuronal
of activity from its presynapse (not shown), a semblance of arrival orders in the cortex provides the vertical component
of activity from its presynapse occurs. The sensory equivalent of the for the oscillations. C-semblance act as a background or
semblance (sensory hallucinations) can be extrapolated from examin- buffer during active computations—for example, during
ing the packets of minimum sensory stimuli capable of stimulating
postsynapse D. The sensory identity of the semblance of activity
the matching process of the formed internal sensation of
occurring at postsynapse D consists of inputs from neuron Y. Neuron retrieved memory with that of the learned item.
Y is normally activated by inputs from a set of lower order neurons The inputs from both the thalamus and those that
{X}. Continuing this extrapolation towards the sensory level identifies directly reach the cortex are expected to maintain an
a set of sensory receptors {SR}. {a}, {b} and {c} are subsets of {SR} and appropriate frequency of the oscillating potentials.
are capable of independently activating postsynapse D. Hypotheti-
cal packets of sensory stimuli activating sensory receptor sets {a},
Any disturbance in the inputs from the thalamus or the
{b} and {c} are called semblions 1, 2 and 3 respectively. Activation of reticular formation can disturb consciousness, which is
postsynapse D through inter-postsynaptic functional LINK B–D by the reflected in the frequency of the waveform of potentials
cue stimulus can lead to the virtual internal sensation of semblions recorded from surface or extracellular electrodes. This
either 1, or 2, or 3 or their integral or their overlapping region. Cue indicates that the conformation of net C-semblance
stimulus-induced activation of postsynapse D reaches the soma of its
occurring through the composition of units of internal
neuron Z. If neuron Z already receives baseline summated EPSP short
of one EPSP to trigger an action potential, then the additional EPSP sensations for the systems property of consciousness in
arriving through inter-postsynaptic functional LINK B–D and through the cortex is dependent on the frequency of oscillating
postsynapse D can add to the sub-threshold EPSP and fire neuron potentials. Factors that regulate the optimal frequency
Z, resulting in latter’s concurrent activation during the formation of of oscillatory potentials determine the optimal con-
internal sensation (Figure modified from Vadakkan 2010)
formation of the C-semblance for consciousness. The
Vadakkan SpringerPlus (2015)4:485 Page 6 of 17

Fig. 3  Sources of potentials that contribute to the horizontal and vertical components of the oscillating potentials. Upper left side A cortical
pyramidal neuron with different locations of spike generation. The source of surface-recorded electro-encephalogram (EEG) waveforms is likely to
have significant contributions from the NMDA spikes from the apical tufts since their magnitude is higher than that of the somatic spikes (neuronal
firing) and they occur close to the pial surface. Upper right side Five islets of inter-LINKed postsynaptic terminals (IILPS) are shown that represent the
abundance of dendritic spines in this area that permits several postsynapses to get inter-LINKed both by innate and acquired mechanisms. The
islets are expected to be connected with each other through recurrent collaterals, layer 1 cortical neurons and cortico-thalamo-cortical pathways.
This pattern of arrangement will provide a mechanism for long-range synchronization that is being recorded as EEG waveforms. Bottom The role of
both thalamus and brain stem inputs in maintaining the frequency of oscillations in the cortex. Various nuclei in the brain stem that provide inputs
to both thalamus and cortex are shown (neurotransmitters are given in brackets). Cortico-thalamo-cortical pathway maintains a significant role in
controlling the oscillating potentials in the cortex. Pontine reticular activating system sends glutamatergic inputs to the thalamus potentially regu-
lating the oscillating potentials in the cortex. RC recurrent collateral, C-T cortico-thalamic pathway, T-C thalamo-cortical pathway, L1 layer 1 cortical
neuron, IILPS islet of inter-LINKed postsynapses, Glu glutamate, ACh acetyl choline, 5HT 5-hydroxy tryptamine (serotonin), NE nor-epinephrine

computational process of composing the semblances Horizontal component of oscillating potentials

that provides optimal conformation of C-semblance Alteration in consciousness is associated with a reduc-
(Vadakkan 2010) requires further investigations. Back tion in the frequency of surface oscillating potentials;
propagation of somatic action potentials from individ- this indicates that either the contribution of the hori-
ual pyramidal neurons is unlikely to reach towards the zontal component increases or that of the vertical com-
apical dendritic spines and disturb the latter’s internal ponent decreases. One of the potential sources of
sensory contributions to consciousness. This is sup- surface recorded potentials is the spontaneous activity
ported by both theoretical estimations (Behabadi and at the dendritic spines (postsynapses) that lead to den-
Mel 2014) and by the failure of back propagation of dritic spikes at the apical tuft area of the cortices. Den-
action potentials to reach the distal dendrites of the dritic spikes that spread to other postsynapses through
apical tuft using calcium imaging experiments (Schil- inter-postsynaptic functional LINKs are a candidate
ler et al. 1995), even though they can be recorded at the mechanism for the horizontal component of oscillating
level in the dendrite at which patch clamping can be potentials. An innate mechanism that inter-LINKs sev-
carried out (Stuart et al. 1997). eral postsynapses is a possible method for the horizontal
Vadakkan SpringerPlus (2015)4:485 Page 7 of 17

Fig. 4  Formation of C-semblance for consciousness and the role of oscillating potentials. Spontaneous activity occurring during events such as
dendritic spikes occurring at the islets of inter-LINKed postsynapses (IILPS) can lead to semblance at all the postsynapses that are activated thor-
ough the LINKs (in the absence of arrival of activity from their presynaptic terminals). In addition, reactivation of large number of scattered single
inter-postsynaptic functional LINKs (B–D) within the cortices also induce semblances. Background sensory stimuli both from within the body (respi-
ration and heart beat) and from the environment reactivate several inter-postsynaptic functional LINKs and also induce semblances. The net result
of all the semblances induced at the postsynapses lead to C-semblance for consciousness. C-semblance is a function of (a) the reactivated inter-
postsynaptic LINKs that in turn is a function of existing innate inter-postsynaptic LINKs, (b) some of the acquired inter-postsynaptic LINKs induced
by associative learning during life that are reactivated during oscillation of potentials and (c) the complexity of the nervous system of a given
species. The synaptic transmission between vertically oriented neuronal orders provides vertical component and the lateral spared of potentials
among the postsynapses during dendritic spikes provide horizontal component that lead to surface or extracellular recorded oscillating potentials.
These oscillating potentials eventually give rise to neuronal firing (somatic spikes) in an oscillating manner (shown by a wave-form). Additional fac-
tors that provide components for oscillations include recurrent collaterals, laterally connected layer 1 neurons, cortico-thalamo-cortical connections
and activity arriving from the thalamus (in response to background sensory stimuli) and the brain stem (connections with respiratory drive). When
frequency of oscillating potentials changes, the nature of consciousness will change (example, in sleep). C C-semblance, Cs subjective changes to
C-semblance due to contributions of semblances induced through reactivation of inter-postsynaptic functional LINKs formed by different associa-
tive learning events during life. P–Q Represents background sensory inputs. Wave shape Represents oscillating pontentials. A Presynaptic terminal
where inputs from oscillatory neuronal activity arrives. B Postsynaptic terminal of the synapse A–B. D Postsynaptic terminal which is functionally
LINKed to the postsynaptic terminal B. B–D Inter-postsynaptic functional LINK. Corresponding presynaptic terminal of postsynapse D is not shown.
N Neurons that are firing. P–Q Represents background sensory inputs arriving at the nervous system either from the environment or from the body
such as respiration and heartbeat. IILPS Islet of inter-LINKed postsynapses (Figure modified from Vadakkan 2010)

spread of potentials. Evidence that the discontinuous both during sleep (Alkire et  al. 2008) and anesthesia
electroencephalogram (EEG) waveforms in very prema- (Sanchez-Vives and McCormick 2000), consciousness is
ture infants (Selton et al. 2000) eventually get connected altered. Thalamo-cortical oscillating potentials that differ
from their lateral ends indicates that lateral connectivity during sleep and awake states (Steriade et al. 1993) have
is an essential component for oscillating surface recorded a significant role in maintaining oscillating potentials in
potentials and is produced through an innate mechanism. the cortex recorded from the surface, in a plane parallel
When the frequency of oscillating potentials is reduced to the pia mater. One of the consequences of oscillating
Vadakkan SpringerPlus (2015)4:485 Page 8 of 17

potentials recorded in the apical tuft area is the firing of understand the probable mechanism of inter-postsyn-
several downstream neurons in an oscillating manner. aptic functional LINK (Vadakkan 2013). Several stud-
ies have shown that dendritic spines (postsynapses)
Inter‑postsynaptic functional LINK enlarge following LTP induction (Buchs and Muller 1996;
The duration of existence of an inter-postsynaptic LINK Maletic-Savatic et  al. 1999). Since extracellular matrix
correlates with the type of internal sensations being between the postsynapses is negligible, especially at the
induced during different higher brain functions. Exam- locations of the convergence of inputs, the dendritic
ining all the different changes can help with understand- spine enlargement increases the probability of getting
ing a possible mechanism of action for anesthetics. For them abut to each other. Since LTP was attenuated by
explaining the internal sensation of perception, inter- the injection of synaptosomal-associated protein (SNAP)
postsynaptic functional LINKs should be either pre- inhibitors, which inhibit membrane fusion, into the cell
existing or have a very rapid turnover of the formation body of CA1 neuron (Lledo et  al. 1998), some stages in
and reversal steps. The duration of persistence of inter- the membrane fusion process are expected to be involved
postsynaptic functional LINKs for generating internal in the induction of LTP (Vadakkan 2013). The ideal can-
sensations during working, short-term and long-term didate mechanism is reversible membrane hemifusion,
memories increases proportionate to the duration of the which is the initial stage during the fusion process com-
persistence of memory. In the case of consciousness, the monly seen in biological systems (Melikyan and Cherno-
background level of the sub-conscious state during sleep mordik 1997; Kozlov et al. 2010).
should operate via a well preserved innate mechanism Postsynaptic membranes at the lateral edges can get
through stable inter-postsynaptic functional LINKs. The constantly exchanged with vesicle membrane lipid bilayer
changes in the level of consciousness during different segments during exocytosis and endocytosis of the GluA1
stages of sleep are expected to depend on the addition of subunits of one type of the glutamate receptors called
a rapidly reversible mechanism. The latter is expected to α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid
take place in different proportions corresponding to dif- (AMPA) receptors (Passafaro et  al. 2001). The observa-
ferent stages of sleep that lead to corresponding devia- tion of an increase in the volume of dendritic spines even
tions in the conformation of C-semblance from that in before the accumulation of GluA1AMPA receptor subu-
the waking state. The semblances that are induced during nits (Kopec et al. 2006) is also a possible mechanism that
arousal from sleep should be occurring through revers- augments membrane hemifusion. Vesicle membranes of
ible mechanisms. From examining different mechanisms GluA1AMPA receptor-subunit-containing endosomes
of the formation and reactivation of inter-postsynaptic (Park et  al. 2004) are primarily involved in the postsyn-
functional LINKs, the effect of anesthetics on a reversible aptic membrane reorganization. The biochemical condi-
mechanism can be understood. tions and membrane lipid composition can determine
Different candidate mechanisms for the inter-post- conversion of direct contact between the membranes to
synaptic functional LINK include direct membrane con- reversible membrane hemifusion. GluA1AMPA recep-
tact excluding the inter-membrane hydrophilic region, tor subunits have been reported to enter the plasma
reversible partial and complete membrane hemifusion membrane of dendrites in response to intense synaptic
(Vadakkan 2013) and a still unknown mechanism oper- activity (Shi et al. 1999). It has recently been found that
ating through the ECM. The hydration repulsive force GluA1AMPA receptor subunits concentrate towards the
between two artificial lipid membranes maintains a dis- extra-synaptic locations extending at least 25 nm beyond
tance of nearly 2  nm between the membranes (Markin the synaptic specialization (Jacob and Weinberg 2014),
et  al. 1984). Diminishing the inter-membrane hydration making this area match the locations where postsynaptic
repulsion is one of the methods of initiating membrane membranes can hemifuse.
contact (Rand and Parsegian 1989). The direct membrane Studies using artificial membranes have shown that
contact excluding the inter-membrane hydrophilic region the membrane fusion process (of which membrane
is an ideal mechanism due to its rapid reversibility. Mem- hemifusion is the initial step) has to overcome a high
brane dynamics at the postsynaptic membrane very close energy barrier (Cohen and Melikyan 2004; Martens and
to the synapse is a favorable location for achieving direct McMahon 2008) and therefore the locations of hemifu-
membrane contact by excluding the inter-membrane sion are expected to be restricted to very small areas of
hydrophilic region (Fig. 5a, b). approximately 10  nm2 similar to the findings in studies
Long-term potentiation (LTP), an electrophysiological using artificial membranes (Leikin et  al. 1987). Dedi-
experimental finding that correlates with the surrogate cated studies to examine inter-postsynaptic membrane
behavioral motor activity indicative of the formation of hemifusion have not been undertaken due to the need for
the internal sensation of retrieved memories, helps us high-resolution microscopic techniques for live imaging
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Fig. 5  Formation of different types of reversible inter-postsynaptic functional LINKs. a Two abutted synapses A–B and C–D. Presynaptic terminals
A and C are shown with synaptic vesicles (in blue color). Action potential arrives at presynaptic terminal A releasing a volley of neurotransmitters
from many synaptic vesicles inducing an excitatory postsynaptic potential (EPSP) at postsynaptic terminal B. The waveform represents the direction
towards which the EPSP propagates. From the presynaptic terminal C, one vesicle is shown to release its contents to the synaptic cleft. This quantal
release is a continuous process (even during rest) providing very small potentials to postsynaptic membrane D. Postsynaptic terminals B and D have
membrane-bound vesicles marked V inside them. These vesicles contain glutamate receptor subtype 1 (GluA1). Activity arriving at the synapse can
lead to exocytosis of GluA1 receptor-subunits and expansion of the postsynaptic membrane. During exocytosis, the vesicle membrane is added to
the postsynaptic membrane at locations of exocytosis making this region of the membrane highly re-organisable. This matches with the location
where α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunits were shown to concentrate at the extra-synaptic loca-
tions extending at least 25 nm beyond the synaptic specialization (Jacob and Weinberg 2014). Note the presence of a hydrophilic region separat-
ing postsynaptic terminals B and D. When action potential arrives at the presynaptic terminal, it activates synapse A–B and an EPSP is induced at
postsynaptic terminal B. The hydrophilic region prevents any type of interaction between postsynapses B and D. Very high energy is required for
excluding the inter-postsynaptic hydrophilic region (Martens and McMahon 2008). b Diagram showing the effect of lipophilic anesthetic molecule
on the membranes. Incorporation of the hydrophobic anesthetic molecule to the lipid membrane especially at the re-organisable areas that lead to
membrane expansion at these locations can provide sufficient energy to exclude the inter-postsynaptic hydrophilic region allowing close contact
between the postsynaptic membranes at this region. Action potential arriving at synapse A–B reactivates the inter-postsynaptic functional LINK
formed by close inter-postsynaptic contact and spreads to postsynaptic terminal D. an membrane segment marked in Turkish blue shows area
where membrane reorganization occurs and anesthetic molecules lead to membrane expansion. Formation of large number of non-specific inter-
postsynaptic functional LINKs disturbs the net C-semblance formation explained in Fig. 4 leading to loss of consciousness. When the anesthetic
molecule is removed, the process reverses back. c Diagram showing formation of a partial inter-postsynaptic membrane hemifusion following
anesthesia. Note the interaction between the outer layers of membranes of the postsynaptic terminals. Depending on the lipid membrane compo-
sition and the type and concentration of anesthetics, the process of close contact between the membranes described in above section (b) can get
converted to a partial hemifusion state. The process can even advance to a reversible complete hemifusion state as described in Fig. 8b depending
on several factors. When the anesthetic molecule is removed, the hemifusion reverses back

and the requirement of high resolution electron micro- Proposed mechanism of anesthetics
scopic imaging to observe areas as small as 10 nm2. Elec- The maintenance of the background set of inter-post-
tron microscopic examination using the best available synaptic membrane functional LINKs is essential for the
tissue preparation and resolution methods has shown specific conformation of the C-semblance for conscious-
a pair of abutted postsynaptic membranes with half the ness (Fig.  4). Any alteration in the conformation of the
number (two) of expected (four) lipid membrane lay- C-semblance can lead to loss of consciousness. The abut-
ers (Burette et al. 2012). In addition to changes that can ted postsynaptic membranes are anchored to the ECM
accompany AMPA receptor expression (Matsuzaki et al. through structural proteins. Extra-synaptic locations on
2001), enlargement of the dendritic spines by dopamine- the postsynaptic membranes extending at least 25  nm
induced mechanisms (Yagishita et al. 2014) can promote beyond the synaptic specialization where GluA1AMPA
membrane hemifusion in the context of associative learn- receptor subunits concentrate (77) are regions of con-
ing. Inter-postsynaptic functional LINKs are formed at tinuous exocytosis and endocytosis. Since this process
specific locations for the formation of internal sensations involves the addition and removal of lipid membrane
of different higher brain functions. However, since anes- segments, lateral aspects of postsynaptic membranes
thetics bind to the lipid membranes non-specifically, they immediately outside the synapse is an area of dynamic
can either block or result in excessive formation of non- membrane reorganization. Membranes at the resting
specific inter-postsynaptic functional LINKs. state have a specific conformational energy. Different
Vadakkan SpringerPlus (2015)4:485 Page 10 of 17

forces that keep the membranes separate include hydra- resulting in changes in consciousness. The inter-post-
tion, electrostatic and steric forces, whereas van der synaptic functional LINKs induced by anesthetics can be
Waal’s forces bring two membranes together (Cevc 1987). readily reversed by removing the anesthetic agent.
Associative learning produces changes at locations of
convergence of stimulus inputs through enlargement of Stages of anesthesia and EEG waveforms
the postsynapses (dendritic spines) of synapses that abut As the anesthetic dose is increased, the patients enter a
each other. This change in spine geometry is found to be state of paradoxical excitation characterized by euphoria
critical in AMPA receptor expression (Matsuzaki et  al. or dysphoria, defensive or purposeless movements, and
2001) and are expected to occur on the abutted postsyn- incoherent speech, along with an increase in beta activity
aptic membranes of those synapses that move close to (13–25 Hz) in the EEG. This state is termed paradoxical
each other. The finding that GluA1AMPA receptor subu- since the anesthetic, intended to induce unconscious-
nits concentrate at the extra-synaptic locations, extending ness, results in excitation (Brown et al. 2010). Initially, as
nearly 25  nm beyond the synaptic specialization (Jacob the gradually increasing number of anesthetic molecules
and Weinberg 2014), matches with the locations where are bound to the lipid membranes, more inter-LINKs
postsynaptic membranes are expected to interact. A very are formed between the existing islets of inter-LINKed
large amount of pressure, nearly 109 N/m2, is required to postsynapses (Fig. 6a, b). Normally, oscillating potentials
merge the outer leaflets of artificial membranes that are are expected to keep the output neurons in layer 5 of the
in contact (Markin et  al. 1984). To minimize the work, motor cortex at a sub-threshold level of activation (Vad-
the membrane hemifusion is expected to take place at a akkan 2013) that will enable them to fire upon the arrival
very small point of contact involving a minimum number of additional potentials. As anesthetics induce more
of lipid molecules, making it a site-restricted process that inter-postsynaptic LINKs, this will lead to firing of sev-
is limited to areas as small as 10 nm2 (Leikin et al. 1987). eral sub-threshold activated motor neurons in the motor
In this respect, the localized area of membrane reorgani- cortex. This can explain the paradoxical excitation stage
zation, 25  nm beyond the synaptic specialization where of anesthesia. As the depth of anesthesia is increased,
AMPA receptor subunit exocytosis takes place (Jacob and EEG shows increasing slowness in the frequency of the
Weinberg 2014), is an ideal candidate location for inter- waveforms. As more islets of inter-LINKed postsynapses
postsynaptic membrane interaction. get inter-LINKed, the magnitude of the horizontal com-
The lipophilic anesthetic molecules are more likely to ponent increases driving the frequency of oscillations to
get partitioned inside the hydrophobic lipid phase in the the lower side (Fig.  6c). This can explain the observed
regions of membrane reorganization at the postsynap- high gamma power during anesthesia (Murphy et  al.
tic membranes. The net result is the dehydration of the 2011). The increase in the extracellular space after
inter-membrane environment, which causes the abut- administration of ketamine/xylazine compared to the
ted membranes to come into physical contact with each wake state (Xie et al. 2013) likely correlates with possible
other (Fig.  5c). The spontaneous curvature induced by increased inter-postsynaptic membrane hemifusion.
anesthetics arriving from the outside aqueous phase can When the anesthetic molecules get removed from the
contribute to asymmetry between the outer and inner membranes after anesthesia is stopped, inter-postsynap-
leaflets of the lipid bilayer (Lipowsky 2014). The direct tic LINKs at various stages revert back to their minimum
contact between the membranes that excludes the inter- energy state. This reverses the unconscious state induced
membrane hydrophilic region is expected to be suffi- by anesthesia back to the background conscious state.
cient for the excitatory postsynaptic potential (EPSP) to Propofol has one of the lowest potencies among the anes-
spread from one postsynaptic membrane to the other. In thetic agents since its octanol/water partition coefficient
this manner, anesthetics can induce a large number of is one of the highest, obeying the Meyer–Overton rule
non-specific inter-postsynaptic functional LINKs. It is (Tonner et  al. 1992). This explains how once anesthesia
observed that only reduced amounts of anesthetic agents is stopped, propofol can get displaced from the mem-
are required for anesthesia in the presence of levodopa branes very quickly, causing rapid reversal of the anes-
(Segal et al. 1990). Levodopa, known to cause the enlarge- thetic effect and it is likely that propofol produces readily
ment of dendritic spines (Meredith et al. 1995; Lee et al. reversible inter-postsynaptic functional LINKs.
2006), supports the effect of dendritic spine enlarge-
ment in achieving direct contact between the spines Pressure reversal of the anesthetic effect
as proposed by the present work. When islets of inter- A large number of studies have confirmed that the gen-
LINKed postsynapses are inter-LINKed non-specifically, eral anesthesia induced by anesthetics is reversed by the
it will lead to alterations in the frequency of oscillating application of pressure over an aquatic or terrestrial ani-
waveforms (Fig.  6) and conformation of C-semblance, mal by increasing the pressure of water or air respectively
Vadakkan SpringerPlus (2015)4:485 Page 11 of 17

Fig. 6  Increasing number of inter-LINKed postsynapses increases the horizontal component and reduces the frequency of oscillating potentials. a
Graph showing the vector component of the oscillations. Four different states are marked. 1 Baseline state represented by equal vertical (synaptic)
and horizontal (inter-postsynaptic functional LINKs) components. 2 As the horizontal component increases with increasing number of inter-LINKs
between the islets of inter-LINKed postsynapses during the initial stage of anesthesia, more subthreshold neurons get activated increasing further
vertical component. 3 Gradual increase in the number of inter-postsynaptic functional LINKs lead to increase in the horizontal component leading
to gradual decrease in the frequency of oscillating potentials. 4 Represents phase 2 vegetative state in anesthesia where the frequency of oscillating
potentials decreases further due to further increase in the horizontal component. b Oscillation of potentials during state 1 in the graph a, which
is the normal baseline. Diagram showing islets of inter-LINKed postsynapses viewed as a cross-sectional view from above. For simplicity, the size
of all the islets are drawn same. Spontaneous activity spreads across all the hemifused spines within that islet inducing semblances. N represents
cortico-thalamic-cortical pathways and recurrent collaterals that contribute to the oscillating potentials. The frequency of oscillating potentials
is determined by the horizontal component that depends on the inter-LINKs between the postsynapses horizontally. c Oscillation of potentials
during state 4 in the graph a. Anesthetic molecules increase the number of inter-LINKed postsynapses and will inter-LINK several of the islets of
already inter-LINKed postsynapses, increasing the magnitude of the horizontal component of the oscillating potentials. This reduces the measured
frequency of these oscillations as shown by the wave form changes

within a closed container (Johnson and Flagler 1950; duct and sac (Carlborg et al. 1982; Carlborg and Farmer
Johnson and Miller 1970; Lever et al. 1971; Miller 1974; 1983; Kishimoto et al. 1983). Recently, a new channel sys-
Halsey and Wardley-Smith 1975; Kent et  al. 1977; Bea- tem called the glymphatic pathway (paravascular space)
ver et al. 1977; Smith et al. 1984; Wann and Macdonald that directly connects CSF space to ECM space was dis-
1988; Daniels 2000; Chau et  al. 2009). This leads to the covered (Iliff et  al. 2012). CSF space continues through
natural question of how the pressure affects anesthetic these channels around the penetrating arteries and
action. Both hydrostatic pressure and gas phase pressure extends around the arterioles and around the capillar-
can be examined. Thermodynamically they act differ- ies. At the level of the capillaries, these channels are con-
ently. While hydrostatic pressure exerts direct pressure, nected to the ECM space. After percolating through the
gas phase pressure changes solubility of the anesthetics ECM space, CSF flows to the paravenular space around
in addition to its direct pressure effect. These observa- the venular side of the capillaries and to the venous sys-
tions lead to the following questions. How does exter- tem. Nearly 5 μl of CSF are added, and the same volume
nally applied pressure get transduced into the nervous is removed from nearly 150  ml of CSF volume during
system? Where is it getting transduced to? How does it the period of one heartbeat, making the movement of
produce the reversal of a general anesthetic-induced loss CSF through the glymphatic pathway a convective flux
of consciousness? Knowledge of the route through which (Kress et  al. 2014). The very low flow of CSF provides
the externally applied pressure can transduce towards the a near-stable fluid compartment through which the
membranes of neuronal processes and the mechanism applied pressure difference can get transduced to the
that displace the membrane-bound anesthetic molecules ECM space. The neuronal processes are attached to the
is required. extracellular matrix through various structural proteins.
First, an examination of the mechanism of hydrostatic At the locations close to the synapse, postsynaptic mem-
pressure was carried out to understand the route through branes undergo membrane reorganization as a result
which externally applied hydrostatic pressure gets trans- of exocytosis and endocytosis of AMPA receptor subu-
duced into the extracellular matrix (ECM) space. It is nit-containing vesicles. This is viewed as an area where
known that pressure in the middle ear can get transmit- anesthetic-induced membrane changes can allow abutted
ted to the perilymph and then to the cerebrospinal fluid postsynaptic membranes to come into close contact by
(CSF) (Martinez 1962), primarily through the cochlear excluding the hydrophilic region (dehydrating the inter-
aqueduct and secondarily through the endolymphatic membrane region) in small areas.
Vadakkan SpringerPlus (2015)4:485 Page 12 of 17

How does the pressure gradient arriving at the ECM The gas phase pressure mechanism is based on Dalton’s
reverse the anesthetic-induced inter-postsynaptic law of partial pressures that estimates the total pressure
functional LINKs? Based on Le Chatelier’s princi- of a mixture of gases as the sum of the partial pressures
ple, when the pressure on a system at equilibrium is of all the gases in the mixture. Gas phase pressure rever-
disturbed, the equilibrium position will shift in the sal can be made to occur by increasing the external pres-
direction necessary to reduce the pressure. One of sure of the gas mixture, which will change the partial
the effects of increased pressure is the extrusion of pressure of dissolved gases in the blood and eventually
anesthetic molecules from the lipid membranes to that of the extracellular matrix volume. During pressure
the ECM volume, and then these molecules get dis- reversal, partial pressure change reduces the solubility of
placed through the paravenular space into the venous anesthetic molecules and leads to their displacement from
system. This in turn will reintroduce the hydrophilic the lipid membranes into the ECM. In addition, the direct
region between the postsynaptic membranes, revers- effect of external pressure on the middle ear that transmit
ing the inter-postsynaptic functional LINKs induced through the perilymph, CSF, and paravascular space route
by anesthetics (Fig.  7). Reversal of all the non-spe- as described for the effect of hydrostatic pressure can also
cific, inter-postsynaptic functional LINKs changing occur. The displaced anesthetic molecules will then escape
the C-semblance back into its normal conformation through the paravenular space into the venous system.
can explain the reversal of the unconscious state back The effect of externally applied pressure in non-anes-
to normal consciousness. In non-mammalian spe- thetized humans (Bennett 1982) and animals (Brauer
cies such as freshwater shrimp (Simon et al. 1983) and 1982) results in a well-studied phenomenon called high-
nematodes (Eckenhoff and Yang 1994), pressure rever- pressure neurological syndrome (HPNS). In humans, it
sal of general anesthetics is not efficient, possibly due leads to tremors, psychomotor impairment, increase in
to the absence of the glymphatic pathway or due to theta activity in EEG and paradoxical hyper-excitability
some other structural variations. (Talpalar 2007). Pressure can lead to the displacement of

Fig. 7  Route through which the externally applied pressure is transduced for the pressure reversal of anesthesia. Externally applied pressure get
transduced to the cerebrospinal fluid (CSF) through the perilymph and cochlear aqueduct. This pressure gradient from CSF reaches the extracellular
matrix (ECM) space through the glymphatic system (paravascular space). The pressure gradient gets transduced through the extracellular matrix
space and result in displacement of the anesthetic molecules from the lipid membranes to the ECM and finally to the paravenular space and to
the venous system. Both the close inter-postsynaptic membrane contacts and the reversible membrane hemifusions established in the presence
of the anesthetics reverse back to the ground state. As the anesthetics get displaced, non-specific semblances induced through non-specific inter-
postsynaptic functional LINKs will get proportionately reduced. This will bring back the normal conformation to the C-semblance as demonstrated
in Fig. 4. Top right On the left side are two synapses with abutted postsynaptic membranes (dendritic spines) B and D in the presence of anesthetics
forming an inter-postsynaptic functional LINK. Note the red color of the region of inter-postsynaptic functional LINK. On the right side is the state
after pressure reversal of the inter-postsynaptic functional LINK. Inter-postsynaptic hydrophilic region forms again when anesthetic molecules are
removed
Vadakkan SpringerPlus (2015)4:485 Page 13 of 17

CSF from the ECM through the paravenular space. This et al. 1994). General anesthetics generally do not impair
can lead to compression of the islets of inter-LINKed existing long-term memory (Bramham and Srebro 1989),
postsynapses. The lateral pressure over the postsynapses since the inter-postsynaptic hemifusions responsible for
provides the energy required to remove the hydrophilic them are well stabilized by different mechanisms. It was
region between the postsynaptic membranes. The result- reported that sevoflurane (0.1 MAC), when administered
ing increased number of non-specific inter-postsynaptic for a specific time, enhances aversive memory forma-
functional LINKs that are likely induced during HPNS tion in rats (Alkire et  al. 2005). Since associative learn-
can produce an effect similar to that of the excite- ing induces the enlargement of dendritic spines, allowing
ment stage of anesthesia (described earlier) leading to them to make close contact and hemifusions, sevoflurane
increased motor activity. at a very low dose can augment this mechanism, permit-
ting the formation of the maximum possible number of
Effect of anesthetics on memory specific inter-postsynaptic functional LINKs during a
The internal sensation of memory was explained in narrow window of time at a specific concentration.
terms of semblances induced by the reactivation of inter-
postsynaptic functional LINKs (26). The LINKs that are Sleep and unconsciousness
readily reversible explain working memory. Since they When the frequency of oscillating potentials is reduced
mimic the readily reversible action of anesthetics, the both during sleep consciousness is altered (Alkire et  al.
inter-postsynaptic functional LINKs induced during 2008). Along with this, thalamo-cortical oscillating
associative learning can be considered to take place via potentials differ during sleep from that in awake states
direct contact between specific postsynaptic membranes (Steriade et  al. 1993). The depth of unconsciousness
by excluding the inter-membrane hydrophilic region (threshold for arousal) during sleep varies between dif-
between them. Knowing that the natures of inter-post- ferent stages of sleep. Unconsciousness during sleep can
synaptic functional LINKs formed to explain working be explained by the observed expansion of the ECM (Xie
memory (specific ones) and anesthetic action (non-spe- et  al. 2013) that reduces the space occupied by the cel-
cific ones) are similar provides an opportunity to exam- lular components. This will exert lateral pressure on
ine the effect of anesthetics on memory. Low doses of the dendritic spines that will increase the probability of
anesthetics leave very short-term memory intact, such them getting inter-LINKed, increasing the magnitude of
that patients can carry on a conversation and appear to the horizontal component contributing to the oscillat-
be lucid (Wang and Orser 2011). As the anesthetic dose ing potentials. This will present as a slowing of oscillating
is increased, more non-specific inter-postsynaptic func- potentials as seen in sleep.
tional LINKs are induced, which will not allow sensory
stimuli that are being associatively learned to converge Cognitive defects and neurodegeneration
at specific locations to form specific inter-postsynaptic An emerging consensus view on the possible link
functional LINKs that can be used for memory retrieval. between Alzheimer’s disease and anesthesia is being
Therefore, new learning will not become possible. Main- examined following reports by several studies of a posi-
taining anesthetic-induced complete inter-postsynaptic tive correlation between them (Baranov et al. 2009). Neu-
hemifusions for long period of time increases the prob- rotoxicity following pediatric anesthesia has also received
ability for their stabilization through the insertion of much attention (Ramsay and Rappaport 2011). These
trans-membrane proteins that can lead to the prolonged studies highlight the importance of verifying reversible
inclusion of non-specific semblances from these postsyn- partial membrane hemifusion as a mechanism of anes-
aptic locations. thetics. The anesthetic-induced changes expected to
A low dose of isoflurane [one-fifth required for immo- occur between the postsynaptic membranes are a spec-
bilization (nearly 0.2 MAC)] suppresses learning and trum of changes that range from close contact between
the explicit memory of verbal cues in healthy volunteers the membranes by excluding the hydrophilic region to
(Newton et  al. 1990). Sub-sedative doses of isoflurane reversible partial and complete hemifusions. Hemifusion
(0.3  %) and nitrous oxide (20  %) also impair immediate is an intermediate stage of the membrane fusion pro-
and delayed word recall (Zacny et al. 1994) by the same cess. Strong checkpoint mechanisms are expected to be
mechanism. Ketamine at sub-anesthetic doses in human present at the level of the postsynaptic membranes that
volunteers reduces memory performance for explicit prevent conversion of hemifusion to a fused state. Since
word recall (Parwani et  al. 2005). A gradual increase in very high pressure is required to induce hemifusion,
the anesthetic dose produces a gradual worsening of it can take place only in favourable conditions. How-
short-term memory and a gradual shortening of the time- ever, various factors—such as membrane lipid compo-
interval after which memories can be retrieved (Andrade sitional changes (Fuller et  al. 2003), electrolyte changes,
Vadakkan SpringerPlus (2015)4:485 Page 14 of 17

Fig. 8  Reversible and irreversible changes induced by the insertion of anesthetic molecules to the lipid membrane. These changes are an extension
of changes described in Fig. 5. a The insertion of an anesthetic molecule (an) within the lipid bilayer results in membrane expansion and formation
of reversible partial hemi-fusion between postsynaptic membranes B and D. Once the anesthetic molecule is removed, this readily reverses back to
normal state. b Complete hemifusion between postsynaptic membranes B and D. This is also a completely reversible process. However, prolonged
maintenance of this state can lead to insertion of trans-membrane proteins across the hemifused membrane segment and stabilize this region for
the duration of the life of that protein. Strong checkpoint mechanisms are expected to be present that prevent conversion of hemifusion to a fused
state. c Inter-postsynaptic membrane fusion. Membrane hemifusion is an intermediate stage in the process of fusion. A well-conserved checkpoint
mechanism that prevents conversion of hemifusion to fusion is expected to present at the postsynaptic membranes. Factors such as membrane
composition changes, type and concentration of anesthetics or failure of checkpoint mechanisms can promote conversion of hemifusion state to
fusion. Fusion occurring between the postsynaptic membranes is most likely an irreversible process and can trigger various neurodegenerative
changes

the presence of abnormal proteins, chemical molecules contact to reversible, inter-postsynaptic membrane
(Haque et al. 2001; Mondal and Sarkar 2011), the nature hemifusion restricted to very small areas of approxi-
and concentration of anesthetics and the failure of check- mately 10  nm2. These inter-membrane interactions
point mechanisms that prevent conversion of hemifusion depend on the membrane lipid composition and the
to fusion (Fig. 8)—can lead to deleterious consequences. nature of anesthetic agents. Development of high-
Fusion between the postsynapses (dendritic spines) can resolution imaging techniques that can resolve real-
lead to cytoplasmic content-mixing between two differ- time changes at nanometer scales (Chen et al. 2014)
ent neurons. The finding that gene expression profiles will help with understanding reorganization, close
among the same neuronal types, such as CA1 pyrami- contact, hemifusion and reversal of hemifusion at
dal neurons, are different (Kamme et  al. 2003) indicates nanoscale domains of postsynaptic membranes.
that cytoplasmic content-mixing—even between similar 3. Studies of the effect of anesthetic molecules on arti-
cell types—can trigger cytotoxic consequences. These ficial membrane hemifusion process can be con-
include dendritic spine loss and the triggering of cellular ducted. Role of membrane proteins and lipid compo-
pathways that lead to apoptosis. All these changes pro- sition on membrane interactions can also be studied.
duce changes similar to those that are seen in neurode- 4. The relationship between neurodegeneration and
generative diseases. the use of anesthetics with different octanol/water
coefficients, their MACs, duration of use and lipid
Testing the present work membrane composition can be examined both by
The following investigations can be undertaken to test clinical studies and by laboratory experiments using
whether the mechanism provided in the present work peripheral blood cells or by using artificial mem-
can explain how anesthetics work. branes.

1. Disruption of the intactness of pachymeninges can Conclusion

prevent the external pressure from getting trans- The problem of understanding the mechanism of
duced through the CSF space to the paravascular anesthesia has been persisted since the mechanism
space and finally to the ECM. This is expected to for consciousness remained unknown. Even though a
prevent the reversal effect contributed through the framework for consciousness was put forward earlier
hydrostatic pressure. (Vadakkan 2010), it was not until the discovery of the
2. The cellular changes of the anesthetic-induced inter- glymphatic system (Iliff et  al. 2012) that a framework
postsynaptic membrane functional LINK are a spec- for a mechanism that can explain different findings in
trum of changes, ranging from direct membrane anesthesia research became possible. The mechanism
Vadakkan SpringerPlus (2015)4:485 Page 15 of 17

presented here is not an alternative to the known Århem P, Klement G, Nilsson J (2003) Mechanisms of anesthesia: towards
integrating network, cellular, and molecular level modeling. Neuropsy-
mechanisms of action of different types of anesthet- chopharmacol 28:S40–S47
ics that act on different membrane bound receptors; Aston-Jones G, Chen S, Zhu Y, Oshinsky ML (2001) A neural circuit for circadian
rather, it provides a common mechanism of anesthet- regulation of arousal. Nat Neurosci 4:732–738
Baranov D, Bickler PE, Crosby GJ, Culley DJ, Eckenhoff MF, Eckenhoff RG, Hogan
ics that can alter the net C-semblance proposed for KJ, Jevtovic-Todorovic V, Palotás A, Perouansky M, Planel E, Silverstein
consciousness. The mechanism that allow the anes- JH, Wei H, Whittington RA, Xie Z, Zuo Z (2009) First international work-
thetics to get removed from the membranes through shop on anesthetics and Alzheimer’s disease consensus statement: first
international workshop on anesthetics and Alzheimer’s disease. Anesth
the paravenular system described in the present work Analg 108(5):1627–1630
is different from previously thought direct effect of Beaver RW, Brauer RW, Lahser S (1977) Interaction of central nervous system
pressure on enzymes (Moss et al. 1991). Changes at the effects of high pressures with barbiturates. J Appl Physiol 43(2):221–229
Beecher HK (1947) Anesthesia’s second power: probing the mind. Science
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molar volume changes described earlier (Imai et  al. Behabadi BF, Mel BW (2014) Mechanisms underlying subunit independence in
2006) can occur along with the changes described in pyramidal neuron dendrites. Proc Natl Acad Sci USA 111(1):498–503
Bennett PB (1982) The high pressure nervous syndrome in man. In: Bennett PB,
the present work. By exploring membrane interac- Elliott DH (eds) The physiology and medicine of diving, 3rd edn. Balliere
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Abbreviations
Acad Sci USA 93(15):8040–8045
AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; AMPAR: AMPA
Burette AC, Lesperance T, Crum J, Martone M, Volkmann N, Ellisman MH, Wein-
receptor; ARAS: ascending reticular activating system; CSF: cerebrospinal fluid;
berg RJ (2012) Electron tomographic analysis of synaptic ultrastructure.
Dendritic spine: postsynapse or postsynaptic membrane; ECG: electroen-
J Comp Neurol 520(12):2611–2697
cephalogram; ECM: extracellular matrix; EPSP: excitatory postsynaptic terminal;
Cantor RS (1997) The lateral pressure profile in membranes: a physical mecha-
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Acknowledgements
anesthetics: a possible mechanism from molecular dynamics simula-
Author acknowledges support from Neurosearch Center, Toronto (Number:
tions. J Mol Liq 147:128–134
3:24/2014) and thanks Selena Beckman-Harned for reading the manuscript.
Chen BC, Legant WR, Wang K, Shao L, Milkie DE, Davidson MW, Janetopoulos
C, Wu XS, Hammer JA 3rd, Liu Z, English BP, Mimori-Kiyosue Y, Romero
Compliance with ethical guidelines
DP, Ritter AT, Lippincott-Schwartz J, Fritz-Llin L, Mullins RD, Mitchell
DM, Bembenek JN, Reymann AC, Böhme R, Wang JT, Wang JT, Seydoux
Competing interests
G, Tulu US, Kiehart DP, Betzig E (2014) Lattice light-sheet microscopy:
Author has applied for a U.S. patent (application number: 14/068,835) for an
imaging molecules to embryos at high spatiotemporal resolution. Sci-
electronic circuit model of the inter-postsynaptic functional LINK. This has not
ence 346(6208):1257998
inappropriately influenced this work.
Cichon J, Gan WB (2015) Branch-specific dendritic Ca(2+) spikes cause persis-
tent synaptic plasticity. Nature 520(7546):180–185
Received: 22 April 2015 Accepted: 28 August 2015
Cohen FS, Melikyan GB (2004) The energetics of membrane fusion from
binding, through hemifusion, pore formation, and pore enlargement. J
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