Maxim Bazhenov, University of California- Riverside
Sleep spindle oscillations - new insights on an old topic
Spindle oscillations are commonly observed during stage two
of non-REM sleep. During sleep spindles, the cerebral cortex and
thalamus interact through feedback connections. Both initiation
and termination of spindle oscillations are thought to originate
in the thalamus, based on thalamic recordings and computational
models. Drawing on results obtained with large-scale biophysical
network models of the thalamocortical system, I will discuss the
role of corticothalamic influences on initiation, termination
and synchronization of sleep spindles.
Victoria Booth, University of Michigan
Modeling the temporal architecture of sleep-wake transition dynamics
Sleep and wake states are regulated by the interactions among
a number of brainstem and hypothalamic neuronal populations and
the expression of their neurotransmitters. Based on different
experimental studies, several different structures have been proposed
for this sleep-wake regulatory network with particular debate
over components involved in rapid-eye movement (REM) sleep regulation.
We have developed a mathematical modeling framework that is uniquely
suited for investigating the structure and dynamics of proposed
sleep-wake regulatory networks. Using this framework, we constructed
a sleep-wake regulatory network model based on the reciprocal
interaction hypothesis for REM sleep regulation. I will discuss
our analysis to determine how the structure of the sleep-wake
regulatory network determines sleep-wake behavior and the dynamics
of behavioral state transitions. I will also discuss the deterministic
and stochastic model properties necessary to generate realistic
rat sleep-wake temporal architecture as assessed by both standard
summary statistics and survival analysis of bout distributions.
ShiNung Ching, Massachusetts General Hospital & Harvard Medical
School
Biophysical models of neuronal dynamics during general anesthesia
and burst suppression
Recent research has revealed new electrophysiological oscillations
that are associated with unconsciousness under general anesthesia.
We are using biophysical modeling to elucidate how the molecular
actions of anesthetic drugs manifest in larger neuronal networks
to create such brain dynamics. As an example, I will first present
recent modeling of an 'alpha' (9-12Hz) EEG oscillation that appears
during surgical levels of propofol-induced general anesthesia.
Such oscillations differ from classical 'alpha' oscillations in
their frequency and spatial location. Using conductance-based
neuronal models, we have shown how propofol - an agonist of GABAergic
neurotransmission - can promote highly synchronous alpha oscillations
in thalamocortical networks, leading to the observed phenomenology.
These oscillations may impede normal thalamocortical dynamics
and thus, correlate with reductions in arousal.
I will then discuss recent models for the state of burst suppression,
which consists of high voltage EEG activity (bursts) that alternates
with isoelectric quiescence (suppression). Burst suppression occurs
at deep levels of general anesthesia and also in pathological
conditions such as coma. Our modeling suggests that the dynamics
of burst suppression arise not simply from neuromodulatory effects,
but also from changes in brain metabolism. Specifically, I will
discuss how a lowered cerebral metabolic rate can lead to epochs
of burst and suppression by inducing transient reductions in cerebral
ATP and subsequent gating of neuronal potassium channels. This
model provides a unified mechanism of burst suppression that is
consistent with each of its etiologies and provides a platform
to study the brain network dynamics associated with other anesthetic
drugs and related pathological states.
Jeffrey Ellenbogen, Harvard University
Oscillatory activity of the brain predicts sound sleep on noisy
nights
Human sleep can be defined as a natural, transient state of reduced
responsiveness. This perspective operationally explains sleep
as a state with diminished processing of external stimuli, such
as noises that we encounter every day (e.g., alarms, people talking,
etc). But in fact, there is a wide range of responsiveness to
noises within sleep, both across a single night and between different
people. Some moments of sleep, and some sleepers themselves, are
more resistant to disruption due to noise. What are the biological
drivers of these phenomena that protect sleep or render it fragile?
Can they be quantified through signal-processing techniques of
human electroencephalography (EEG)? I will discuss some current
techniques, and some novel ones, that are employed to analyze
human EEG of sleep. I will demonstrate their effectiveness and
limitations at examining sleep depth by showing experimental data
of people awoken from sleep from various noises. I will also discuss
future implications, including real-time analysis techniques that
might interface with novel therapies for disrupted sleep.
Sean Hill, Karolinska Institute
Wakefulness and Sleep: A computational model of thalamocortical
circuitry
I will present a model cat visual thalamocortical system (Hill
and Tononi, 2005) containing ~65,000 integrate-and-fire neurons
and 6 million connections capable of producing rich spontaneous
activity as well as orientation-selective responses to visual
stimuli during wakefulness. The model encompasses two visual areas
divided into three layers (supragranular, infragranular and layer
IV) with the associated thalamic and reticular thalamic nuclei.
Model neurons (both excitatory and inhibitory) are highly interconnected
with patterned thalamocortical, corticothalamic, and intra- and
interareal corticocortical connections. The model also incorporates
experimentally observed intrinsic currents that are thought to
affect sleep rhythms. The model exhibits a waking mode, characterized
by highly variable spontaneous activity throughout the cortex
as well as orientation selective responses to visual stimuli.
Evoked visual activity displayed gamma frequency thalamocortical
synchronization. In the sleep mode, the model displays spontaneously
occurring slow oscillations that resemble those observed in vivo
and in vitro. I will also present results from studies in which
this model has been used to explore homeostatic processes and
plasticity - including the synaptic homeostasis hypothesis of
sleep.
Richard L. Horner, University of Toronto
Sleep: Brain rewiring for flexible behaviour, with implications
for the evolutionary trajectory of species
On July 1st 2005 Science published its 125th anniversary issue
and highlighted the most compelling but unresolved scientific
questions. Why we sleep and why we dream were two of them. This
paper will first present a logical construct derived from evolutionary
theory that any explanation of sleep must be able to fit in order
to be applicable to diverse organisms across the tree of life.
This construct is then used to satisfy the identification of the
primary function of sleep (defined as the reason that sleep evolved
for the function it still serves), and distinguishes this from
secondary functions (defined as those that are associated with
sleep but which are not part of its fundamental nature). Identification
of the primary adaptive property of sleep that is visible to natural
selection is then used to explain how sleep powerfully affects
the individual fitness of organisms and the evolutionary trajectory
of species. This identification of the primary function of sleep
explains the diversity of sleep-wake behaviour between species
and individuals across the lifespan, and the consequences of sleep
disruption and drug-induced sedation on brain activity and behaviour.
L. Stan Leung, University of Western
Basal forebrain participation in general anesthesia
The basal forebrain is highly interconnected with a number of
brain regions involved in sleep-wake regulation, including cholinergic
inputs from the pedunculopontine nucleus and laterodorsal nucleus
of the pons, histaminergic inputs from tuberomammillary nucleus
(TM) of the posterior hypothalamus, noradrenergic inputs from
the locus coeruleus and serotonergic inputs from the raphe. The
basal forebrain nuclei consist of the nucleus basalis (NB) that
projects to the neocortex and the medial septum/ diagonal band
area (MS) that project to the hippocampus and entorhinal cortex.
We have used reversible inactivation (by local brain application
GABAA receptor agonist muscimol) and permanent lesion of the basal
forebrain, and selective lesion of histaminergic neurons in the
TM, to study whether these structures participate in the emergence
and induction of general anesthesia in rats. The main indicator
of general anesthesia was a loss of righting reflex (LORR); tail
pinch response and frontal cortical and hippocampal EEGs were
also recorded.
Muscimol inactivation of the MS and NB prolonged the duration
of LORR induced by both injectable (propofol, pentobarbital) and
volatile anesthetic (isoflurane, halothane). The dose of anesthetic
that induced slow delta EEG waves in the frontal cortex or suppress
high gamma activity (70-100 Hz) in the hippocampus was reduced
when either the MS or NB was inactivated. However, high-amplitude
neocortical delta waves could occur in a standing, non-anesthetized
rat after inactivation of NB, and thus neocortical delta EEG by
itself does not indicate general anesthesia. Selective lesion
of cholinergic neurons in the MS and NB, by local infusion of
cholinotoxin 192 IgG-saporin, prolonged the duration of LORR following
an anesthetic. Lesion of the histaminergic neurons in the TMN
by orexin-saporin also delayed emergence (recovery of LORR) following
isoflurane in addition to enhance the sensitivity to isoflurane.
NB application of histamine facilitated, while H1 receptor antagonist
triprolidine delayed, emergence from isoflurane anesthesia.
Other than the basal forebrain, bilateral inactivation of structures
in the limbic system, including the nucleus accumbens, ventral
tegmental area, ventral pallidum supramammillary area and amygdala
prolonged the duration of LORR following pentobarbital or halothane.
The latter inactivation, as compared to saline infusion, also
increased delta waves and decreased hippocampal theta and gamma
waves following a general anesthetic. By contrast, infusion of
muscimol in the median raphe did not significantly alter the behavioral
or EEG effects of halothane or pentobarbital. Bilateral inactivation
of the entorhinal or piriform cortex prolonged the duration of
LORR induced by pentobarbital but not halothane. The effect of
inactivation on anesthetic-induced LORR may be explained in part
by the connection of the brain area to the basal forebrain. Limbic
system inactivation also suppressed the delirium state induced
by a dose of anesthestic, including that induced by halothane,
isoflurane, pentobarbital and ketamine.
Our research suggests that subcortical histaminergic and cholinergic
inputs participate in activating the brain during wake and general
anesthesia, such that removal of histaminergic or cholinergic
activation of the forebrain increases anesthetic sensitivity and
delays emergence. Other work suggests that norepinephrinergic
and orexinergic pathways also participating in brain activation
and general anesthesia. Our work highlights the limbic system,
including the medial septum, hippocampus and nucleus accumbens,
as important participants in general anesthesia, and in mediating
the delirium state.
Beverly Orser, University of Toronto
Atypical GABA-A receptors regulate the memory blocking properties
of general anesthetics
Memory blockade is one of the most potent and essential properties
of general anesthetics. Unfortunately, some patients experience
persistent memory deficits long after the anesthetic has been
eliminated. Paradoxically, other patients experience inadequate
memory loss leading to “intraoperative awareness”. The
molecular mechanisms underlying the memory blocking properties
of anesthetics remain poorly understood and have been a focus
of our research. I will present studies that identify a subtype
of inhibitory GABAA receptor that is highly sensitive to up-regulation
by inhaled and intravenous anesthetics. The role of these receptors
in normal memory processes and persistent memory deficits after
exposure to anesthetics will be discussed.
Patrick L. Purdon, Ph.D., Massachusetts General Hospital, Harvard
Medical School
Electroencephalogram Signatures of Loss and Recovery of Consciousness
During Propofol-Induced General Anesthesia
How can anesthesiologists tell when patients are unconscious
under general anesthesia? Since the 1930's, stereotyped electroencephalogram
(EEG) patterns have been observed during general anesthesia, yet
the specific signals that demarcate loss and recovery of consciousness
have remained elusive. In this talk, I will be presenting results
from human studies showing behavioral changes and EEG signatures
that occur in the transition between consciousness and unconsciousness
during gradual induction and emergence from general anesthesia.
We characterized level of consciousness using an auditory response
task, and observed that the probability of response decreased
gradually in the transitions to and from unconsciousness. The
transition to loss of consciousness was marked by increased gamma
and beta power that decreased in center frequency and bandwidth
as the probability of response decreased. At loss of consciousness,
low-frequency and globally-coherent frontal alpha oscillations
developed, while occipital alpha oscillations were abolished.
During emergence from propofol anesthesia, these EEG patterns
reversed. These results establish electrophysiological signatures
that can be used to monitor and manage the state of unconsciousness
under general anesthesia, and provide important insights into
the mechanisms underlying this state.
Igor Timofeev, The Centre de Recherche Institut Universitaire en
Santé Mentale de Québec (CRIUSMQ), Laval University
Slow-wave activity during sleep and ketamine-xylazine anesthesia
Deep anesthesia is commonly used as a model of slow-wave sleep
(SWS). Ketamine-xylazine anesthesia reproduces the main features
of sleep slow oscillation: slow, large amplitude waves in field
potential, which are generated by the alternation of hyperpolarized
and depolarized states of cortical neurons. However, detailed
comparison of field potential and membrane potential fluctuations
during natural sleep and anesthesia was absent tile resent, so
it remaine unclear how well the properties of sleep slow oscillation
are reproduced by the ketamine-xylazine anesthesia model of slow-wave
sleep. I will present resent data on field potential and intracellular
recordings in different cortical areas in the cat, to directly
compare properties of slow oscillation during natural sleep and
ketamine-xylazine anesthesia. During SWS cortical activity showed
higher power in the slow/delta (0.1-4 Hz) and spindle (8-14 Hz)
frequency range, while under anesthesia the power in the gamma
band (30-100 Hz) was higher. During anesthesia, slow waves were
more rhythmic and more synchronous across the cortex. Intracellular
recordings revealed that silent states were longer and the amplitude
of membrane potential around transition between active and silent
states was bigger under anesthesia. Slow waves were largely uniform
across cortical areas under anesthesia, but in SWS they were most
pronounced in associative and visual areas, but smaller and less
regular in somatosensory and motor cortices. We conclude that
although the main features of the slow oscillation in sleep and
anesthesia appear similar, multiple cellular and network features
are differently expressed during natural SWS as compared to ketamine-xylazine
anesthesia.
Martin Wechselberger, University of
Sydney
Canard theory and neuronal dynamics
An important feature of most physiological systems is that they
evolve on multiple scales. For example, the bursting activity
of neurons consists of a long interval of quasi steady-state followed
by an interval of rapid variation, which is the burst itself.
It is the interplay of the dynamics on different temporal or spatial
scales that creates complicated rhythms and patterns.
Multiple scales problems of physiological systems are usually
modelled by singularly perturbed systems. The geometric theory
of multiple scales dynamical systems -- known as Fenichel Theory
-- has provided powerful tools for studying singular perturbation
problems. In conjunction with the innovative blow-up technique,
geometric singular perturbation theory delivers rigorous results
on pattern generation in multiple time-scale problems.
As a case study of geometric singular perturbation theory, I
will focus on a single neuron model by McCarthy et al. (2008)
that looks at the effect of the anesthetic propofol on such a
neuron. It is well known that propofol causes paradoxical excitation
in low doses. I will show that "canards", exceptional
solutions in singular perturbation problems which occur on boundaries
of regions corresponding to different dynamic behaviors, provide
a possible explanation of the observed paradox.
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