ondes de dépression corticales envahissantes migraine et avc e. grenier
TRANSCRIPT
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Ondes de dépression corticales envahissantes
Migraine et AVC
E. Grenier
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Biological aspects
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• Ionic exchanges : reaction term
• Ions diffuse in extracellular space
• Ions diffuse through « gap junctions » (small holes in the membranes of cells).
Reaction diffusion equations in the center of the model
Are there travelling waves ? YES: spreading depressions
• observed in various species: rat, chicken, …
• observed during stroke in rats
• conjectured in man during migraine with aura
Spreading depression
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Spreading depression
In Rat cortex
• Injection of KCl in some part of the brain
• At injection point, depolarization of the cells
• Depolarization propagates 2 – 4 mm / min
• Recovery after depolarization
• Progressive wave: depolarization wave
• Two waves do not cross
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Spreading depression
Occurs in • Migraine with aura
– Starts in visual areas– Stop at different locations, depending of the patients– Speed of a few mm / min
• Strokes in rat– Created at the border of the dying area– Propagate in the penumbra – Exhausts cells in the penumbra – Final size of the dead zone is proportionnal to the number of
spreading depressions which propagate.
• No evidence during stroke in human.
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Principaux mécanismes impliqués dans la propagation des ondes de dépolarisation de la zone infarcie vers la zone saine par un processus de diffusion des ions K+ et du glutamate dans l'espace extracellulaire et par un
processus de propagation d'ondes calciques dans les astrocytes
K + , glutamate Ca 2+
transporteur du glutamate
inversé
glutamate K +
canal K + voltage-
dépendant
récepteur AMPA
Ca 2+ Ca 2+
Ca 2+
récepteur NMDA
glutamate
transporteur du glutamate
inversé
K +
récepteur purinergique
ATP
gap - junction
canal K + voltage-
dépendant
neurone
astrocyte
propagation de l’onde de dépolarisation
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Spreading depression in a cat brain
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Mathematical models
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Spreading depression: simple model
• State described by a variable u(t,x)• 0 <= u <= 1: 0 normal state / 1 fully depressed state.• Evolution of u under
– Diffusion– Local reaction of the tissu f(u)
∂t u – ν∂Δ u = f(u)– In grey matter:
• F(u) is negative if u is small (normal state is stable)• F(u) is positive if u is large (fully depressed state is stable, up to
recovery phenomena)
f(u) = a u (1 – u) (u – u0)– In white matter: recovery
f(u) = - b u
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Spreading depression: ionic model
• Introduce all extra and intracellular ionic concentrations: K+, Na+, Ca2+, Glu, Cl-, …
• Extracellular ionic concentrations diffuse in extracellular space
• Some species diffuse from glial cells to glial cells through gap junctions
• Reaction term is given by all local ionic exchanges through voltage dependent gates, exchangers, pumps …
• Very complex system !
• Still to be studied completly !
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Spreading depression: ionic model
Simulation of a spreading depression following Shapiro (2001)
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Spreading depressions in migraine with aura
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The domain of propagation
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Numerical domain of propagation
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Discussion
• Topography of grey matter may explain by itself that spreading depression do not propagate in the whole brain during stroke
• Topography of grey matter may explain why spreading depressions have never been observed during stroke
– Should also come from experimental difficulties
– Observed in vitro on small cuts of grey substance (coherent)
• Big difference with Rat, where the final size of dead area is proportional to the number of spreading depressions !
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Numerical computation: Rolando sulcus
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Simulation for Rolando sulcus
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Discussion
• Topography of Rolando sulcus by itself may explain that spreading depressions always stop there during migraine with aura
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Spreading depressions in stroke:Global models
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Global models of stroke
Very large models, combining
• Ionic models:– Simple bistable equations– Complete ionic model of the first section
• Oedema models• Blood flow• Death of cells (apoptosis / necrosis)
– Programmed cell death : a kind of cell suicide
• Energy management• Topography• Toxicity
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Typical simulation
Dead zone Spreading depressions
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Influence of diffusion / apoptosis / toxicity
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Influence of diffusion / apoptosis / toxicity
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Spreading depressions
• In Rat, spreading depressions are observed in vivo– Important in the progression of the dead core
– Important to try to block them
• In human, no spreading depressions are observed at large scales– Coherent with previous section
– Remains to be checked numerically on the whole model
– Explains failures of some therapeutics ?
• Existence of spreading depressions for very small strokes ?– Stroke in young men
– Trace of the propagations of spreading depressions ?
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Perspectives
• To complete model– Include complete ionic model
– Add free radicals
– Realistic 2D geometries (in progress)
– Realistic 3D geometries (very challenging)
• To compare with clinical cases– Basis of clinical images already set up
• Numerical challenges– Very different time scales (from 1ms to 12h)
– Very complex topography (already in 2D, … 3D …)
– Very expensive !