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Migraine strikes as neuronal excitability reaches a tipping point.

Scheffer M, van den Berg A, Ferrari MD - PLoS ONE (2013)

Bottom Line: We show that this hypothesis is consistent with current pathogenetic insights and observed dynamics.Our view implies that migraine strikes when modulating factors further raise the neuronal excitability in genetically predisposed subjects to a level where even minor perturbations can trigger spreading depolarisations.A corollary is that recently discovered generic early warning indicators for critical transitions may be used to predict the onset of migraine attacks even before patients are clinically aware.

View Article: PubMed Central - PubMed

Affiliation: Department of Aquatic Ecology & Water Quality Management, Wageningen University, Wageningen, the Netherlands. marten.scheffer@wur.nl

ABSTRACT
Self-propagating waves of cerebral neuronal firing, known as spreading depolarisations, are believed to be at the roots of migraine attacks. We propose that the start of spreading depolarisations corresponds to a critical transition that occurs when dynamic brain networks approach a tipping point. We show that this hypothesis is consistent with current pathogenetic insights and observed dynamics. Our view implies that migraine strikes when modulating factors further raise the neuronal excitability in genetically predisposed subjects to a level where even minor perturbations can trigger spreading depolarisations. A corollary is that recently discovered generic early warning indicators for critical transitions may be used to predict the onset of migraine attacks even before patients are clinically aware. This opens up new avenues for dissecting the mechanisms for the onset of migraine attacks and for identifying novel prophylactic treatment targets for the prevention of attacks.

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Graphical model showing how a tipping point for cortical spreading depression can arise.a) Three equilibriums may occur at intersection points where the rate of generation of new pulses (sigmoidal curve) equals the rate of decay (dashed line) of neural pulses. Activity increases when the generation of new pulses exceeds the decay of pulses (sections I and III) and decreases in the other sections (sections II and IV). It can be seen from the arrows representing this direction of change that the middle intersection point is a repellor that marks the border between the basins of attraction of the two alternative stable states. b) Increasing base-line excitability promotes the generation of new pulses causing the unstable equilibrium (open dot) and the stable normal state (left hand solid dot) to move closer together. This reduces resilience of the normal state in the sense that a smaller perturbation is needed to invoke a shift to the Aura state (horizontal dashed arrows in panel). c) Plotting how the intersection points representing equilibriums move as a function of base-line excitability, a catastrophe fold arises. The fold bifurcation point (F) marks the loss of stability of the normal state.
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pone-0072514-g002: Graphical model showing how a tipping point for cortical spreading depression can arise.a) Three equilibriums may occur at intersection points where the rate of generation of new pulses (sigmoidal curve) equals the rate of decay (dashed line) of neural pulses. Activity increases when the generation of new pulses exceeds the decay of pulses (sections I and III) and decreases in the other sections (sections II and IV). It can be seen from the arrows representing this direction of change that the middle intersection point is a repellor that marks the border between the basins of attraction of the two alternative stable states. b) Increasing base-line excitability promotes the generation of new pulses causing the unstable equilibrium (open dot) and the stable normal state (left hand solid dot) to move closer together. This reduces resilience of the normal state in the sense that a smaller perturbation is needed to invoke a shift to the Aura state (horizontal dashed arrows in panel). c) Plotting how the intersection points representing equilibriums move as a function of base-line excitability, a catastrophe fold arises. The fold bifurcation point (F) marks the loss of stability of the normal state.

Mentions: Figure 2 explains graphically how a tipping point can arise from the above assumptions (for the mathematical model, and a more specific definition of the parameters and variables see the material and methods section). Imagine a dynamic equilibrium of neural activity in a small brain region, resulting from the balance between generation and decay of pulses. If we plot the generation and decay of pulses together, it can be seen that multiple equilibriums may arise at their intersections if the generation of activity rises relatively sharply when the contagious local neural firing kicks in (positive feedback) around a critical excitability level (εcrit). The unstable middle equilibrium marks the boundary between the two ‘basins of attraction’ around the stable states.


Migraine strikes as neuronal excitability reaches a tipping point.

Scheffer M, van den Berg A, Ferrari MD - PLoS ONE (2013)

Graphical model showing how a tipping point for cortical spreading depression can arise.a) Three equilibriums may occur at intersection points where the rate of generation of new pulses (sigmoidal curve) equals the rate of decay (dashed line) of neural pulses. Activity increases when the generation of new pulses exceeds the decay of pulses (sections I and III) and decreases in the other sections (sections II and IV). It can be seen from the arrows representing this direction of change that the middle intersection point is a repellor that marks the border between the basins of attraction of the two alternative stable states. b) Increasing base-line excitability promotes the generation of new pulses causing the unstable equilibrium (open dot) and the stable normal state (left hand solid dot) to move closer together. This reduces resilience of the normal state in the sense that a smaller perturbation is needed to invoke a shift to the Aura state (horizontal dashed arrows in panel). c) Plotting how the intersection points representing equilibriums move as a function of base-line excitability, a catastrophe fold arises. The fold bifurcation point (F) marks the loss of stability of the normal state.
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Related In: Results  -  Collection

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pone-0072514-g002: Graphical model showing how a tipping point for cortical spreading depression can arise.a) Three equilibriums may occur at intersection points where the rate of generation of new pulses (sigmoidal curve) equals the rate of decay (dashed line) of neural pulses. Activity increases when the generation of new pulses exceeds the decay of pulses (sections I and III) and decreases in the other sections (sections II and IV). It can be seen from the arrows representing this direction of change that the middle intersection point is a repellor that marks the border between the basins of attraction of the two alternative stable states. b) Increasing base-line excitability promotes the generation of new pulses causing the unstable equilibrium (open dot) and the stable normal state (left hand solid dot) to move closer together. This reduces resilience of the normal state in the sense that a smaller perturbation is needed to invoke a shift to the Aura state (horizontal dashed arrows in panel). c) Plotting how the intersection points representing equilibriums move as a function of base-line excitability, a catastrophe fold arises. The fold bifurcation point (F) marks the loss of stability of the normal state.
Mentions: Figure 2 explains graphically how a tipping point can arise from the above assumptions (for the mathematical model, and a more specific definition of the parameters and variables see the material and methods section). Imagine a dynamic equilibrium of neural activity in a small brain region, resulting from the balance between generation and decay of pulses. If we plot the generation and decay of pulses together, it can be seen that multiple equilibriums may arise at their intersections if the generation of activity rises relatively sharply when the contagious local neural firing kicks in (positive feedback) around a critical excitability level (εcrit). The unstable middle equilibrium marks the boundary between the two ‘basins of attraction’ around the stable states.

Bottom Line: We show that this hypothesis is consistent with current pathogenetic insights and observed dynamics.Our view implies that migraine strikes when modulating factors further raise the neuronal excitability in genetically predisposed subjects to a level where even minor perturbations can trigger spreading depolarisations.A corollary is that recently discovered generic early warning indicators for critical transitions may be used to predict the onset of migraine attacks even before patients are clinically aware.

View Article: PubMed Central - PubMed

Affiliation: Department of Aquatic Ecology & Water Quality Management, Wageningen University, Wageningen, the Netherlands. marten.scheffer@wur.nl

ABSTRACT
Self-propagating waves of cerebral neuronal firing, known as spreading depolarisations, are believed to be at the roots of migraine attacks. We propose that the start of spreading depolarisations corresponds to a critical transition that occurs when dynamic brain networks approach a tipping point. We show that this hypothesis is consistent with current pathogenetic insights and observed dynamics. Our view implies that migraine strikes when modulating factors further raise the neuronal excitability in genetically predisposed subjects to a level where even minor perturbations can trigger spreading depolarisations. A corollary is that recently discovered generic early warning indicators for critical transitions may be used to predict the onset of migraine attacks even before patients are clinically aware. This opens up new avenues for dissecting the mechanisms for the onset of migraine attacks and for identifying novel prophylactic treatment targets for the prevention of attacks.

Show MeSH
Related in: MedlinePlus