Cortical Spreading Depolarizations

DEFINITION: profound disruptions of homeostasis that slowly propagate through gray matter, and induced suppression of cortical activity (termed “spreading depression”)

COSBID – Co-Operative Studies on Brain Injury Depolarizations), an international research consortium, first meeting 2003

⁃ focus on SDs in the setting of NCC, testing the idea that SDs contribute to injury

⁃ potential therapeutic improbable

⁃ Evolved into iCSD (International Conference on Spreading Depolarizations)

CHALLENGE QUESTIONS:

“Which SDs are deleterious to brain tissue?”

“Which factors render some SDs more injurious than others?”

Pathological changes in major tissue variables seen in SD: reduced CBF or intercellular Ca loading,

MAJOR Mechanisms SDs thought to cause cellular injury:

1. ATP depletion

2. Excitotoxicity

3. Spreading ischemia – SD-induced, local decrease in cbf seen in animals and patients, prolongs electrophysiologic depolarized state.

Energy Challenge presented by SD:

⁃ Membrane potential almost completely dissipated for tens of seconds to minutes, energy required to depolarize is extreme

⁃ Dramatic structural changes including cellular swelling, fragmentation of ER, disruption of dendritic spines, etc.

GLUCOSE

⁃ SD results in sharp decreases in local brain glucose levels

⁃ Moves Brian to a more metabolicallyi compromised state

⁃ Repetitive SDs progressively drive glucose to detrimental levels

*would be helpful to have methods to observe SDs over larger regions.

Potential Benefits of SD:

⁃ synaptic strengthening

⁃ Increase in neurotrophic factors

⁃ Neuroproctective preconditions

⁃ Neurogenesis

*limit expansion of ICH in the mouse

*hyperemic response to SD observed in healthy tissues could have positive effects

At present, there is little or no direct evidence that SD has meaningful beneficial effects, in contrast to strong evidence for injury. Any evidence for benefit would have to be dramatic to outweigh potential therapeutic gains of treating and preventing SDs.

Consider improving tissue perfusion rather than solely focusing on SD blockade.

Reference:

Shuttleworth, C., Andrew, R., Akbari, Y., Ayata, C., Balu, R., & Brennan, K. et al. (2019). Which Spreading Depolarizations Are Deleterious To Brain Tissue?. Neurocritical Care. doi: 10.1007/s12028-019-00776-7

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