Intracranial pressure spikes trigger spreading depolarizations

Abstract

Abstract Spreading depolarizations are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply–demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure are also prevalent in the injured brain. Here, using a mouse model of large hemispheric ischaemic stroke, we show that mild and brief intracranial pressure elevations (20 or 30 mmHg for just 3 min) potently trigger spreading depolarizations in ischaemic penumbra (4-fold increase in spreading depolarization occurrence). We also show that 30 mmHg intracranial pressure spikes as brief as 30 s are equally effective. In contrast, sustained intracranial pressure elevations to the same level for 30 min do not significantly increase the spreading depolarization rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger a spreading depolarization. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the intracranial pressure spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply–demand mismatch. These haemodynamic changes during intracranial pressure spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, a higher rate of intracranial pressure spikes was associated with spreading depolarization clusters in a retrospective series of patients with aneurysmal subarachnoid haemorrhage with strong temporal correspondence. Altogether, our data show that intracranial pressure spikes, even when mild and brief, are capable of triggering spreading depolarizations. Aggressive prevention of intracranial pressure spikes may help reduce spreading depolarization occurrence and improve outcomes after brain injury.