Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma

Cortical spreading depolarization causes a breakdown of electrochemical gradients following acute brain injury, and also elicits dynamic changes in regional cerebral blood flow that range from physiological neurovascular coupling (hyperaemia) to pathological inverse coupling (hypoperfusion). In this study, we determined whether pathological inverse neurovascular coupling occurred as a mechanism of secondary brain injury in 24 patients who underwent craniotomy for severe traumatic brain injury. After surgery, spreading depolarizations were monitored with subdural electrode strips and regional cerebral blood flow was measured with a parenchymal thermal diffusion probe. The status of cerebrovascular autoregulation was monitored as a correlation between blood pressure and regional cerebral blood flow. A total of 876 spreading depolarizations were recorded in 17 of 24 patients, but blood flow measurements were obtained for only 196 events because of technical limitations. Transient haemodynamic responses were observed in time-locked association with 82 of 196 (42%) spreading depolarizations in five patients. Spreading depolarizations induced only hyperaemic responses (794% increase) in one patient with intact cerebrovascular autoregulation; and only inverse responses (-24% decrease) in another patient with impaired autoregulation. In contrast, three patients exhibited dynamic changes in neurovascular coupling to depolarizations throughout the course of recordings. Severity of the pathological inverse response progressively increased (-14%, -29%, -79% decrease, P < 0.05) during progressive worsening of cerebrovascular autoregulation in one patient (Pearson coefficient 0.04, 0.14, 0.28, P < 0.05). A second patient showed transformation from physiological hyperaemic coupling (44% increase) to pathological inverse coupling (-30% decrease) (P < 0.05) coinciding with loss of autoregulation (Pearson coefficient 0.19 -> 0.32, P < 0.05). The third patient exhibited a similar transformation in brain tissue oxygenation, a surrogate of blood flow, from physiologic hyperoxic responses (20% increase) to pathological hypoxic responses (-14% decrease, P < 0.05). Pathological inverse coupling was only observed with electrodes placed in or adjacent to evolving lesions. Overall, 31% of the pathological inverse responses occurred during ischaemia (<18 ml/100 g/min) thus exacerbating perfusion deficits. Average perfusion was significantly higher in patients with good 6-month outcomes (46.8 +/- 6.5 ml/100 g/min) than those with poor outcomes (32.2 +/- 3.7 ml/100 g/min, P < 0.05). These results establish inverse neurovascular coupling to spreading depolarization as a novel mechanism of secondary brain injury and suggest that cortical spreading depolarization, the neurovascular response, cerebrovascular autoregulation, and ischaemia are critical processes to monitor and target therapeutically in the management of acute brain injury.