The term cortical spreading depolarization (CSD) describes a wave of mass neuronal depolarization associated with net influx of cations and water. Clusters of prolonged CSDs were measured time-locked to progressive ischaemic damage in human cortex. CSD induces tone alterations in resistance vessels, causing either transient hyperperfusion (physiological haemodynamic response) in healthy tissue; or hypoperfusion [inverse haemodynamic response = cortical spreading ischaemia (CSI)] in tissue at risk for progressive damage, which has so far only been shown experimentally. Here, we performed a prospective, multicentre study in 13 patients with aneurysmal subarachnoid haemorrhage, using novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry (LDF) and direct current-electrocorticography, combined with measurements of tissue partial pressure of oxygen (ptiO2). Regional cerebral blood flow and electrocorticography were simultaneously recorded in 417 CSDs. Isolated CSDs occurred in 12 patients and were associated with either physiological, absent or inverse haemodynamic responses. Whereas the physiological haemodynamic response caused tissue hyperoxia, the inverse response led to tissue hypoxia. Clusters of prolonged CSDs were measured in five patients in close proximity to structural brain damage as assessed by neuroimaging. Clusters were associated with CSD-induced spreading hypoperfusions, which were significantly longer in duration (up to 144 min) than those of isolated CSDs. Thus, oxygen depletion caused by the inverse haemodynamic response may contribute to the establishment of clusters of prolonged CSDs and lesion progression. Combined electrocorticography and perfusion monitoring also revealed a characteristic vascular signature that might be used for non-invasive detection of CSD. Low-frequency vascular fluctuations (LF-VF) (f < 0.1 Hz), detectable by functional imaging methods, are determined by the brain's resting neuronal activity. CSD provides a depolarization block of the resting activity, recorded electrophysiologically as spreading depression of high-frequency-electrocorticography activity. Accordingly, we observed a spreading suppression of LF-VF, which accompanied spreading depression of high-frequency-electrocorticography activity, independently of whether CSD was associated with a physiological, absent or inverse haemodynamic response. Spreading suppressions of LF-VF thus allow the differentiation of progressive ischaemia and repair phases in a fashion similar to that shown previously for spreading depressions of high-frequency-electrocorticography activity. In conclusion, it is suggested that (i) CSI is a novel human disease mechanism associated with lesion development and a potential target for therapeutic intervention in stroke; and that (ii) prolonged spreading suppressions of LF-VF are a novel ‘functional marker’ for progressive ischaemia.

Spreading depolarizations (SDs) occur spontaneously with high incidence in patients with acute brain injury. They can be detected by subdural electrocorticographic recordings. We here characterize the dynamic metabolic response to these events. A microdialysis catheter was inserted into perilesional cortical tissue adjacent to a strip for electrocorticography following craniotomy in 10 patients. The microdialysis catheter was connected to an online microdialysis assay measuring glucose and lactate concentrations every 30 to 60 secs. Spontaneously occurring SDs systematically caused a reduction in dialysate glucose by -32.0 micromol/L (range: -92.3 to -18.4 micromol/L, n=90) and increase in lactate by +23.1 micromol/L (range: +5.5 to +93.6 micromol/L, n=49). The changes were sustained at 20 mins after the SD events and highly significant using an area under the curve analysis (P<0.0001). Multiple and frequent SDs led to a progressive stepwise depletion of brain glucose. Hence, SD events cause a massive energy imbalance and their frequent occurrence leads to a local insufficiency of glucose supply. Such a failure would compromise cellular repolarization and hence tissue viability. The findings offer a new mechanism to account for otherwise unexplained instances of depletion of brain microdialysate glucose.

Here we investigated the incidence of cortical spreading depolarizations (spreading depression and peri-infarct depolarization) after traumatic brain injury (TBI) and their relationship to systemic physiologic values during neurointensive care. Subdural electrode strips were placed on peri-contusional cortex in 32 patients who underwent surgical treatment for TBI. Prospective electrocorticography was performed during neurointensive care with retrospective analysis of hourly nursing chart data. Recordings were 84 hr (median) per patient and 2,503 hr in total. In 17 patients (53%), 280 spreading depolarizations (spreading depressions and peri-infarct depolarizations) were observed. Depolarizations occurred in a bimodal pattern with peak incidence on days 1 and 7. The probability of a depolarization occurring increased significantly as a function of declining mean arterial pressure (MAP; R(2) = 0.78; p < 0.001) and cerebral perfusion pressure (R(2) = 0.85; p < 0.01), and increasing core temperature (R(2) = 0.44; p < 0.05). Depolarization probability was 7% for MAP values of >100 mm Hg but 33% for MAP of < or =70 mm Hg. Temperatures of < or =38.4 degrees C were associated with a 21% depolarization risk, compared to 63% for >38.4 degrees C. Intracranial pressures were higher in patients with depolarizations (18.3 +/- 9.3 vs. 13.5 +/- 6.7 mm Hg; p < 0.001). We conclude that depolarization phenomena are a common cortical pathology in TBI. Their association with lower perfusion levels and higher temperatures suggests that the labile balance of energy supply and demand is an important determinant of their occurrence. Monitoring of depolarizations might serve as a functional measure to guide therapeutic efforts and their blockade may provide an additional line of defense against the effects of secondary insults.

Regional cerebral blood flow (rCBF) is spatially and temporally adjusted to local energy needs. This coupling involves dilation of vessels both at the site of metabolite exchange and upstream of the activated region. Deficits in upstream blood supply limit the ‘capacity to raise rCBF' in response to functional activation and therefore compromise brain function. We here demonstrate in rats that the ‘capacity to raise rCBF' can be determined from real-time measurements of rCBF using laser speckle imaging during an energy challenge induced by cortical spreading depolarizations (CSDs). Cortical spreading depolarizations (CSDs) occur with high incidence in stroke and various other brain injuries and cause large metabolic changes. Various conditions of cerebral perfusion were induced, either by modifying microvascular tone, or by altering upstream blood supply independently. The increase in rCBF per unit of time in response to CSD was linearly correlated to the upstream blood supply. In an experimental model of stroke, we found that this marker of the capacity to raise rCBF which, in pathologic tissue may be additionally limited by impaired vasoactive signaling, was a better indicator of the functional status of cerebral tissue than local rCBF levels.