In a recent research article in The Lancet Neurology,1Hartings JA Bullock MR Okonkwo DO et al.Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study.Lancet Neurol. 2011; 10: 1058-1064Summary Full Text Full Text PDF PubMed Scopus (209) Google Scholar Jed A Hartings and colleagues reported their findings of electrocorticography in 103 patients requiring intensive care and surgery for traumatic brain injury (TBI). They found an association between the presence and type of spreading depolarisations during acute ictus and survival and functional outcome 6 months later. The investigators suggest that, after further clinical studies, individualised care could include monitoring and treatment of spreading depolarisations. Two issues arise from this excellent report. Patients were recruited into the study within 7 days of TBI and electrocorticography was done for the duration of other clinical invasive monitoring, or to a maximum of 7 days. Electrocorticography monitoring continued for 67 h (IQR 40–102) but, theoretically, a patient could have been monitored as late as 14 days after injury. First, what was the time course of the spreading depolarisations? Were cortical spreading depolarisations clustered in the early phase after injury, as in experimental middle cerebral artery occlusion?2Hartings JA Rolli ML Lu XC Tortella FC Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection.J Neurosci. 2003; 27: 11602-11610Google Scholar Alternatively, were isoelectric spreading depolarisations predominantly preterminal phenomena? In this regard, I note that isoelectric spreading depolarisations occurred in 12 of 28 patients that died compared with their occurrence in eight of 75 patients that survived (43% vs 11%, SD 3·6 difference in the hypothesis test for proportions, p<0·001). In 1999, Morris and colleagues3Morris GF Bullock R Marshall SB et al.Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials.J Neurosurg. 1999; 91: 737-743Crossref PubMed Scopus (208) Google Scholar reported the failure of two phase 3 clinical trials of a competitive NMDA-receptor antagonist (Selfotel, CGS 19755) in the treatment of severe TBI. In the international arm of the trial, there was a subgroup assessment of patients who underwent operation for mass lesions (which was similar to the types of operations and patients in Hartings and colleagues' study1Hartings JA Bullock MR Okonkwo DO et al.Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study.Lancet Neurol. 2011; 10: 1058-1064Summary Full Text Full Text PDF PubMed Scopus (209) Google Scholar). On inspection of these data—in view of the limitations of small sample size and a quick post-hoc analysis using information from the tables—the use of intravenous Selfotel (5 mg/kg once a day) for 4 days did not seem to reduce the proportion of patients dying (more deaths in the Selfotel group, 31% vs 20%, SD 1·5, p>0·05). Also, in the Selfotel group, there was a smaller proportion of favourable outcomes (42% vs 67%, SD 2·9 difference, p<0·01) than in the placebo group. The electrophysiological and ionic transients of cortical spreading depolarisations are NMDA-receptor mediated, and inhibition can be induced by agents acting at the NR2B, glycine, or non-competitive binding sites.4McLachlan RS Suppression of spreading depression of Leao in neocortex by an N-methyl-D-aspartate receptor antagonist.Can J Neurol Sci. 1992; 19: 487-491PubMed Google Scholar, 5Nellgard B Wieloch T NMDA-receptor blockers but not NBQX, an AMPA-receptor antagonist, inhibit spreading depression in the rat brain.Acta Physiol Scand. 1992; 146: 497-503Crossref PubMed Scopus (92) Google Scholar, 6Obrenovitch TP Zilkha E Inhibition of cortical spreading depression by L-701,324, a novel antagonist at the glycine site of the N-methyl-D-aspartate receptor complex.Br J Pharmacol. 1996; 117: 931-937Crossref PubMed Scopus (72) Google Scholar, 7Somjen GG Mechanisms of spreading depression and hypoxic spreading depression-like depolarization.Physiol Rev. 2001; 81: 1065-1096Crossref PubMed Scopus (836) Google Scholar The Selfotel trials3Morris GF Bullock R Marshall SB et al.Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials.J Neurosurg. 1999; 91: 737-743Crossref PubMed Scopus (208) Google Scholar can be considered a proof of concept or even a test of the hypothesis proposed by Hartings and colleagues' in their conclusion—short-term inhibition of a cortical NMDA receptor-mediated process in severe TBI cases requiring neurosurgery fails to improve outcome. Therefore, the second point of discussion that I would like to raise is the type of tests of their hypothesis they envisage. For example, they could take the form of a longer duration of interventional therapy, up to 14 days—for which it would be important to know more about the clustering and preterminal information. Alternatively, tests could involve the use of NMDA-receptor antagonists that have both a neuronal and oligodendrocyte profile.8Bakiri Y Hamilton NB Karadottir R Attwell D Testing NMDA receptor block as a therapeutic strategy for reducing ischemic damage to CNS white matter.Glia. 2008; 56: 233-240Crossref PubMed Scopus (74) Google Scholar, 9Giacino JT Whyte J Bagiella E et al.Placebo-controlled trial of amantadine for severe traumatic brain injury.N Engl J Med. 2012; 366: 819-826Crossref PubMed Scopus (472) Google Scholar Such protection of white matter injury in severe TBI would indeed be inkeeping with outcome long after such injury.10Tasker RC Westland AG White DK Williams GB Corpus callosum and inferior forebrain white matter microstructure are related to functional outcome from raised intracranial pressure in child traumatic brain injury.Dev Neurosci. 2010; 32: 374-384PubMed Google Scholar I declare that I have no conflicts of interest. Spreading depolarisations and traumatic brain injury: time course and mechanisms – Authors' replyWe appreciate Robert C Tasker's interest in our report1 and thank him for his interesting questions. His concerns relate to the temporal patterning of cortical spreading depolarisations and to the implications for design of therapeutic trials. Full-Text PDF