50 In cooperation with Rosenblueth he studied www.selleckchem.com/products/lee011.html electric activity in a rabbit brain under general anesthesia. Following electrical stimulation a most unexpected and contradictory result was observed: “the activity of the nearest pair of electrodes did not increase, but ceased almost entirely.” Davis was called in for consultation and said “nothing resembles a new phenomenon as much as a good artifact.”50 The response, however, was reasonably reproducible.10 It consisted of a marked, enduring, reduction of electrical

activity, a reduction which appears first at the region that has been stimulated, and spreads out from that location in all directions, involving successively more and more distant parts of the cerebral

cortex (Fig. 4). The recovery usually took 5-10 minutes. In a second paper, Leão described a wave of marked dilatation of the pial vessels traveling over the cerebral hemispheres concomitant with the CSD.51 In a third paper, it was demonstrated that CSD was not inhibited by anoxia.52 The paper proposed that CSD might be related to migraine with aura because of the slow development of scotomata and sensory symptoms of migraine aura.10,52 It should be noted, however, that the authors were unaware of Lashley’s 1941 description.50 Interestingly, Leão did not attempt to calculate the speed of CSD in these 3 papers.10,51,52 It was later calculated to be 3 mm/minute.53 Milner in 1958 in a short communication drew attention to the similarity of the findings

of Leão CAL-101 in vitro and Lashley.54 The relationship between CSD and migraine was first studied in the 1980s, when spreading oligemia was observed during migraine with aura12 (vide infra). The literature on CSD is significant in its scale and beyond the scope of this review. For recent updates, see the studies by Smith et al see more and Charles and Brennan.55,56 Serotonin and the Introduction of Methysergide (1959).— Between 1948 and 1953, serotonin, a serum (“sero”) vasoconstrictor (“tonin”) factor, was identified, isolated, and synthesized. In the 1950s and 1960s, its role in migraine was gradually established by Wolff et al.57 Serotonin was one of the agents they examined and by perivascular injection, they were able to produce migraine-like symptoms.58 The search for an effective 5-HT antagonist led to the synthesis of methysergide, derived from LSD25 that is an effective agent with this respect, but hallucinogenic. In 1959, methysergide was introduced in the clinic as a drug for the preventive treatment of migraine by Federico Sicuteri, an Italian neurologist.11 As migraine and cluster headache were both considered “vasodilating headaches,” both kinds of patients were entered in Sicuteri’s study and he considered the results most promising. Doing further research on serotonin and migraine, he found increased excretion of 5-HIAA during migraine attacks.