Perspective 10.1586/14737175.8.5.759 © 2008 Expert Reviews Ltd ISSN 1473-7175 759 www.expert-reviews.com Translational imaging studies of cortical spreading depression in experimental models for migraine aura Expert Rev. Neurotherapeutics. 8(5), 759–768 (2008) Justin M Smith, Michael F James, James A Fraser and Christopher L-H Huang † † Author for correspondence Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK Tel.: +44 1223 333 822 Fax: +44 1223 333 840 clh11@cam.ac.uk This perspective discusses cortical spreading depression (CSD) phenomena and their translational significance for human migraine aura and the peri-infarct events following cerebral ischemia and injury. They begin with interstitial K + release and accumulation following neuronal stimulation, and a buffering astrocytic K + influx and remote liberation propagating waves of neuronal hyperexcitability and depression. Diffusion-weighted echoplanar MRI demonstrates CSD features in gyrencephalic brains recapitulating human migraine aura, spatial and temporal features of single primary events and multiple secondary events, their stimulus dependence, pharmacological properties, and their relationship to blood oxygenation level-dependant signals and late cerebrovascular changes. The article finally explores prospects for physiological studies of CSD gaining fuller insights both into mechanisms underlying the pathology of the corresponding human condition and possible approaches to management. KEYWORDS: cerebral ischemia • cortical spreading depression • head injury • migraine • MRI The pathophysiological phenomenon of corti- cal spreading depression (CSD) was first identi- fied in the cerebral cortex of rabbits [1–3] as a propagating wave of neuronal excitation fol- lowed by transient quiescence. It has since been implicated in a wide range of clinical situations [4]. For example, the distinct aura of classical migraine follows a prodromal phase and accom- panies disturbances in visual, general sensory and/or motor function [5–9]. This is followed by neurovascular events that produce a generalized headache that lasts for minutes or hours; addi- tionally there may be 1–3 s episodes of sharp scalp or orbital pain. Recent reports associate the clinical findings occurring during the aura phase of migraine and CSD [10–14]. They sug- gest a hyperexcitability in widespread regions throughout the occipital cortex providing the site for a potential CSD to be triggered in migraine, and describe CSD-like activity during migrainous aura [15–19]. Direct current magneto- encephalography (DC-MEG), used to non- invasively map magnetic fields from different areas of cortical electrical activity during spon- taneous and visually-induced migraine with aura, demonstrated multiple areas of hyper- excitability in the right primary visual cortex and occipital parietal regions during the aura [20]. Neurophysiological studies between attacks suggest that migrainous brains show a lack of habituation of evoked responses for a number of different sensory modalities; this could reflect an increased cortical hyperexcitability, or alter- natively an abnormal responsivity owing to decreased preactivation levels [21]. CSD-like phenomena in the form of peri-infarct depolari- zation (PID) may also occur with the cerebral pathology following ischemia or head trauma [22–24]. Depolarization-like events in post- operative neurosurgical patients affected by traumatic or ischemic neocortical injury have recently been directly demonstrated and quanti- tatively characterized using neurophysiological methods [25]. Such depolarization events might contribute to tissue pathology in acute clinical disorders in the brain [24,26]. For reprint orders, please contact: reprints@expert-reviews.com