Chang JC, Shook LL, Biag J, Nguyen EN, Toga AW, Charles AC, Brennan KCBiphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression. Brain 133:996-1012

Headache Research and Treatment Program, Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South, Neuroscience Research Building 1, Room 555a, Los Angeles, CA 90095, USA.
Brain (Impact Factor: 9.2). 03/2010; 133(Pt 4):996-1012. DOI: 10.1093/brain/awp338
Source: PubMed


Cortical spreading depression is a propagating wave of depolarization that plays important roles in migraine, stroke, subarachnoid haemorrhage and brain injury. Cortical spreading depression is associated with profound vascular changes that may be a significant factor in the clinical response to cortical spreading depression events. We used a combination of optical intrinsic signal imaging, electro-physiology, potassium sensitive electrodes and spectroscopy to investigate neurovascular changes associated with cortical spreading depression in the mouse. We identified two distinct phases of altered neurovascular function, one during the propagating cortical spreading depression wave and a second much longer phase after passage of the wave. The direct current shift associated with the cortical spreading depression wave was accompanied by marked arterial constriction and desaturation of cortical haemoglobin. After recovery from the initial cortical spreading depression wave, we observed a second phase of prolonged, negative direct current shift, arterial constriction and haemoglobin desaturation, lasting at least an hour. Persistent disruption of neurovascular coupling was demonstrated by a loss of coherence between electro-physiological activity and perfusion. Extracellular potassium concentration increased during the cortical spreading depression wave, but recovered and remained at baseline after passage of the wave, consistent with different mechanisms underlying the first and second phases of neurovascular dysfunction. These findings indicate that cortical spreading depression is associated with a multiphasic alteration in neurovascular function, including a novel second direct current shift accompanied by arterial constriction and decrease in tissue oxygen supply, that is temporally and mechanistically distinct from the initial propagated cortical spreading depression wave. Vascular/metabolic uncoupling with cortical spreading depression may have important clinical consequences, and the different phases of dysfunction may represent separate therapeutic targets in the disorders where cortical spreading depression occurs.

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Available from: Joshua C Chang, Feb 03, 2014
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    • "The same methodological approach was used, although 2PLSM images were taken through the cranial window over the somatosensory cortex of the mouse. Previously, several studies in mice have reported that normoxic SD induces vasoconstriction/hypoperfusion and that it takes 1 h for blood flow to recover to initial values (Ayata et al., 2004; Chang et al., 2010). Hence, 2D maps of cerebral blood flow acquired by laser speckle imaging was used to confirm return of blood flow to baseline when SDs were evoked with an 1 h time interval (Fig. 7A) and to ensure sustainability of circulation throughout the experiment. "
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    • "In migraine with aura, CSD is likely a central event initiating ictal disturbance in neural activity and CBF [102]. A study measuring multiple parameters of neural and vascular response in mice has shown that the propagating CSD wave initiates two large desaturations of cortical hemoglobin, the first during the CSD wave and the second, after a brief recovery , in its aftermath, which may reach levels observed during middle cerebral artery occlusion and points to mismatch between tissue metabolic demands and vascular response [103]. The response of microvessels during CSD wave in this study was vasoconstriction, as opposed to proposed vasodilation in initial hyperemia in humans [89]. "
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    • "To the authors' knowledge, however, no animal model has been established for shock wave-induced SD and related hemodynamic responses. Although there are various animal models for SD, e.g., electrical stimulation [87], [88], KCl application/injection [88]–[91], pinprick [92]–[94], hypoxia [75], [95] and ischemia [88], [89], [96], their characteristics and outcomes should be different. Our rats with application of an LISW to the brain can be used as a reliable animal model to reproduce SD and related events. "
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