Article

Cortical spreading depression impairs oxygen delivery and metabolism in mice

Department of Radiology, Neurovascular Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism (Impact Factor: 5.34). 02/2012; 32(2):376-86. DOI: 10.1038/jcbfm.2011.148
Source: PubMed

ABSTRACT Cortical spreading depression (CSD) is associated with severe hypoperfusion in mice. Using minimally invasive multimodal optical imaging, we show that severe flow reductions during and after spreading depression are associated with a steep decline in cerebral metabolic rate of oxygen. Concurrent severe hemoglobin desaturation suggests that the oxygen metabolism becomes at least in part supply limited, and the decrease in cortical blood volume implicates vasoconstriction as the mechanism. In support of oxygen supply-demand mismatch, cortical nicotinamide adenine dinucleotide (NADH) fluorescence increases during spreading depression for at least 5 minutes, particularly away from parenchymal arterioles. However, modeling of tissue oxygen delivery shows that cerebral metabolic rate of oxygen drops more than predicted by a purely supply-limited model, raising the possibility of a concurrent reduction in oxygen demand during spreading depression. Importantly, a subsequent spreading depression triggered within 15 minutes evokes a monophasic flow increase superimposed on the oligemic baseline, which markedly differs from the response to the preceding spreading depression triggered in naive cortex. Altogether, these data suggest that CSD is associated with long-lasting oxygen supply-demand mismatch linked to severe vasoconstriction in mice.

Download full-text

Full-text

Available from: Izumi Yuzawa, Jul 07, 2015
0 Followers
 · 
140 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Spreading depolarization (SD) is a slowly propagating, coordinated depolarization of brain tissue, which is followed by a transient (5-10min) depression of synaptic activity. The mechanisms for synaptic depression after SD are incompletely understood. We examined the relative contributions of action potential failure and adenosine receptor activation to the suppression of evoked synaptic activity in murine brain slices. Focal micro-injection of potassium chloride (KCl) was used to induce SD and synaptic potentials were evoked by electrical stimulation of Schaffer collateral inputs to hippocampal area Cornu Ammonis area 1 (CA1). SD was accompanied by loss of both presynaptic action potentials (as assessed from fiber volleys) and field excitatory postsynaptic potentials (fEPSPs). Fiber volleys recovered rapidly upon neutralization of the extracellular direct current (DC) potential, whereas fEPSPs underwent a secondary suppression phase lasting several minutes. Paired-pulse ratio was elevated during the secondary suppression period, consistent with a presynaptic mechanism of synaptic depression. A transient increase in extracellular adenosine concentration was detected during the period of secondary suppression. Antagonists of adenosine A1 receptors (8-cyclopentyl-1,3-dipropylxanthine [DPCPX] or 8-cyclopentyl-1,3-dimethylxanthine [8-CPT]) greatly accelerated fEPSP recovery and abolished increases in paired-pulse ratio normally observed after SD. The duration of fEPSP suppression was correlated with both the duration of the DC shift and the area of tissue depolarized, consistent with the model that adenosine accumulates in proportion to the metabolic burden of SD. These results suggest that in brain slices, the duration of the DC shift approximately defined the period of action potential failure, but the secondary depression of evoked responses was in large part due to endogenous adenosine accumulation after SD.
    Neuroscience 08/2012; 223:365-76. DOI:10.1016/j.neuroscience.2012.07.053 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Laser Speckle Contrast Imaging (LSCI) is a wide field of view, non scanning optical technique for observing blood flow. Speckles are produced when coherent light scattered back from biological tissue is diffracted through the limiting aperture of focusing optics. Mobile scatterers cause the speckle pattern to blur; a model can be constructed by inversely relating the degree of blur, termed speckle contrast to the scatterer speed. In tissue, red blood cells are the main source of moving scatterers. Therefore, blood flow acts as a virtual contrast agent, outlining blood vessels. The spatial resolution (~ 10 ìm) and temporal resolution (10 ms to 10 s) of LSCI can be tailored to the application. Restricted by the penetration depth of light, LSCI can only visualize superficial blood flow. Additionally, due to its non scanning nature, LSCI is unable to provide depth resolved images. The simple setup and non-dependence on exogenous contrast agents have made LSCI a popular tool for studying vascular structure and blood flow dynamics. We discuss the theory and practice of LSCI and critically analyze its merit in major areas of application such as retinal imaging, imaging of skin perfusion as well as imaging of neurophysiology.
    01/2013; 6. DOI:10.1109/RBME.2013.2243140
  • [Show abstract] [Hide abstract]
    ABSTRACT: Observation of brain activities in freely moving animals has become an important approach for neuroscientists to understand the correlation between brain function and behavior. We describe an extendable fiber-optic-based multi-modal imaging system that can concurrently carry out laser speckle contrast imaging (LSCI) of blood flow and optical intrinsic signal (OIS) imaging in freely moving animals, and it could be extended to fluorescence imaging. Our imaging system consists of a multi-source illuminator, a fiber multi-channel optical imaging unit, and a head-mounted microscope. The imaging fiber bundle delivers optical images from the head-mounted microscope to the multi-channel optical imaging unit. Illuminating multi-mode fiber bundles transmit light to the head-mounted microscope which has a mass of less than 1.5 g and includes a gradient index lens, giving the animal maximum movement capability. The internal optical components are adjustable, allowing for a change in magnification and field of view. We test the system by observing hemodynamic changes during cortical spreading depression (CSD) in freely moving and anesthetized animals by simultaneous LSCI and dual-wavelength OIS imaging. Hemodynamic parameters were calculated. Significant differences in CSD propagation durations between the two states were observed. Furthermore, it is capable of performing fluorescence imaging to explore animal behavior and the underlying brain functional activity further.
    Optics Express 01/2013; 21(2):1911-24. DOI:10.1364/OE.21.001911 · 3.53 Impact Factor