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Review
. 2017 May;37(5):1553-1570.
doi: 10.1177/0271678X16657092. Epub 2016 Jan 1.

'Spreading Depression of Leão' and Its Emerging Relevance to Acute Brain Injury in Humans

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Free PMC article
Review

'Spreading Depression of Leão' and Its Emerging Relevance to Acute Brain Injury in Humans

Martin Lauritzen et al. J Cereb Blood Flow Metab. .
Free PMC article

Abstract

A new research field in translational neuroscience has opened as a result of the recognition since 2002 that "spreading depression of Leão" can be detected in many patients with acute brain injury, whether vascular and spontaneous, or traumatic in origin, as well as in those many individuals experiencing the visual (or sensorimotor) aura of migraine. In this review, we trace from their first description in rabbits through to their detection and study in migraine and the injured human brain, and from our personal perspectives, the evolution of understanding of the importance of spread of mass depolarisations in cerebral grey matter. Detection of spontaneous depolarisations occurring and spreading in the periphery or penumbra of experimental focal cortical ischemic lesions and of their adverse effects on the cerebral cortical microcirculation and on the tissue glucose and oxygen pools has led to clearer concepts of how ischaemic and traumatic lesions evolve in the injured human brain, and of how to seek to improve clinical management and outcome. Recognition of the likely fundamental significance of spreading depolarisations for this wide range of serious acute encephalopathies in humans provides a powerful case for a fresh examination of neuroprotection strategies.

Keywords: Cortical spreading depolarisation; migraine; stroke; subarachnoid haemorrhage; traumatic brain injury.

Figures

Figure 1.
Figure 1.
Professor Leão’s original note. ‘Tutorial’ diagrams drawn by Leão, probably around 1990, and discovered recently by a younger colleague of Leão, Dr. Pericles Maranhão Filho. Various possible alternative designations for ‘spreading depression’ shown here had been rejected. At (second) top right, is Leão illustrating the fortification pattern, a typical visual percept of migraineurs-with-aura. Reproduced with permission from Dr. Pericles Maranhão Filho.
Figure 2.
Figure 2.
Intraoperative microphotograph of the cerebral cortex during surgical decompression for malignant hemisphere stroke. The image shows an area of cortical pallor (centre and lower left field) suggestive of microvascular constriction consistent with cortical spreading ischemia in this highly pathological type of stroke.,
Figure 3.
Figure 3.
Repetitive spreading depolarisation events in a patient following evacuation of a traumatic intracerebral hematoma. Before wound closure, a six-contact Wyler subdural electrocorticogram strip was placed on cortex close to the hematoma site but judged still to be viable, and connected in bipolar sequential montage to a ADInstruments Octal Bioamp and Powerlab A:D converter running ADInstruments Labchart v6 (five of the contacts on the strip are shown: top left). Top four traces are AC coupled with low frequency cut off below 0.02 Hz. Lowest two traces are the uppermost two raw traces, but now band-pass filtered to 0.5–15 Hz. Typical AC-coupled slow potential change (SPC) complexes are seen in the upper two channels, with simultaneous suppressions of the band-pass filtered signal. Figures above upper trace are inter-SD intervals (minutes): the constant interval is compatible with repetitive cycling at constant velocity of a single depolarisation around the periphery of a fully depolarised core lesion.
Figure 4.
Figure 4.
Original recordings of spontaneous potassium transients (pial surface potassium concentration, Kp) on adjacent gyri 2 and 5 min after occlusion (time zero) of the right middle cerebral artery in a cat. Recordings were taken by AJS and colleagues, 1981–1983 and are unpublished, but please see Strong et al., A twin barrel valinomycin/reference electrode was spring-suspended in light contact with the suprasylvian gyrus (typically inner penumbra). The peak potassium amplitude is much less, and the duration longer, than are seen with microelectrodes, attributed to the averaging effect of the 2 mm diameter of the electrodes and to their locations on the pial surface with probable diffusion delay through the pia. Immediate post-clip increases were common on both gyri, but the increase on suprasylvian (inner penumbra) did not return to baseline.
Figure 5.
Figure 5.
Original recordings of recurrent, spontaneous potassium (pial surface potassium concentration, Kp) transients on adjacent gyri 2 and 5 min after occlusion (time zero) of the right middle cerebral artery in a cat. Recordings were taken by AJS and colleagues, 1981–1983 and are unpublished, but please see Strong et al., Experimental system was as for Figure 4. The ‘staircase’ increase in pre-transient baseline was noted during the studies, and post calibration in this experiment had excluded baseline drift. The stepwise increase following the events finds some parallels with: (a) stepwise increase in infarct size coupled to recurrent penumbral SDs in distal MCAO in rats, and (b) with stepwise decline in brain tissue glucose in the injured brain in humans.
Figure 6.
Figure 6.
Schematic diagrams of potential mechanisms involved in neurovascular control in SD. (a) Control conditions. Neurovascular coupling responses are triggered by glutamate release from incoming or local presynaptic axons, and the interaction of glutamate with receptors on neurons and astrocytes. N-methyl-d-aspartate receptor (NMDAR) activation in neurons triggers nitric oxide (NO) production by NO synthase (nNOS) activity. The rise in Ca2+ in neurons via NMDAR and voltage-sensitive Ca2+ channels, and in astrocytes via metabotropic glutamate receptors (mGluR), stimulates activity of phospholipase A2 (PLA2) that catalytically hydrolyzes the bond releasing arachidonic acid (AA). Upon downstream enzymatic activity, AA is modified into active compounds such as prostaglandins (PG) and epoxyeicosanotrienoic acid (EET) that are mainly vasodilators and 20-hydroxyeicosatetraenoic acid (20-HETE) which is a vasoconstrictor. NO dilates arterioles via the cyclic GMP (cGMP) pathway and inhibits (dashed lines) the synthesis by cytochrome P-450 of 20-HETE from AA. Under control conditions, the concentration of 20-HETE is very low, and the net balance of constrictor and dilator activity results in an intermediate level of constrictor tone in vascular smooth muscle and pericytes, enabling transient responses to occur in either direction. (b) In the acute phase of SD, there is massive release of K+ and glutamate. This leads to a huge global rise in cytosolic Ca2+ which leads to a substantial production and release of vasoactive mediators. The massive increase in Ca2+ during SD also causes an increase in 20-HETE synthesis, which leads to a buildup of internal 20-HETE stores in the lipid biomembrane of various cell types. During the acute phase of SD, vasodilation dominates due to a net release of vaosodilators from multiple sources leading to increased availability of glucose and O2 that is rapidly consumed due to the extra activity of the Na,K-ATPase. (c) After CSD, 20-HETE may be slowly released from lipid biomembranes, causing the characteristic prolonged oligemia lasting for 1½ h. At the same time, the production of vascular mediators by multiple pathways is affected due to impairment of stimulation-induced Ca2+ activity. Drugs that block 20-HETE synthesis rescue the basal blood flow, but cannot affect the persistent strong reduction in blood flow responses to local or systemic vasodilator stimuli. The causes of the impaired neurovascular responsiveness after CSD include both lack of stimulation-induced Ca2+ responses in neurons and astrocytes and an unknown mechanism, intrinsic to the resistance vessels, that hinders the drop in resistance which precedes or accompanies any flow increase. These vascular mechanisms, we believe, are in play during the course of attacks of migraine with aura. (d) In the acutely or subacutely injured human brain cortex, the interplay between SD, vascular reactions, and brain energy homeostasis days may cause cell death due to a growing mismatch between energy demand and supply. For example, after subarachnoid haemorrhage, K+ is released (by haemolysis), which in combination with hypoxia and the reduced ATP pool because of reduced glucose and oxygen availability increases the susceptibility to SD. The repeated SD waves cause repeated rises of Ca2+ in neurons and astrocytes that facilitate the production of vasoactive substances. However, the low level of tissue O2 will limit the NO synthesis because the Km of O2 for NOS is very high. Furthermore, the NO produced is likely to be captured by heme groups in the brain’s extracellular space as indicated by the red circles. Therefore, under these conditions, NO cannot inhibit the synthesis of 20-HETE, which is known to be very high and cause strong vasoconstriction, and due to the embedding of 20-HETE in the lipid membranes, this effect can be protracted and contribute to the ‘spreading ischemia’ as described by Dreier and Reiffurth even in periods between SDs (e).

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