Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Abstract

Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

Copyright © 2015 the American Physiological Society.

Figures

FIGURE 1.

Electrophysiological, ionic, and optical changes during SD. A: although possibly observed by others in one form or another as early as 1930s (99, 274), Leão (270) was the first to recognize, systematically investigate, and describe in detail the hallmarks of SD. In his 1944 paper, he demonstrated the suppression of electrocorticogram (ECoG) activity that spreads in contiguous grey matter in a relatively concentric manner at an approximate rate of 3 mm/min using serially placed surface electrodes on rabbit cortex as shown in this figure. Recovery follows the same order within 10 min. [Modified from Leão (270).] B: typical electrophysiological tracings showing ECoG depression spatiotemporally coincident with a large negative extracellular direct coupled (DC) potential shift that lasts up to a minute when recorded by two serial intracortical microelectrodes in the rat as shown in the inset. [Modified from Ayata (15) with permission.] C: sample ECoG and DC potential tracings from human brain showing SDs in the setting of traumatic brain injury recorded by subdural electrode strips. ECoG traces are bipolar between adjacent channels on the strip. DC traces are relative to an extracranial reference. Note the sequential involvement of electrode pairs by SD. (Courtesy of Dr. Jed Hartings.) D: representative time-lapse images of intrinsic optical signal changes taken every 6.4 s from rat cortex show relative reflectance (upper two rows) and rate of change in reflectance (lower two rows) during pinprick-induced SD expanding in a concentric fashion regardless of functional or vascular territories. [Modified from Chen et al. (56) with permission.] E: the transmembrane ionic shifts during SD lead to a large drop in [Na+]o, [Ca2+]o, [Cl−]o, and pH, and a surge in [K+]o simultaneously with the extracellular DC potential shift (V), as shown by ion-selective microelectrodes (147, 339, 477). [Modified from Hansen and Zeuthen (180) with permission.] F: time-lapse images taken every 2 s show retinal SD changing the optical properties of isolated chick retinal cup, seen as a concentric pallor spreading from the point of induction (arrowhead). [Modified from Hanke and de Lima (173) with permission.]

FIGURE 2.

Reaction-diffusion model of SD propagation and regenerative processes. Basic mechanisms believed to be responsible for the self-regenerating propagation of SD within contiguous grey matter and the mechanisms of recovery.

FIGURE 3.

Metabolic impact of SD. A summary diagram showing changes in metabolic indexes as a function of time after SD onset. Blue scale indicates the magnitude of change (darker is bigger change). Some degree of uncertainty exists in the literature in terms of the precise timing and magnitude of metabolic changes. Therefore, we included in the diagram only those indices with reproducible changes reported in the literature. Notably, temporal changes in Po2, CMRO2, and NADH have been complex and highly variable among studies, as described in detail in the text, possibly related to differences such as measurement technique, species, experimental conditions, and the hemodynamic response. The latter is an important determinant of supply-demand mismatch and supply limitation.

FIGURE 4.

CBF response to SD. Sample tracings show a range of CBF responses to SD in the rat (A–G), cat (H), and mouse (I) cortex obtained by laser Doppler (A–H) or speckle flowmetry (I) from different laboratories, selected to demonstrate the variable presence, timing, and magnitude of the four vasomotor components (I–IV) shaping the CBF response as described in text. A–C: CBF responses to single or consecutive cortical SDs and their temporal relationship to the DC shift recorded using intracortical microelectrodes under isoflurane anesthesia. [Modified from Ayata et al. (17) and Sukhotinsky et al. (456).] D: CBF responses to two consecutive cortical SDs 15–20 min apart, and their temporal relationship to the depolarization as imaged using a voltage-sensitive dye under halothane anesthesia. [Modified from Farkas et al. (124).] E and F: CBF responses to cortical SD under halothane anesthesia. [Modified from Fabricius and Lauritzen (119) and Farkas et al. (123).] G: evolution of the CBF response to cortical SDs triggered consecutively every 30 min under halothane anesthesia. Note diminished initial hypoperfusion (component I), augmented hyperemia (component II), decreased latency to component III merging into the hyperemia, and absence of a change in post-SD oligemia (component IV). [Modified from Fabricius et al. (114).] H: CBF response to cortical SD in a cat under urethane/α-chloralose anesthesia. Note the prominent vasomotion at resting state and its disappearance after the SD. [Modified from Piper et al. (376).] I: CBF responses to two consecutive cortical SDs triggered 15 min apart in a mouse under isoflurane anesthesia. Although the pronounced hypoperfusion (component I) dominates the response, all other components are also readily identifiable. The second SD is superimposed on severe post-SD oligemia (component IV) after the first SD, and does not show component I, closely resembling the response to SD in other species. [Modified from Yuzawa et al. (532).]

FIGURE 5.

CBV, capillary flow, and pial artery diameter responses to SD. A: time-lapse subtraction images of transilluminated cortical light transmission show a spreading concentric wave of an initial increase in light transmittance (i.e., CBV reduction, I) followed by a decrease in light transmittance (i.e., CBV increase, II) images in a rat (left panel) and a cat (right panel) under urethane/α-chloralose anesthesia. Time after SD induction is indicated on the top left of each image. Arrow: the site of KCl injection. [Modified from Tomita et al. (481).] B: capillary blood flow dynamics during SD studied by line scans using in vivo multi-photon microscopy (top panel) through a closed cranial window in a representative isoflurane-anesthetized rat (postnatal day 15) show blood cell flow arrest (middle panel) during the DC shift (bottom panel) that corresponds to component I. Following repolarization, there was a rebound increase in blood flow (component II). [Modified from Chuquet et al. (59).] C: combined electrophysiological recording and multimodal optical imaging in a representative isoflurane-anesthetized mouse show changes in total hemoglobin ([Hbtot]), pial artery diameter (PAD), hemoglobin O2 saturation (SatO2; %), and optical intrinsic signal (OIS) in relation to the DC shift (field potential; mV). Different vasomotor components (I–IV) are labeled as described in the text as well as in Figure 3. Note the severe vasoconstriction and hemoglobin desaturation during the DC shift (I), and long-lasting and severe post-SD oligemia (IV). [Hbtot], PAD, and OIS are normalized to pre-CSD baseline. [Modified from Chang et al. (54).]

FIGURE 6.

A conceptual framework of vasomotor components shaping the CBF response to SD. Four distinct vasomotor components can often be identified in response to SD. Local depolarization (i.e., DC shift) coincides with a vasoconstrictive tone that creates an initial hypoperfusion (component I). This component has been rather capricious; in some cases it is large and conspicuous, in others it is small to only create a brief dip or a notchy pattern superimposed on the upstroke of hyperemia, or it may be absent. The second component (II) is a vasodilator tone that gradually builds after the depolarization onset and gives rise to a peak hyperemia that reaches a peak after full repolarization. This is often the most conspicuous component of the vasomotor response to SD. The vasodilator component subsides within minutes, giving way to a prolonged vasoconstrictive tone leading to post-SD oligemia for an hour or more (component IV). More often than not, a second smaller CBF rise (late hyperemia; component III) is interposed between the peak hyperemia and post-SD oligemia. [Modified from Ayata (14).]

FIGURE 7.

Systemic physiological and pharmacological modulation of CBF response to SD. A: hypotension (blood pressure ∼40–45 mmHg) transforms the large predominantly hyperemic response to SD (left) into a biphasic or triphasic response with predominantly hypoperfusion during the DC shift (middle); resting CBF was only mildly reduced (∼10%). The addition of hypoxia (Po2 ∼55 mmHg) on to hypotension did not further alter the response (right). Note also the prolongation of DC shift (top tracings) during hypotension. CBF was recorded by LDF in isoflurane-anesthetized rats. [Modified from Sukhotinsky et al. (456).] B: systemic administration of nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME) also transforms the response by bringing out an initial hypoperfusion (component I), as shown by [14C]-iodoantipyrine autoradiography. [Modified from Duckrow (94).] C: systemic NOS inhibitor N-nitro-l-arginine (l-NNA) exerts a similar effect in rats recorded by laser Doppler flowmetry. Note the appearance of an initial hypoperfusion (component I) and diminished hyperemia (component II). Top two tracings show two consecutive cortical SDs under control conditions. The effect is reversed by systemic l-arginine. [Modified from Fabricius et al. (114).]

FIGURE 8.

Propagation of SD across the dense cerebral vascular network and the neurovascular unit. SD invading the tissue profoundly impacts all cells and constituents of the cerebrovascular unit. The intense pandepolarization causes massive extracellular ionic, neurotransmitter, and metabolic changes. The cerebrovascular response is the result of numerous complex processes and interactions within the unit, mediated by key cell types and molecular signals, some of which are listed. The large number of mediators and modulators simultaneously released from multiple different cell types has made it extremely difficult to dissect the role of individual factors in the hemodynamic response, further complicated by the heterogeneity of the normal response among studies. Therefore, we have refrained from attempting a contrived representation of the vasomotor actions of each potential mediator or modulator, and instead summarized the available data in Table 1. EDHF, endothelium-derived hyperpolarizing factor; PACAP, pituitary adenylate cyclase activating peptide; NE, norepinephrine; NPY, neuropeptide Y; ACh, acetylcholine; SP, substance P; NK-A, neurokinin A.

FIGURE 9.

CBF response to PIDs in focal ischemic brain. A hypothetical diagram showing the transformation of the CBF response (top graphs) to peri-infarct SDs (PIDs) recorded in tissue with increasing severity of ischemia as shown on the CBF profile across focal ischemic tissue (bottom graph). In nonischemic tissue, SD evokes a predominantly hyperemic response (A), whereas in mildly ischemic penumbra (B), a biphasic response is observed. In moderately ischemic penumbra (C), the response is mainly a monophasic hypoperfusion. In the severely ischemic core-penumbra junction (D), both the DC shift and the hypoperfusion may not recover completely after a PID. Horizontal bars represent the DC shift during PIDs.

FIGURE 10.

The wave-width of various physiological signals that serve as footprints of SD. The duration of each signal (min) and the cortical width (mm) that undergoes the specific changes at any given time are shown based on the known propagation rate of SD in normal cortex. Most electrophysiological and neuroimaging signatures occupy a strip of cortical tissue not more than several millimeters in width, a major factor that limits noninvasive clinical detection of SD.