Cortical Spreading Depression Waves Research Articles

The 80th Anniversary of Cortical Spreading Depression of Leao: A Major Component in Experimental and Clinical Neuropathology

Understanding of the mechanisms behind brain neuropathology is a major factor in diagnosis as well as treatment of patients. The discovery of the reversible event of cortical spreading depression (CSD) in conjunction with epileptic activity led a new era in better understanding of brain pathology. Eighty years ago, A.A.P. Leao discovered this unique response, of the cerebral cortex of animals, to mechanical, chemical or electrical stimulation. A single CSD wave that propagate in the rate of 3-6 mm/minute includes electrical, ionic, circulatory and metabolic responses. The metabolic changes include activation of oxygen consumption as evaluated by monitoring of mitochondrial NADH redox state. It was found that CSD could be developed spontaneously after various perturbations such as moderate hypoxia or ischemia, epileptic activity, hyperbaric oxygenation, head injury and brain retraction. Our conclusion is that better clinical monitoring of the brain that will detect the appearance of CSD will improve patient’s care in critical situations.

Accurate numerical simulation of electrodiffusion and water movement in brain tissue.

Mathematical modelling of ionic electrodiffusion and water movement is emerging as a powerful avenue of investigation to provide a new physiological insight into brain homeostasis. However, in order to provide solid answers and resolve controversies, the accuracy of the predictions is essential. Ionic electrodiffusion models typically comprise non-trivial systems of non-linear and highly coupled partial and ordinary differential equations that govern phenomena on disparate time scales. Here, we study numerical challenges related to approximating these systems. We consider a homogenized model for electrodiffusion and osmosis in brain tissue and present and evaluate different associated finite element-based splitting schemes in terms of their numerical properties, including accuracy, convergence and computational efficiency for both idealized scenarios and for the physiologically relevant setting of cortical spreading depression (CSD). We find that the schemes display optimal convergence rates in space for problems with smooth manufactured solutions. However, the physiological CSD setting is challenging: we find that the accurate computation of CSD wave characteristics (wave speed and wave width) requires a very fine spatial and fine temporal resolution.

KCl-induced cortical spreading depression waves more heterogeneously propagate than optogenetically-induced waves in lissencephalic brain: an analysis with optical flow tools

Although cortical spreading depolarizations (CSD) were originally assumed to be homogeneously and concentrically propagating waves, evidence obtained first in gyrencephalic brains and later in lissencephalic brains suggested a rather non-uniform propagation, shaped heterogeneously by factors like cortical region differences, vascular anatomy, wave recurrences and refractory periods. Understanding this heterogeneity is important to better evaluate the experimental models on the mechanistics of CSD and to make appropriate clinical estimations on neurological disorders like migraine, stroke, and traumatic brain injury. This study demonstrates the application of optical flow analysis tools for systematic and objective evaluation of spatiotemporal CSD propagation patterns in anesthetized mice and compares the propagation profile in different CSD induction models. Our findings confirm the asymmetric angular CSD propagation in lissencephalic brains and suggest a strong dependency on induction-method, such that continuous potassium chloride application leads to significantly higher angular propagation variability compared to optogenetically-induced CSDs.

Parametric exploration of cellular swelling in a computational model of cortical spreading depression.

Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of brain cells, followed by temporary silenced electrical brain activity. Major structural changes during CSD are linked to neuronal and possibly glial swelling. However, basic questions still remain unanswered. In particular, there are open questions regarding whether neurons or glial cells swell more, and how the cellular swelling affects the CSD wave propagation.In this study, we computationally explore how different parameters affect the swelling of neurons and astrocytes (starshaped glial cells) during CSD and how the cell swelling alters the CSD wave spatial distribution. We apply a homogenized mathematical model that describes electrodiffusion in the intraand extracellular space, and discretize the equations using a finite element method. The simulations are run with a twocompartment (extracellular space and neurons) and a threecompartment version of the model with astrocytes added. We consider cell swelling during CSD in four scenarios: (A) incorporating aquaporin-4 channels in the astrocytic membrane, (B) increasing the neuron/astrocyte ratio to 2:1, (C) blocking and increasing the Na+/K+-ATPase rate in the astrocytic compartment, and (D) blocking the Cl- channels in astrocytes. Our results show that increasing the water permeability in the astrocytes results in a higher astrocytic swelling and a lower neuronal swelling than in the default case. Further, elevated neuronal density increases the swelling in both neurons and astrocytes. Blocking the Na+/K+-ATPase in the astrocytes leads to an increased wave width and swelling in both compartments, which instead decreases when the pump rate is raised. Blocking the Cl- channels in the astrocytes results in neuronal swelling, and a shrinkage in the astrocytes. Our results suggest a supporting role of astrocytes in preventing cellular swelling and CSD, as well as highlighting how dysfunctions in astrocytes might elicit CSD.

Simultaneous calcium recordings of hippocampal CA1 and primary motor cortex M1 and their relations to behavioral activities in freely moving epileptic mice.

Epilepsy is a common neurological disorder characterized by recurrent epileptic seizures. The cause of most cases of epilepsy is unknown. Although changes of calcium events in a single brain region during seizures have been reported before, there have been few studies on relations between calcium events of two different brain regions and epileptic behaviors in freely moving mice. To analyze calcium events simultaneously recorded in hippocampal CA1 (CA1) and primary motor cortex M1 (M1), and to explore their relations to various epileptic behaviors in freely moving epileptic models. Epileptic models were induced by Kainic acid (KA), a direct agonist of glutamatergic receptor, on adult male C57/BL6J mice. Calcium events of neurons and glia in CA1 and M1 labeled by a calcium indicator dye were recorded simultaneously with a multi-channel fiber photometry system. Three typical types of calcium events associated with KA-induced seizures were observed, including calcium baseline-rising, cortical spreading depression (CSD) and calcium flashing with a steady rate. Our results showed that the calcium baseline-rising occurred in CA1 was synchronized with that in M1, but the CSD waves were not. However, synchronization of calcium flashing in the two areas was uncertain, because it was only detected in CA1. We also observed that different calcium events happened with different epileptic behaviors. Baseline-rising events were accompanied by clonus of forelimbs or trembling, CSD waves were closely related to head movements (15 out of 18, 6 mice). Calcium flashing occurred definitely with drastic convulsive motor seizures (CMS, 6 mice). The results prove that the synchronization of calcium event exists in CA1 and M1, and different calcium events are related with different seizure behaviors. Our results suggest that calcium events involve in the synchronization of neuralnetwork and behaviors in epilepsy.

Fremanezumab and its isotype slow propagation rate and shorten cortical recovery period but do not prevent occurrence of cortical spreading depression in rats with compromised blood-brain barrier.

Most centrally acting migraine preventive drugs suppress frequency and velocity of cortical spreading depression (CSD). The purpose of the current study was to determine how the new class of peripherally acting migraine preventive drug (ie, the anti-CGRP-mAbs) affect CSD-an established animal model of migraine aura, which affects about 1/3 of people with migraine-when allowed to cross the blood-brain barrier (BBB). Using standard electrocorticogram recording techniques and rats in which the BBB was intentionally compromised, we found that when the BBB was opened, the anti-CGRP-mAb fremanezumab did not prevent the induction, occurrence, or propagation of a single wave of CSD induced by a pinprick, but that both fremanezumab and its isotype were capable of slowing down the propagation velocity of CSD and shortening the period of profound depression of spontaneous cortical activity that followed the spreading depolarization. Fremanezumab's inability to completely block the occurrence of CSD in animals in which the BBB was compromised suggests that calcitonin gene-related peptide (CGRP) may not be involved in the initiation of CSD, at least not to the extent that it can prevent its occurrence. Similarly, we cannot conclude that CGRP is involved in the propagation velocity or the neuronal silencing period (also called cortical recovery period) that follows the CSD because similar effects were observed when the isotype was used. These finding call for caution with interpretations of studies that claim to show direct central nervous system effects of CGRP-mAbs.

Stereological Analysis of Early Gene Expression Using Egr-1 Immunolabeling After Spreading Depression in the Rat Somatosensory Cortex.

Early growth response-1 (Egr-1), defined as a zinc finger transcription factor, is an upstream master switch of the inflammatory response, and its expression can be used to investigate the spatial and temporal extent of inflammatory changes in the brain. Cortical spreading depression (CSD) is characterized as a slowly propagating (2–5 mm/min) depolarization wave through neurons and astrocytes in humans that contributes to migraines and possibly to other brain pathologies. In rodents, CSD can be induced experimentally, which involves unilateral depolarization that is associated with microglial and astrocyte responses. The impact of CSD on structures beyond the affected hemisphere has not been explored. Here, we used an optical fractionator method to investigate potential correlations between the number of and period of the eletrophysiologic record of CSD phenomena and Egr-1 expression in ipsilateral and contralateral hemispheres. CSD was elicited by the restricted application of a 2% KCl solution over the left premotor cortex. Electrophysiological events were recorded using a pair of Ag/AgCl agar-Ringer electrodes for 2 or 6 h. An optical fractionator was applied to count the Egr-1 positive cells. We found that CSD increased Egr-1 expression in a time- and event-dependent manner in the ipsilateral/left hemisphere. Although CSD did not cross the midline, multiple CSD inductions were associated with an increased number of Egr-1 positive cells in the contralateral/right hemisphere. Thus, repeated CSD waves may have far reaching effects that are more global than previously considered possible. The mechanism of contralateral expression is unknown, but we speculate that callosal projections from the depolarized hemisphere may be related to this phenomenon.

Clinical correlates of mathematical modeling of cortical spreading depression: Single-cases study.

IntroductionConsiderable connections between migraine with aura and cortical spreading depression (CSD), a depolarization wave originating in the visual cortex and traveling toward the frontal lobe, lead to the hypothesis that CSD is underlying migraine aura. The highly individual and complex characteristics of the brain cortex suggest that the geometry might impact the propagation of cortical spreading depression.MethodsIn a single‐case study, we simulated the CSD propagation for five migraine with aura patients, matching their symptoms during a migraine attack to the CSD wavefront propagation. This CSD wavefront was simulated on a patient‐specific triangulated cortical mesh obtained from individual MRI imaging and personalized diffusivity tensors derived locally from diffusion tensor imaging data.ResultsThe CSD wave propagation was simulated on both hemispheres, despite in all but one patient the symptoms were attributable to one hemisphere. The CSD wave diffused with a large wavefront toward somatosensory and prefrontal regions, devoted to pain processing.DiscussionThis case‐control study suggests that the cortical geometry may contribute to the modality of CSD evolution and partly to clinical expression of aura symptoms. The simulated CSD is a large and diffuse phenomenon, possibly capable to activate trigeminal nociceptors and to involve cortical areas devoted to pain processing.

CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior.

The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

S146 The modulation of CSD in animals

Objectives Cortical spreading depression (CSD) is thought to be the electrophysiological correlate of migrainous aura, thus its modulation might revail further details of migraine pathomechanism. We summarize scientific data from previous animal experiments regarding CSD modulation. Methods The characteristics of KCl induced CSD waves were examined after various pretreatments (migraine prophylactic drugs, kinurenines, gonadal hormones) in rats. Results Lamotrigine was able to supress CSD-s, while valproic acid decreased only its propagation velocity. In other experiments kynurenic acid, an endogenous glutamate antagonist proved to be effective in the reduction of rat CSD waves. Both progesteron and estradiol pretreatment increased the CSD frequency. Discussion Some of the migraine prophylactic drugs are able to modulate CSD, but others not, which suggests that these medications act at different levels of migraine genesis. The suppressing effect of kynurenines is possibly related to their anti-glutamatergic action. Interestingly female gonadal steroids have a marked effect on CSD generation, which might be linked to the strong sexual dimorphism of migraine headache.

Effects of experimental traumatic brain injury and impaired glutamate transport on cortical spreading depression

Cortical spreading depression (CSD) is associated with traumatic brain injury (TBI), stroke, migraines, and seizures. Typically, following TBIs and other insults, neuronal excitability in and around the area of the injury is affected, with reported increases in local glutamate signaling. Astrocytic glutamate transporters are critical for precise regulation of the extracellular glutamate availability. However, it remains unclear how impaired astrocytic glutamate transport or an acute TBI affect characteristics of the CSD. We quantified the properties of CSD using whole-cell and extracellular electrophysiological recordings, and voltage-sensitive dye imaging (VSDI) in rat visual cortex in vitro. To model impaired astrocytic glutamate transport, we used astrocytic glutamate transporter blocker (2S, 3S)-3-[3-[4-(trifluoromethyl) benzoylamino] benzyloxy] aspartate (TFB-TBOA). In addition, an acute incision through the superficial cortical layers was used to model the effects of acute traumatic brain injury (TBI) on CSD characteristics. Both manipulations; impaired glutamate cycling and acute cut profoundly affected the physiological properties of cell firing, latency to CSD formation, and its frequency of occurrence. VSD imaging analysis revealed significant changes in spatiotemporal dynamics and propagation of the CSD, suggesting that the cut itself may not initiate CSD depolarizing waves, but rather attract them. Blockade of GLT-1 caused significant reduction in whole-cell sodium currents and changes in CSD wave spatiotemporal characteristics as well, slowing it or even ‘trapping’ its propagation. Our results reveal new information about CSD properties in these pathological conditions and demonstrate an important role of GLT-1 in regulation of CSD.

Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache.

Functioning of the glymphatic system, a network of paravascular tunnels through which cortical interstitial solutes are cleared from the brain, has recently been linked to sleep and traumatic brain injury, both of which can affect the progression of migraine. This led us to investigate the connection between migraine and the glymphatic system. Taking advantage of a novel in vivo method we developed using two-photon microscopy to visualize the paravascular space (PVS) in naive uninjected mice, we show that a single wave of cortical spreading depression (CSD), an animal model of migraine aura, induces a rapid and nearly complete closure of the PVS around surface as well as penetrating cortical arteries and veins lasting several minutes, and gradually recovering over 30 min. A temporal mismatch between the constriction or dilation of the blood vessel lumen and the closure of the PVS suggests that this closure is not likely to result from changes in vessel diameter. We also show that CSD impairs glymphatic flow, as indicated by the reduced rate at which intraparenchymally injected dye was cleared from the cortex to the PVS. This is the first observation of a PVS closure in connection with an abnormal cortical event that underlies a neurological disorder. More specifically, the findings demonstrate a link between the glymphatic system and migraine, and suggest a novel mechanism for regulation of glymphatic flow.SIGNIFICANCE STATEMENT Impairment of brain solute clearance through the recently described glymphatic system has been linked with traumatic brain injury, prolonged wakefulness, and aging. This paper shows that cortical spreading depression, the neural correlate of migraine aura, closes the paravascular space and impairs glymphatic flow. This closure holds the potential to define a novel mechanism for regulation of glymphatic flow. It also implicates the glymphatic system in the altered cortical and endothelial functioning of the migraine brain.

Transcranial Magnetic Stimulation: Basic Principles and Clinical Applications in Migraine.

Transcranial magnetic stimulation (TMS) is a neurophysiological technique with a long established pedigree of safety, tolerability, and efficacy. Initially TMS was used to study the function of the cerebral cortex, but it has now become a treatment for migraine, one of the most common and debilitating neurological conditions. In this review we discuss the scientific background and development of the technique. We explore its application for the treatment of migraine and ponder the possible mechanisms of action in this most common neurological condition. The generation of brief magnetic pulses by a suitable coil can induce electrical fields in the body. When applied to the cerebral cortex, currents are painlessly induced in cortical neurons. These currents can lead to neuronal depolarization and may influence cortical excitability by means that are as yet not fully understood. This ability to modulate cortical excitability has been exploited as a treatment for migraine with aura. Aura is implicated in the pathophysiology of migraine. Experimental studies have shown that transcranial magnetic pulses can block waves of cortical spreading depression - the experimental equivalent of migrainous aura. Migraine is a debilitating condition characterized by headache, nausea, and sensory hypersensitivity. It may affect up to 15% of the population, yet current drug treatments are often poorly tolerated. Clinical studies have shown that TMS is an effective treatment for migraine. In addition, it has the added advantages of being safe and well tolerated by patients.

Shining light on the role of Parvalbumin interneurons in cortical spreading depression

Shining light on the role of Parvalbumin interneurons in cortical spreading depression

Variation of repetitive cortical spreading depression waves is related with relative refractory period: a computational study

Cortical spreading depression (CSD) is an important experimental model for diseases such as stroke, epilepsy and migraine. Previous observations indicated that the amplitude and velocity of the typical direct current potential shift during repetitive CSD waves were varying. The recovery state of the tissue was found related with the variation of successive CSD waves. A computational model in this paper aimed to investigate the role of relative refractory period of CSD. This model simulated that continuous injection of KCl solution induced repetitive CSD waves. The first CSD wave often had a larger amplitude and faster velocity than those of the succeeding secondary waves. The relative refractory period lasted much longer than the recovery of ions turbulence. If the induction interval was long enough for recovery, a series of CSD waves would have the same profile as the first one. In the relative refractory period, an early stimulation might lead to a late initiation of CSD, i.e., “haste makes waste”. The amplitude and velocity of CSD waves were found increasing with the initiation interval and asymptotic to those of the first CSD wave. This study verified that the propagation dynamics of CSD waves is modulated by the relative refractory period. It suggested that the refractory period is critical for preventing undesirable CSD waves.

Annals of Neurology: Volume 78, Number 2, August 2015

ON THE COVER: In vivo multiphoton microscopy image of dendrites within the somatosensory cortex of a familial hemiplegic migraine mutant mouse expressing the genetically encoded Ca2+‐indicator yellow cameleon YC3.6. Epidural application of KCl onto the occipital cortex triggered a cortical spreading depression wave that was associated with dendritic beading and a rapid surge in neuronal [Ca2+]i as indicated by change in pseudocolor (from basal nanoM levels marked in blue to microM levels marked in red; see also Video 7). Elevated neuronal [Ca2+]i and synaptic structural changes were apparent in migraine mutant mice and can explain cortical hyperexcitability. Field dimension: 126 μm × 126 μm. For more information, see the article by Eikermann‐Haerter et al. (pages 193–210).

Dynamics of Ionic Shifts in Cortical Spreading Depression.

Cortical spreading depression is a slowly propagating wave of near-complete depolarization of brain cells followed by temporary suppression of neuronal activity. Accumulating evidence indicates that cortical spreading depression underlies the migraine aura and that similar waves promote tissue damage in stroke, trauma, and hemorrhage. Cortical spreading depression is characterized by neuronal swelling, profound elevation of extracellular potassium and glutamate, multiphasic blood flow changes, and drop in tissue oxygen tension. The slow speed of the cortical spreading depression wave implies that it is mediated by diffusion of a chemical substance, yet the identity of this substance and the pathway it follows are unknown. Intercellular spread between gap junction-coupled neurons or glial cells and interstitial diffusion of K+ or glutamate have been proposed. Here we use extracellular direct current potential recordings, K+-sensitive microelectrodes, and 2-photon imaging with ultrasensitive Ca2+ and glutamate fluorescent probes to elucidate the spatiotemporal dynamics of ionic shifts associated with the propagation of cortical spreading depression in the visual cortex of adult living mice. Our data argue against intercellular spread of Ca2+ carrying the cortical spreading depression wavefront and are in favor of interstitial K+ diffusion, rather than glutamate diffusion, as the leading event in cortical spreading depression.

Hyperperfusion counteracted by transient rapid vasoconstriction followed by long-lasting oligemia induced by cortical spreading depression in anesthetized mice.

Cortical spreading depression (CSD) involves mass depolarization of neurons and glial cells accompanied with changes in regional cerebral blood flow (rCBF) and energy metabolism. To further understand the mechanisms of CBF response, we examined the temporal diametric changes in pial arteries, pial veins, and cortical capillaries. In urethane-anesthetized mice, the diameters of these vessels were measured while simultaneously recording rCBF with a laser Doppler flowmeter. We observed a considerable increase in rCBF during depolarization in CSD induced by application of KCl, accompanied by a transient dip of rCBF with marked vasoconstriction of pial arteries, which resembled the response to pin-prick-induced CSD. Arterial constriction diminished or disappeared during the second and third passages of CSD, whereas the rCBF increase was maintained without a transient dip. Long-lasting oligemia with a decrease in the reciprocal of mean transit time of injected dye and mild constriction of pial arteries was observed after several passages of the CSD wave. These results indicate that CSD-induced rCBF changes consist of initial hyperemia with a transient dip and followed by a long-lasting oligemia, partially corresponding to the diametric changes of pial arteries, and further suggest that vessels other than pial arteries, such as intracortical vessels, are involved.

Serotonin depletion can enhance the cerebrovascular responses induced by cortical spreading depression via the nitric oxide pathway

Serotonin (5-HT) is an important neurotransmitter involved in the control of neural and vascular responses. 5-HT depletion can induce several neurological disorders, including migraines. Studies on a cortical spreading depression (CSD) migraine animal model showed that the cortical neurons sensitivity, vascular responses, and nitric oxide (NO) production were significantly increased in 5-HT depletion. However, the involvement of NO in the cerebrovascular responses in 5-HT depletion remains unclear. This study aimed to investigate the role of NO in the CSD-induced alterations of cerebral microvessels in 5-HT depletion. Rats were divided into four groups: control, control with L-NAME treatment, 5-HT depleted, and 5-HT depleted with L-NAME treatment. 5-HT depletion was induced by intraperitoneal injection with para-chlorophenylalanine (PCPA) 3 days before the experiment. The CSD was triggered by KCl application. After the second wave of CSD, N-nitro-l-arginine methyl ester (L-NAME) or saline was intravenously injected into the rats with or without L-NAME treatment groups, respectively. The intercellular adhesion molecules-1 (ICAM-1), cell adhesion molecules-1 (VCAM-1), and the ultrastructural changes of the cerebral microvessels were examined. The results showed that 5-HT depletion significantly increased ICAM-1 and VCAM-1 expressions in the cerebral cortex. The number of endothelial pinocytic vesicles and microvilli was higher in the 5-HT depleted group when compared to the control. Interestingly, L-NAME treatment significantly reduced the abnormalities observed in the 5-HT depleted group. The results of this study demonstrated that an increase of NO production is one of the mechanisms involved in the CSD-induced alterations of the cerebrovascular responses in 5-HT depletion.

Fast vascular component of cortical spreading depression revealed in rats by blood pulsation imaging

Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of neurons and glia and has a less characterized vascular component. CSD is a commonly used phenomenon to test new methods of live brain imaging. Application of a blood pulsations imaging (BPI) technique to study of CSD induced with high-potassium solution in rat cortex allowed us to visualize for the first time the novel vascular component of a CSD wave. In our study, this wave component propagated in the limited part of the cortex along the bow-shaped trajectory in sharp contrast with concentric development of CSD measured by concurrently applied optical intrinsic signal (OIS) imaging technique. It was associated with a significant increase of the blood pulsations amplitude (BPA), started with a delay of 20 to 90 s comparing to signal measured with OIS, and propagated 40% faster than OIS signal. These findings suggest that the BPA and slower change of the cerebral blood volume are not directly related to each other even though both characterize the same vascular system. Our study indicates that the BPI technique could be used for characterization of the new pulsatile vascular component of CSDs in animal models of migraine, stroke, and brain trauma.