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International audience; The development of ischemic lesions has primarily been studied in horizontal cortical space. However, how ischemic lesions develop through the cortical depth remains largely unknown. We explored this question using direct current coupled recordings at different cortical depths using linear arrays of iridium electrodes in the focal epipial endothelin-1 (ET1) ischemia model in the rat barrel cortex. ET1-induced impairments were characterized by a vertical gradient with (i) rapid suppression of the spontaneous activity in the superficial cortical layers at the onset of ischemia, (ii) compartmentalization of spreading depolarizations (SDs) to the deep layers during progression of ischemia, and (iii) deeper suppression of activity and larger histological lesion size in superficial cortical layers. The level of impairments correlated strongly with the rate of spontaneous activity suppression, the rate of SD onset after ET1 application, and the amplitude of giant negative ultraslow potentials (∼−70 mV), which developed during ET1 application and were similar to the tent-shaped ultraslow potentials observed during focal ischemia in the human cortex. Thus, in the epipial ET1 ischemia model, ischemic lesions develop progressively from the surface to the cortical depth, and early changes in electrical activity at the onset of ET1-induced ischemia reliably predict the severity of ischemic damage.

Although migraine in adult and pediatric patients are overall very similar to each other, differences in prevalence, presentation, and treatment efficacy may reflect slight differences in the pathophysiological processes underlying migraine in these patient groups, perhaps because of ongoing development of the nervous system during childhood and adolescence. Although major gains have been made in understanding the pathophysiology of migraine in adults in recent years, equivalent research on migraine in pediatric patients continues to lag behind. In this review, we will describe the current state of migraine research in pediatric patients with regard to presentation and frequency of prodromal and postdromal symptoms, ictal and interictal calcitonin gene-related peptide elevation, and evidence for cortical spreading depression, thus covering all phases of migraine, and discuss how the findings seen here may relate to possible underlying pathophysiological mechanisms of migraine. We aim to elucidate possible differences between migraine in children and adults, and the need for further research specific to pediatric patients with migraine in order to improve treatment in this patient group.

The objective of this study is to characterize the effects of the sleep-wake cycle on neurovascular and behavioral characteristics of cortical spreading depression (CSD).There is an important bi-directional relationship between migraine and the sleep-wake cycle, but the basic mechanisms of this relationship are poorly understood.We have developed a minimally invasive microchip system to continuously monitor cerebral blood volume (CBV) with optical intrinsic signal (OIS), head movement, and multiple other physiological and behavioral parameters in freely behaving mice over weeks. Behavior is also monitored with simultaneous video recording. This system can also be used to intermittently trigger and record CSD and accompanying neurovascular and behavioral responses. CSD was triggered optically in different stages of the sleep-wake cycle.The optical stimulus threshold to trigger CSD was significantly higher in the wake state compared to sleep (stimulation duration = 16.4 ± 9.7 s vs. 10.8 ± 5.8 s, p = 0.037, n = 6 mice). CSD evoked in the wake versus sleep state produced changes in CBV that were smaller (largest relative change -4.5 ± 5.0% ∆OIS vs. -14.3 ± 8.5% ∆OIS, p = 0.001) and shorter in duration (33:22 ± 6:37 vs. 49:42 ± 8:05 min:s, p = 0.012, n = 6 mice). The threshold for CSD and kinetics of associated CBV changes were correlated with the time since falling asleep or awakening (n = 47 CSDs in 6 mice). CSD triggered in the wake state was associated with a transient freezing behavior. CSD triggered during sleep typically caused a transient awakening and behavioral response. This was followed by a return to sleep until recovery from the sustained phase of decreased CBV that occurred 30-60 min later, at which time there was consistent awakening with behaviors similar to those that occurred at CSD onset. CSD triggered in the wake state evoked a transient decrease in heart rate (from 11.9 ± 0.8 to 9.6 ± 0.8 Hz, p = 0.002, n = 5), whereas when triggered in the sleep state there was a transient increase in HR (from 7.5 ± 0.4 Hz to 9.3 ± 1.1 Hz, p = 0.016, n = 5).The sleep-wake cycle has significant effects on CSD that may have relevance to the clinical presentations of migraine and brain injury.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). Animal models are required to assess whether CSDs can worsen outcomes or are an epiphenomenon; however, little is known about the presence of CSDs in existing animal models. Therefore, we designed a study to determine whether CSDs occur in a mouse model of SAH. METHODS: A total of 36 mice were included in the study. We used the anterior prechiasmatic injection model of SAH under isoflurane anesthesia. A needle was inserted through the mouse olfactory bulb with the point terminating at the base of the skull, and arterial blood or saline (100 μl) was injected over 10 s. Changes in cerebral blood volume over the entire dorsal cortical surface were assessed with optical intrinsic signal imaging for 5 min following needle insertion. RESULTS: CSDs occurred in 100% of mice in the hemisphere ipsilateral to olfactory bulb needle insertion (CSD1). Saline-injected mice had 100% survival (n = 10). Blood-injected mice had 88% survival (n = 23 of 26). A second, delayed, CSD ipsilateral to CSD1 occurred in 31% of blood-injected mice. An increase in the time interval between CSD1 and blood injection was associated with the occurrence of a second CSD in blood-injected mice (mean intervals 26.4 vs. 72.7 s, p < 0.0001, n = 18 and 8). We observed one blood-injected animal with a second CSD in the contralateral hemisphere and observed terminal CSDs in mice that died following SAH injection. CONCLUSIONS: The prechiasmatic injection model of SAH includes CSDs that occur at the time of needle insertion. The occurrence of subsequent CSDs depends on the timing between CSD1 and blood injection. The mouse prechiasmatic injection model could be considered an SAH plus CSD model of the disease. Further work is needed to determine the effect of multiple CSDs on outcomes following SAH.

Background Noninvasive vagus nerve stimulation (nVNS) has recently emerged as a promising therapy for migraine. We previously demonstrated that vagus nerve stimulation inhibits cortical spreading depression (CSD), the electrophysiological event underlying migraine aura and triggering headache; however, the optimal nVNS paradigm has not been defined. Methods Various intensities and doses of nVNS were tested to improve efficacy on KCl-evoked CSD frequency and electrical threshold of CSD in a validated rat model. Chronic efficacy was evaluated by daily nVNS delivery for four weeks. We also examined the effects of nVNS on neuroinflammation and trigeminovascular activation by western blot and immunohistochemistry. Results nVNS suppressed susceptibility to CSD in an intensity-dependent manner. Two 2-minute nVNS 5 min apart afforded the highest efficacy on electrical CSD threshold and frequency of KCl-evoked CSD. Daily nVNS for four weeks did not further enhance efficacy over a single nVNS 20 min prior to CSD. The optimal nVNS also attenuated CSD-induced upregulation of cortical cyclooxygenase-2, calcitonin gene-related peptide in trigeminal ganglia, and c-Fos expression in trigeminal nucleus caudalis. Conclusions Our study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.

BACKGROUND How widely spreading depolarizations (SDs) propagate through the gyrencephalic brain, including sulci and deeper cortical areas, remains an important clinical question. Here, we investigated SDs that occur spontaneously after subarachnoid placement of autologous blood clots in sulci of the juvenile swine brain. METHODS To investigate the three-dimensional spread of waves, animals underwent continuous diffusion-weighted magnetic resonance imaging (DW-MRI) for up to 6 h following clot placement. SD is the mechanism of the cytotoxic edema of developing infarction that is diagnosed by DW-MRI, and DW-MRI also captures transient diffusion restriction caused by SD in less injured or healthy brains. Here, images (b = 0, 375, and 750) were acquired across five coronal slices with 1.25 × 1.25-mm in-plane resolution and 5-mm slice thickness, and the protocol was repeated every 6.83-9.15 s. Spatial drift correction, temporal smoothing, and signal intensity normalization were applied to generate videos of diffusion signal intensity changes for each coronal slice. RESULTS Review of video data from five animals revealed ten discrete events consisting of focal diffusion restriction that propagated through cerebral cortex. All events originated in the cortex surrounding the sulcal clot, either in the gyrus (n = 4) or in the sulcal depth (n = 6). In six cases, two to three independent waves spread simultaneously in medial, lateral, and antero-posterior directions. Waves traveled within sulcal walls, traversed the depths of sulci to re-emerge on the adjacent gyrus, and, in three cases, spread fully around the dorsolateral convexity. One event spread deep to olfactory regions along midline cortex, and no events were observed contralateral to the subarachnoid clot. CONCLUSIONS Together, these results suggest that SDs in the injured gyrencephalic brain originate near the injury focus and can spread extensively through the cortex to wide and deep uninjured regions. These findings have implications for transient neurologic deficits in the neurocritically ill patient and relevance to patient monitoring and therapeutics.

Animal models of migraine have been widely used during the last decades to provide clues for understanding mechanisms underlying pathophysiology of migraine attacks and for developing specific therapeutic agents. They can be grouped into two main types: vascular and neurovascular. Trigemino-vascular system (TVS) is the most relevant efferent component and the mediators of its activity have been thoroughly studied along with some of the receptors involved to characterize anatomical and functional aspects of the system and to test efficacy and mechanisms of therapeutic agents. Neurovascular models are numerous. Plasma protein extravasation (PPE) model consists of measuring the amount of proteins leaking from vessels when TVS is either electrically or chemically stimulated and evaluating its blockade by systemically administered therapeutic agents of which specific receptors have also been identified. Activation of trigeminal nucleus caudalis (TNC) through meningeal stimulation of the superior sagittal sinus served to better understand the mechanisms of central nociceptive pathway. The cortical spreading depression (CSD) model has been used to activate the TVS through application of potassium chloride and evaluate Fos expression in the trigeminal nucleus caudalis (TNC). Finally, neurochemical, cerebrovascular, and nociceptive response to systemic or central administration of nitric oxide (NO) donors served to study central nociceptive pathway and autonomic response interaction. Transgenic mouse expressing human migraine mutations has been genetically engineered to provide an understanding of familial hemiplegic migraine (FHM). Animal models of migraine also served to better understand the role of hormones, genes, and environmental factors on migraine pathophysiology.

Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD. For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma. In brain slice studies, memantine (10–300 µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine. These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.

Migraine is characterized by symptoms related to cortical hyperexcitability such as photophobia , phonophobia , osmophobia and allodynia . One-third of migraineurs experience aura, whose neurophysiological substrate is thought to be cortical spreading depression (CSD). Functional magnetic resonance imaging (MRI) has shown the migraine aura to be characterized by cerebral hyperactivity/hyperperfusion followed by hypometabolism/hypoperfusion spreading along the occipital cortex with the same spatiotemporal organization as the experimentally triggered CSD. The link between migraine aura and headache remains undetermined. Neuroimaging studies have failed to show a leakage of the blood–brain barrier, which was suspected to occur during CSD and to cause the stimulation of trigeminal nociceptive receptors. However, recent studies have highlighted the involvement of neuroglial inflammation and other studies have suggested that a common central network plays a role in the link between CSD and migraine pain. Finally, MRI has made it possible to study the contribution of metabolites such as glutamic acid , γ-amino-butyric acid and sodium in the pathophysiology of hyperexcitability in migraine.

Around 15% to one-third of migraineurs experience aura. Aura is a fully reversible focal neurological phenomenon involving visual, sensory, speech, and/or motor symptoms that develops gradually and usually precedes the headache phase. The pivotal role of cortical spreading depression (CSD) as a mechanism underlying aura has been widely supported by a large body of studies. The diagnosis is based on the International Headache Classification Disorders III edition criteria. Aura is characterized by gradual development, duration of each symptom no longer than one hour, a mix of positive and negative features, and complete reversibility. Visual aura is the most common type of aura, occurring in over 90% of patients. When aura symptoms are multiple, they usually follow one another in succession, beginning with visual, then sensory, then aphasic; but the reverse and other orders have been noted. The accepted duration for most aura symptoms is one hour, but motor symptoms, which are rare, are often longer lasting. When a patient experiences for the first time a possible aura phase it's sometimes difficult to know if there was gradual or brutal onset of the symptoms. If the patient has no visual aura symptoms or simultaneous neurological symptoms, or presents neurological symptoms corresponding to a cerebral vascular territory, emergency exploration of a possible transient ischemic attack is necessary. Long duration (greater than one hour) of what may or may not be an aura phase, late onset of aura, or a dramatic increase in aura attacks should also be explored. The relative risk of ischemic stroke is significantly increased in migraine with aura. Combined hormonal contraception with estrogens significantly increases the risk of stroke in women with migraine with aura. It is recommended to start non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin as soon as possible during the aura phase, not to treat the aura, but to avoid or to diminish the headache phase. In case of failure of NSAIDs or aspirin it is recommended to use a triptan when the headache begins. The prophylactic treatments for migraine with aura are those used in migraine without aura based on very few randomized clinical trials specifically dedicated to migraine with aura.

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) remains an important problem with a complex pathophysiology. We used data from a single-center randomized trial to assess the effect of a phosphodiesterase inhibitor, cilostazol, in patients with aneurysmal SAH to explore the relationships of DCI with vasospasm, spreading depolarization (SD) and microcirculatory disturbance. A post hoc analysis of a single-center, prospective, randomized trial of the effect of cilostazol on DCI and SD after aneurysmal SAH was performed. From all randomized cohorts, patients who underwent both SD monitoring and digital subtraction angiography (DSA) on day 9 ± 2 from onset were included. Cerebral circulation time (CCT), which was divided into proximal CCT and peripheral CCT (as a measure of microcirculatory disturbance), was obtained from DSA. Logistic regression was conducted to determine factors associated with DCI. Complete data were available for 28 of 50 patients. Of the 28 patients, 8 (28.5%) had DCI during the study period. Multivariate analysis indicated a strong association between the number of SDs on the day DSA was performed (i.e., a delayed time point after SAH onset) and DCI (odds ratio 2.064, 95% confidence interval 1.045–4.075, P = 0.037, area under the curve 0.836), whereas the degree of angiographic vasospasm and peripheral CCT were not significant factors for DCI. There is a strong association between SD and DCI. Our results suggest that SD is an important therapeutic target and a potentially useful biomarker for DCI.

Spreading depolarizations are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply–demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure are also prevalent in the injured brain. Here, using a mouse model of large hemispheric ischaemic stroke, we show that mild and brief intracranial pressure elevations (20 or 30 mmHg for just 3 min) potently trigger spreading depolarizations in ischaemic penumbra (4-fold increase in spreading depolarization occurrence). We also show that 30 mmHg intracranial pressure spikes as brief as 30 s are equally effective. In contrast, sustained intracranial pressure elevations to the same level for 30 min do not significantly increase the spreading depolarization rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger a spreading depolarization. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the intracranial pressure spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply–demand mismatch. These haemodynamic changes during intracranial pressure spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, a higher rate of intracranial pressure spikes was associated with spreading depolarization clusters in a retrospective series of patients with aneurysmal subarachnoid haemorrhage with strong temporal correspondence. Altogether, our data show that intracranial pressure spikes, even when mild and brief, are capable of triggering spreading depolarizations. Aggressive prevention of intracranial pressure spikes may help reduce spreading depolarization occurrence and improve outcomes after brain injury.

Background Spreading depolarizations (SDs) occur in some 60% of patients receiving intensive care following severe traumatic brain injury and often occur at a higher incidence following serious subarachnoid hemorrhage and malignant hemisphere stroke (MHS); they are independently associated with worse clinical outcome. Detection of SDs to guide clinical management, as is now being advocated, currently requires continuous and skilled monitoring of the electrocorticogram (ECoG), frequently extending over many days. Methods We developed and evaluated in two clinical intensive care units (ICU) a software routine capable of detecting SDs both in real time at the bedside and retrospectively and also capable of displaying patterns of their occurrence with time. We tested this prototype software in 91 data files, each of approximately 24 h, from 18 patients, and the results were compared with those of manual assessment (“ground truth”) by an experienced assessor blind to the software outputs. Results The software successfully detected SDs in real time at the bedside, including in patients with clusters of SDs. Counts of SDs by software (dependent variable) were compared with ground truth by the investigator (independent) using linear regression. The slope of the regression was 0.7855 (95% confidence interval 0.7149–0.8561); a slope value of 1.0 lies outside the 95% confidence interval of the slope, representing significant undersensitivity of 79%. R2 was 0.8415. Conclusions Despite significant undersensitivity, there was no additional loss of sensitivity at high SD counts, thus ensuring that dense clusters of depolarizations of particular pathogenic potential can be detected by software and depicted to clinicians in real time and also be archived.

Transient focal neurologic episodes (TFNEs) are brief disturbances in motor, somatosensory, visual, or language functions that can occur in patients with cerebral amyloid angiopathy (CAA) and may be difficult to distinguish from TIAs or other transient neurologic syndromes. They herald a high rate of future lobar intracerebral hemorrhage, making it imperative to differentiate them from TIAs to avoid potentially dangerous use of antithrombotic drugs. Cortical spreading depression or depolarization triggered by acute or chronic superficial brain bleeding, a contributor to brain injury in other neurologic diseases, may be the underlying mechanism. This review discusses diagnosis, pathophysiology, and management of CAA-related TFNEs.

Ischemia is one of the most common causes of acquired brain injury. Central to its noxious sequelae are spreading depolarizations (SDs), waves of persistent depolarizations which start at the location of the flow obstruction and expand outwards leading to excitotoxic damage. The majority of acute stage of stroke studies to date have focused on the phenomenology of SDs and their association with brain damage. In the current work, we investigated the role of peri-injection zone pyramidal neurons in triggering SDs by optogenetic stimulation in an endothelin-1 rat model of focal ischemia. Our concurrent two photon fluorescence microscopy data and local field potential recordings indicated that a ≥ 60% drop in cortical arteriolar red blood cell velocity was associated with SDs at the ET-1 injection site. SDs were also observed in the peri-injection zone, which subsequently exhibited elevated neuronal activity in the low-frequency bands. Critically, SDs were triggered by low- but not high-frequency optogenetic stimulation of peri-injection zone pyramidal neurons. Our findings depict a complex etiology of SDs post focal ischemia and reveal that effects of neuronal modulation exhibit spectral and spatial selectivity.

Spreading depolarization is a slowly propagating wave of massive cellular depolarization associated with acute brain injury and migraine aura. Genetic studies link depolarizing molecular defects in Ca2+ flux, Na+ current in interneurons, and glial Na+-K+ ATPase with spreading depolarization susceptibility, emphasizing the important roles of synaptic activity and extracellular ionic homeostasis in determining spreading depolarization threshold. In contrast, although gene mutations in voltage-gated potassium ion channels that shape intrinsic membrane excitability are frequently associated with epilepsy susceptibility, it is not known whether epileptogenic mutations that regulate membrane repolarization also modify spreading depolarization threshold and propagation. Here we report that the Kcnq2/Kv7.2 potassium channel subunit, frequently mutated in developmental epilepsy, is a spreading depolarization modulatory gene with significant control over the seizure-spreading depolarization transition threshold, bi-hemispheric cortical expression, and diurnal temporal susceptibility. Chronic DC-band cortical EEG recording from behaving conditional Kcnq2 deletion mice (Emx1cre/+::Kcnq2flox/flox) revealed spontaneous cortical seizures and spreading depolarization. In contrast to the related potassium channel deficient model, Kv1.1-KO mice, spontaneous cortical spreading depolarizations in Kcnq2 cKO mice are tightly coupled to the terminal phase of seizures, arise bilaterally, and are observed predominantly during the dark phase. Administration of the non-selective Kv7.2 inhibitor XE991 to Kv1.1-KO mice partly reproduced the Kcnq2 cKO-like spreading depolarization phenotype (tight seizure coupling and bilateral symmetry) in these mice, indicating that Kv7.2 currents can directly and actively modulate spreading depolarization properties. In vitro brain slice studies confirmed that Kcnq2/Kv7.2 depletion or pharmacological inhibition intrinsically lowers the cortical spreading depolarization threshold, whereas pharmacological Kv7.2 activators elevate the threshold to multiple depolarizing and hypometabolic spreading depolarization triggers. Together these results identify Kcnq2/Kv7.2 as a distinctive spreading depolarization regulatory gene, and point to spreading depolarization as a potentially significant pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes. Our results also implicate KCNQ2/Kv7.2 channel activation as a potential adjunctive therapeutic target to inhibit spreading depolarization incidence., Aiba and Noebels show that the Kcnq2/Kv7.2 gene has a key regulatory role in cortical spreading depolarization, and identify spreading depolarization as a potential pathophysiological component of KCNQ2-linked epileptic encephalopathy syndromes.

Suture-line injections of onabotulinumtoxinA alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine that is secondary to appearance of SNAP25 in dural nerve fibers., OnabotulinumtoxinA (BoNT-A) is an Food and Drug Administration-approved, peripherally acting preventive migraine drug capable of inhibiting meningeal nociceptors. Expanding our view of how else this neurotoxin attenuates the activation of the meningeal nociceptors, we reasoned that if the stimulus that triggers the activation of the nociceptor is lessened, the magnitude and/or duration of the nociceptors' activation could diminish as well. In the current study, we further examine this possibility using electrocorticogram recording techniques, immunohistochemistry, and 2-photon microscopy. We report (1) that scalp (head) but not lumbar (back) injections of BoNT-A shorten the period of profound depression of spontaneous cortical activity that follows a pinprick-induced cortical spreading depression (CSD); (2) that neither scalp nor lumbar injections prevent the induction, occurrence, propagation, or spreading velocity of a single wave of CSD; (3) that cleaved SNAP25—one of the most convincing tools to determine the anatomical targeting of BoNT-A treatment—could easily be detected in pericranial muscles at the injection sites and in nerve fibers of the intracranial dura, but not within any cortical area affected by the CSD; (4) that the absence of cleaved SNAP25 within the cortex and pia is unrelated to whether the blood–brain barrier is intact or compromised; and (5) that BoNT-A does not alter vascular responses to CSD. To the best of our knowledge, this is the first report of peripherally applied BoNT-A's ability to alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine.

Background We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. Methods Trigeminocervical complex neurons ( n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. Results A sub-population ( n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. Conclusion The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

Our laboratory has recently shown that there is a decrease in neuronal complexity in head pain processing regions in mouse models of chronic migraine-associated pain and aura. Importantly, restoration of this neuronal complexity corresponds with anti-migraine effects of known and experimental pharmacotherapies. The objective of the current study was to expand this work and examine other brain regions involved with pain or emotional processing. We also investigated the generalizability of our findings by analyzing neuronal cytoarchitectural changes in a model of complex regional pain syndrome (CRPS), a peripheral pain disorder.We used the nitroglycerin (NTG) model of chronic migraine-associated pain in which mice receive 10 mg/kg NTG every other day for 9 days. Cortical spreading depression (CSD), a physiological corelate of migraine aura, was evoked in anesthetized mice using KCl. CRPS was induced by tibial fracture followed by casting. Neuronal cytoarchitecture was visualized with Golgi stain and analyzed with Simple Neurite Tracer.In the NTG model, we previously showed decreased neuronal complexity in the trigeminal nucleus caudalis (TNC) and periaqueductal gray (PAG). In contrast, we found increased neuronal complexity in the thalamus and no change in the amygdala or caudate putamen in this study. Following CSD, we observed decreased neuronal complexity in the PAG, in line with decreases in the somatosensory cortex and TNC reported with this model previously. In the CRPS model there was decreased neuronal complexity in the hippocampus, as reported by others; increased complexity in the PAG; and no change within the somatosensory cortex.Collectively these results demonstrate that alterations in neuronal complexity are a feature of both chronic migraine and chronic CRPS. However, each type of pain presents a unique cytoarchitectural signature, which may provide insight on how these pain states differentially transition from acute to chronic conditions.

To investigate the spatiotemporal dynamics of early cerebral blood flow (CBF) changes, cerebrovascular reactivity (CVR), and vascular responses to cortical spreading depolarization (CSD) in an experimental mild traumatic brain injury (mTBI) model with laser speckle contrast imaging (LSCI) technique.The weight-drop model was used to induce blunt head trauma. The mice were divided into two groups as mild TBI (n=12), and sham (n=6). The animals underwent continuous LSCI before and for 1 hour after trauma to evaluate the regional CBF changes, CVR in response to CO2, and CSD-associated vascular responses induced by pinprick.Our minor blunt head trauma protocol induced CSD in only 2 (16.7%) animals, which were excluded from further analyses. Of the remaining animals, 30% showed slight hyperemia following trauma, with mild ipsilateral hemisphere oligemia (15%?20% decrease in CBF) on average compared to baseline (p=0.027) and contralateral hemisphere (p=0.029). Maximal CBF decrease was measured in the peri-impact area (24.1% ± 5.1%). No significant difference was found between the sham and mTBI groups and two hemispheres of the mTBI group or pre/post-CSD periods of CO2 reactivity, as well as the characteristics of vascular CSD responses (net ischemia: 52.3% ± 2.6% vs. 56.3% ± 1.9% and prolonged oligemia duration 44.8 ± 1.8 min vs. 49.8 ± 2.3 min).The ipsilateral hemisphere, particularly in the peri-impact area, had mild hypoperfusion, within the first hour of minor blunt head trauma in mice. Nonetheless, mTBI does not alter CVR and vascular responses to an induced CSD, thus the overall CVR is largely preserved in mTBI without significant structural damage despite a mildly decreased CBF in the hyperacute phase.

Background: unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight into how migraine starts in an otherwise healthy brain, remain largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain. Methods: cortex was made susceptible to CSD with partial inhibition of Na+/K+-ATPase by epidural application of a low concentration of Na+/K+-ATPase blocker ouabain, allowing longer than 30-min intervals between CSDs or by knocking-down ?2 subunit of Na+/K+-ATPase, which is crucial for K+ and glutamate re-uptake, with shRNA. Stimulation-triggered CSDs and extracellular K+ changes were monitored in vivo electrophysiologically and a K+-sensitive fluoroprobe (IPG-4), respectively. Results: after priming with ouabain, photic stimulation significantly increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p < 0.001). Whisker stimulation also significantly increased the CSD incidence, albeit less effectively (14.9 vs. 2.4%, p = 0.02). Knocking-down Na+/K+-ATPase (50% decrease in mRNA) lowered the CSD threshold in all mice tested with KCl but triggered CSDs in 14.3% and 16.7% of mice with photic and whisker stimulation, respectively. Confirming Na+/K+-ATPase hypofunction, extracellular K+ significantly rose during sensory stimulation after ouabain or shRNA treatment unlike controls. In line with the higher CSD susceptibility observed, K+ rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the probability of stimulus-evoked CSDs, we applied an A1-receptor antagonist (DPCPX) to the occipital cortex, because adenosine formed during stimulation from ATP can reduce CSD susceptibility. DPCPX induced spontaneous CSDs but only small-DC shifts along with suppression of EEG spikes during photic stimulation, suggesting that the inhibition co-activated with sensory stimulation could limit CSD ignition when K+ uptake was not sufficiently suppressed as with ouabain. Conclusions: normal brain is well protected against CSD generation. For CSD to be ignited under physiological conditions, priming and predisposing factors are required as seen in migraine patients. Intense sensory stimulation has potential to trigger CSD when co-existing conditions bring extracellular K+ and glutamate concentrations over CSD-ignition threshold and stimulation-evoked inhibitory mechanisms are overcome., Scientific and Technological Research Council of Turkey (TÜBİTAK); Hacettepe University Scientifc Research Projects Unit

BACKGROUND: Transcranial electrical stimulation at an appropriate dose may demonstrate intracranial effects, including neuronal stimulation and cerebral blood flow responses. OBJECTIVE: We performed in vivo experiments on mouse cortex using transcranial alternating current [AC] stimulation to assess whether cerebral blood flow can be reliably altered by extracranial stimulation. METHODS: We performed transcranial AC electrical stimulation transversely across the closed skull in anesthetized mice, measuring transcranial cerebral blood flow with a laser Doppler probe and intracranial electrical responses as endpoint biomarkers. We calculated a stimulation dose–response function between intracranial electric field and cerebral blood flow. RESULTS: Stimulation at electric field amplitudes of 5–20 mV/mm at 10–20 Hz rapidly increased cerebral blood flow (within 100 ms), which then quickly decreased with no residual effects. The time to peak and blood flow shape varied with stimulation intensity and duration, showing a linear correlation between stimulation dose and peak blood flow increase. Neither afterdischarges nor spreading depression occurred from this level of stimulation. CONCLUSIONS: Extracranial stimulation amplitudes sufficient to evoke reliable blood flow changes requires electric field strengths higher than what is tolerable in unanesthetized humans (< 1 mV/mm), but less than electroconvulsive therapy levels (> 40 mV/mm). However, anesthesia effects, spontaneous blood flow fluctuations, and sampling error may accentuate the apparent field strength needed for enhanced blood flow. The translation to a human dose–response function to augment cerebral blood flow (i.e., in stroke recovery) will require significant modification, potentially to pericranial, focused, multi-electrode application or intracranial stimulation.

OBJECTIVE: The aim of this study was to determine if the non-convulsant delta opioid receptor agonist, KNT-127, could inhibit migraine-associated endpoints. BACKGROUND: The delta opioid receptor has been identified as a therapeutic target for migraine. However, development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro- and non-convulsant delta agonists can reduce migraine associated allodynia, only the pro-convulsant agonist, SNC80, has been shown to decrease cortical spreading depression. It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce pro-convulsant effects. METHODS: The effects of the non-convulsant delta agonist, KNT-127, were examined. Repetitive cortical spreading depression was induced in female C57BL6/J (n=6/group) mice by continuous application of KCl; and the effect of KNT-127/vehicle on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT-127 on established chronic migraine-associated pain, male and female C57BL6/J mice were treated with nitroglycerin (10 mg/kg, IP) every other day for 9 days; and tested with KNT-127 (5 mg/kg SC) or vehicle on day 10 (n=6/group). DOR-eGFP mice (n=4/group) were used to confirm the internalization properties of KNT-127 in the trigeminal ganglia, trigeminal nucleus caudalis, and the somatosensory cortex. RESULTS: KNT-127 inhibited cortical spreading depression events (t((10))=3.570, p=0.0051). In addition, this delta agonist also reversed established cephalic allodynia in the nitroglycerin model of chronic migraine (F((1, 20)) = 12.80, p

Objective Monitoring of the ultra-low frequency potentials, particularly cortical spreading depression (CSD), is excluded in epilepsy monitoring due to technical barriers imposed by the scalp ultra-low frequency electroencephalogram (EEG). As a result, clinical studies of CSD have been limited to invasive EEG. Therefore, the occurrence of CSD and its interaction with epileptiform field potentials (EFP) require investigation in epilepsy monitoring. Methods Using a novel AC/DC-EEG approach, the occurrence of DC potentials in patients with intractable epilepsy presenting different symptoms of aura was investigated during long-term video-EEG monitoring. Results Various forms of slow potentials, including simultaneous negative direct current (DC) potentials and prolonged EFP, propagated negative DC potentials, and non-propagated single negative DC potentials were recorded from the scalp of the epileptic patients. The propagated and single negative DC potentials preceded the prolonged EFP with a time lag and seizure appeared at the final shoulder of some instances of the propagated negative DC potentials. The slow potential deflections had a high amplitude and prolonged duration and propagated slowly through the brain. The high-frequency EEG was suppressed in the vicinity of the negative DC potential propagations. Conclusions The study is the first to report the recording of the propagated and single negative DC potentials with EFP at the scalp of patients with intractable epilepsy. The negative DC potentials preceded the prolonged EFP and may trigger seizures. The propagated and single negative DC potentials may be considered as CSD. Significance Recordings of CSD may serve as diagnostic and prognostic monitoring tools in epilepsy.

Background OnabotulinumtoxinA and agents that block calcitonin gene‒receptor peptide action have both been found to have anti-migraine effects, but they inhibit different populations of meningeal nociceptors. We therefore tested the effects of combined treatment with onabotulinumtoxinA and the calcitonin gene‒receptor peptide antagonist atogepant on activation/sensitization of trigeminovascular neurons by cortical spreading depression. Material and methods Single-unit recordings were obtained of high-threshold and wide-dynamic-range neurons in the spinal trigeminal nucleus, and cortical spreading depression was then induced in anesthetized rats that had received scalp injections of onabotulinumtoxinA 7 days earlier and intravenous atogepant infusion 1 h earlier. The control group received scalp saline injections and intravenous vehicle infusion. Results OnabotulinumtoxinA/atogepant pretreatment prevented cortical spreading depression-induced activation and sensitization in both populations (control: Activation in 80% of high-threshold and 70% of wide-dynamic-range neurons, sensitization in 80% of high-threshold and 60% of wide-dynamic-range neurons; treatment: activation in 10% of high-threshold and 0% of wide-dynamic-range neurons, sensitization in 0% of high-threshold and 5% of wide-dynamic-range neurons). Discussion We propose that the robust inhibition of high-threshold and wide-dynamic-range neurons by the combination treatment was achieved through dual blockade of the Aδ and C classes of meningeal nociceptors. Combination therapy that inhibits meningeal C-fibers and prevents calcitonin gene‒receptor peptide from activating its receptors on Aδ-meningeal nociceptors may be more effective than a monotherapy in reducing migraine days per month in patients with chronic migraine.

Objective Growing evidence shows a critical role of network disturbances in the pathogenesis of migraine. Unilateral pattern of neurological symptoms of aura suggests disruption of interhemispheric interactions during the early phase of a migraine attack. Using local field potentials data from the visual and motor cortices, this study explored effects of unilateral cortical spreading depression, the likely pathophysiological mechanism of migraine aura, on interhemispheric functional connectivity in freely behaving rats. Methods Temporal evolution of the functional connectivity was evaluated using mutual information and phase synchronization measures applied to local field potentials recordings obtained in homotopic points of the motor and visual cortices of the two hemispheres in freely behaving rats after induction of a single unilateral cortical spreading depression in the somatosensory S1 cortex and sham cortical stimulation. Results Cortical spreading depression was followed by a dramatic broadband loss of interhemispheric functional connectivity in the visual and motor regions of the cortex. The hemispheric disconnection started after the end of the depolarization phase of cortical spreading depression, progressed gradually, and terminated by 5 min after initiation of cortical spreading depression. The network impairment had region- and frequency-specific characteristics and was more pronounced in the visual cortex than in the motor cortex. The period of impaired neural synchrony coincided with post-cortical spreading depression electrographic aberrant activation of the ipsilateral cortex and abnormal behavior. Conclusion The study provides the first evidence that unilateral cortical spreading depression induces a reversible loss of functional hemispheric connectivity in the cortex of awake animals. Given a critical role of long-distance cortical synchronization in sensory processing and sensorimotor integration, the post-cortical spreading depression breakdown of functional connectivity may contribute to neuropathological mechanisms of aura generation.

Aim To use an animal model of migraine to test whether migraine headache might arise from a brainstem-trigeminal nucleus pathway. Methods We measured evoked and spontaneous activity of second-order trigeminovascular neurons in rats to test whether the activity of these neurons increased following the induction of cortical spreading depression or the imposition of light flash – two potential migraine triggers, or headache provokers. We then tested whether drugs that could activate, or inactivate, neurons of the nucleus raphe magnus or the periaqueductal gray matter, would affect any such increases selectively for the dura mater. Results Injection of sodium glutamate (a neuronal excitant) into these two nuclei selectively inhibited the responses of trigeminovascular second-order neurons to dura mater, but not to facial skin, stimulation. Injection of lignocaine (a local anaesthetic) into these nuclei selectively potentiated the responses of these neurons to dura, but not to facial skin, stimulation. Furthermore, injections into either nucleus of glutamate inhibited the increase in the ongoing discharge rate of these neurons produced by cortical spreading depression and light flash. Conclusions These results provide indirect evidence that trigeminovascular nociception may be tightly controlled by these two nuclei, whereas cutaneous trigeminal sensation may be less so. These nuclei may be relays of one possible brainstem-trigeminal pathway that could mediate migraine headache. Modification of neuronal activity in these two nuclei produced by migraine (headache) triggers may lie behind the pain of a migraine attack, at least in some cases.

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

Migraine and sleep disorders in children exhibit a bidirectional relationship. This relationship is based on shared pathophysiology. Migraine involves activation of the trigeminal vascular system. Nociceptive neurons that innervate the dura release various vasoactive peptides. Calcitonin gene-related peptide is the most active of these peptides. Neural pathways that are involved in sleep generation are divided into those responsible for circadian rhythm, wake promotion, non-rapid eye movement, and rapid eye movement sleep activation. Sleep state switches are a critical component of these systems. The cerebral structures, networks, and neurochemical systems that are involved in migraine align closely with those responsible for the regulation of sleep. Neurochemical systems that are involved with both the pathogenesis of migraine and regulation of sleep include adenosine, melatonin, orexin, and calcitonin gene-related peptide. Sleep disorders represent the most common comorbidity with migraine in childhood. The prevalence of parasomnias, obstructive sleep apnea, and sleep-related movement disorders is significantly greater in children migraineurs. Infantile colic is a precursor of childhood migraine. Treatment of comorbid sleep disorders is important for the appropriate management of children with migraine. Sleep-based behavioral interventions can be of substantial benefit. These interventions are particularly important in children due to limited evidence for effective migraine pharmacotherapy.

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated l-glutamate-evoked firing, but not in the presence of GABAA/B antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABAA/B antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits. Electronic supplementary material The online version of this article (10.1007/s13311-020-00879-6) contains supplementary material, which is available to authorized users.

Cortical spreading depolarization (CSD) is recognized as a cause of transient neurological symptoms (TNS) in various clinical entities. Although scientific literature has been flourishing in the field of CSD, it remains an underrecognized pathophysiology in clinical practice. The literature evoking CSD in relation to subdural hematoma (SDH) is particularly scarce. Patients with SDH frequently suffer from TNS, most being attributed to seizures despite an atypical semiology, evolution, and therapeutic response. Recent literature has suggested that a significant proportion of those patients’ TNS represent the clinical manifestations of underlying CSD. Recently, the term Non-Epileptical Stereoytpical Intermittent Symptoms (NESIS) has been proposed to describe a subgroup of patients presenting with TNS in the context of SDH. Indirect evidence and recent research suggest that the pathophysiology of NESIS could represent the clinical manifestation of CSD. This review should provide a concise yet thorough review of the current state of literature behind the pathophysiology of CSD with a particular focus on recent research and knowledge regarding the presence of CSD in the context of subdural hematoma. Although many questions remain in the evolution of knowledge in this field would likely have significant diagnostic, therapeutic, and prognostic implications.

Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. Vagus nerve stimulation acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or noninvasively (nVNS) in male Sprague-Dawley rats. Cortical spreading depression susceptibility was evaluated 40 minutes after the stimulation. iVNS elevated the electrical CSD threshold more than 2-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs sham). By contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius, the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in nucleus tractus solitarius and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.

Clinical and experimental evidence suggests that spreading depolarizations (SD) usually occur in patients with ischemic or hemorrhagic stroke when the gray matter of the brain is affected. In this study, we evaluated spatiotemporal changes of cerebral blood flow (CBF) during middle cerebral artery (MCA) occlusion and examined the relationship between SD occurrence and cerebral infarct development. In male isoflurane-anesthetized C57BL/6J mice, CBF changes over the ipsilateral parietal bone were recorded by laser speckle flowgraphy during and after transient (45 min, n = 22) or permanent occlusion (n = 22) of the distal MCA. Infarct volume was evaluated 24 hr after the operation. Upon MCA occlusion, CBF decreased by -55.6 ± 8.5 % in the lowest CBF and linearly recovered with increasing distance from the region. At 1-10 min after onset of occlusion, SD occurred and concentrically propagated from the core region, showing a decrease of CBF in the whole observed area along with a transient hyperemia and oligemia in the normal region. SD spontaneously re-occurred and propagated around the ischemic area in 37 % of mice, accompanied with a marked decrease of CBF in the core or a marked increase of CBF in the normal region. The CBF response to SDs gradually changed from the core to the normal area, depending upon the distance from the core region. Infarction was not observed in transiently (n = 2) or permanently (n = 4) occluded mice without SD. The infarct area tended to be larger with increasing number of SDs in transiently occluded mice. In conclusion, our findings suggest that the occurrence of SD during ischemia might elicit infarct formation and/or influence infarct development.

BACKGROUND: Cortical Spreading Depolarization (SD) is a propagating depolarization wave of neurons and glial cells in the cerebral gray matter. SD occurs in all forms of severe acute brain injury as documented using invasive detection methods. Based on many experimental studies of mechanical brain deformation and concussion, the occurrence of SDs in human concussion has often been hypothesized. However, this hypothesis cannot be confirmed in humans as SDs can only be detected with invasive detection methods that would require either a craniotomy or a burr hole to be performed on athletes. Typical electroencephalography (EEG) electrodes, placed on the scalp, can detect the possible presence of SD but have not been able to accurately and reliably identify SDs. METHODS: To explore the possibility of a non-invasive method to resolve this hurdle, we developed a finite element numerical model that simulates scalp voltage changes that are induced by a brain-surface SD. We then compared our simulation results with retrospectively evaluated data in aneurysmal subarachnoid hemorrhage (aSAH) patients from Drenckhahn et al. (Brain 135:853, 2012). RESULTS: The ratio of peak scalp to simulated peak cortical voltage, Vscalp/Vcortex, was 0.0735, whereas the ratio from the retrospectively evaluated data was 0.0316 (0.0221, 0.0527) [median (1(st) quartile, 3(rd) quartile), n = 161, p < 0.001, one sample Wilcoxon signed rank test]. These differing values provide validation because their differences can be attributed to differences in shape between concussive- and aSAH-SDs, as well as the inherent limitations in human study voltage measurements. This simulated scalp surface potential was used to design a virtual scalp detection array. Error analysis and visual reconstruction showed that 1 cm is the optimal electrode spacing to visually identify the propagating scalp voltage from a cortical SD. Electrode spacings of 2 cm and above produce distorted images and high errors in the reconstructed image. CONCLUSION: Our analysis suggests that concussive (and other) SDs can be detected from the scalp, which could confirm SD occurrence in human concussion, provide concussion diagnosis based on an underlying physiological mechanism, and lead to non-invasive SD detection in the setting of severe acute brain injury.

Background: Cortical spreading depolarization (CSD) is a massive neuro-glial depolarization wave, which propagates across the cerebral cortex. In stroke, CSD is a necessary and ubiquitous mechanism for the development of neuronal lesions that initiates in the ischemic core and propagates through the penumbra extending the tissue injury. Although CSD propagation induces dramatic changes in cerebral blood flow, the vascular responses in different ischemic regions and their consequences on reperfusion and recovery remain to be defined. Methods: Ischemia was performed using the thrombin model of stroke and reperfusion was induced by r-tPA (recombinant tissue-type plasminogen activator) administration in mice. We used in vivo electrophysiology and laser speckle contrast imaging simultaneously to assess both electrophysiological and hemodynamic characteristics of CSD after ischemia onset. Neurological deficits were assessed on day 1, 3, and 7. Furthermore, infarct sizes were quantified using 2,3,5-triphenyltetrazolium chloride on day 7. Results: After ischemia, CSDs were evidenced by the characteristic propagating DC shift extending far beyond the ischemic area. On the vascular level, we observed 2 types of responses: some mice showed spreading hyperemia confined to the penumbra area (penumbral spreading hyperemia) while other showed spreading hyperemia propagating in the full hemisphere (full hemisphere spreading hyperemia). Penumbral spreading hyperemia was associated with severe stroke-induced damage, while full hemisphere spreading hyperemia indicated beneficial infarct outcome and potential viability of the infarct core. In all animals, thrombolysis with r-tPA modified the shape of the vascular response to CSD and reduced lesion volume. Conclusions: Our results show that different types of spreading hyperemia occur spontaneously after the onset of ischemia. Depending on their shape and distribution, they predict severity of injury and outcome. Furthermore, our data show that modulating the hemodynamic response to CSD may be a promising therapeutic strategy to attenuate stroke outcome., Stroke, 53 (4), ISSN:0039-2499, ISSN:1524-4628

Background After the initiation of the COVID-19 vaccination program in Thailand, thousands of patients have experienced unusual focal neurological symptoms. We report 8 patients with focal neurological symptoms after receiving inactivated virus vaccine, CoronaVac. Case series Patients were aged 24–48 years and 75% were female. Acute onset of focal neurological symptoms occurred within the first 24 h after vaccination in 75% and between 1-7d in 25%. All presented with lateralized sensory deficits, motor deficits, or both, of 2–14 day duration. Migraine headache occurred in half of the patients. Magnetic resonance imaging of the brain during and after the attacks did not demonstrate any abnormalities suggesting ischemic stroke. All patients showed moderately large regions of hypoperfusion and concurrent smaller regions of hyperperfusion on SPECT imaging while symptomatic. None developed permanent deficits or structural brain injury. Discussions Here, we present a case series of transient focal neurological syndrome following Coronavac vaccination. The characteristic sensory symptoms, history of migraine, female predominant, and abnormal functional brain imaging without structural changes suggest migraine aura as pathophysiology. We propose that pain related to vaccine injection, component of vaccine, such as aluminum, or inflammation related to vaccination might trigger migraine aura in susceptible patients.

Background: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. Methods: In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na/K pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. Results: We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na/K ATPase elicits SD. Elevated K or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. Conclusions: Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory., This work was supported by grants from the Heart and Stroke Foundation of Canada and the National Science and Engineering Research Council of Canada to RDA, an NIH grant (NS106901) to CWS, a National Research, Development and Innovation Office of Hungary grant (K1343777) and EU Horizon 2020 research and innovation program (739953) to EF and from DFG Deutsche Forschungsgemeinschaft (German Research Council) (DFG DR 323/5-1), DFG DR 323/10-1, and BMBF Bundesministerium fuer Bildung und Forschung (EraNet Neuron EBio2, with funds from BMBF 01EW2004) to JPD.

Background Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments. Body Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura. Conclusion Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine.

After more than 50 years since Fisher and Adams’ original description in 1964,1 transient global amnesia (TGA) is still a puzzling syndrome. Over time, several mechanisms have been proposed for TGA pathogenesis, including venous congestion, cortical spreading depression, seizures and arterial ischaemia.2–4 A sufficient amount of studies in favour and against each of these mechanisms has emerged, fostering uncertainty regarding aetiology as well as prognosis. To this extent, most of the controversy stands on whether TGA represents a risk factor for stroke, or whether this is just as benign as originally thought.5 In this volume of Stroke and Vascular Neurology, Lee and colleagues add a further episode to the saga, building on data from a large propensity-matched cohort study.6 Using records from the Korean National Health Insurance Service, they selected 10 447 patients with TGA and 20 493 controls through greedy nearest neighbour method, following both cohorts for up to 11 years to assess the occurrence of stroke. After adjusting for enrolment year—a strategy to mitigate differences in follow-up duration—TGA was associated with a higher risk of stroke compared with control population. Hypertension, diabetes and atrial fibrillation substantially increased the risk …

Background: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s Methods: Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. Results: Excitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury. Conclusions: Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate., Grants to RDA from the Canadian Heart & Stroke Foundation, National Science Engineering and Research Council and the New Frontiers in Research Fund, to E.F from the National Research, Development and Innovation Office of Hungary, grant no. K134377; and the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, and to JPD from the DFG (German research Council) (DFG DR323/5-1,DFG DR 323/10-1) BMBF Bundesministerium fuer Bildung und Forschung (Era-Net Neuron EBio2, with funds from BMBF 01EW2004).

Background Purinergic P2X7 receptor plays an important role in migraine pathophysiology. Yet precise molecular mechanism underlying P2X7R signaling in migraine remains unclear. This study explores the hypothesis that P2X7 receptor transmits signaling to Src family kinases (SFKs) during cortical spreading depression (CSD) and neuroinflammation after CSD. Methods CSD was recorded using electrophysiology in rats and intrinsic optical imaging in mouse brain slices. Cortical IL-1β and TNFα mRNA levels were detected using qPCR. Glutamate release from mouse brain slices was detected using glutamate assay. Results The data showed that deactivation of SFKs by systemic injection of PP2 reduced cortical susceptibility to CSD in rats and CSD-induced IL-1β and TNF-α gene expression in rat ipsilateral cortices. Consistently, in mouse brain slices, inhibition of SFKs activity by saracatinib and P2X7 receptor by A740003 similarly reduced cortical susceptibility to CSD. When the interaction of P2X7 receptor and SFKs was disrupted by TAT-P2X7, a marked reduction of cortical susceptibility to CSD, IL-1β gene expression and glutamate release after CSD induction were observed in mouse brain slices. The reduced cortical susceptibility to CSD by TAT-P2X7 was restored by NMDA, and disrupting the Fyn-NMDA interaction using TAT-Fyn (39-57) but not disrupting Src-NMDA receptor interaction using TAT-Src (40-49) reduced cortical susceptibility to CSD. Furthermore, activation of P2X7 receptor by BzATP restored the TAT-Fyn (39-57)-reduced cortical susceptibility to CSD. Conclusion This study reveals that SFKs activity transmits P2X7 receptor signaling to facilitate CSD propagation via glutamatergic pathway and promote neuroinflammation, which is of particular relevance to migraine.

Cortical spreading depolarizations (CSDs) are characterized by waves of diminished electroencephalography activity that propagate across the cortex with subsequent loss of ionic homeostasis. CSDs have been found in many pathological conditions, including migraine, traumatic brain injury, and ischemic stroke. Because of CSD-associated ionic and metabolic disturbances at the peri-infarct area after ischemic stroke, it is thought that CSDs exacerbate tissue infarction and worsen clinical outcomes. Microglia, the main innate immune cells in the brain, are among the first responders to brain tissue damage. Recent studies demonstrated that microglia play a critical role in CSD initiation and propagation. In this article, we discuss the significance of CSD in the setting of ischemic stroke and how microglia may modulate peri-infarct CSDs, also known as iso-electric depolarizations. Finally, we discuss the significance of microglial Ca2+ and how it might be used as a potential therapeutic target for patients with ischemic stroke.

The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their related large vessels. Yet, the exact mechanisms underlying this peripheral meningeal nociceptive response remain poorly understood. We investigated the relative contribution of cortical astrocytes to CSD-evoked meningeal nociception using extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity, in combination with 2 pharmacological approaches to inhibit astrocytic function. We found that fluoroacetate and l-α-aminoadipate, which inhibit astrocytes through distinct mechanisms, suppressed CSD-evoked afferent mechanical sensitization, but did not affect afferent activation. Pharmacological inhibition of astrocytic function, which ameliorated meningeal afferents' sensitization, reduced basal astrocyte calcium activity but had a minimal effect on the astrocytic calcium wave during CSD. We propose that calcium-independent signaling in cortical astrocytes plays an important role in driving the sensitization of meningeal afferents and the ensuing intracranial mechanical hypersensitivity in migraine with aura.

Physiological effects of spreading depolarizations (SD) are only well studied in the first hours after experimental stroke. In patients with malignant hemispheric stroke (MHS), monitoring of SDs is restricted to the postoperative ICU stay, typically day 2-7 post-ictus. Therefore, we investigated the role of physiological variables (temperature, intracranial pressure, mean arterial pressure and cerebral perfusion pressure) in relationship to SD during the late phase after MHS in humans. Additionally, an experimental stroke model was used to investigate hemodynamic consequences of SD during this time window. In 60 patients with MHS, the occurrence of 1692 SDs was preceded by a decrease in mean arterial pressure (−1.04 mmHg; p = .02) and cerebral perfusion pressure (−1.04 mmHg; p = .03). Twenty-four hours after middle cerebral artery occlusion in 50 C57Bl6/J mice, hypothermia led to prolonged SD-induced hyperperfusion (+2.8 min; p

Introduction Migraine involves neurovascular, functional, and anatomical alterations. Migraine sufferers experience an intense unilateral and pulsatile headache frequently accompanied with vomiting, nausea, photophobia, etc. Although there is no ideal preventive medication, frequency in migraine days may be partially decreased by some prophylactics, including antihypertensives, antidepressants, antiepileptics and CGRPergic inhibitors. However, the mechanisms of action involved in antimigraine prophylaxis remain elusive. Areas covered This review recaps some of the main neurovascular phenomena related to migraine and currently available preventive medications. Moreover, it discusses the major mechanisms of action of the recommended prophylactic medications. Expert opinion In the last three years, migraine prophylaxis has evolved from purely non-specific to specific antimigraine treatments. Overall, non-specific treatments involve neural actions, whereas specific pharmacotherapy (represented by CGRP receptor antagonists and CGRPergic monoclonal antibodies) is predominantly mediated by neurovascular mechanisms that may include, to a greater or lesser extent: (i) reduction in the frequency of cortical spreading depression (CSD) events; (ii) inhibition of pain sensitization; (iii) blockade of neurogenic inflammation; and/or (iv) increase in cranial vascular tone. Accordingly, the novel antimigraine prophylaxis promises to be more effective, devoid of significant adverse effects (unlike non-specific treatments), and more beneficial to the quality of life of migraine patients.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8–14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10(−7) CHI without CSD [CSD−] vs. 1.17 ± 0.04 × 10(−7) CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD− (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1–2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD− mice (n = 11 CHI CSD−). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

Background We report the first case of a patient who suffered transient focal neurological deficit mimicking stroke following CoronaVac vaccination. However, instead of an ischemic stroke, motor aura was suspected. Case presentations A 24 year-old Thai female presented with left hemiparesis fifteen minutes after receiving CoronaVac. She also had numbness of her left arm and legs, flashing lights, and headaches. On physical examination, her BMI was 32.8. Her vital signs were normal. She had moderate left hemiparesis (MRC grade III), numbness on her left face, arms, and legs. Her weakness continued for 5 days. A brain CT scan was done showing no evidence of acute infarction. Acute treatment with aspirin was given. MRI in conjunction with MRA was performed in which no restricted diffusion was seen. A SPECT was performed to evaluate the function of the brain showing significant hypoperfusion of the right hemisphere. The patient gradually improved and was discharged. Discussions In this study, we present the first case of stroke mimic after CoronaVac vaccination. After negative imaging studies had been performed repeatedly, we reach a conclusion that stroke is unlikely to be the cause. Presumably, this phenomenon could possibly have abnormal functional imaging study. Therefore, we believed that it might be due to cortical spreading depression, like migraine aura, which we had conducted a literature review.

Peri-infarct depolarization (PID), one kind of spreading depolarization, contributes to infarct volume enlargement after ischemic stroke. Astrocytes participate in PIDs by various mechanisms. The roles of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins in astrocytes, however, in PIDs induction and propagation remain unknown. Middle cerebral artery occlusion (MCAO) model was made in 9 GFAP−/−Vim−/− and 9 wild-type (WT) C57BL/6 mice. Using 4-wavelength optical intrinsic signal imaging (OIS), we identified PIDs as consistent, red and blue interaction waves in the cortical reflectance that slowly propagated peripherally from the origin site. Five propagation patterns of PIDs were observed after MCAO in mice, namely, latero-medial, medial-lateral, rostro-caudal, caudo-rostral, and collision. Additionally, the frequency, propagation velocity, and duration of PIDs between GFAP−/−Vim−/− and WT mice were not significantly different (p > 0.05). Furthermore, no significant difference was found in infarct volume and brain edema between the two groups. In conclusion, the 4-wavelength OIS system allows acquisition of high temporal-spatial resolution color images for analyzing temporal-spatial characteristics of PIDs in detail. GFAP and Vim in astrocytes are not involved in PIDs after MCAO in mice.