Cortical Spreading Depression Threshold Research Articles

Mechanisms of initiation of cortical spreading depression

BackgroundThere is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in the brain of migraineurs remain unknown, and the mechanisms of initiation of experimentally induced CSD in normally metabolizing brain tissue remain incompletely understood and controversial. Here, we investigated the mechanisms of CSD initiation by focal application of KCl in mouse cerebral cortex slices.MethodsHigh KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded. This was done before and after the application of a specific blocker of either NMDA or AMPA glutamate receptors (NMDARs, AMPARs) or voltage-gated Ca2+ (CaV) channels. If the drug blocked CSD, stimuli up to 12–15 times the threshold were applied.ResultsBlocking either NMDARs with MK-801 or CaV channels with Ni2+ completely inhibited CSD initiation by both CSD threshold and largely suprathreshold KCl stimuli. Inhibiting AMPARs with NBQX was without effect on the CSD threshold and velocity. Analysis of the CSD subthreshold and threshold neuronal depolarizations in control conditions and in the presence of MK-801 or Ni2+ revealed that the mechanism underlying ignition of CSD by a threshold stimulus (and not by a just subthreshold stimulus) is the CaV-dependent activation of a threshold level of NMDARs (and/or of channels whose opening depends on the latter). The delay of several seconds with which this occurs underlies the delay of CSD initiation relative to the rapid neuronal depolarization produced by KCl.ConclusionsBoth NMDARs and CaV channels are necessary for CSD initiation, which is not determined by the extracellular K+ or neuronal depolarization levels per se, but requires the CaV-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. Our data give insights into potential mechanisms of CSD initiation in migraine.

Cortical spreading depression can be triggered by sensory stimulation in primed wild type mouse brain: a mechanistic insight to migraine aura generation

BackgroundUnlike 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.MethodsCortex 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 α2 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.ResultsAfter 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.ConclusionsNormal 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.

Different characteristics of cortical spreading depression in the sleep and wake states.

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±9.7s vs. 10.8±5.8s, p=0.037, n=6mice). 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±8:05min:s, p=0.012, n=6mice). The threshold for CSD and kinetics of associated CBV changes were correlated with the time since falling asleep or awakening (n=47 CSDs in 6mice). 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 30-60min 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±0.8Hz, p=0.002, n=5), whereas when triggered in the sleep state there was a transient increase in HR (from 7.5±0.4Hz to 9.3±1.1Hz, 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.

Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model

BackgroundNoninvasive 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.MethodsVarious 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.ResultsnVNS 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.ConclusionsOur study provides insight on optimal nVNS parameters to suppress CSD and suggests its benefit on CSD-induced neuroinflammation and trigeminovascular activation in migraine treatment.

Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 2.

Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in ATP1A2 exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the Atp1a2 orthologous gene. To investigate the characteristics of cortical spreading depression in a mouse model with E700K mutation in the Atp1a2. Cortical spreading depression was induced by applying stepwise increases of KCl concentration or electrical stimulation intensity to C57BL/6J-Tg(Atp1a2*E700K)9151Kwk mice (Tg, both sexes) and corresponding wild-type animals. Under urethane anesthesia, the responsiveness and threshold to cortical spreading depression were examined and the distribution of c-Fos expression, a neuronal activity marker, was immunohistochemically determined. Overall, Tg mice showed significantly faster propagation velocity (p < 0.01) and longer full-width-at-half-maximum (p < 0.01) than wild-type animals, representing a slower recovery from direct current potential deflection. The cortical spreading depression threshold tended to be lower in Tg, especially in females. c-Fos-positive cells were significantly enhanced in the ipsilateral somatosensory cortex, piriform cortex, amygdala and striatum (each p < 0.05 vs. contralateral side). Numbers of c-Fos positive cells were significantly higher in the ipsilateral amygdala of Tg, as compared with wild-type animals (p < 0.01). The effect of cortical spreading depression may be greater in E700K transgenic mice than that in wild-type animals, while the threshold for cortical spreading depression shows little change. Higher c-Fos expression in the amygdala may indicate alterations of the limbic system in Tg, suggesting an enhanced linkage between cortical spreading depression and amygdala connectivity in familial hemiplegic migraine 2 patients.

Vagus nerve stimulation inhibits cortical spreading depression exclusively through central mechanisms.

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.

Stress modulates cortical excitability via α-2 adrenergic and glucocorticoid receptors: As assessed by spreading depression

An increase in cortical excitability may be one of the factors mediating stress-induced vulnerability to neuropsychiatric disorders. Since stress increases extracellular glutamate and predisposes to migraine with aura attacks, we aimed to study the effect of stress on cortical spreading depression (CSD), the biological substrate of migraine aura and a measure of cortical excitability. CSD was induced by increasing concentrations of KCl applied over the dura with 5-minute intervals and recorded from parieto-occipital cortex to assess the CSD-induction threshold in acutely-stressed, chronically-stressed and naive mice. To study the mechanisms of acute stress-induced decrease in CSD threshold, we systemically administered clonidine, yohimbine, propranolol, CRH1 receptor antagonist NBI27914, mifepristone and spironolactone at doses shown to be effective on stress as well as a central noradrenergic neurotoxin (DSP-4) before acute stress. CSD threshold was significantly lowered by acute and chronic stress as well as central noradrenergic denervation. Clonidine and mifepristone further decreased the CSD threshold below the acute stress-induced levels, whereas yohimbine reversed the acute stress-induced decrease in CSD threshold compared to the saline-injected and stressed control groups. Propranolol, NBI27914 and spironolactone did not modify the effect of acute stress on CSD threshold. Stress increases cortical excitability as illustrated by a decrease in CSD-induction threshold. This action of acute stress is mediated by α2-adrenergic and glucocorticoid receptors. The decrease in CSD threshold may account for the stress-induced susceptibility to migraine. CSD may be used as a tool to study the link between stress-related disorders and cortical excitability.

Inadequate brain glycogen or sleep increases spreading depression susceptibility.

Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K+ concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches. We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD. DAB caused neuronal pannexin-1 large pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking down the neuronal lactate transporter MCT2 with an antisense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly delivered phloretin reduced the CSD threshold. In vivo recordings with a K+ -sensitive/selective fluoroprobe, Asante Potassium Green-4, revealed that DAB treatment or SD caused a significant rise in extracellular K+ during whisker stimulation, illustrating the critical role of glycogen in extracellular K+ clearance. Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lower the CSD threshold. Therefore, conditions that limit energy supply to synapses (eg, SD) may predispose to migraine attacks, as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. Ann Neurol 2018;83:61-73.

Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders

Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome-wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients.

Vision and migraine.

Migraine, a common brain disorder, disrupts vision more than any other motor or sensory function. The possible visual aura symptoms vary from occasional small flashes of light to complex visual hallucinations, the stereotyped teichopsia being the most typical pattern. It is unclear as to why aura occurs serendipitously, sometimes preceding, but also occurring after the headache, and why aura can present with multiple phenotypes. To better understand the nature of visual disturbances in migraine, 4 aspects must be considered: What are the visual perceptions in migraine; why vision is affected in migraine; the role of cortical spreading depression (CSD); how does vision could affect migraine. Evidence supporting each of these topics is reviewed. CSD travels at a similar pace as the march of symptoms in the visual field. Functional neuroimaging studies show spreading changes compatible with CSD regardless of aura. Computerized models reproducing the CSD march on the visual cortex predict a sensory experience compatible with naturally occurring visual auras. Rather than spreading in all directions, these models suggest that CSD moves preferentially in one direction. Migraine-preventive drugs increase the CSD threshold and reduce CSD velocity. Blind migraineurs may present atypical visual aura, with more colors, shorter duration, different shapes, and atypical symptoms, such as auditory experiences. CSD is the underlying phenomenon in migraine with and without aura. In migraine without aura, CSD probably does not run over silent areas of the cortex, but rather does not reach symptomatology threshold. Normal vision is important in migraine, as lack of sight may change the visual experience during migraine aura, probably due to cortical reorganization and changes in local susceptibility to CSD.

Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache

The objective of this article is to evaluate electrically evoked thresholds for cortical spreading depression (CSD) and stress-induced activation of trigeminal afferents in a rat model of medication-overuse headache (MOH). Sumatriptan or saline was delivered subcutaneously by osmotic minipump for six days to Sprague-Dawley rats. Two weeks after pump removal, animals were anesthetized and recording/stimulating electrodes implanted. The animals were pretreated with vehicle or topiramate followed by graded electrical stimulation within the visual cortex. CSD events were identified by decreased EEG amplitude and DC potential shift. Additional unanesthetized sumatriptan or saline-pretreated rats were exposed to bright light environmental stress and periorbital and hindpaw withdrawal thresholds were measured. Following CSD stimulation or environmental stress, immunohistochemical staining for Fos in the trigeminal nucleus caudalis (TNC) was performed. Sumatriptan pre-exposure significantly decreased electrical stimulation threshold to generate a CSD event. Topiramate normalized the decreased CSD threshold as well as stress-induced behavioral withdrawal thresholds in sumatriptan-treated rats compared to saline-treated animals. Moreover, CSD and environmental stress increased Fos expression in the TNC of sumatriptan-treated rats, and these effects were blocked by topiramate. Environmental stress did not elicit cutaneous allodynia or elevate TNC Fos expression in saline-treated rats. A previous period of sumatriptan exposure produced long-lasting increased susceptibility to evoked CSD and environmental stress-induced activation of the TNC that was prevented by topiramate. Lowered CSD threshold, and enhanced consequences of CSD events (increased activation of TNC), may represent an underlying biological mechanism of MOH related to triptans.

Minimum Conditions for the Induction of Cortical Spreading Depression: Implications for Migraine with Aura (S16.002)

Objective: Determine whether cortical spreading depression can be induced under conditions physiologically compatible with migraine. Background Cortical spreading depression (CSD) is thought to be the mechanism of the migraine aura. If so, it must occur in awake humans, be focally inducible, and not be overtly injurious. In contrast, laboratory models of CSD use conditions that are associated with brain injury in humans. It is important to define the parameters under which CSD can be triggered, and determine whether any of these are plausible in migraine aura. Design/Methods: We used a novel microfluidic device to precisely vary extracellular potassium concentration (Ke) as well as the area exposed to this increased Ke, in a mouse brain slice model. Ke was varied over a range from 15 to 140 mM above normal baseline of 3 mM. Microfluidic port radius was varied from 75 to 250 µm. Whole slice perfusion was also performed. Results: We found that CSD was inducible with small areas exposed to high Ke, and large areas exposed to lower Ke levels, in an approximately hyperbolic relationship. For elevations in Ke unlikely to be associated with tissue damage ( 300 µm (on the order of magnitude of a cortical column or penetrating artery territory). Smaller areas supported CSD when Ke was raised to levels that can only be achieved by cell lysis. Perfusion of the whole brain slice yielded the lowest CSD threshold (15 mM Ke). Conclusions: Our results show that relatively large focal regions must be depolarized to generate CSD in a manner compatible with migraine aura. However they also suggest that the induction of CSD in migraine is physiologically plausible. Supported by: NIH NS 059072, NS 070084 (KCB). Disclosure: Dr. Brennan has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Lopez-Valdes has nothing to disclose. Dr. Charles has received personal compensation for activites with MAP Pharmaceuticals and Merck & Co., Inc. Dr. Charles has received research support from MAP Pharmaceuticals. Dr. Ju has nothing to disclose.

Role of different voltage-gated Ca2+ channels in cortical spreading depression: Specific requirement of P/Q-type Ca2+ channels

Gain-of-function mutations in CaV2.1 (P/Q-type) Ca2+ channels cause familial hemiplegic migraine type 1 (FHM1), a subtype of migraine with aura. Knockin (KI) mice carrying FHM1 mutations show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We recently studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 KI mice, and showed i. gain-of-function of excitatory neurotransmission, due to increased action potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, and ii. a causative link between enhanced glutamate release and facilitation of CSD induced by brief pulses of high K+ in cortical slices.1 Here, we show that after blockade of either the P/Q-type Ca2+ channels or the NMDA receptors, CSD cannot be induced in wild-type mouse cortical slices. In contrast, blockade of N- or R-type Ca2+ channels has only a small inhibitory effect on CSD threshold and velocity of propagation. Our findings support a model in which Ca2+ influx through presynaptic P/Q-type Ca2+ channels with consequent release of glutamate from recurrent cortical pyramidal cell synapses and activation of NMDA receptors are required for initiation and propagation of the CSD involved in migraine.

The Effect of Prophylactic Medications on TMS for Migraine Aura

Low frequency transcranial magnetic stimulation (TMS) has recently been shown to be effective for the acute treatment of migraine with aura. TMS has recently been shown to inhibit cortical spreading depression (CSD). Prophylactic medications (PM) may reduce the frequency of migraine attacks by elevating CSD threshold. The interaction between PM and TMS is unknown. Subgroup analysis was performed on a double-blind, Sham-controlled study that evaluated the efficacy and safety of TMS for the acute treatment of migraine with aura. Analysis of the primary efficacy endpoint pain-free at 2 hours (pain-free rate [PFR]) between TMS and Sham groups was performed based on the non-randomized use of PM. A total of 164 subjects eligibly treated at least 1 migraine with aura attack with TMS (n = 82) or Sham stimulation (n=82). Baseline pain intensity at the time of treatment for the first attack was no pain (31%), mild (40%), moderate (23%), or severe pain (6%). PM were used by 37% (31/82) and 41.5% (34/82) in the Sham- and TMS-treated patients, respectively. Sham patients on no PM (Sham without) had significantly higher PFR than Sham-treated patients on PM (Sham with) (P = .0014). There was no difference in PFR between TMS-treated patients on (TMS with) or off (TMS without) PM (P = .5513). However, TMS with had significantly higher PFR than Sham with patients (P= .002). There was no difference in PFR between TMS without and Sham without patients (P = .4061). Prophylactic medications do not appear to influence the treatment response to TMS. The better response in Sham-treated patients not on PM may indicate a more responsive subgroup or different patient phenotype than those currently using PM. These findings will need to be verified in a larger patient sample randomized by presence or absence of PM.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine

Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

Gabapentin Suppresses Cortical Spreading Depression Susceptibility

Cortical spreading depression (CSD) is an intense depolarization wave implicated in the pathophysiology of brain injury states and migraine aura. As Ca(v)2.1 channels modulate CSD susceptibility, we tested gabapentin, which inhibits Ca(v)2.1 through high-affinity binding to its alpha(2)delta subunit, on CSD susceptibility in anesthetized rats. Gabapentin, 100 or 200 mg/kg, elevated the electrical threshold for CSD and diminished recurrent CSDs evoked by topical KCl, when administered 1 hour before testing. With its favorable safety and tolerability profile, gabapentin may have a role in suppression of injury depolarizations in stroke, intracranial hemorrhage, and traumatic brain injury.

High cortical spreading depression susceptibility and migraine‐associated symptoms in Cav2.1 S218L mice

The CACNA1A gene encodes the pore-forming subunit of neuronal Ca(V)2.1 Ca2+ channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma. We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences. Cacna1a(S218L) mice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage-dependent negative shift in voltage dependence of Ca(V)2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1a(S218L) mice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus. The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema.

History of migraine with aura and cortical spreading depression from 1941 and onwards

Several personal descriptions of migraine with aura from 1870 onwards reported a slow, gradual progression of symptoms. Lashley in 1941 meticulously chartered his own auras and concluded that the symptomatology reflected a cortical process progressing with a speed of 3 mm/min across the primary visual cortex. Leão described cortical spreading depression (CSD) in rabbits in 1944 and noticed its similarity to the migraine aura. Despite these scattered pieces of evidence, the prevailing theory was that the migraine aura was caused by a vasospasm and cortical ischaemia. The advent of a technique for measurements of regional cerebral blood flow (rCBF) in 1974 made it possible to detect spreading oligaemia during migraine aura. Between 1981 and 1990 a series of studies of rCBF during migraine attacks showed reduced brain blood flow posteriorly spreading slowly and contiguously anteriorly and crossing borders of supply of major cerebral arteries. These observations refuted the ischaemic hypothesis. The human studies showed initial hyperaemia followed by prolonged hypoperfusion. The relation between aura and CSD was known to cause short-lasting, and therefore not obvious vasodilation and it was considerably strengthened by the demonstration of a long-lasting oligaemia in rats in the wake of CSD. In the primates CSD is not easily elicited, but it has in recent years been clearly demonstrated in patients with brain trauma and stroke. Finally, mutations for familial hemiplegic migraine have been expressed in mice and lower the threshold for CSD. The seminal papers on rCBF and CSD published in the 1980s caused a dramatic shift in our concepts of migraine aura. They moved attention from ischaemia to CSD and thereby to the brain itself, and paved the way for subsequent discoveries of brainstem mechanisms.

Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice

The association between the clinical use of nitroglycerin (NTG) and headache has led to the examination of NTG as a model trigger for migraine and related headache disorders, both in humans and laboratory animals. In this study in mice, we hypothesized that NTG could trigger behavioural and physiological responses that resemble a common manifestation of migraine in humans. We report that animals exhibit a dose-dependent and prolonged NTG-induced thermal and mechanical allodynia, starting 30-60 min after intraperitoneal injection of NTG at 5-10 mg/kg. NTG administration also induced Fos expression, an anatomical marker of neuronal activity in neurons of the trigeminal nucleus caudalis and cervical spinal cord dorsal horn, suggesting that enhanced nociceptive processing within the spinal cord contributes to the increased nociceptive behaviour. Moreover, sumatriptan, a drug with relative specificity for migraine, alleviated the NTG-induced allodynia. We also tested whether NTG reduces the threshold for cortical spreading depression (CSD), an event considered to be the physiological substrate of the migraine aura. We found that the threshold of CSD was unaffected by NTG, suggesting that NTG stimulates migraine mechanisms that are independent of the regulation of cortical excitability.

Possible Precipitation of Migraine Attacks with Prophylactic Treatment

The initiation of a prophylactic treatment in a migraine sufferer depends upon the stratification of the patient’s frequency of attacks and the disability they cause, as well as the patient’s acute consumption and comorbid diseases. We report on 14 patients who were among a group of 618 migraine sufferers who received a new preventative treatment. These 14 patients developed an increase in the frequency of their migraine attacks that was possibly induced by this new prophylactic treatment. The clinical description of the migraine attacks remained the same but the frequency of the attacks of migraine without aura was dramatically increased. This is, to our knowledge, the first description of a possible precipitation of attacks of migraine without aura with a prophylactic treatment. There is no link with a specific class of prophylactic treatment. We hypothesize that the migraine sufferers who experienced aggravation after the new prophylactic drug had been introduced had a paradoxical decrease in the induction threshold for cortical spreading depression (CSD). Mechanisms of such a decrease are unknown and are probably multifactorial, but changes in serotonin neurotransmission have been experimentally demonstrated to modify cortical excitability and favour CSD. The aggravation was described only for attacks without aura. However, with only 14 patients, it is not possible to predict whether suffering from that the type of migraine is a factor that predisposes a patient to aggravation. While additional cases are necessary, physicians should be aware of the possibility that prophylactic treatment may exacerbate migraine attacks.