Episodes Of Cortical Spreading Depression Research Articles

Estrogen, migraine, and vascular risk.

Migraine has a predilection for female sex and the course of symptoms is influenced by life stage (presence of menstrual cycle, pregnancy, puerperium, menopause) and use of hormone therapy, such as hormonal contraception and hormone replacement therapy. Hormonal changes figure among common migraine triggers, especially sudden estrogen drop. Moreover, estrogens can modulate neuronal excitability, through serotonin, norepinephrine, dopamine, and endorphin regulation, and they interact with the vascular endothelium of the brain. The risk of vascular disease, and ischemic stroke in particular, is increased in women with migraine with aura (MA), but the link is unclear. One hypothesis posits for a causal association: migraine may cause clinical or subclinical brain lesions following repeated episodes of cortical spreading depression (CSD) and a second hypothesis that may explain the association between migraine and vascular diseases is the presence of common risk factors and comorbidities. Estrogens can play a differential role depending on their action on healthy or damaged endothelium, their endogenous or exogenous origin, and the duration of their treatment. Moreover, platelet activity is increased in migraineurs women, and it is further stimulated by estrogens.This review article describes the course of migraine during various life stages, with a special focus on its hormonal pathogenesis and the associated risk of vascular diseases.

Migraine with visual aura associated with thicker visual cortex.

Until recent years it was believed that migraine with aura was a disorder causing intermittent neurological symptoms, with no impact on brain structure. However, recent MRI studies have reported increased cortical thickness of visual and somatosensory areas in patients with migraine with aura, suggesting that such structural alterations were either due to increased neuronal density in the areas involved, or a result of multiple episodes of cortical spreading depression as part of aura attacks. Subsequent studies have yielded conflicting results, possibly due to methodological reasons, e.g. small number of subjects. In this cross-sectional study, we recruited females aged 30-60 years from the nationwide Danish Twin Registry. Brain MRI of females with migraine with aura (patients), their co-twins, and unrelated migraine-free twins (controls) were performed at a single centre and assessed for cortical thickness in predefined cortical areas (V1, V2, V3A, MT, somatosensory cortex), blinded to headache diagnoses. The difference in cortical thickness between patients and controls adjusted for age, and other potential confounders was assessed. Comparisons of twin pairs discordant for migraine with aura were also performed. Comparisons were based on 166 patients, 30 co-twins, and 137 controls. Compared with controls, patients had a thicker cortex in areas V2 [adjusted mean difference 0.032 mm (95% confidence interval 0.003 to 0.061), V3A [adjusted mean difference 0.037 mm (95% confidence interval 0.008 to 0.067)], while differences in the remaining areas examined were not statistically significant [adjusted mean difference (95% confidence interval): V1 0.022 (-0.007 to 0.052); MT: 0.018 (-0.011 to 0.047); somatosensory cortex: 0.020 (-0.009 to 0.049)]. We found no association between the regions of interest and active migraine, or number of lifetime aura attacks. Migraine with aura discordant twin pairs (n = 30) only differed in mean thickness of V2 (0.039 mm, 95% CI 0.005 to 0.074). In conclusion, females with migraine with aura have a thicker cortex corresponding to visual areas and our results indicate this may be an inherent trait rather than a result of repeated aura attacks.

Do the accelerating actions of tianeptine and l-arginine on cortical spreading depression interact? An electrophysiological analysis in young and adult rats

In the rat, we previously demonstrated that serotonin-enhancing drugs impair cortical spreading depression (CSD) and that l-arginine (arginine) treatment enhances CSD. Here, we investigated the interaction between topical application of the serotonin uptake enhancer tianeptine and systemic arginine administration on CSD. From postnatal day 7–28, female Wistar rats (n=40) received by gavage 300mg/Kg/day arginine (n=20) or water (n=20). Half of the arginine- or water-treated rats underwent CSD recording at 30–40days of age (young), while the other half was recorded at 90–120days (adult). Following baseline recording (four episodes of CSD), we applied tianeptine solution (10mg/ml) to a rectangular portion of the intact dura mater for 10-min and then elicited CSD. This procedure was repeated three times. Compared to baseline values, CSD velocities and amplitudes following tianeptine application increased, and CSD duration decreased significantly (p<0.05) in both young and adult rats, regardless of treatment group. CSD acceleration caused by systemic treatment with arginine is in agreement with previous findings. Topical cortical application of tianeptine replicated the effect of systemic application, suggesting a cortically based mechanism for tianeptine’s action. However, the absence of interaction between arginine and tianeptine treatments suggests that they probably act through separate mechanisms.

High-mobility group box 1 is an important mediator of microglial activation induced by cortical spreading depression

Single episodes of cortical spreading depression (CSD) are believed to cause typical migraine aura, whereas clusters of spreading depolarizations have been observed in cerebral ischemia and subarachnoid hemorrhage. We recently demonstrated that the release of high-mobility group box 1 (HMGB1) from cortical neurons after CSD in a rodent model is dependent on the number of CSD episodes, such that only multiple CSD episodes can induce significant HMGB1 release. Here, we report that only multiple CSD inductions caused microglial hypertrophy (activation) accompanied by a greater impact on the transcription activity of the HMGB1 receptor genes, TLR2 and TLR4, while the total number of cortical microglia was not affected. Both an HMGB1-neurtalizing antibody and the HMGB1 inhibitor glycyrrhizin abrogated multiple CSD-induced microglial hypertrophy. Moreover, multiple CSD inductions failed to induce microglial hypertrophy in TLR2/4 double knockout mice. These results strongly implicate the HMGB1–TLR2/4 axis in the activation of microglia following multiple CSD inductions. Increased expression of the lysosomal acid hydrolase cathepsin D was detected in activated microglia by immunostaining, suggesting that lysosomal phagocytic activity may be enhanced in multiple CSD-activated microglia.

The missing link: Enhanced functional connectivity between amygdala and visceroceptive cortex in migraine

Migraine is a neurovascular disorder in which altered functional connectivity between pain-modulating circuits and the limbic system may play a role. Cortical spreading depression (CSD), which underlies migraine aura (MWA), induces C-fos expression in the amygdala. The role of CSD and amygdala connectivity in migraine without aura (MwoA) is less clear and may differentiate migraine from other chronic pain disorders. Using resting-state functional MRI, we compared functional connectivity between the amygdala and the cortex in MWA and MWoA patients as well as in healthy subjects and in two other chronic pain conditions not associated with CSD: trigeminal neuralgia (TGN) and carpal tunnel syndrome (CTS). Amygdala connectivity in both MWA and MWoA was increased to the visceroceptive insula relative to all other groups examined. The observed increased connectivity within the limbic/viscerosensory network, present only in migraineurs, adds to the evidence of a neurolimbic pain network dysfunction and may reflect repetitive episodes of CSD leading to the development of migraine pain.

Cortical spreading depression-induced preconditioning in mouse neocortex is lamina specific

Cortical spreading depression (CSD) is able to confer neuroprotection when delivered at least 1 day in advance of an ischemic event. However, its ability to confer neuroprotection in a more immediate time frame has not previously been investigated. Here we have used mouse neocortical brain slices to study the effects of repeated episodes of CSD in layer V and layer II/III pyramidal neurons. In layer V, CSD evoked at 15-min intervals caused successively smaller membrane depolarizations and increases in intracellular calcium compared with the response to the first CSD. With an inter-CSD interval of 30 min this preconditioning effect was much less marked, indicating that preconditioning lasts between 15 and 30 min. A single episode of CSD also provided a degree of protection in oxygen-glucose deprivation (OGD) by significantly lengthening the time a cell could withstand OGD before anoxic depolarization occurred. In layer II/III pyramidal neurons no preconditioning by CSD on subsequent episodes of CSD was observed, demonstrating that the response of pyramidal neurons to repeated CSD is lamina specific. The A1 receptor antagonist 8-cyclopentyl theophylline (8-CPT) reduced the layer V preconditioning in a concentration-related manner. Inhibition of extracellular formation of adenosine by blocking ecto-5'-nucleotidase with α,β-methyleneadenosine 5'-diphosphate prevented preconditioning in most but not all cells. Block of equilibrative nucleoside transporters 1 and 2 with dipyramidole alone or in combination with 6-[(4-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine also prevented preconditioning in some but not all cells. These data provide evidence that rapid preconditioning of one CSD by another is primarily mediated by adenosine.

Critical role of calcitonin gene-related peptide receptors in cortical spreading depression.

Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug topiramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents.

Suppressive effect of chronic peroral topiramate on potassium-induced cortical spreading depression in rats

To evaluate the chronic effect of topiramate (TPM) on cortical spreading depression (CSD), which is thought to be related to migraine aura. Male rats (n = 30) were randomized to once-daily peroral treatment with TPM (50, 100, 200 or 600 mg/kg) or vehicle for 6 weeks. We evaluated the characteristics of CSD induced by topical application of KCl under isoflurane anesthesia and the changes in plasma level of TPM in each group. The effect of single administration of TPM on CSD was also evaluated. After the final administration of TPM, when the plasma level of TPM was high, KCl-induced CSD frequency and CSD propagation velocity were dose-dependently reduced and the interval between CSD episodes was elongated, compared with the vehicle control. However, before the final administration of TPM, when the plasma level was very low, the KCl-induced CSD profile was the same as that in the vehicle control. Single administration of TPM did not alter the CSD profile. Local cerebral blood flow was not significantly altered by chronic administration of TPM. TPM suppressed the frequency and propagation of CSD along the cerebral cortex, and might be a candidate for relief of migraine.

Persistent Increase in Oxygen Consumption and Impaired Neurovascular Coupling after Spreading Depression in Rat Neocortex

Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is the mechanism of migraine, and involved in progressive neuronal injury in stroke and head trauma. Here we tested the hypothesis that single episodes of CSD induced acute hypoxia, and prolonged impairment of neurovascular and neurometabolic coupling. Cortical spreading depression was induced in rat frontal cortex, whereas cortical electrical activity and local field potentials (LFPs) were recorded by glass microelectrodes, cerebral blood flow (CBF) by laser-Doppler flowmetry, and tissue oxygen tension (tpO(2)) with polarographic microelectrodes. Cortical spreading depression increased cerebral metabolic rate of oxygen (CMRO(2)) by 71%+/-6.7% and CBF by 238%+/-48.1% for 1 to 2 mins. For the following 2 h, basal tpO(2) and CBF were reduced whereas basal CMRO(2) was persistently elevated by 8.1%+/-2.9%. In addition, within first hour after CSD we found impaired neurovascular coupling (LFP versus CBF), whereas neurometabolic coupling (LFP versus CMRO(2)) remained unaffected. Impaired neurovascular coupling was explained by both reduced vascular reactivity and suppressed function of cortical inhibitory interneurons. The protracted effects of CSD on basal CMRO(2) and neurovascular coupling may contribute to cellular dysfunction in patients with migraine and acutely injured cerebral cortex.

Brivaracetam inhibits spreading depression in rat neocortical slices in vitro

Epilepsy and migraine are episodic neurological disorders with marked co-morbidity, making migraine common among epileptic patients. Conversely, several antiepileptic drugs (AEDs) are used as migraine-preventive medication. Cortical spreading depression (CSD) represents a transient suppression of bioelectric activity and is considered a key event in migraine and stroke. This study assessed the novel AED candidate brivaracetam (BRV) vs. the chemically related AED levetiracetam in a rat neocortical slice model allowing consistent quantification of drug effects on CSD. CSD episodes were regularly elicited on slices upon delivery of calibrated KCl drops and were recorded via two micropipette electrodes. After control CSDs, the drug was added to the perfusion and five subsequent CSDs were elicited during drug perfusion. Effects were assessed via CSD amplitude ( Ampl) and duration at half-amplitude ( D 1/2). BRV, 10 and 32 μM reduced the Ampl and transiently the D 1/2. Levetiracetam, 32 and 100 μM had no effect on either Ampl or D 1/2. The anti-CSD effect of BRV in this in vitro model might suggest a potential anti-migraine activity of this compound, which warrants further investigation.

Recent Advancements in Anti-Migraine Drug Research: Focus on Attempts to Decrease Neuronal Hyperexcitability

Migraine is a painful, sometimes debilitating disorder, which is frequently associated with various neurological symptoms. Its prevalence in the population is higher than that of any other neurological disorders, thus the burden of this disease on society is considerable. Although the introduction of triptans nearly two decades ago revolutionized the treatment of the disease there is still a huge unmet need regarding drugs with better properties. Formerly, migraine therapy primarily aimed at treating the pathological alterations of meningeal blood vessels that are thought to directly initiate a migraine headache attack. By now, it has been increasingly recognized by drug companies that abnormal neural function may be more important in the development of the disease and also in triggering an attack. Migraine is associated with an increased neuronal excitability and episodes of cortical spreading depression. Understanding the molecular mechanisms underlying the abnormal functioning of over-activated neuronal circuits may help to identify novel anti-migraine drug targets. Besides a general description of the pathophysiology and pharmacotherapy of migraine this review paper aims at discussing the possible drug targets through which migraine-related hyperexcitability and over-excitation can be attenuated. It will be shown how these new ideas appear in the recent patent literature.

Visualization of cortical spreading depression using manganese‐enhanced magnetic resonance imaging

Cortical spreading depression (CSD) was visualized using manganese-enhanced MRI (MEMRI) following topical application of KCl to the exposed rat cortex. MEMRI signal increase in the ipsilateral cortex relative to the contralateral control region was 60 +/- 30% following two KCl applications. MEMRI signal increase for a single (40%) versus double (80%) KCl application suggests an integration effect over successive CSD episodes. CSD-induced MEMRI enhancement involved cortical layers containing dense regions of apical dendrites, supporting the contention that these neuronal structures are necessary for propagation of CSDs. Subcortical enhancement was present in hippocampal and thalamic regions, most likely a result of neuronal connections with cortical layers 4 and 5. These results are consistent with previous studies of CSD using diffusion-weighted MRI and T(2) (*)-weighted MRI and should be useful for investigating CSD itself and its role in other neurologic disorders.

Induction of Tolerance to Focal Ischemia in Rat Brain: Dissociation between Cortical Lesioning and Spreading Depression

Cortical application of KCl has previously been shown to induce tolerance to a subsequent episode of cerebral ischemia. KCl triggers recurrent episodes of cortical spreading depression and produces a small lesion at the cortical application site. To determine whether a cortical lesion alone is sufficient to induce tolerance to ischemia, the authors used 5-mol/L NaCl to precondition rat brain 3 days before permanent occlusion of the middle cerebral artery. NaCl produced a small lesion at the application site without evoking cortical spreading depression. Preconditioning with 5-mol/L NaCl significantly attenuated the decrease in CBF after middle cerebral artery occlusion and reduced the volume of cortical infarction by 35%. The results show that a small cortical lesion, by itself, is sufficient to induce tolerance to ischemia.

Atrial natriuretic peptide expression is increased in rat cerebral cortex following spreading depression: possible contribution to sd-induced neuroprotection

Cortical spreading depression (CSD) is characterised by slowly propagating waves of cellular depolarization and depression and involves transient changes in blood flow, ion balance and metabolism. In cerebral ischaemia, peri-infarct CSD-like depolarization potentiates infarct growth, whereas preconditioning with a CSD episode protects against subsequent ischaemic insult. Thus, many of the long-lasting molecular changes that occur in CSD-affected tissue are presumed to be part of a ‘neuroprotective cascade.’ 3′,5′-Cyclic guanosine monophosphate (cGMP) has been shown to be a neuroprotective mediator and the nitric oxide system, which increases cGMP production by soluble guanylate cyclase, is up-regulated by CSD. Atrial and C-type natriuretic peptide (ANP/CNP) are present in cerebral cortex and their actions are mediated via particulate guanylate cyclase receptors and cGMP production. Therefore, in further efforts to characterise the role of cGMP-related systems in CSD and neuroprotection, this study investigated possible changes in cortical natriuretic peptide expression following acute, unilateral CSD in rats. Using in situ hybridisation, significant 20–80% increases in ANP mRNA were detected in layers II and VI of ipsilateral cortex at 6 h and 1–14 days after CSD. Ipsilateral cortical levels were again equivalent to control contralateral values after 28 days. Assessment of cortical concentrations of ANP immunoreactivity by radioimmunoassay revealed a significant 57% increase at 7 days after CSD. Despite using a sensitive signal-amplification protocol, authentic ANP-like immunostaining was readily detected in subcortical nerve fibres, but was not reliably detected in normal or CSD-affected neocortex, suggesting the presence of very low levels, and/or active or differential processing of the peptide. Cortical CNP mRNA levels are not altered by CSD, indicating the specificity of the observed effects. Overall, these novel findings demonstrate a prolonged increase in cortical ANP expression after an acute episode of CSD. The overlap between the described time course of CSD-induced protection against ischaemic insult and demonstrated increases in ANP levels, suggest that ANP (like nitric oxide) may contribute to CSD-induced neuroprotection, via effects on cGMP production and other signal-transduction pathways.

Cortical spreading depression and gene regulation: relevance to migraine.

Ann Neurol. 2002;51:499‐506.Cortical spreading depression (CSD) may be the underlying mechanism of migraine aura. The role of CSD in initiating a migraine headache remains to be determined, but it might involve specific changes in gene expression in the brain. To examine these changes, four episodes of CSD at 5‐minute intervals were induced in the mouse brain by application of 300 mM KCl, and gene expression was examined 2 hours later using cDNA array and reverse transcriptase‐polymerase chain reaction. Controls consisted of groups that received anesthesia only, attachment of recording electrodes only, and application of 0.9% NaCl. Of the over 1180 genes examined in our experiments, those consistently regulated by CSD included vasoactive peptides; the vasodilator atrial natriuretic peptide was induced by CSD, while the vasoconstrictor neuropeptide Y was downregulated. Other genes specifically regulated by CSD were involved in oxidative stress responses (major prion protein, glutathione‐S‐transferase‐5, and apolipoprotein E). L‐type calcium channel mRNA was upregulated. In summary, CSD regulates genes that are intrinsic to its propagation, that identify accompanying vascular responses as a potential source of pain, and that protect against its potential pathological consequences. We believe these observations have strong relevance to the mechanisms of migraine and its outcomes. Comment: Dr. Welch's group is systematically searching for gene expression targets which may lead to improvement both in understanding migraine at a molecular level and in development of new treatment strategies. SJT

Cortical spreading depression causes a long-lasting decrease in cerebral blood flow and induces tolerance to permanent focal ischemia in rat brain.

Cortical spreading depression (CSD) has previously been shown to induce tolerance to a subsequent episode of transient cerebral ischemia. The objective of the present study was to determine whether CSD also induces tolerance to permanent focal ischemia and, if so, whether tolerance may be mediated by alterations in cerebral blood flow (CBF). Sprague-Dawley rats were preconditioned by applying potassium chloride to one hemisphere for 2 hours, evoking 19 +/- 5 episodes of CSD (mean +/- SD, n = 19). Three days later, the middle cerebral artery (MCA) was permanently occluded using an intraluminal suture. In a subset of animals, laser Doppler blood flow (LDF) was monitored over the parietal cortex before and during the first 2 hours of MCA occlusion. Preconditioning with CSD reduced the hemispheric volume of infarction from 248 +/- 115 mm3 (n = 18) in sham-conditioned animals to 161 +/- 81 mm3 (n = 19, P< 0.02). Similarly, CSD reduced the neocortical volume of infarction from 126 +/- 82 mm3 to 60 +/- 61 mm3 (P < 0.01). Moreover, preconditioning with CSD significantly improved LDF during MCA occlusion from 21% +/- 7% (n = 9) of preischemic baseline in sham-conditioned animals to 29% +/- 9% (n = 7, P< 0.02). Preconditioning with CSD therefore preserved relative levels of CBF during focal ischemia and reduced the extent of infarction resulting from permanent MCA occlusion. To determine whether CSD may have altered preischemic baseline CBF, [14 C]iodoantipyrine was used in additional animals to measure CBF 3 days after CSD conditioning or sham conditioning. CSD, but not sham conditioning, significantly reduced baseline CBF in the ipsilateral neocortex to values 67% to 75% of those in the contralateral cortex. Therefore, CSD causes a long-lasting decrease in baseline CBF that is most likely related to a reduction in metabolic rate. A reduction in the rate of metabolism may contribute to the induction of tolerance to ischemia after preconditioning with CSD.

Cortical spreading depression and gene regulation: relevance to migraine.

Cortical spreading depression (CSD) may be the underlying mechanism of migraine aura. The role of CSD in initiating a migraine headache remains to be determined, but it might involve specific changes in gene expression in the brain. To examine these changes, four episodes of CSD at 5-minute intervals were induced in the mouse brain by application of 300mM KCl, and gene expression was examined 2 hours later using cDNA array and reverse transcriptase-polymerase chain reaction. Controls consisted of groups that received anesthesia only, attachment of recording electrodes only, and application of 0.9% NaCl. Of the over 1,180 genes examined in our experiments, those consistently regulated by CSD included vasoactive peptides; the vasodilator atrial natriuretic peptide was induced by CSD, while the vasoconstrictor neuropeptide Y was downregulated. Other genes specifically regulated by CSD were involved in oxidative stress responses (major prion protein, glutathione-S-transferase-5, and apolipoprotein E). L-type calcium channel mRNA was upregulated. In summary, CSD regulates genes that are intrinsic to its propagation, that identify accompanying vascular responses as a potential source of pain, and that protect against its potential pathological consequences. We believe these observations have strong relevance to the mechanisms of migraine and its outcomes.

Dose-dependent induction of mRNAs encoding brain-derived neurotrophic factor and heat-shock protein-72 after cortical spreading depression in the rat

Previous studies have demonstrated that cortical spreading depression (CSD) increases the expression of putative neuroprotective proteins. The objective of the present study was to elucidate the relationship between the number of episodes of CSD and steady-state levels of mRNAs encoding brain-derived neurotrophic factor (BDNF), heat-shock protein-72 (hsp72) and c-fos. Wistar rats were administered one, five, or twenty-five episodes of CSD evoked by application of 2 M KCl to the frontal cortex of one hemisphere. Animals were permitted to recover for 30 min, 2 h or 24 h prior to sacrifice. Total RNA was isolated from the parietal cortex of each hemisphere and analyzed using Northern blots. At 30 min recovery, levels of BDNF mRNA were not significantly elevated after 1 episode of CSD, but were increased 4-fold after five episodes of CSD and 11-fold after twenty-five episodes of CSD, relative to levels in the contralateral hemisphere. At 2 h recovery, BDNF mRNA levels increased 2-, 3- and 9-fold, respectively. At 24 h, BDNF mRNA had returned to control levels in all groups. Thus, CSD increased levels of BDNF mRNA in a dose-dependent fashion at the early recovery times. Hsp72 mRNA was below the level of detection after 1 and 5 episodes of CSD. However, after twenty-five episodes of CSD, hsp72 mRNA levels were increased in the ipsilateral hemisphere at 30 min and 2 h recovery. Unlike levels of BDNF and hsp72 mRNA, levels of c-fos mRNA were increased nearly to the same extent at 30 min and 2 h after one, five or twenty-five episodes of CSD before returning to control by 24 h recovery. These results demonstrate that CSD triggers a dose-dependent increase in the expression of genes encoding neuroprotective proteins, which may mediate tolerance to ischemia induced by CSD.

Recurring episodes of spreading depression are spontaneously elicited by an intracerebral hemorrhage in the swine

Intracranial bleeding damages the surrounding tissue in a complex fashion that involves contamination by blood-borne products and loss of ionic homeostasis. We used electrophysiological techniques to examine the functional changes in the developing intracerebral bleed and in surrounding regions using an in vivo swine model. Intracerebral hemorrhage (ICH) was induced by collagenase injection into the primary somatosensory cortex (SI). Somatic evoked potential (SEP) elicited by electrical stimulation of the contralateral snout as well as changes in DC-coupled potential were monitored in the SI from the time of collagenase injection in order to measure the effects of ICH. The SEP decreased in amplitude within minutes of the intracerebral injection. Its short-latency component was abolished within the first hour after collagenase injection without any sign of recovery for the duration of the experiment. As the SEP started decreasing in amplitude, we observed spontaneous, recurring episodes of cortical spreading depression (SD) as early as 20 min post-injection. The timing of SDs in SI is consistent with our interpretation that SDs were initially generated at multiple sites adjacent to the lesion core and propagated into the surrounding area. With time, SD became less frequent near the injection site, shifting to more distant electrodes in the surrounding area. Our results indicate that ICH leads to the reduction in SEP amplitude and induces spontaneous episodes of SD. Loss of ionic homeostasis is most likely the physiological basis for the SEP change and for the induction of SD. Recurring SD spontaneously generated in experimental ICH needs further study in humans with ICH.

Scanning Laser-Doppler Flowmetry of Rat Cerebral Circulation during Cortical Spreading Depression

Scanning laser-Doppler flowmetry (SLDF) generates two-dimensional images of blood flow. This study compared SLDF to conventional laser-Doppler flowmetry (LDF) in the cerebral circulation. Test stimuli were episodes of cortical spreading depression (CSD) elicited in brains of halothane anaesthetised rats (n = 9). The LDF instrument used two wavelengths of laser light to record relative changes of cerebral blood flow (CBF) up to an approximate depth of 250 µm (543 nm) and 500 µm (780 nm). Under resting conditions, SLDF images showed a heterogeneous pattern of flow in pial vessels with high flow rates in arterioles, and lower rates in venules and small vessels (<30 µm). Arterioles constituted about 6%, venules 12% and small vessels 2% of the image area, while approximately 80% were background with a laser-Doppler signal corresponding to zero calibration. During CSD, the relative increase of area was largest for small vessels and less for venules and arterioles. Similar changes were observed for blood flow in the three vessel structures. For both wavelengths of LDF, flow changes correlated with SLDF (r ≈ 0.7). In conclusion, SLDF provides images of flow in pial vessels and capillaries at, or just beneath the cortical surface. SLDF and LDF are complementary, but cannot substitute for one another as they measure flow in different layers of the cortex.