Publications by authors named "Cenk Ayata"

167 Publications

Rho-Kinase Inhibition Improves the Outcome of Focal Subcortical White Matter Lesions.

Stroke 2022 07 3;53(7):2369-2376. Epub 2022 Jun 3.

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Charlestown (S.A.A., H.X., Y.Z., D.Y.C., J.H.L., T.D.E., A.M., I.T., D.Y., C.A.).

Background: Subcortical white matter lesions are exceedingly common in cerebral small vessel disease and lead to significant cumulative disability without an available treatment. Here, we tested a rho-kinase inhibitor on functional recovery after focal white matter injury.

Methods: A focal corpus callosum lesion was induced by stereotactic injection of N-(1-iminoethyl)-L-ornithine in mice. Fasudil (10 mg/kg) or vehicle was administered daily for 2 weeks, starting one day after lesion induction. Resting-state functional connectivity and grid walk performance were studied longitudinally, and lesion volumes were determined at one month.

Results: Resting-state interhemispheric functional connectivity significantly recovered between days 1 and 14 in the fasudil group (<0.001), despite worse initial connectivity loss than vehicle before treatment onset. Grid walk test revealed an increased number of foot faults in the vehicle group compared with baseline, which persisted for at least 4 weeks. In contrast, the fasudil arm did not show an increase in foot faults and had smaller lesions at 4 weeks. Immunohistochemical examination of reactive astrocytosis, synaptic density, and mature oligodendrocytes did not reveal a significant difference between treatment arms.

Conclusions: These data show that delayed fasudil posttreatment improves functional outcomes after a focal subcortical white matter lesion in mice. Future work will aim to elucidate the mechanisms.
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http://dx.doi.org/10.1161/STROKEAHA.121.037358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245195PMC
July 2022

The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

Stroke 2022 05 31;53(5):1802-1812. Epub 2022 Mar 31.

Departments of Radiology and Biomedical Imaging (B.G.S., J.M.M., F.H.), Yale University, New Haven, CT.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.
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http://dx.doi.org/10.1161/STROKEAHA.121.038047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038686PMC
May 2022

Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition.

J Headache Pain 2022 Mar 14;23(1):36. Epub 2022 Mar 14.

Department of Neurology and Algology, Neuropsychiatry Center, Neuroscience and Neurotechnology Center (NÖROM), Gazi University Faculty of Medicine, Besevler, Ankara, Turkey.

Background/aim: Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.

Methods: Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples.

Results: Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles.

Conclusion: Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.
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http://dx.doi.org/10.1186/s10194-022-01405-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919627PMC
March 2022

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention.

Neurocrit Care 2022 06 7;37(Suppl 1):83-101. Epub 2022 Mar 7.

Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; and the Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health., Berlin, Germany.

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.
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http://dx.doi.org/10.1007/s12028-021-01431-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259543PMC
June 2022

CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis.

J Clin Invest 2022 04;132(8)

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular K+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL.
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http://dx.doi.org/10.1172/JCI149759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012276PMC
April 2022

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization.

Neurocrit Care 2022 06 22;37(Suppl 1):11-30. Epub 2022 Feb 22.

Center for Stroke Research Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1007/s12028-021-01429-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9259542PMC
June 2022

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

J Headache Pain 2022 Jan 21;23(1):12. Epub 2022 Jan 21.

Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, 5th floor, Shouren Building, No. 155, Sec. 2, Linong St., Beitou District, 112, Taipei, Taiwan.

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.
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http://dx.doi.org/10.1186/s10194-022-01384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903561PMC
January 2022

Correction to: Cortical Spreading Depolarizations in a Mouse Model of Subarachnoid Hemorrhage.

Neurocrit Care 2022 Apr;36(2):689

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Charlestown, MA, 02129, USA.

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http://dx.doi.org/10.1007/s12028-022-01447-wDOI Listing
April 2022

Migraine.

Nat Rev Dis Primers 2022 01 13;8(1). Epub 2022 Jan 13.

Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA.

Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1 receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management.
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http://dx.doi.org/10.1038/s41572-021-00328-4DOI Listing
January 2022

Cortical Spreading Depolarizations in a Mouse Model of Subarachnoid Hemorrhage.

Neurocrit Care 2022 06 3;37(Suppl 1):123-132. Epub 2022 Jan 3.

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Charlestown, MA, 02129, USA.

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.
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http://dx.doi.org/10.1007/s12028-021-01397-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250554PMC
June 2022

Intracranial pressure spikes trigger spreading depolarizations.

Brain 2022 03;145(1):194-207

Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.

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.
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http://dx.doi.org/10.1093/brain/awab256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126007PMC
March 2022

Focal Subcortical White Matter Lesions Disrupt Resting State Cortical Interhemispheric Functional Connectivity in Mice.

Cereb Cortex 2021 10;31(11):4958-4969

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.

The corpus callosum is the largest white matter tract and critical for interhemispheric connectivity. Unfortunately, neurocognitive deficits after experimental white matter lesions are subtle and variable, limiting their translational utility. We examined resting state functional connectivity (RSFC) as a surrogate after a focal lesion in the lateral corpus callosum induced by stereotaxic injection of L-NIO in mice. RSFC was performed via optical intrinsic signal imaging through intact skull before and on days 1 and 14 after injection, using interhemispheric homotopic and seed-based temporal correlation maps. We measured the lesion volumes at 1 month in the same cohort. L-NIO induced focal lesions in the corpus callosum. Interhemispheric homotopic connectivity decreased by up to 50% 24 h after L-NIO, partially sparing the visual cortex. All seeds showed loss of connectivity to the contralateral hemisphere. Moreover, ipsilesional motor and visual cortices lost connectivity within the same hemisphere. Sham-operated mice did not show any lesion or connectivity changes. RSFC imaging reliably detects acute disruption of long interhemispheric and intrahemispheric connectivity after a corpus callosum lesion in mice. This noninvasive method can be a functional surrogate to complement neurocognitive testing in both therapeutic and recovery studies after white matter injury.
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http://dx.doi.org/10.1093/cercor/bhab134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491690PMC
October 2021

Cerebral Amyloid Angiopathy-Related Transient Focal Neurologic Episodes.

Neurology 2021 08 20;97(5):231-238. Epub 2021 May 20.

From the Department of Clinical Neurosciences (E.E.S.), Hotchkiss Brain Institute, University of Calgary, Canada; Hemorrhagic Stroke Research Program (A.C., S.M.G.), Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School; Stroke Service and Neurovascular Research Lab (C.A.), Department of Neurology, Massachusetts General Hospital, Boston; and Stroke Research Centre (D.J.W.), University College London Queen Square Institute of Neurology, UK.

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.
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http://dx.doi.org/10.1212/WNL.0000000000012234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356377PMC
August 2021

Spreading depression as an innate antiseizure mechanism.

Nat Commun 2021 04 13;12(1):2206. Epub 2021 Apr 13.

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.
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http://dx.doi.org/10.1038/s41467-021-22464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044138PMC
April 2021

Optical coherence tomography of arteriolar diameter and capillary perfusion during spreading depolarizations.

J Cereb Blood Flow Metab 2021 09 16;41(9):2256-2263. Epub 2021 Feb 16.

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.

Spreading depolarization (SD) is associated with profound oligemia and reduced oxygen availability in the mouse cortex during the depolarization phase. Coincident pial arteriolar constriction has been implicated as the primary mechanism for the oligemia. However, where in the vascular bed the hemodynamic response starts has been unclear. To resolve the origin of the hemodynamic response, we used optical coherence tomography (OCT) to simultaneously monitor changes in the vascular tree from capillary bed to pial arteries in mice during two consecutive SDs 15 minutes apart. We found that capillary flow dropped several seconds before pial arteriolar constriction. Moreover, penetrating arterioles constricted before pial arteries suggesting upstream propagation of constriction. Smaller caliber distal pial arteries constricted stronger than larger caliber proximal arterioles, suggesting that the farther the constriction propagates, the weaker it gets. Altogether, our data indicate that the hemodynamic response to cortical SD originates in the capillary bed.
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http://dx.doi.org/10.1177/0271678X21994013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393288PMC
September 2021

Intravascular Endothelin-1 does not trigger or increase susceptibility to Spreading Depolarizations.

J Headache Pain 2020 Oct 27;21(1):127. Epub 2020 Oct 27.

Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, 6408, Charlestown, MA, 02129, USA.

Objectives: Spreading depolarizations (SD) likely manifest as aura in migraineurs. Triggers are unknown although vascular events have been implicated. Direct carotid puncture has been reported to trigger migraine with aura. The potent vasoconstrictor endothelin-1 (ET-1), which can be released from the endothelium under pathological conditions, may play a role. Here, we tested whether intracarotid ET-1 infusion triggers SD and whether systemic ET-1 infusion increases the susceptibility to SD.

Methods: Carotid infusions were performed in mice (C57BL/6, male) through a catheter placed at the carotid bifurcation via the external carotid artery. Intracarotid ET-1 (1.25 nmol/ml) was infused at various rates (2-16 μl/min) with or without heparin in the catheter and compared with vehicle infusion (PBS with 0.01% acetic acid) or sham-operated mice (n = 5). Systemic infusions ET-1 (1 nmol/kg, n = 7) or vehicle (n = 7) infusions were performed in rats (Sprague-Dawley, male) via the tail vein. Electrical SD threshold and KCl-induced SD frequency were measured after the infusion.

Results: Intracarotid infusion of saline (n = 19), vehicle (n = 7) or ET-1 (n = 12) all triggered SDs at various proportions (21%, 14% and 50%, respectively). These were often associated with severe hypoperfusion prior to SD onset. Heparinizing the infusion catheter completely prevented SD occurrence during the infusions (n = 8), implicating microembolization from carotid thrombi as the trigger. Sham-operated mice never developed SD. Systemic infusion of ET-1 did not affect the electrical SD threshold or KCl-induced SD frequency.

Conclusion: Intravascular ET-1 does not trigger or increase susceptibility to SD. Microembolization was the likely trigger for migraine auras in patients during carotid puncture.
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http://dx.doi.org/10.1186/s10194-020-01194-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590662PMC
October 2020

Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior.

Ann Neurol 2021 01 27;89(1):99-110. Epub 2020 Oct 27.

Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.

Objective: Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior.

Methods: Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice.

Results: A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD-induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point.

Interpretation: Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99-110.
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http://dx.doi.org/10.1002/ana.25926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075185PMC
January 2021

Therapeutic implications of cortical spreading depression models in migraine.

Prog Brain Res 2020 27;255:29-67. Epub 2020 Jun 27.

Department of Medical Research & Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address:

Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.
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http://dx.doi.org/10.1016/bs.pbr.2020.05.009DOI Listing
July 2021

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage.

J Cereb Blood Flow Metab 2021 06 16;41(6):1264-1276. Epub 2020 Sep 16.

Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.

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.
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http://dx.doi.org/10.1177/0271678X20951993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142136PMC
June 2021

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

J Cereb Blood Flow Metab 2021 05 16;41(5):975-985. Epub 2020 Sep 16.

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.
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http://dx.doi.org/10.1177/0271678X20940152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054726PMC
May 2021

Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.

Stroke 2020 10 11;51(10):3083-3094. Epub 2020 Sep 11.

Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (T.Y., T.S., T.T., D.Y.C., T.Q., A.M., C.A.).

Background And Purpose: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture.

Methods: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting.

Results: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups.

Conclusions: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.
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http://dx.doi.org/10.1161/STROKEAHA.120.029651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530050PMC
October 2020

Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations.

Stroke 2020 08 9;51(8):2526-2535. Epub 2020 Jul 9.

Department of Radiology (K.S., D.Y.C., M.B., P.F., T.T., S.A.A., T.Q., T.Y., F.O., C.A.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background And Purpose: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate.

Methods: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice.

Results: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; =0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs.

Conclusions: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.
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http://dx.doi.org/10.1161/STROKEAHA.120.029618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387208PMC
August 2020

Acute sleep deprivation enhances susceptibility to the migraine substrate cortical spreading depolarization.

J Headache Pain 2020 Jul 6;21(1):86. Epub 2020 Jul 6.

Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.

Background: Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models.

Methods: Acute sleep deprivation was achieved using the "gentle handling method", chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of chronic sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold.

Results: Acute sleep deprivation of 6 h (n = 17) or 12 h (n = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls; p = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged. Acute total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (p = 0.037 and p = 0.095, respectively). Chronic partial sleep deprivation in contrast did not affect CSD susceptibility in rats.

Conclusions: Acute but not chronic sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.
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http://dx.doi.org/10.1186/s10194-020-01155-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339460PMC
July 2020

Anti-migraine Calcitonin Gene-Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice.

Ann Neurol 2020 10 7;88(4):771-784. Epub 2020 Aug 7.

Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objective: Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.

Methods: Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro.

Results: Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta.

Interpretation: Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020;88:771-784.
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http://dx.doi.org/10.1002/ana.25831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540520PMC
October 2020

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

Pain 2020 07;161(7):1661-1669

Department of Radiology, Neurovascular Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, United States.

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.
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http://dx.doi.org/10.1097/j.pain.0000000000001856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305968PMC
July 2020

Intravenous Endothelin-1 Infusion Does Not Induce Aura or Headache in Migraine Patients With Aura.

Headache 2020 04 29;60(4):724-734. Epub 2020 Jan 29.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark.

Objective: To investigate whether intravenously infused provokes migraine aura and migraine headache in migraine patients with aura.

Background: Migraine with aura has been associated with endothelial dysfunction and increased stroke risk. The initiating mechanism of migraine aura symptoms is not known. Experimental provocation of migraine headache using vasoactive peptides has provided tremendous advances in the understanding of migraine pathophysiology but substances that can induce migraine aura have not been identified. Endothelin-1 (ET-1), an endogenous, potent vasoconstrictor peptide released from the vascular endothelium, has been proposed to trigger migraine aura. This hypothesis is based on reports of increased plasma ET-1 levels early during the migraine attacks and the observation that ET-1 applied to the cortical surface potently induces the cortical spreading depolarization, the underlying electrophysiological phenomenon of migraine aura, in animals. Further, endothelial damage due to, for example, carotid puncture and vascular pathology is known to trigger aura episodes.

Methods: We investigated whether intravascular ET-1 would provoke migraine aura in patients. Using a two-way crossover, randomized, placebo-controlled, double-blind design, we infused high-dose (8 ng/kg/minutes for 20 minutes) intravenous ET-1 in patients with migraine with typical aura. The primary end-point was the difference in incidence of migraine aura between ET-1 and placebo. Experiments were carried out at a public tertiary headache center (Danish Headache Center, Rigshospitalet Glostrup, Denmark).

Results: Fourteen patients received intravenous ET-1. No patients reported migraine aura symptoms or migraine headache during or up to 24 hours following the ET-1 infusion. Four patients reported mild to moderate headache only on the ET-1 day, 3 patients reported moderate headache on the placebo day, and 1 patient reported mild headache on both days. No serious adverse events occurred during or after infusion.

Conclusions: Provocation of migraine aura by procedures or conditions involving vascular irritation is unlikely to be mediated by ET-1.
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http://dx.doi.org/10.1111/head.13753DOI Listing
April 2020

Mapping optogenetically-driven single-vessel fMRI with concurrent neuronal calcium recordings in the rat hippocampus.

Nat Commun 2019 11 20;10(1):5239. Epub 2019 Nov 20.

Research Group of Translational Neuroimaging and Neural Control, High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, 72076, Tuebingen, Germany.

Extensive in vivo imaging studies investigate the hippocampal neural network function, mainly focusing on the dorsal CA1 region given its optical accessibility. Multi-modality fMRI with simultaneous hippocampal electrophysiological recording reveal broad cortical correlation patterns, but the detailed spatial hippocampal functional map remains lacking given the limited fMRI resolution. In particular, hemodynamic responses linked to specific neural activity are unclear at the single-vessel level across hippocampal vasculature, which hinders the deciphering of the hippocampal malfunction in animal models and the translation to critical neurovascular coupling (NVC) patterns for human fMRI. We simultaneously acquired optogenetically-driven neuronal Ca signals with single-vessel blood-oxygen-level-dependent (BOLD) and cerebral-blood-volume (CBV)-fMRI from individual venules and arterioles. Distinct spatiotemporal patterns of hippocampal hemodynamic responses were correlated to optogenetically evoked and spreading depression-like calcium events. The calcium event-related single-vessel hemodynamic modeling revealed significantly reduced NVC efficiency upon spreading depression-like (SDL) events, providing a direct measure of the NVC function at various hippocampal states.
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http://dx.doi.org/10.1038/s41467-019-12850-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868210PMC
November 2019

Headache after ischemic stroke: A systematic review and meta-analysis.

Neurology 2020 01 6;94(1):e75-e86. Epub 2019 Nov 6.

From the Neurovascular Research Laboratory (A.M.H., C.A.), Department of Radiology, Massachusetts General Hospital, Charlestown; Vascular Division (A.M.H., C.A.) and Headache and Neuropathic Pain Division (A.M.H.), Department of Neurology, Massachusetts General Hospital, Boston; and University of Massachusetts Dartmouth (F.K.).

Objective: Headache associated with ischemic stroke is poorly understood. To gain further insight, we systematically reviewed studies examining the prevalence and characteristics of new-onset poststroke headache.

Methods: Medline and PubMed databases were queried. A total of 1,812 articles were identified. Of these, 50 were included in this systematic review. Twenty were included in a meta-analysis and meta-regression.

Results: Headache occurred in 6%-44% of the ischemic stroke population. Most headaches had tension-type features, were moderate to severe, and became chronic in nature. Meta-analysis using an inverse-variance heterogeneity model revealed a pooled prevalence of 0.14 (95% confidence interval [CI] 0.07-0.23) with heterogeneity among studies. Metaregression revealed a significant association between prevalence and study location, the source population's national human development index (HDI), and study quality. We found higher prevalence in European (0.22, 95% CI 0.14-0.30) and North American (0.15, 95% CI 0.05-0.26) studies compared with Middle Eastern and Asian studies (0.08, 95% CI 0.01-0.18). However, within each region, populations from countries with higher HDI ( = 0.03) and studies with higher quality ( = 0.001) had lower prevalence. Calculated crude odds ratios (ORs) showed that posterior circulation stroke (pooled OR 1.92, 95% CI 1.4-2.64; n = 7 studies) and female sex (pooled OR 1.25, 95% CI 1.07-1.46; n = 11 studies) had greater odds of headache associated with ischemic stroke.

Conclusions: Taken together, these data suggest that headache is common at the onset of or shortly following ischemic stroke and may contribute to poststroke morbidity. Better understanding of headache associated with ischemic stroke is needed to establish treatment guidelines and inform patient management.
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http://dx.doi.org/10.1212/WNL.0000000000008591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011689PMC
January 2020

Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers.

J Cereb Blood Flow Metab 2020 08 9;40(8):1685-1694. Epub 2019 Sep 9.

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Glostrup, Denmark.

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.
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http://dx.doi.org/10.1177/0271678X19874295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370364PMC
August 2020

cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice.

J Cereb Blood Flow Metab 2019 12 18;39(12):2379-2391. Epub 2019 Aug 18.

Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.

Recent works highlight the therapeutic potential of targeting cyclic guanosine monophosphate (cGMP)-dependent pathways in the context of brain ischemia/reperfusion injury (IRI). Although cGMP-dependent protein kinase I (cGKI) has emerged as a key mediator of the protective effects of nitric oxide (NO) and cGMP, the mechanisms by which cGKI attenuates IRI remain poorly understood. We used a novel, conditional cGKI knockout mouse model to study its role in cerebral IRI. We assessed neurological deficit, infarct volume, and cerebral perfusion in tamoxifen-inducible vascular smooth muscle cell-specific cGKI knockout mice and control animals. Stroke experiments revealed greater cerebral infarct volume in smooth muscle cell specific cGKI knockout mice (males: 96 ± 16 mm; females: 93 ± 12 mm, mean±SD) than in all control groups: wild type (males: 66 ± 19; females: 64 ± 14), cGKI control (males: 65 ± 18; females: 62 ± 14), cGKI control with tamoxifen (males: 70 ± 8; females: 68 ± 10). Our results identify, for the first time, a protective role of cGKI in vascular smooth muscle cells during ischemic stroke injury. Moreover, this protective effect of cGKI was found to be independent of gender and was mediated via improved reperfusion. These results suggest that cGKI in vascular smooth muscle cells should be targeted by therapies designed to protect brain tissue against ischemic stroke.
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http://dx.doi.org/10.1177/0271678X19870583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893979PMC
December 2019
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