Publications by authors named "Cenk Ayata"

156 Publications

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

Cereb Cortex 2021 May 25. Epub 2021 May 25.

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
May 2021

Cerebral Amyloid Angiopathy-Related Transient Focal Neurologic Episodes.

Neurology 2021 May 20. Epub 2021 May 20.

Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA, USA.

Transient focal neurological 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 transient ischemic attacks (TIAs) or other transient neurological 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 neurological 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
May 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 Feb 16:271678X21994013. 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
February 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
June 2020

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage.

J Cereb Blood Flow Metab 2021 Jun 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 May 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

Which Spreading Depolarizations Are Deleterious To Brain Tissue?

Neurocrit Care 2020 02;32(1):317-322

Department of Neurosurgery, University of Cincinnati (UC) College of Medicine, Cincinnati, OH, USA.

Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.
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http://dx.doi.org/10.1007/s12028-019-00776-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002178PMC
February 2020

What Should a Clinician Do When Spreading Depolarizations are Observed in a Patient?

Neurocrit Care 2020 02;32(1):306-310

Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.

The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in the September of 2018 devoted a section to address the question, "What should a clinician do when spreading depolarizations are observed in a patient?" Discussants represented a wide range of expertise, including neurologists, neurointensivists, neuroradiologists, neurosurgeons, and pre-clinical neuroscientists, to provide both clinical and basic pathophysiology perspectives. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was formally collated, reviewed, and incorporated into the final document which was subsequently approved by all authors.
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http://dx.doi.org/10.1007/s12028-019-00777-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980932PMC
February 2020

Relief Following Chronic Stress Augments Spreading Depolarization Susceptibility in Familial Hemiplegic Migraine Mice.

Neuroscience 2019 09 9;415:1-9. Epub 2019 Jul 9.

Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address:

Cortical spreading depolarization (CSD) is the electrophysiological substrate of migraine aura, and a putative trigger of trigeminovascular activation and migraine headache. Many migraineurs report stress or relief after a stress triggers an attack. We tested whether various stress conditions might modulate CSD susceptibility and whether this is dependent on genetic factors. Male and female wild type and familial hemiplegic migraine type1 (FHM1) knock-in mice heterozygous for the S218L missense mutation were subjected to acute or chronic stress, or chronic stress followed by relief (36 h). Acute stress was induced by restraint and exposure to bright light and white noise (3 h). Chronic stress was induced for 28 days by two cycles of repeated exposure of mice to a rat (7 days), physical restraint (3 days), and forced swimming (3 days). Electrical CSD threshold and KCl-induced (300 mM) CSD frequency were determined in occipital cortex in vivo at the end of each protocol. Relief after chronic stress reduced the electrical CSD threshold and increased the frequency of KCl-induced CSDs in FHM1 mutants only. Acute or chronic stress without relief did not affect CSD susceptibility in either strain. Stress status did not affect CSD propagation speed, duration or amplitude. In summary, relief after chronic stress, but not acute or chronic stress alone, augments CSD in genetically susceptible mice. Therefore, enhanced CSD susceptibility may explain why, in certain patients, migraine attacks typically occur during a period of stress relief such as weekends or holidays.
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http://dx.doi.org/10.1016/j.neuroscience.2019.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731136PMC
September 2019

Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex.

J Cereb Blood Flow Metab 2020 05 26;40(5):1117-1131. Epub 2019 Jun 26.

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

Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical , and mRNA expression peaking around 1, 2 and 4 h, respectively. and were only modestly elevated. A single CSD also increased , and , and revealed an ultra-early response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.
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http://dx.doi.org/10.1177/0271678X19859381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181092PMC
May 2020

Pathophysiology of Lacunar Stroke: History's Mysteries and Modern Interpretations.

J Stroke Cerebrovasc Dis 2019 Aug 28;28(8):2079-2097. Epub 2019 May 28.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Since the term "lacune" was adopted in the 1800s to describe infarctions from cerebral small vessels, their underlying pathophysiological basis remained obscure until the 1960s when Charles Miller Fisher performed several autopsy studies of stroke patients. He observed that the vessels displayed segmental arteriolar disorganization that was associated with vessel enlargement, hemorrhage, and fibrinoid deposition. He coined the term "lipohyalinosis" to describe the microvascular mechanism that engenders small subcortical infarcts in the absence of a compelling embolic source. Since Fisher's early descriptions of lipohyalinosis and lacunar stroke (LS), there have been many advancements in the understanding of this disease process. Herein, we review lipohyalinosis as it relates to modern concepts of cerebral small vessel disease (cSVD). We discuss clinical classifications of LS as well as radiographic definitions based on modern neuroimaging techniques. We provide a broad and comprehensive overview of LS pathophysiology both at the vessel and parenchymal levels. We also comment on the role of biomarkers, the possibility of systemic disease processes, and advancements in the genetics of cSVD. Lastly, we assess preclinical models that can aid in studying LS disease pathogenesis. Enhanced understanding of this highly prevalent disease will allow for the identification of novel therapeutic targets capable of mitigating disease sequelae.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416422PMC
August 2019

Differential effects of anesthetics on resting state functional connectivity in the mouse.

J Cereb Blood Flow Metab 2020 04 15;40(4):875-884. Epub 2019 May 15.

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

Blood oxygen level-dependent (BOLD) functional MRI (fMRI) is a standard approach to examine resting state functional connectivity (RSFC), but fMRI in animal models is challenging. Recently, functional optical intrinsic signal imaging-which relies on the same hemodynamic signal underlying BOLD fMRI-has been developed as a complementary approach to assess RSFC in mice. Since it is difficult to ensure that an animal is in a truly resting state while awake, RSFC measurements under anesthesia remain an important approach. Therefore, we systematically examined measures of RSFC using non-invasive, widefield optical intrinsic signal imaging under five different anesthetics in male C57BL/6J mice. We find excellent seed-based, global, and interhemispheric connectivity using tribromoethanol (Avertin) and ketamine-xylazine, comparable to results in the literature including awake animals. Urethane anesthesia yielded intermediate results, while chloral hydrate and isoflurane were both associated with poor RSFC. Furthermore, we found a correspondence between the strength of RSFC and the power of low-frequency hemodynamic fluctuations. In conclusion, Avertin and ketamine-xylazine provide robust and reproducible measures of RSFC in mice, whereas chloral hydrate and isoflurane do not.
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http://dx.doi.org/10.1177/0271678X19847123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168791PMC
April 2020

Neurovascular coupling during optogenetic functional activation: Local and remote stimulus-response characteristics, and uncoupling by spreading depression.

J Cereb Blood Flow Metab 2020 04 7;40(4):808-822. Epub 2019 May 7.

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

Neurovascular coupling is a fundamental response that links activity to perfusion. Traditional paradigms of neurovascular coupling utilize somatosensory stimulation to activate the primary sensory cortex through subcortical relays. Therefore, examination of neurovascular coupling in disease models can be confounded if the disease process affects these multisynaptic pathways. Optogenetic stimulation is an alternative to directly activate neurons, bypassing the subcortical relays. We employed minimally invasive optogenetic cortical activation through intact skull in Thy1-channelrhodopsin-2 transgenic mice, examined the blood flow changes using laser speckle imaging, and related these to evoked electrophysiological activity. Our data show that optogenetic activation of barrel cortex triggers intensity- and frequency-dependent hyperemia both locally within the barrel cortex (>50% CBF increase), and remotely within the ipsilateral motor cortex (>30% CBF increase). Intriguingly, activation of the barrel cortex causes a small (∼10%) but reproducible hypoperfusion within the contralateral barrel cortex, electrophysiologically linked to transhemispheric inhibition. Cortical spreading depression, known to cause neurovascular uncoupling, diminishes optogenetic hyperemia by more than 50% for up to an hour despite rapid recovery of evoked electrophysiological activity, recapitulating a unique feature of physiological neurovascular coupling. Altogether, these data establish a minimally invasive paradigm to investigate neurovascular coupling for longitudinal characterization of cerebrovascular pathologies.
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http://dx.doi.org/10.1177/0271678X19845934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168797PMC
April 2020

Secondary Bleeding During Acute Experimental Intracerebral Hemorrhage.

Stroke 2019 05;50(5):1210-1215

From the Neurovascular Research Laboratory, Department of Radiology (F.S., M.B., T.Q., I.T., P.F., C.A.), Massachusetts General Hospital, Harvard Medical School, Charlestown.

Background and Purpose- Mechanisms contributing to acute hematoma growth in intracerebral hemorrhage are not well understood. Neuropathological studies suggest that the initial hematoma may create mass effect that can tear vessels in the vicinity by shearing, causing further bleeding and hematoma growth. Methods- To test this in mice, we simulated initial intracerebral hemorrhage by intrastriatal injection of a liquid polymer that coagulates upon contact with tissue and measured the presence and volume of bleeding secondary to the mass effect using Hemoglobin ELISA 15 minutes after injection. Results- Secondary hemorrhage occurred in a volume-dependent (4, 7.5, or 15 μL of polymer) and rate-dependent (0.05, 0.5, or 5 μL/s) manner. Anticoagulation (warfarin or dabigatran) exacerbated the secondary hemorrhage volume. In a second model of hematoma expansion, we confirmed that intrastriatal whole blood injection (15 μL, 0.5 μL/s) also caused secondary bleeding, using acute Evans blue extravasation as a surrogate. Anticoagulation once again exacerbated secondary hemorrhage after intrastriatal whole blood injection. Secondary hemorrhage directly and significantly correlated with arterial blood pressures in both nonanticoagulated and anticoagulated mice, when modulated by phenylephrine or labetalol. Conclusions- Our study provides the first proof of concept for secondary vessel rupture and bleeding as a potential mechanism for intracerebral hematoma growth.
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http://dx.doi.org/10.1161/STROKEAHA.118.021732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478448PMC
May 2019

Noninvasive Vagus Nerve Stimulation Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice.

Stroke 2019 05;50(5):1216-1223

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

Background and Purpose- Inflammation is a critical determinant of aneurysmal wall destabilization, growth, and rupture risk. Targeting inflammation may suppress aneurysm rupture. Vagus nerve stimulation (VNS) has been shown to suppress inflammation both systemically and in the central nervous system. Therefore, we tested the effect of a novel noninvasive transcutaneous VNS approach on aneurysm rupture and outcome in a mouse model of intracranial aneurysm formation with wall inflammation. Methods- Aneurysms were induced by a single stereotaxic injection of elastase into the cerebrospinal fluid at the skull base, combined with systemic deoxycorticosterone-salt hypertension, without or with high-salt diet, for mild or severe outcomes, respectively. Cervical VNS (two 2-minute stimulations 5 minutes apart) was delivered once a day starting from the day after elastase injection for the duration of follow-up. Transcutaneous stimulation of the femoral nerve (FNS) served as control. Multiple aneurysms developed in the circle of Willis and its major branches, resulting in spontaneous ruptures and subarachnoid hemorrhage, neurological deficits, and mortality. Results- In the milder model, VNS significantly reduced aneurysm rupture rate compared with FNS (29% versus 80%, respectively). Subarachnoid hemorrhage grades were also lower in the VNS group. In the more severe model, both VNS and FNS arms developed very high rupture rates (77% and 85%, respectively). However, VNS significantly improved the survival rate compared with FNS after rupture (median survival 13 versus 6 days, respectively), without diminishing the subarachnoid hemorrhage grades. Chronic daily VNS reduced MMP-9 (matrix metalloproteinase-9) expression compared with FNS, providing a potential mechanism of action. As an important control, chronic daily VNS did not alter systemic arterial blood pressure compared with FNS. Conclusions- VNS can reduce aneurysm rupture rates and improve the outcome from ruptured aneurysms.
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http://dx.doi.org/10.1161/STROKEAHA.118.023928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476688PMC
May 2019

Neurovascular origin of primary headaches.

J Cereb Blood Flow Metab 2019 04;39(4):571-572

2 Neurovascular Research Laboratory, Department of Radiology, and Stroke Service, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1177/0271678X18775811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446421PMC
April 2019

Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need.

Neurocrit Care 2020 02;32(1):238-251

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

Background: Delayed cerebral ischemia (DCI) is among the most dreaded complications following aneurysmal subarachnoid hemorrhage (SAH). Despite advances in neurocritical care, DCI remains a significant cause of morbidity and mortality, prolonged intensive care unit and hospital stay, and high healthcare costs. Large artery vasospasm has classically been thought to lead to DCI. However, recent failure of clinical trials targeting vasospasm to improve outcomes has underscored the disconnect between large artery vasospasm and DCI. Therefore, interest has shifted onto other potential mechanisms such as microvascular dysfunction and spreading depolarizations. Animal models can be instrumental in dissecting pathophysiology, but clinical relevance can be difficult to establish.

Methods: Here, we performed a systematic review of the literature on animal models of SAH, focusing specifically on DCI and neurological deficits.

Results: We find that dog, rabbit and rodent models do not consistently lead to DCI, although some degree of delayed vascular dysfunction is common. Primate models reliably recapitulate delayed neurological deficits and ischemic brain injury; however, ethical issues and cost limit their translational utility.

Conclusions: To facilitate translation, clinically relevant animal models that reproduce the pathophysiology and cardinal features of DCI after SAH are urgently needed.
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http://dx.doi.org/10.1007/s12028-018-0650-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387950PMC
February 2020