Details of a Researcher - Takizawa, Tsubasa

Papers - Takizawa, Tsubasa

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Real-world evidence of galcanezumab for migraine treatment in Japan: a retrospective analysis.

Tsubasa Takizawa, Seiya Ohtani, Narumi Watanabe, Naoki Miyazaki, Kei Ishizuchi, Koji Sekiguchi, Chisato Iba, Mamoru Shibata, Ryo Takemura, Satoko Hori, Jin Nakahara

BMC neurology (BMC Neurology) 22 ( 1 ) 512 - 512 2022.12

OBJECTIVE: To evaluate the efficacy and safety of galcanezumab in patients with migraine in a real-world setting in Japan. BACKGROUND: Galcanezumab is the first anti-calcitonin gene-related peptide monoclonal antibody approved in Japan. To the best of our knowledge, no real-world studies on galcanezumab have been published in any international journal from Japan. METHODS: We retrospectively examined patients with migraine who received three doses of galcanezumab between August 2021 and February 2022 at the Keio University Hospital. We assessed changes in monthly migraine days, responder rate, and migraine-associated and premonitory symptoms. We also investigated injection site reactions and adverse events. RESULTS: Fifty-two patients received three doses of galcanezumab during the study period. Compared with those at baseline, the monthly migraine days decreased by 5.9 days (95% confidence interval, 4.2-7.7) at 3 months. The 50% responder rate was 61.5% at 3 months. A total of 64.9%, 50.0%, and 63.9% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Premonitory symptoms without subsequent headache were reported in 62.5% of patients. Moreover, injection site reaction was the most common adverse event (34.6%). CONCLUSION: This study revealed the efficacy and safety of galcanezumab for migraineurs in Japan. Galcanezumab also improved migraine-associated symptoms. However, despite a reduction in headaches, premonitory symptoms without subsequent headache were reported in > 50% of the patients at 3 months.

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Effect of Goreisan, a Japanese Traditional Medicine, on Cortical Spreading Depolarization in Mice.

Chisato Iba, Miyuki Unekawa, Yoshikane Izawa, Jin Nakahara, Tsubasa Takizawa

International journal of molecular sciences (International Journal of Molecular Sciences) 23 ( 22 ) 2022.11

ISSN 16616596

Goreisan, a traditional Japanese Kampo medicine, is often used to treat headaches, including migraines; however, the underlying mechanisms remain unknown. Therefore, we investigated whether chronic treatment with Goreisan affects cortical spreading depolarization (CSD) in migraines. CSD susceptibility was assessed in male and female C57BL/6 mice by comparing CSD threshold, propagation velocity, and CSD frequency between animals treated with Goreisan for approximately 3 weeks and the corresponding controls with a potassium-induced CSD model. No significant differences were observed in CSD susceptibility between mice that were chronically treated with Goreisan and the control mice. Additionally, no significant differences were observed in other physiological parameters, including body weight, blood gases, and blood pressure. CSD susceptibility was not affected by chronic treatment with Goreisan, which suggests that the drug treats headaches via mechanisms that do not involve CSD modulation.

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Immunodeficiency in patients with thymoma-associated myasthenia gravis.

Kei Ishizuchi, Tsubasa Takizawa, Yuko Ohnuki, Koji Sekiguchi, Haruhiko Motegi, Munenori Oyama, Jin Nakahara, Takashi Shiina, Shigeaki Suzuki

Journal of neuroimmunology (Journal of Neuroimmunology) 371 577950 - 577950 2022.10

ISSN 01655728

Thymoma with immunodeficiency is sometimes accompanied by myasthenia gravis (MG), but the clinical characteristics have not been elucidated. This study aimed to characterize its clinical and immunological features. Of the 132 thymoma-associated MG patients, 9 patients presented with immunodeficiency. All suffered from severe pneumonia, and most had invasive thymoma and autoimmune disorders. DRB1*08:03 and DQB1*06:01 alleles were frequently detected. Compared to group without immunodeficiency, they showed no significant differences in the severity of MG, significantly lower IgG concentrations and higher mortality rate. Thymoma-associated MG with immunodeficiency is a distinct subset requiring special attention to prevent infection during the follow-up period.

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Anemia in female patients with myasthenia gravis.

Koji Sekiguchi, Kei Ishizuchi, Tsubasa Takizawa, Haruhiko Motegi, Munenori Oyama, Jin Nakahara, Shigeaki Suzuki

PloS one (PLoS ONE) 17 ( 9 September ) e0273720 2022.09

Myasthenia gravis (MG) is the most common autoimmune neuromuscular disorder, and is more common in women than in men. Anemia is also more common in women. The purpose of this study was to investigate factors associated with anemia and the negative impact of anemia in female MG patients. We investigated factors related to MG and anemia in 215 female patients with MG, who were attending the MG clinic of Keio Hospital between January and December 2021. We statistically evaluated clinical factors related to anemia in patients with and without anemia. Eighty-five patients (40%) had anemia in the past, and 130 patients did not have anemia in the past. There were no significant differences in age at study, age at MG onset, body mass index, or frequency of autoantibodies between the anemia and non-anemia groups. MG severity evaluated by the MG Foundation of America classification was greater in the anemia group than in the non-anemia group. History of anemia was associated with immunosuppressive treatment, such as prednisolone and calcineurin inhibitor treatment. There was a correlation between hemoglobin levels and the MG-quality of life score. Long term immunosuppressive therapy can cause anemia in female MG patients. Anemia may negatively affect the quality of life of female MG patients.

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Obstructive sleep apnea syndrome in migraine patients with early morning headache

Sekiguchi Koji, Watanabe Narumi, Watanabe Risa, Usuda Sho, Yamasawa Wakako, Shibata Mamoru, Fukunaga Koichi, Nakahara Jin, Takizawa Tsubasa

Japanese Journal of Headache (The Japanese Headache Society) 48 ( 3 ) 566 - 570 2022.04

ISSN 1345-6547

In clinical practice, we sometimes experience migraine patients with early morning headaches. We investigated the characteristics and relationship between early morning headache and obstructive sleep apnea syndrome (OSAS）in eight migraine patients with morning headaches who visited Headache Clinic of Keio University Hospital. Seven of eight patients had OSAS. Six patients had mild OSAS and one patient had moderate OSAS. There was tendency of positive correlation between AHI and percentage of morning headache. There is the possibility that OSAS may exacerbate migraine, and the treatment of migraine patients with early morning headache and OSAS may be a subject of future research．

Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study.

Koji Sekiguchi, Narumi Watanabe, Naoki Miyazaki, Kei Ishizuchi, Chisato Iba, Yu Tagashira, Shunsuke Uno, Mamoru Shibata, Naoki Hasegawa, Ryo Takemura, Jin Nakahara, Tsubasa Takizawa

Cephalalgia : an international journal of headache (Cephalalgia) 42 ( 3 ) 266 - 272 2022.03

ISSN 03331024

BACKGROUND: Headache is an adverse event of coronavirus 2019 (COVID-19) vaccination. Whether patients with history of headache suffer more from vaccination-induced headaches is unknown. We aimed to uncover if headache patients develop more headaches after COVID-19 mRNA vaccination than healthy controls. METHODS: We performed a questionnaire survey for nursing staff in our hospital from April to May 2021. Based on baseline characteristics, we divided the participants into migraine, non-migrainous headache, and healthy control, and examined the occurrence and features of headache after COVID-19 vaccinations. RESULTS: We included 171 participants (15.2% migraine and 24.6% non-migrainous headache). Headache incidence after vaccinations was significantly higher in the migraine (69.2%) and non-migrainous headache (71.4%) groups than in the healthy control (37.9%) group. The incidence of headaches was significantly higher after the second dose compared to the first (45.6% vs. 20.5%). CONCLUSION: Migraineurs and non-migrainous headache participants developed more headaches compared to the healthy controls after COVID-19 vaccination.

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大学での教育（卒後教育を中心に）

滝沢翼

Japanese Journal of Headache (The Japanese Headache Society) 48 ( 3 ) 506 - 508 2022

ISSN 13456547

頭痛が視野障害より2ヵ月先行した視神経脊髄炎関連疾患の1例

砂金瑛実, 石鎚啓, 滝沢翼, 藤原広和, 伊澤良兼, 中原仁

臨床神経学 ((一社)日本神経学会) 61 ( 11 ) 722 - 726 2021.11

ISSN 0009-918X

症例は50代女性で,2ヵ月前より持続する右上眼瞼周囲の頭痛のため受診となった.頭部MRI T2強調画像で脳梁,両側放線冠に多発性の高信号病変を認めた.自己免疫疾患を考えステロイドパルス療法を施行したが,右眼に下方水平性半盲と対光反射減弱が出現した.眼窩MRIのT2強調画像で右視神経腫大,視神経上半側の高信号,ガドリニウム造影増強効果を認め,抗AQP4抗体陽性と併せ視神経脊髄炎関連疾患(neuromyelitis opticaspectrum disorders,以下NMOSDと略記)と診断した.NMOSDの初発症状として頭痛がみられることがあるので,鑑別の際に念頭に置く必要がある.(著者抄録)

特集頭痛診療の基本から最新の知見まで最近の話題　片頭痛の最新の知見

滝沢翼, 伊庭知里

小児科診療 ((株)診断と治療社) 84 ( 10 ) 1357 - 1362 2021.10

ISSN 03869806

特集片頭痛　病態の理解と薬物療法の最前線片頭痛薬物療法の新たな潮流!新薬の最新エビデンス　抗CGRP抗体・抗CGRP受容体抗体

滝沢翼, 鈴木則宏

薬局 ((株)南山堂) 72 ( 8 ) 2791 - 2797 2021.07

ISSN 00440035

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage.

Paul Fischer, Kazutaka Sugimoto, David Y Chung, Isra Tamim, Andreia Morais, Tsubasa Takizawa, Tao Qin, Carlos A Gomez, Frieder Schlunk, Matthias Endres, Mohammad A Yaseen, Sava Sakadzic, Cenk Ayata

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (Journal of Cerebral Blood Flow and Metabolism) 41 ( 6 ) 1264 - 1276 2021.06

ISSN 0271678X

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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Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior.

Andrea M Harriott, David Y Chung, Aylin Uner, Refik O Bozdayi, Andreia Morais, Tsubasa Takizawa, Tao Qin, Cenk Ayata

Annals of neurology (Annals of Neurology) 89 ( 1 ) 99 - 110 2021.01

ISSN 03645134

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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A case of neuromyelitis optica spectrum disorder in which headache preceded visual field disturbances by 2 months

M.D. Isago Eimi, M.D. Ishizuchi Kei, M.D. Ph.D. Takizawa Tsubasa, M.D. Ph.D. Fujiwara Hirokazu, M.D. Ph.D. Izawa Yoshikane, M.D. Ph.D. Nakahara Jin

Rinsho Shinkeigaku (Societas Neurologica Japonica) 61 ( 11 ) 722 - 726 2021

ISSN 0009918X

A quinquagenarian woman visited our hospital due to experiencing headache around the right upper eyelid for the previous 2 months. T2-weighted MRI of the head showed multiple high-signal-intensity lesions in the corpus callosum and bilateral corona radiata. She was thought to have an autoimmune disease and was treated with steroid pulse therapy, but the light reflex of the right eye diminished and the patient developed inferior horizontal hemianopsia. T2-weighted orbital MRI showed an enlarged right optic nerve, a high-intensity signal in the superior half of the optic nerve, and an enhancing effect. She also tested positive for anti–aquaporin 4 antibodies, so she was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). This case shows that headache can be an initial symptom of NMOSD and that clinicians should consider NMOSD when attempting to diagnose patients presenting with headaches.

Painless Thyroiditis Presenting with Headache

Takizawa Tsubasa, Kurihara Isao, Suzuki Norihiro, Nakahara Jin, Shibata Mamoru

Internal Medicine (The Japanese Society of Internal Medicine) 60 ( 16 ) 2693 - 2696 2021

ISSN 09182918

Although headache attributed to hypothyroidism is coded within The International Classification of Headache Disorders, 3rd edition, an association between headache and thyrotoxicosis (hyperthyroidism) is mentioned only in the appendix. Reports on relevant cases are too scarce to establish a causal relationship. A young man with a history of migraine with aura arrived at our headache clinic with a 10-day history of headache and weight loss. Brain MRI revealed normal findings. Blood tests revealed thyrotoxicosis. A test for thyroid-related antibodies was negative. Thus, the patient was diagnosed with painless thyroiditis. The patient's headache resolved as his thyroid hormone levels decreased. To the best of our knowledge, this is the first reported case of headache exaggerated by painless thyrotoxicosis.

[123I]-IMP single-photon emission computed tomography imaging in visual snow syndrome: A case series.

Mamoru Shibata, Kei Tsutsumi, Yu Iwabuchi, Masashi Kameyama, Tsubasa Takizawa, Tadaki Nakahara, Hirokazu Fujiwara, Masahiro Jinzaki, Jin Nakahara, David W Dodick

Cephalalgia : an international journal of headache 40 ( 14 ) 1671 - 1675 2020.12

BACKGROUND: Visual snow syndrome (VSS) is a neurological condition characterized by persistent flickering dots in the visual fields, palinopsia, enhanced entoptic phenomenon, photophobia, and nyctalopia. Neuroimaging evidence supports the role of the visual association cortex in visual snow syndrome.Case series: We provided clinical care to three patients with visual snow syndrome, in whom [123I]-IMP single-photon emission computed tomography (SPECT) imaging was performed. Case 1 was a 21-year-old male with a past history of migraine with aura who exhibited visual snow and entoptic phenomenon. In this patient, [123I]-IMP SPECT imaging revealed right occipital and temporal hypoperfusion with a distribution matching the ventral visual stream. [123I]-IMP SPECT imaging detected only mild bilateral frontal hypoperfusion in Case 2 and no overt abnormalities in Case 3. CONCLUSION: Although visual snow syndrome seems to be a heterogenous condition, our observations indicate that abnormal visual processing within the ventral visual stream may play a role in the pathogenesis of this condition.

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

Takeshi Yanagisawa, Hua Zhang, Tomoaki Suzuki, Yoshinobu Kamio, Tsubasa Takizawa, Andreia Morais, David Y Chung, Tao Qin, Yuichi Murayama, James E Faber, Aman B Patel, Cenk Ayata

Stroke 51 ( 10 ) 3083 - 3094 2020.10

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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Cluster headache in Asian populations: Similarities, disparities, and a narrative review of the mechanisms of the chronic subtype.

Kuan-Po Peng, Tsubasa Takizawa, Mi Ji Lee

Cephalalgia : an international journal of headache 40 ( 10 ) 1104 - 1112 2020.09

OBJECTIVE: Headache disorders like migraine show geographic and ethnic differences between Asian and European/North American countries. In cluster headache, these differences are rarely mentioned and discussed. This article aimed to review the characteristics of cluster headache in Asian countries and compare the clinical features to those in European and North American populations. METHODS: We conducted a narrative literature review on the demographics, clinical presentations, and treatments of cluster headache in Asian countries. RESULTS: Patients with cluster headache in Asian populations showed a stronger male predominance compared to European and North American populations. Chronic cluster headache was rare in Asian countries. The clinical presentation of restlessness was not as common in Asian as it was in European and North American countries, and Asian patients with aura were extremely rare. Patients in Asian countries may have a lower circadian rhythmicity of cluster headache and a lower headache load, as demonstrated by lower attack frequencies per day, bout frequencies, and bout durations. CONCLUSIONS: Regional differences in the presentation of cluster headache exist. Greater awareness for cluster headache should be raised in Asian regions, and further studies are warranted to elucidate the mechanisms behind observed differences.

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

Kazutaka Sugimoto, David Y Chung, Maximilian Böhm, Paul Fischer, Tsubasa Takizawa, Sanem Aslihan Aykan, Tao Qin, Takeshi Yanagisawa, Andrea Harriott, Fumiaki Oka, Mohammad A Yaseen, Sava Sakadžić, Cenk Ayata

Stroke 51 ( 8 ) 2526 - 2535 2020.08

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%; P=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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Cortical spreading depolarisation-induced facial hyperalgesia, photophobia and hypomotility are ameliorated by sumatriptan and olcegepant.

Chunhua Tang, Miyuki Unekawa, Satoshi Kitagawa, Tsubasa Takizawa, Yohei Kayama, Jin Nakahara, Mamoru Shibata

Scientific reports 10 ( 1 ) 11408 - 11408 2020.07

Cortical spreading depolarisation (CSD), the neural mechanism underlying migraine aura, may cause headache by sensitising the trigeminal system. Photophobia, the most bothersome accompanying symptom during migraine attacks, is more prevalent in migraine with aura than in migraine without aura. Whether CSD plays a role in developing photophobia remains unknown. Moreover, migraine-induced physical hypoactivity contributes to loss of productivity. We aimed to investigate the development of trigeminal sensitisation, photophobia and locomotive abnormality after KCl-induced CSD using 86 male C57BL/6 mice. Sham-operated mice were used as controls. We confirmed the presence of trigeminal sensitisation and photophobia at 24 h after CSD. CSD-subjected mice also exhibited significantly reduced locomotive activity in both light and dark zones. Hence, the CSD-induced hypomobility was likely to be independent of photophobia. The 5-HT1B/1D agonist, sumatriptan, corrected all these CSD-induced abnormalities. Moreover, dose dependency was demonstrated in the ameliorating effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, olcegepant, on these abnormalities. Sumatriptan and olcegepant improved mouse locomotion with therapeutic lags ranging from 20 to 30 min. Collectively, CSD caused trigeminal sensitisation, photophobia and hypomobility that persisted for at least 24 h by a mechanism involving the 5-HT1B/1D and CGRP activity.

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

Tsubasa Takizawa, Tao Qin, Andreia Lopes de Morais, Kazutaka Sugimoto, Joon Yong Chung, Liza Morsett, Inge Mulder, Paul Fischer, Tomoaki Suzuki, Maryam Anzabi, Maximilian Böhm, Wen-Sheng Qu, Takeshi Yanagisawa, Suzanne Hickman, Joseph El Khoury, Michael J Whalen, Andrea M Harriott, David Y Chung, Cenk Ayata

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 40 ( 5 ) 1117 - 1131 2020.05

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 interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β 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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