Full contact address 6 Whittier Pl. Apt 9C. Boston, MA Current working address th St, 6403, Charlestown, MA 02129

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1 FELLOWSHIP REPORT FORM Please complete this form giving details of your IHS Fellowship. Personal details Name Nationality Homa Sadeghian M.D. Iranian Date of birth 10/01/1986 Full contact address 6 Whittier Pl. Apt 9C. Boston, MA Current working address th St, 6403, Charlestown, MA address hsadeghian@mgh.harvard.edu homa.sadeghian@gmail.com Fellowship Dates of fellowship Second year of Institution name Mentor name Title of study Massachusetts General Hospital, Harvard Medical School Cenk Ayata, M.D. Cortical Spreading Depression and Blood Brain Barrier Research details Short summary of initial plan Migraine, a common and disabling headache disorder, is preceded by aura in one third of the patients. Migraine aura is indicative of a reversible cerebral cortical dysfunction most probably caused by Cortical Spreading Depression (CSD). The normal brain has efficient regulatory mechanisms to keep extracellular ion concentrations within a physiologic range during neuronal activity; however, more recent studies has described that those genetic factors that predispose to migraine may also enhance the intensity of excitotoxic burden during CSD and predispose to neuronal injury. For example, Familial hemiplegic migraine type 1 (FHM1) is a monogenic migraine syndrome associated with gain-of-function mutations in Cav2.1 channels. FHM1 mutations enhance Ca2+ influx through single Cav2.1 channels and reduce the threshold for CSD with increased probability of glutamate release. Thus, a relatively weak depolarizing stimulus, such as minor head trauma or transient ischemic attack may initiate CSD in FHM1 patients. Also, a more intriguing recent finding is enhanced CSD susceptibility in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) mutant mice; CADASIL with mutations in NOTCH3 gene is another monogenic migraine syndrome characterized by microcirculation disturbance which leads to increase extracellular [K + ] during occurrence of CSD and migraine attacks in CADASIL. 1

2 FHM1 and CADASIL knock-in mice are two frequently employed animal models for genetic and hormonal regulation of migraine with aura. Together, these two genetic mice models formed the basis of my investigation of neuropathological changes induced in migraineurs. Short summary of your actual research In first year, to target the primary cause of neuronal damage after systemic stroke or cardiac arrest in migraine patients, we investigated the susceptibility of FHM1 mutant mice to hypoxia and global ischemia and their benefits from migraine prophylaxis treatment targeting CSD. We showed that genetic susceptibility to spreading depression increases the sensitivity of brain tissue not only to focal ischemic but also hypoxic, global ischemic or excitotoxic insults, in vivo and in vitro. Moreover, we determined that suppressing hyperexcitability and CSD with migraine prophylaxis treatment confers protection in FHM1 mutant mice after bilateral common carotid artery occlusion (manuscript in preparation). While at during first year of fellowship, I also co-authored additional publications, focusing on the mechanisms of VNS and cortical spreading depression (Pain. 157(4): , 2016), environmental stress and cortical spreading depression (manuscript in preparation), and functional improvement after focal cerebral ischemia (J Cereb Blood Flow Metab. 35(6): , 2015) as well as microvascular cerebral blood flow assessement after repetitive concussions (J Cereb Blood Flow Metab. 35(12): , 2015) and altered inhibition in the hippocampal neural networks after spreading depression (Neuroscience.24;304:190-7, 2015). In the second year, I aimed to characterize the integrity of the neurovascular unit (NVU) and the important role of the blood-brain barrier (BBB) in maintaining proper brain function as a major pathophysiological mechanism underlying the consequences of CSD in migraine attacks. Using transmission electron microscopy (TEM) analysis and confocal microscopy in migraine mouse models, we provided the first multi-step, time control demonstration that CSD enhances number of transcytosis as the initial response of endothelium, without any disorganization of tight junctions, an effect which was prevented by pharmacological inhibition (manuscript in preparation). More recently, as a follow up study, I started two more projects focusing on extracellular [K + ] concentration changes after spreading depression in CADASIL-R169C mutant mice, as well as extracellular [K + ] concentration changes after filament middle cerebral artery occlusion in a mouse model of stroke. Overview of activities on a monthly basis Dr Ayata s lab has provided me with extensive training and intellectual development in migraine with a wide array of surgical, optical, electrophysiological, biochemical and molecular biological methods, tools and technologies. As a research fellow I have a dedicated in vivo electrophysiology bench fully equipped with mechanical ventilation, systemic physiological monitoring, anesthesia and stereotaxic equipment, as well as an ion-selective microelectrode amplifier, all of which are connected to a real-time analog-digital converter to record all parameters simultaneously in the computer using in cutting-edge in vivo experimentation with microsurgical methods, imaging techniques and monitoring/maintenance of systemic physiology under anesthesia (i.e. arterial cannulation, tracheostomy and mechanical ventilation, cardiovascular, fluid, acid/base balance). Having the chance being surrounded by top of the words clinician scientist helped me to get involve in different projects in closely related topics with other laboratories. I was able to complete my second year fellowship project as collaboration at Harvard Medical School, and presented my preliminary results at the 2015 International Headache Society Congress in Valencia in a scheduled talk entitled Cortical Spreading Depression and Blood Brain Barrier. Also in 2015, I received the Frontiers in Headache Research Scholarship award as well as the New Investigator Research Tournament award from American Headache Society, which continues to be a successful venue for providing information on the diagnosis, management, and treatment of headache patients. In 2015 and 2016, I was selected as delegate faculty for the second and third International Headache Academy (IHA), held at the National Institutes of Health and Mayo Clinic Hospital. The IHA, sponsored by the American Headache Society, International Headache Society, American Migraine Foundation and the Canadian Headache Society, was designed to inspire long term commitment to headache medicine by young neurologists and research scientists 2

3 via an educational program focused on clinical and research aspects of headache medicine. Moreover, I had a chance to participate in a one-month observership at the Veterans Affair Hospital in Boston University Medical School, where I was exposed to an intellectual environment for acquiring the knowledge, skills, clinical judgment, attitudes, and values that are essential to headache medicine. In addition, weekly Neurology grand rounds sponsored by the Department of Neurology at Massachusetts General Hospital provided the opportunity to interact with leaders in Neurology from other institutions. Also, the monthly Headache meetings at Beth Israel-Deaconess Hospital, Harvard University provided an excellent series of seminars and less formal presentations featuring scientists from Harvard and other universities. Has the Fellowship met all your initial aims? Yes, of course! My main aim during the Fellowship was to participate in an academically and clinically rigorous training program and to achieve outstanding skills in neurology as well as advanced training in neurovascular research. I engaged in numerous research projects that combined my interests in neurology and electrophysiology. I received the basic and clinical knowledge, procedural skills, scientific judgment, professionalism and interpersonal skills required as a researcher. Thanks to generous support of Dr. Ayata, I had access to all resources I needed to fulfill the goals of my project and as a principle, Dr. Ayata dedicated all the time and resources it took to quickly and efficiently train me in the methods proposed for my fellowship and additional studies as needed, including but not limited to extracellular ion-selective recording, confocal microscopy and laser doppler flowmetry. In addition, Harvard Medical School provided numerous opportunities for collaboration and resource sharing when I needed to utilize a technique that was not readily available at Massachusetts General Hospital. This training prepared me to function not only as highly competent scientist, but also as either subspecialists in a clinical area or investigators in the field of neurovascular research. What, if any, problems did you encounter I believe that the research skills I have acquired throughout my first year training made me an asset to the second year of fellowship. I discussed my data and progress with Dr. Ayata almost on a daily basis, who guided me on how to overcome challenges that inevitably occur in the course of experimental research. In addition, our weekly lab meetings were an excellent opportunity for group discussions that enhanced the exchange of ideas and collaboration within the lab, and prepared me in critically reviewing my data and communicating my findings. As such, all lab members and various collaborators in MGH and HMS altogether form an excellent medium to provide the essential substrates for me to overcome all challenges. How will the fellowship affect your future career? This fellowship was an excellent environment with extensive opportunities for interaction and collaboration with other scientists. I have been encouraged by the time in the Fellowship and now looking for a position where I can thrive as a clinician neurologist-scientist and have dedicated research time. I have confidence that after my residency in Neurology, I will be able to transition back into headache research. I am committed to building a solid academic and clinical career with the aim of becoming a national and international expert in the field. In light of my fellowship, my multimodal in vivo projects expanded my horizon and enhanced my competitiveness for independent award funding. As such, my goal is to apply for a pathway to independent NIH-K award within 4 years. What would you recommend to future IHS Fellowship applicants? The scholarship was a unique experience for me, where I had the opportunity to develop and grow as a specialist in the area of neurology and headache particularly. Receiving the Fellowship was not only prestigious, but a valuable experience that enhanced my academic, professional, and personal development. Hundreds of applications are submitted each year for competitive fellowships that are only offered to a limited number of individuals; therefore there is no certain formula to ensure that an application will result in a fellowship award. However, not applying at all will guarantee that you will not receive a fellowship award. Also, there are benefits to the application process itself. It helps you to understand yourself on a deeper level by making you define your 3

4 interests and future goals and assess your strengths and weaknesses and most important how to present myself. Please include five photos/images of your stay Having had the honor of being an IHS fellow during brings me great memories, while it would be impossible to include all the special moments, milestones and memories from the past two years, I want to take this opportunity to remind you of a few of the major events I experienced together. Perhaps most impressive and clearly most important is the work that goes on in each of the MGH/HMS/IHS alumni on every day basis. I extend my deepest gratitude to all members of the IHS family for their support, sharing their experience and knowledge, for satisfying my curiosity and your warm welcome you do every moment. I particularly want to thank Dr. Cenk Ayata for accepting me as a research fellow, for his time and for sharing his enthusiasm and inspiration, I feel honored to be part of a such caring, compassionate and dedicated lab making such a meaningful impact across the country and around the world. 4

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6 Signature: Date: 06/06/2016 6