Junior

on real and for for arteries, protein extravasation (PPE) were the administration of fremanezumab, anti-CGRP CGRP infusion dilatation in pial vessels dural vessels, which could be effectively blocked by fremanezumab. dilatation of dural the of PPE, the CGRP-induced dilatation of dural CSD-evoked activation of A δ meningeal nociceptors and high-threshold trigeminovascular action of CGRP likely to CSD-evoked vascular or neurogenic responses. that a single model system could explain the pathophysiology of migraine, a heterogenous. nitric oxide (NO)-induced activation of trigeminal neurons in an animal model of medication overuse headache (MOH) induced by a triptan. They found an abnormal activation of Nav1.9 channels in meningeal nerve fibres and dural afferent neurons in MOH mice, which subsequently triggers CGRP release, arterial dilation, and mast cell degranulation. The deletion of the Scn11a gene, which encodes the voltage-gated sodium channel Nav1.9, abrogates the NO-induced hypersensitivity. another clinical study showed that botulinum toxin A in combination with acute withdrawal provides no additional benefit over acute withdrawal alone. Therefore, Nav1.9 channel inhibitors might be a new treatment target for patients with MOH. In a randomized, sham-controlled, parallel-group, double-blinded study, patients who received sphenopalatine ganglion (SPG) stimulation were more likely to achieve the primary endpoint, defined as relief from pain within 15 minutes (62.5% vs 38.9%, p = 0.008). 13 Among the 45 patients in the SPG stimulation group, nine developed serious adverse events, four of which were implantation related. The SPG stimulation seems efficacious and well tolerated for patients with chronic CH. 13 Unfortunately, the producer of the device has filed for bankruptcy and whether the device will be available again remains unknown. example, or interviewed 2,219 unrelated migraine patients, accessed their acute and prophylactic drugs response, and genotyped all of them and calculated their polygenic risk scores (PRS) for the likelihood of migraine. 14 Among all the medications investigated, the authors found an association between higher PRS, suggestive of a higher risk of migraine, and a positive treatment response to triptan (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.05–1.49) but not other medications. They replicated their findings in an independent cohort comprising 5,616 triptan users with an OR of 3.20 (95% CI 1.26–8.14). 14 This is the first study to show that the response to medication in headache disorders may be genetically determined and the mechanism of how triptans work is closely related to the mechanism behind a migraine generation. The main aim of our project was to explore retinal-thalamocortical pathways that may be responsible for abnormal processing of thalamic visual inputs, commonly observed in migraine patients. We predicted that thalamocortical dysregulation may lead to altered cortical excitability and modified susceptibility to migraine aura. Lately, a refined transgenic Cre reporter mouse model based on the expression of the Sox14 transcription factor has been validated as a specific tool to modulate the activity of GABAergic interneurons located in the dorsal (d) part of the lateral geniculate nucleus (LGN). Using this specific mouse model, we precisely modulated the activity of GABAergic interneurons located in the dLGN by using the latest state-of-the-art techniques such as chemogenetics (DREADDS) and viral-based cell ablation. We then determined its impact on clinically relevant migraine-related phenotypes in mice such as cortical spreading depression (CSD; aura), facial mechanical hypersensitivity (cephalic allodynia) and aversion to light (photophobia). We validated the DREADDS approach by showing an increase of dLGN interneuron activation following stereotaxic targeting of dLGN interneurons with an excitatory DREADDS virus and administration of the DREADDs specific ligand CNO in Sox14 Cre/+ mice. We then established five cohorts of mice (WT, Sox14 Cre/+ and dummy virus, Sox14 Cre/+ and excitatory DREADDS, Sox14 Cre/+ and inhibitory DREADDS, Sox14 Cre/+ and dTA virus (ablation); all injections targeted dLGN only). for migraine aura susceptibility and attack triggering. In two final experiments, mice were primed with nitroglycerin (clinical migraine trigger) and assessed for light aversion or facial mechanical hypersensitivity following a bright light stress paradigm. Nitroglycerin-induced sensitisation was not affected by GABAergic interneuron activity modulation/ablation. The IHS fellowship allowed a smooth transition into the headache field by integrating into one of the most prestigious research labs conducted by Philip Holland. He has been a very understanding and helpful mentor allowing me to bring and develop my own ideas. I acquired many new skills and techniques which now make me feel comfortable within the headache field. I attended two congresses (MTIS 2018 and IHC 2019) where I got the opportunity to present my results and foster some future collaborations. Overall, it has been a fantastic year and I am now applying for larger fellowships to continue my progress towards establishing my own research group exploring sex differences in primary headache disorders, and establishing myself as a principal investigator in the migraine field. The IHS fellowship represents a strong and meaningful support for such applications. I focused on inducing cortical spreading depression (CSD) in a non-invasive manner with optogenetics to find the threshold for the induction of neuroinflammation and pain mimics in relation to the number of CSDs, without confounding factors of recent invasive surgery or the use of a restrainer. To further increase the translational value of the work we extended the research to mouse mutants that carry the S218L missense mutation in the oti A subunit of voltage-gated Ca V2 .1 channels that have been linked to FHM1, and can be considered a valuable mouse model to study certain aspects of migraine. Importantly, the mutant mice allowed me to investigate neuroinflammation and pain behaviour in the context of a hyperexcitable brain with an increased susceptibility to CSD. I assessed the consequences of optogenetically-induced CSD on the extent of neuroinflammation in the context of HMGB1 release at different timing points, and simultaneously, the occurrence of pain-related behaviours, separately for female and male mice. To further enhance the clinical relevance of the study, I tested the effect of TAT-Panx-308, which is an interfering peptide that mimics the C-terminal epitope of Panx1 including the Y308 site and blocks activation of Panx1 channels, as a potential novel drug for the treatment of migraine. CSDs were non-invasively induced by optogenetics in freely moving mice. The neuroinflammatory marker HMGB1 in (sub)cortical brain areas, and the neuronal activation marker pERK in trigeminal ganglia (TG) were studied by immunohistochemistry in WT and FHM1 mice with and without CSDs. Pain-related behaviours were analysed in all conditions. Effects of the Panx1 channel inhibitor were examined by TAT-Panx-308. Results: Non-invasively triggered CSDs induced para-inflammatory responses in both FHM1 and WT mice combined with increased mouse grimace scale scores and head grooming (HG) but decreased nest building behaviours. In mutant mice, neuronal HMGB1 release was bilateral and prolonged (for 48 hours) following CSD in line with enhanced and prolonged higher scores of pain mimics and HG. Trigeminal ganglia were activated bilaterally after CSDs in both genotypes. CSD-related neuroinflammation and pain behaviour were blocked by inhibitor of Panx1 channels. trigeminal


International Classification on Facial Pain published in Cephalalgia
Overview of publications which contribute greatly to the understanding and treatment of headache disorders Looking to the future The Board of Trustees and representatives of some committees held a strategic meeting in Copenhagen at the end of February to discuss future activities and necessary administrative changes in IHS. Although it is still too early to publish any details, we would like to inform our members that IHS as a growing scientific society will have more impact and more activities in the future which need a more professional management and participation of our members. We also will have growing activities in social media and public relations for which we will depend on the support of all our members. More information will be shared in the coming months.

IHS Social Media
For all the latest IHS and headache news, don't forget to follow IHS on our social media channels.

Stefan Evers everss@uni-muenster.de
In research on headache disorders in 2019, migraine remained the focus of attention as the antibodies against calcitonin gene-related peptide (CGRP) and its receptors have become available in several countries along with the publication of phase III clinical trials of the newer generation oral CGRP receptor antagonists. 1,2 Aside from the overshadowing CGRP research, several other interesting studies have been published. We provide an overview of the publications that, in our opinion, contribute greatly to the understanding and treatment of headache disorders. Of note, the selection for the list is subjective and does not include all research works published in 2019 worthy of mention. We hope that our selection serves as a short summary and a catalyst to increase the interests of headache researchers. In the current editorial, we will discuss preclinical and clinical studies, which provide a better understanding of the disease mechanisms or a potential to future treatment targets.

Nav1.9 channel inhibitors might be a new treatment target for patients with MOH
PTH might be mediated through a CGRP-dependent mechanism and serves as the first step to PTH-specific treatment options Newer targets other than CGRP remain to be explored for severely disabled chronic CH patients fremanezumab could block CSD-evoked activation of Aδ meningeal nociceptors and highthreshold trigeminovascular neurons, 4 the action of CGRP blockade is likely irrelevant to the CSD-evoked vascular or neurogenic inflammatory responses. Therefore, it is unlikely that a single model system could explain the pathophysiology of migraine, a disease considered biologically heterogenous.

New treatment target for medication overuse headache
Bonnet et al. examined nitric oxide (NO)-induced activation of trigeminal neurons in an animal model of medication overuse headache (MOH) induced by a triptan. They found an abnormal activation of Nav1.9 channels in meningeal nerve fibres and dural afferent neurons in MOH mice, which subsequently triggers CGRP release, arterial dilation, and mast cell degranulation. The deletion of the Scn11a gene, which encodes the voltage-gated sodium channel Nav1.9, abrogates the NO-induced hypersensitivity. 5 Meanwhile, another clinical study showed that botulinum toxin A in combination with acute withdrawal provides no additional benefit over acute withdrawal alone. 6 Therefore, Nav1.9 channel inhibitors might be a new treatment target for patients with MOH.

Animal model for post-traumatic headache has arrived
The awareness of post-traumatic headache (PTH) has accumulated over the years; however, the underlying mechanisms remain poorly understood. Bree and Levy used a weight-drop device to induce concussion in rats. After the acute phase (by 2 weeks postinjury) of pain hypersensitivity had resolved, the authors could reproduce cephalic pain hypersensitivity by low-dose glyceryl trinitrate (GTN) administration in PTH mice but not in sham animals. This hypersensitivity can be inhibited by the treatment of either sumatriptan or anti-CGRP antibody. 7 This study suggests that PTH might be mediated through a CGRP-dependent mechanism and serves as the first step to PTH-specific treatment options.

Clinical studies and advances in treatment
Role of CGRP in migraine and other headaches: the story continues The results of two phase III trials of CGRP antagonists (gepants) in the acute treatment of migraine, ubrogepant and rimegepant, have been published. In both randomised controlled trials, gepants were superior to placebo: 2-hour pain freedom 19.6% with rimegepant, 1 and 19.2-21.2% with ubrogepant; 2 however, the therapeutic gain (placebo-subtracted value) was low, only 7.6% with rimegepant, 1 and 7.4-9.4% with ubrogepant, 2 compared with other migraine-specific acute treatment options: 26% with sumatriptan 8 and 12.9-16.9% with lasmiditan (5-HT 1F agonist). 9 Nevertheless, no head-to-head comparison has been conducted. It remains a question whether the effects of both gepants are clinically relevant. Besides, patients either with contraindications for or not responding to triptans were not investigated in gepant studies, and these are the patients who could specifically benefit from them.

CGRP antibodies in treating cluster headache
Two anti-CGRP antibodies have been studied on patients with cluster headache (CH). The study which evaluated the efficacy of fremanezumab for the prevention of episodic CH (NCT02945046) has been terminated early due to the results from a prespecified futility analysis. 10 Conversely, galcanezumab has been shown to be superior to placebo in reducing headache attacks in patients with episodic CH. 11 During weeks 1-3, the patients who received galcanezumab had a mean weekly reduction of 8.7 attacks with a therapeutic gain of 3.5 attacks. At week 3, 71% in the galcanezumab group versus 53% in the placebo group reached at least a 50% reduction in headache frequency. 11 Instead, the placebo-controlled study of galcanezumab in patients with chronic CH did not achieve the primary or secondary endpoints. 12 Newer targets other than CGRP remain to be explored for the severely disabled chronic CH patients.

Response to medication in headache disorders may be genetically determined
Important role of K ATP in migraine pathophysiology and blocking of the K ATP channel may be a potential target in migraine treatment Neuromodulation on patients with chronic CH In a randomized, sham-controlled, parallel-group, double-blinded study, patients who received sphenopalatine ganglion (SPG) stimulation were more likely to achieve the primary endpoint, defined as relief from pain within 15 minutes (62.5% vs 38.9%, p = 0.008). 13 Among the 45 patients in the SPG stimulation group, nine developed serious adverse events, four of which were implantation related. The SPG stimulation seems efficacious and well tolerated for patients with chronic CH. 13 Unfortunately, the producer of the device has filed for bankruptcy and whether the device will be available again remains unknown.
Has the era of personalised medicine in headache disorders finally arrived? It remains difficult to predict whether a patient responds to a specific medication, for example, an abortive medication like a triptan or a preventive medication like topiramate. Kogelman et al. interviewed 2,219 unrelated migraine patients, accessed their acute and prophylactic drugs response, and genotyped all of them and calculated their polygenic risk scores (PRS) for the likelihood of migraine. 14 Among all the medications investigated, the authors found an association between higher PRS, suggestive of a higher risk of migraine, and a positive treatment response to triptan (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.05-1.49) but not other medications. They replicated their findings in an independent cohort comprising 5,616 triptan users with an OR of 3.20 (95% CI 1.26-8.14). 14 This is the first study to show that the response to medication in headache disorders may be genetically determined and the mechanism of how triptans work is closely related to the mechanism behind a migraine generation.
Central or peripheral origin: the debate is everlasting It has been long debated whether the origin of a migraine attack is central or peripheral. More to the debate, whether certain migraine-specific medications act peripherally or centrally. Sumatriptan has long been considered to act peripherally because of its hydrophilicity and theoretically poor CNS penetration. Deen et al. studied eight patients with a positron emission tomographic scan after the injection of a specific 5-HT 1B receptor radiotracer. They found that after sumatriptan administration, the central 5-HT 1B receptor binding in pain-modulating regions was reduced by 16%, suggestive of a binding of sumatriptan to central 5-HT 1B receptors. 15 The mechanism by which it crosses the blood-brain barrier (BBB) is unknown. The finding in this study raises another interesting question: whether the newer generation migraine-specific medications, for example, anti-CGRP or CGRP receptor antibodies, could possibly cross the BBB and exert a central action? The theoretical probability of that is considered negligible given an intact BBB; however, some suggested that the BBB might be 'leaky' in certain variants of migraine with aura. 16,17 One recent animal study observed a small proportion (0.34%) of anti-CGRP antibodies in central regions like the hypothalamus, where an effective BBB is lacking. 18 Future studies are still needed to address whether a central effect of CGRP antibodies is possible.
Potential new treatment target in migraine ATP-sensitive potassium channels (K ATP ) locate downstream in the signaling pathway of either CGRP or NO in triggering migraine. Al-Karagholi et al. investigated whether the opening of K ATP is associated with a migraine attack. In a randomised, double-blind, placebo-controlled, crossover design, among the 16 migraine patients who received the infusion of levcromakalim, a K ATP channel opener, 16 of 16 (100%) developed migraine attacks after levcromakalim compared to one of 16 (6%) after placebo. 19 This 100% induction rate is higher than other substances, such as GTN, CGRP, or sildenafil, 19 and therefore, a validation study is warranted. Nevertheless, the study suggests an important role of K ATP in migraine pathophysiology and the blocking of the K ATP channel may be a potential target in migraine treatment.

Closing remarks
The articles selected reflect the tremendous contribution from different research groups to improve the treatment of headache disorders and to advance our understanding of their disease pathophysiology. Aside from the CGRP antibodies and antagonists, new potential treatment targets have emerged thanks to the progress made in studies focusing on disease mechanism. Less progress has been made in fields concerning less frequent but disabling headache disorders, for example, chronic CH and facial pain disorders. In summary, it has been a good and fruitful year for headache research, and we look forward to an even brighter future in 2020.

We need to have crossprofession scientific and clinical agreement to study these diseases
Chronic facial pain that has no dental cause is probably underdiagnosed but also certainly undertreated. 1 Because chronic facial pain is in most cases perceived orally or in the mandibular/maxillar region, patients consult dentists who do not find any dental pathology. When cranio-mandibular disorders have also been excluded it becomes clear that the patient needs to be seen by a pain specialist, but more often than not consults another dentist. 2 One of the reasons why we do not recognise chronic facial pain is that we know so little about it and have no specific treatments to offer. The consequence is a life-long odyssey for affected patients which often ends with all teeth removed and the pain still ongoing. 3,4 This situation resembles in many facets the situation of headache patients some 30 years ago. 5 The cornerstone allowing to study the pathogenesis and find highly specific treatments for headache has been the IHS International Classification of Headache Disorders (ICHD). 6 ICHD has proven to be extremely valuable and indeed indispensable for scientific and clinical progress in the field of headache medicine.
There are certainly several reasons for the fact that, compared to the headache field, the investigation and treatment options of facial pain disorders remained slow. An important factor was certainly the lack of a comprehensive facial pain classification. 7 By acknowledging and using such a classification we make sure that scientific progress is comparable between labs and that clinicians all over the world speak about the same disease when discussing for example atypical odontalgia. With the recent implementation of the first International Classification of Orofacial Pain (ICOP) 8 a huge step has been undertaken allowing standardised communication between professions, scientists and clinicians.
One of the enigmas of non-dental facial pain is the question whether facial pain is indeed a pain disorder in its own right or rather just a headache syndrome which slipped from the ophthalmic to the second and third trigeminal branch. 5 Headache is often referred to orofacial regions and may even be located exclusively within the orofacial region. [9][10][11] Orofacial pains that are referred to the head present a difficult clinical entity with manifold phenotypes. Rafael Benoliel was one of the first voices in the wilderness, never tiring to point out to headache specialists that the headache field needs to become interested in chronic facial pain. 12 And indeed facial pain and its many facets is not reduced to trigeminal neuralgia, we need to see facial pain as an independent and distinct trigeminal disorder and such syndromes need to find a home in the headache field. In order to investigate we need to distinguish 13 -the issue becomes important or indeed decisive when facial pain has to be distinguished from headache syndromes. 9 Facial pain has also been defined in the ICHD, but the facial pain chapter in ICHD excluded many dental and other facial disorders and thus was incomplete. With the advent of ICOP this has changed. The classification committee covered dentists, temporomandibular joint dysfunction (TMD) specialists, neurologists and psychologists and also included members of the Orofacial and Head Pain Special Interest Group (OFHP SIG) of the International Association for the Study of Pain (IASP), the International Network for Arne May

Facial Pain is coming home -ICOP Editorial
New developments in pathophysiology and treatment are our long-term target and we need to use ICOP in scientific and daily life Orofacial Pain and Related Disorders Methodology (INfORM), the American Academy of Orofacial Pain (AAOP) and IHS. This represents the major associations involved in orofacial and head pain, raising the acceptance and strengthening the future of ICOP. For the same reason a lot of work went into harmonising ICHD and ICOP. The recent definitions of trigeminal neuralgia and TMD were copied 1:1 to avoid having different definitions for the same disease. As such ICHD-3 and ICOP can be cited pari passu, but given that ICOP is more specific for facial pain it should be favoured at the moment.
Classifications are definitions and definitions are per se agreements 13,14 and the (in the pain field) unparalleled success story of headache has taught us that we need to have that agreement in order to study these diseases. 9 Starting with a unifying and internationally accepted classification such as ICOP 8 we start turning around and redefining the field of facial pain and also strongly encourage active collaboration. 15 New developments in pathophysiology and treatment are our long-term target and we need to use ICOP in scientific and clinical daily life -starting today.
We explored the retinalthalamocortical pathways that may be responsible for abnormal processing of thalamic visual inputs commonly observed in migraine patients

The role of the visual thalamus in migraine Fellowship from August 2018 to August 2019 King's College London, London, UK Mentor: Phillip R Holland
The main aim of our project was to explore retinal-thalamocortical pathways that may be responsible for abnormal processing of thalamic visual inputs, commonly observed in migraine patients. We predicted that thalamocortical dysregulation may lead to altered cortical excitability and modified susceptibility to migraine aura. Lately, a refined transgenic Cre reporter mouse model based on the expression of the Sox14 transcription factor has been validated as a specific tool to modulate the activity of GABAergic interneurons located in the dorsal (d) part of the lateral geniculate nucleus (LGN). Using this specific mouse model, we precisely modulated the activity of GABAergic interneurons located in the dLGN by using the latest state-of-the-art techniques such as chemogenetics (DREADDS) and viral-based cell ablation. We then determined its impact on clinically relevant migraine-related phenotypes in mice such as cortical spreading depression (CSD; aura), facial mechanical hypersensitivity (cephalic allodynia) and aversion to light (photophobia). The IHS fellowship allowed a smooth transition into the headache field by integrating into one of the most prestigious research labs for migraine aura susceptibility and attack triggering.
In two final experiments, mice were primed with nitroglycerin (clinical migraine trigger) and assessed for light aversion or facial mechanical hypersensitivity following a bright light stress paradigm. Nitroglycerininduced sensitisation was not affected by GABAergic interneuron activity modulation/ablation.
The IHS fellowship allowed a smooth transition into the headache field by integrating into one of the most prestigious research labs conducted by Philip Holland. He has been a very understanding and helpful mentor allowing me to bring and develop my own ideas. I acquired many new skills and techniques which now make me feel comfortable within the headache field. I attended two congresses (MTIS 2018 and IHC 2019) where I got the opportunity to present my results and foster some future collaborations. Overall, it has been a fantastic year and I am now applying for larger fellowships to continue my progress towards establishing my own research group exploring sex differences in primary headache disorders, and establishing myself as a principal investigator in the migraine field. The IHS fellowship represents a strong and meaningful support for such applications. I focused on inducing cortical spreading depression (CSD) in a non-invasive manner with optogenetics to find the threshold for the induction of neuroinflammation and pain mimics in relation to the number of CSDs, without confounding factors of recent invasive surgery or the use of a restrainer. To further increase the translational value of the work we extended the research to mouse mutants that carry the S218L missense mutation in the oti A subunit of voltage-gated Ca V2 .1 channels that have been linked to FHM1, and can be considered a valuable mouse model to study certain aspects of migraine. Importantly, the mutant mice allowed me to investigate neuroinflammation and pain behaviour in the context of a hyperexcitable brain with an increased susceptibility to CSD. I assessed the consequences of optogeneticallyinduced CSD on the extent of neuroinflammation in the context of HMGB1 release at different timing points, and simultaneously, the occurrence of pain-related behaviours, separately for female and male mice. To further enhance the clinical relevance of the study, I tested the effect of TAT-Panx-308, which is an interfering peptide that mimics the C-terminal epitope of Panx1 including the Y308 site and blocks activation of Panx1 channels, as a potential novel drug for the treatment of migraine.
CSDs were non-invasively induced by optogenetics in freely moving mice. The neuroinflammatory marker HMGB1 in (sub)cortical brain areas, and the neuronal activation marker pERK in trigeminal ganglia (TG) were studied by immunohistochemistry in WT and FHM1 mice with and without CSDs. Pain-related behaviours were analysed in all conditions. Effects of the Panx1 channel inhibitor were examined by TAT-Panx-308. The contribution of Panx1 channel activation to this inflammatory response and pain outcome highlights its key role in aura para-inflammatory profile and migraine headache leading to a potential therapeutic route to cure migraine

Results
The IHS fellowship allowed me to work in the high-profile migraine research lab in Leiden but decreased nest building behaviours. In mutant mice, neuronal HMGB1 release was bilateral and prolonged (for 48 hours) following CSD in line with enhanced and prolonged higher scores of pain mimics and HG. Trigeminal ganglia were activated bilaterally after CSDs in both genotypes. CSD-related neuroinflammation and pain behaviour were blocked by inhibitor of Panx1 channels.
I developed a novel method showing that non-invasively induced CSD triggers a parainflammatory response that increases pain-related behaviour; both stayed enhanced for a longer period in FHM1 mutant compared to WT. The contribution of Panx1 channel activation to this inflammatory response and pain outcome highlights its key role in aura parainflammatory profile and migraine headache leading to a potential therapeutic route to cure migraine.
In my initial plan I aimed to do also RNA sequencing, but given the interesting results on HMGB1 release and pain mimics I instead increased the number of experimental groups to study the timing threshold for HMGB1 release and pain-related behaviour in both genotypes and genders. I also added another dimension of pain-related behaviour as HG and its different types such as oculotemporal strokes and laterality to investigate the importance of CSD effect on headache.
The IHS fellowship allowed me to have the opportunity to work in the high-profile migraine research group in Leiden which will be an enormous boost for my career in neuroscience, and particularly in the migraine field, and an extremely important step for me in becoming a capable neuroscientist. By using the newest techniques related to optogenetics I have broadened my skills. The fellowship enabled me to investigate the pathophysiological mechanisms of migraine more efficiently and independently, and completion of the project with high-impact publications will provide more opportunities and chances in my career to gain funding for research. It also helped me to expand my network of scientists in different fields to perform future joint research and enabled me to participate in additional studies in the group because of my specific skills. I will remain in Professor van den Maagdenberg's group and do a follow-up study based on my research with the IHS fellowship. The main purpose of the master class was to increase knowledge of headaches, recognise primary forms of headache, improve the quality of care for patients and learn how to prescribe effective treatment.
This was the first meeting in Kyrgyzstan dedicated to headache medicine. Over 120 doctors from different regions of the country attended the master class, including paediatric and adult neurologists, family doctors, therapists, pharmacologists, cardiologists and medical university teachers, clinical residents and students whose activities are related to the study, diagnosis, treatment, rehabilitation and prevention of headaches. On the first day of the master class, a short test was conducted among the participants to assess their basic knowledge on headache medicine, after which Vera Osipova reported on the international classification and principles for diagnosing headaches. It is very important to note that not only in Kyrgyzstan, but also in Russia, there are problems with incorrect diagnosis of primary headache.

Case presentations added an interactive element to the meeting The Kyrgyzstan doctors learned a lot of new information and increased their knowledge in the field of headache medicine
Sait Ashina presented a lecture on tensiontype headache: how to correctly recognise the symptoms and how to properly diagnose and prescribe the necessary evidencebased treatment.
Assistant Professor of the Department of Neurology and Clinical Genetics of KSMA Kunduz Karbozova reported results of research work (within the framework of her PhD) on clinical characteristics of primary headache among patients who attended a headache specialist centre in Bishkek. Dr Karbozova also introduced the audience to the IHS mission and possibilities of IHS membership, which is free of charge to researchers and physicians from the Kyrgyz Republic.
The first day concluded with a presentation of clinical cases of two patients with headaches; the invited professors had a conversation with the patients, collected their history and made recommendations for subsequent diagnosis and treatment.
During the second day Sait Ashina spoke about patient management of migraine, including the new monoclonal antibodies to CGRP (calcitonin gene-related peptide) therapies for the treatment of migraine. Vera Osipova shared her knowledge and experience in diagnosing and treating patients with chronic forms of primary headaches, and talked about the risks of chronicity and the burden of chronic headaches. She also taught about TACs and other headache and clearly identified the differentiation between the forms of TACs such as cluster headache, paroxysmal hemicrania, SUNCT and SUNA syndromes. Elmira Mamytova then gave a presentation on secondary headaches which are most commonly seen by family doctors and neurologists. Differential diagnosis and an algorithm of action were also clearly given to identify the secondary aetiology of headaches.
The final presentation by Sait Ashina was a lecture on the risk factors and treatment methods for medication overuse headache which arises from excessive use of drugs to relieve headaches, such as analgesics, triptans, NSAIDs, and opiates.
Following the presentations, a second test was conducted among the participants, which showed excellent results compared to the pre-test, indicating the lectures, presentations and discussions had proved useful for the attendees. Thanks to the master class the doctors learned a lot of new information, improved their knowledge in the field of headaches, and received important practical assistance from the world's foremost specialists. Many attendees have indicated they would like to organise more meetings and conferences in the headache field because it is very important to gain new knowledge from international headache specialists. Participants in the congress included 450 physicians, researchers and other healthcare professionals from all over Iran. Our IHS Visiting Professors were Jes Olesen from Denmark and Hossein Ansari from the USA. Parvin Allahyarova from Azerbaijan was another international invited speaker who discussed some challenging cases and participated in one of the panel discussions. Also for the first time, we used video conference where Sait Ashina from the USA delivered his presentation and Messoud Ashina, current President of IHS, delivered a video lecture and closed the conference during closing ceremony.
This scientific meeting provided updated information on most primary and some secondary headache disorders through various lectures and workshops. Attendees had an excellent opportunity to communicate with well-known national and international scientists in the field of headache. Thirty-nine Iranian speakers also presented lectures on a variety of headache and pain disorders including acute treatment of migraine headache, drug interactions in migraine treatment, non-medical therapies of headache, reversible cerebral vasoconstriction syndrome, treatment of trigeminal autonomic cephalalgias other than cluster headache, epidemiology and burden of headache disorders, neuroimaging in headache disorders, migraine with brainstem aura: defining the core syndrome, evaluation and management of headache in the emergency department, trigeminal neuralgia: MR imaging features, headaches and behaviour, and headache and epilepsy.

Mansoureh Togha and Hossein Ansari
Abstracts of the lectures were available online on our website from the first day of the congress and an abstract booklet freely available to all participants upon registration.
In addition, there were a number of lectures on pain, neurostimulation techniques and various types of nerve blocks and pain injections presented by Iranian neurologists and 15 lectures on different headache topics were also delivered by young researchers during the congress.
Three workshops were offered on Botulinum toxin injection for chronic migraine, peripheral nerve block in the treatment of headache, and neurosonology with emphasis on diagnosis of giant cell arteritis. All workshops involved live patient demonstrations and participants had the opportunity to have hands-on experience.
Three panel discussions also took place during the congress which explored management of trigeminal neuralgia, idiopathic intracranial hypertension; challenges in diagnosis and treatment and giant cell arteritis. This interactive panel was a new feature in this congress, and following positive feedback received from participants we will in future congresses increase the time for panel discussions. Drs S Haghighi, H Hemasian and P Emami conducted a scientific competition with two teams in which 36 neurology residents from different medical universities of Iran participated.
Feedback from our international guests and participants was impressive and positive, commending the well-organised congress and highly interactive lectures. This headache congress was unquestionably able to play an important role in promoting the level of knowledge in the fields of The Latin America Master School took place in Bogotá, Colombia, from 3-5 October 2019 at the NH Hotel Collection. The event was the culmination of many months of work by the Colombian Neurology Society committee (Joe Muñoz, Fidel Sobrino, Bernardo Uribe, Sergio Ramirez, Oscar Pradilla and Michel Volcy as leader and Coordinator) in collaboration with Mario Peres, and Allan Purdy, IHS Education Committee Chair, whose strong guidance, patience and assertiveness was of great value.
Following completion of the Master School, all attendees who achieve 70% over the three mandatory written examinations (before, at the end of the course and 6 months after) will be given a certificate. opening welcome video from Allan Purdy, the programme proceeded with a mixture of lectures in plenary sessions, case-based plenary activities, controversy sessions and a special interactive session during which the international speakers were interviewed on their experiences as headache specialists and why they would recommend it as an important field to work in.
Two sets of exams each containing 30 questions took place during the master school, the first after the introduction and methodology explanation, the second on the last day of the academic sessions. Visiting the Danish Headache Center has more than met all my initial aims professionally, as well as personally. The traineeship introduced me to professional aspects I haven't experienced before, hence refining my knowledge, clinical skills, mindset and starting to perceive things from different viewpoints. I have grown a lot as a professional and started to think wider about the possible opportunities for my further career development. Now, while leading the neurology department at one of the biggest hospitals in Tbilisi, Georgia, also having a private practice at the ambulatory service, I will try to develop the headache field more and share my entire experience in practical ways. My mentor, Professor Zaza Katsarava, who is the biggest support I have, and I are already trying to develop headache practice not only in Tbilisi, but throughout the whole of Georgia. I'm sure this international experience will play its role for the big plans and hope this won't be the last platform for gaining international experiences in the future.
I would like to once again express my sincere appreciation and gratitude to Professor Ashina and the whole Danish Headache Center team who welcomed me from the very beginning and made me feel part of the big headache family. Professor Messoud Ashina is a real master of his work, a team leader, mentor and colleague, and supported me at every point and shared his priceless experience, which helped me to become a better clinician and person, to think further and deeper and dream big.
International Headache Society, thank you for everything! And thank you for that emotional feeling I was having while updating my report and remembering the best international experience I have had so far, by means of your help! Spread the word in your institution IHS is an international professional organisation working with others for the benefit of people affected by headache disorders. As a charity, the purpose of IHS is to advance headache science, education, and management, and promote headache awareness worldwide.