Concussion (mild traumatic brain injury) affects approximately 50 million people annually. Headache is the most common symptom after concussion and persists in up to 50% of those affected for at least one-year. The biological underpinnings of and the efficacy and tolerability of treatments for post-traumatic headache has historically received little attention. While treatment in clinical practice is mostly directly at the underlying phenotype of the headache, persistent post-traumatic headache is considered to be less responsive to treatments used to treat migraine or tension-type headache. Over the past several years, significant pre-clinical research has begun to elucidate the mechanism(s) involved in the development of post-traumatic headache, and a concerted effort to evaluate the efficacy of selected treatments for persistent post-traumatic headache has begun. This presentation will review the epidemiology, pathophysiology, and emerging data on the prevention and treatment of post-traumatic headache.

Migraine is the third most prevalent disease worldwide and is estimated to affect upwards of 14% of the population. Our lab has used novel preclinical models to identify the delta opioid receptor (DOR) as a therapeutic target for multiple headache disorders, including migraine. We have also investigated the relationship between DOR with the pro-migraine peptide, CGRP. There is regional variation between the co-expression of DOR with CGRP or its receptor in the trigeminal complex. This work indicates that DOR agonists can moderate both CGRP release and signaling, thus regulating pro-migraine effects at two different levels. Recent work in our lab has also explored how cytoarchitectural changes in pain processing regions are critical for the maintenance of the chronic migraine state. We show that there is decreased neuronal complexity in two different models of migraine, and that restoration of tubulin dynamics, directly by HDAC6 inhibitor or indirectly by CGRP receptor antagonist, can inhibit migraine-associated symptoms. These studies provide fundamental information on how cytoskeletal dynamics are altered in chronic migraine, and form the basis for the development of HDAC6 inhibitors for headache treatment.

In this talk I will present data from imaging studies that we have been conducting for the past 20 years trying to shed light on migraine physiopathology, from anatomical and functional MRI to positron emission tomography.

Migraine is much more than an episodic headache. It is a complex brain disorder, characterized by a global dysfunction in multisensory information processing and integration. In a third of patients, the headache is preceded by transient sensory disturbances (aura), whose neurophysiological correlate is cortical spreading depression (CSD). The molecular, cellular and circuit mechanisms of the primary brain dysfunctions that underlie migraine onset, susceptibility to CSD and altered sensory processing remain largely unknown and are major open issues in the neurobiology of migraine. Genetic mouse models of a rare monogenic form of migraine with aura provide a unique experimental system to tackle these key unanswered questions. I will describe the functional alterations we have uncovered in the cerebral cortex of genetic mouse models and discuss the insights into the cellular and circuit mechanisms of migraine obtained from these findings.

This talk will address important aspects of pediatric migraine research, including: 1) Who is affected by pediatric migraine? 2) What does pediatric migraine look like, and what does a clinician need to do to reach a migraine diagnosis in a child? 3) When does pediatric migraine begin, and how might it present clinically before it presents as headache (e.g., infant colic, benign paroxysmal torticollis, cyclic vomiting syndrome etc.) 4) Where does responsibility for decreasing pediatric migraine frequency rest? What is society's role in preventing migraine in young people?

This seminar will focus on the extraordinary shift in migraine research during the last 4 decades with the discovery of the trigeminovascular system (TVS) and it’s major impact on pathophysiology and treatment.  Compelling evidence supporting the importance of TVS, cortical spreading depression and parameningeal inflammation will be explored as will the implications of newly discovered microvascular channels within the meninges on an attack.

In this presentation I will describe how the CGRP project started and culminated in the development of gepants and mAbs for successful therapy. The outstanding question regarding the preponderance of female migraineurs also remains. I will present views on the reason behind this and suggest that understanding the hormonal influence will pave the way to alleviating hormone related migraine.

Lifelong devotion to headache research has led to many discoveries. First a series of studies of brain blood flow during attacks of migraine. The results showed changes compatible with cortical spreading depression in migraine without aura effectively negating the then prevailing vasospastic/ischemic theory. In migraine without aura no changes in brain blood flow. This difference was crucial for the separation of migraine with aura and migraine without aura in the first and subsequent editions of the international headache classification headed by me. Then a human migraine provocation model that has elucidated the molecular mechanisms of migraine. Successively we showed in series of papers the importance of nitric oxide, histamine, CGRP, PACAP and prostanoids. Therapeutic effectiveness of antagonizing these provokers by tonabersat, L-NMMA, CGRP receptor antagonists and monoclonal antibodies and of NSAIDs. Present and future attempts to put all these signaling mechanisms into a framework but it is not easy

Genetic mutations of the SCN1A gene, the voltage gated sodium channel NaV1.1, cause well-defined epilepsies, including the severe developmental and epileptic encephalopathy Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+), as well as a severe form of migraine with aura, familial hemiplegic migraine (FHM). More recently, they have been identified in an extremely severe early infantile encephalopathy. Functional studies and animal models have contributed to disclose pathological mechanisms, which can be often linked to a straightforward loss- vs gain- of channel function. However, although this simple dichotomy is pertinent and useful, detailed pathological mechanisms in neuronal circuits can be more complex, sometimes because of unexpected homeostatic or pathologic responses. I will compare pathological mechanisms of epilepsy and migraine mutations studied with cellular, animal and computational models, highlighting a novel homeostatic response implemented by CCK-positive GABAergic neurons in a mouse model of Dravet syndrome, which may be boosted in therapeutic approaches.