We are delighted to present the Emerging Trends in Headache 2022 article collection. This collection showcases the high-quality work of internationally recognized researchers in the early to mid stages of their research careers. These rising star researchers have been recognized by the Frontiers in Pain Research Editors for their potential to influence future directions in their respective fields. The work presented here highlights the diversity of research performed across the entire breadth of headache and presents advances in theory, experimental techniques, and methodology along with their application. New articles will be added to this collection as they are published.

University of Maryland

School of Medicine, Acıbadem University

Istituti Clinici Scientifici Maugeri IRCCS, Milan

Frontiers in Pain Research

Headache

Emerging Trends in Headache

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/46719/emerging-trends-in-headache">Emerging trends in headache</a>Headaches are a common ailment that afflicts individuals across the globe, transcending age, gender, and geographic boundaries. They can be debilitating, impacting the quality of life and productivity of those who suffer from them (<a href="#B1">1</a>).In recent years, the scientific community has made significant strides in understanding the complexities of headaches, particularly migraine, and has explored novel approaches to their diagnosis, treatment, and management. The collection of papers presented in this Research Topic, &#x201c;Emerging Trends in Headache&#x201d;, showcases some of the latest advancements in this field, shedding light on various aspects of headaches and their implications for healthcare. They represent a diverse range of research, from basic science to clinical real-world experience.Migraine is one of the most frequent and disabling diseases worldwide (<a href="#B1">1</a>). Its etiopathogenesis is complex and involves a combination of factors. Multiple genetic variants contribute to an individual's susceptibility risk, with each variant typically exerting a modest influence (<a href="#B2">2</a>). Genes interact with an intricate web of influences encompassing endocrine and metabolic factors, comorbidities, environmental influences, life events, and behavioral choices. These dynamic forces converge to determine the presentation of the disease and shape its manifestation. Migraine is associated with obesity and diabetes mellitus (<a href="#B3">3</a>), depression, anxiety, post-traumatic stress disorder, and sleep disorders (<a href="#B4">4</a>). Increasing migraine headache frequency was associated with gastric ulcers, diabetes, anxiety, depression, insomnia, asthma and allergies (<a href="#B5">5</a>). Recent studies highlight a link between the gut-brain-immune (GBI) axis and migraine (<a href="#B6">6</a>). These associations imply bidirectional causality, shared genetic factors, and/or common pathophysiological mechanisms (<a href="#B7">7</a>).Understanding these determinants, their interactions, and the biological mechanisms thereof, is a multidisciplinary endeavor with the potential to uncover innovative and better management strategies.<a href="https://doi.org/10.3389/fpain.2021.766718">Fitzgerald et al.'s</a> paper, “Sex Differences in Migraine: A Twin Study”, explores the intriguing dimension of gender disparities in migraine. Migraine is known to affect women disproportionately, and this twin study delves into the genetic and environmental factors contributing to this phenomenon. The study found that migraine is equally heritable in females and males, but that there may be subtle differences in the genes underlying migraine across the sexes. The study also found that females with a male co-twin have an increased risk of migraine, suggesting that masculinization of the prenatal environment may increase migraine risk for females. The authors suggest a potential prenatal neuroendocrine factor in the development of migraine. Migraine and migraine related syndromes can indeed begin in the early infancy (<a href="#B8">8</a>). Migraine is a multifactorial condition, with its features probably arising from gene–gene and gene–environment interactions. It is stimulating to think that such environmental exposure can act as early as the intrauterine life. Throughout the life of a subject, these interactions shape the development of the brain and influence the connectivity between brain areas through plastic remodeling (<a href="#B9">9</a>), with significant consequences on health. For example, <a href="https://doi.org/10.3389/fpain.2021.767162">Gecse et al.</a> found that there are sex differences in the functional connectivity of the periaqueductal gray matter (PAG), a region of the brain that is involved in pain processing. The study suggests that these sex differences contribute to the different clinical presentations of migraine in females and males.Calcitonin gene related peptide (CGRP) is a peptide that participates in the transmission of pain signals. CGRP inhibitors are a new class of drugs that are effective in preventing migraine attacks. As new drugs are being introduced on the market, important questions arise about real world experiences, intentional and unintentional effects of combinations and interactions. The paper by <a href="https://doi.org/10.3389/fpain.2023.1130239">Shah et al.</a> gives a review of the current evidence about the effects of combining different CGRP inhibitors in the same patient.The COVID-19 pandemic has brought forth an array of health challenges, including a surge in post-vaccination side effects (<a href="#B10">10</a>). The paper by <a href="https://doi.org/10.3389/fpain.2022.994140">Ceccardi et al.</a> investigates the incidence of headache after COVID-19 vaccination. The study found that headache is a common side effect of vaccination, but that it is more likely to occur in people who have a history of migraine. The study also found that headache after vaccination is usually benign, mild and resolves on its own within a few days. This article provides some of the first insights into the incidence and management of headache in this population and offers some clinical hints for distinguishing the rare severe forms.The articles comprising this Research Topic illuminate significant advancements in headache research, yielding fresh insights into its etiology and mechanisms while propelling the development of novel, efficacious therapies.Within these papers, emerging trends in headache research are discernible. These trends encompass the intricate interplay of genetic and environmental factors underpinning migraine. They involve the application of neuroimaging techniques to scrutinize its cerebral mechanisms. Exciting new preventative and treatment modalities are entering clinical practice, warranting optimal management strategies. Moreover, the COVID-19 pandemic has introduced novel challenges into both our daily lives and clinical endeavors.As we contemplate these four papers, it becomes apparent that the headache research landscape is in a state of rapid evolution. These studies collectively underscore the significance of incorporating gender-specific variables into migraine investigations, probing innovative neurobiological pathways, and exploring inventive therapeutic interventions. Furthermore, they underscore the ongoing necessity for vigilant health outcome monitoring during the ongoing global vaccination campaigns.Headaches persist as a multifaceted issue, and it is heartening to observe interdisciplinary cooperation among researchers in unraveling their complexities. This collection signifies a juncture where genetics, neurobiology, pharmacology, and epidemiology converge, ushering in new avenues for headache research and treatment. Our aspiration is that these nascent trends will kindle further inquiries, culminating in enhanced management and relief for those afflicted by headaches.We anticipate that this Research Topic will captivate the interests of researchers, clinicians, and patients alike. We believe that the body of work presented herein constitutes a substantial addition to the headache research domain.We would like to thank all the authors who contributed to this Research Topic. Their work is helping to improve our understanding of headache and to develop new treatments for this common and disabling condition.LG: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. PY: Writing &#x2013; review &amp; editing, Writing &#x2013; original draft.The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Emerging trends in headache

The discovery of calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology has led to advances in the treatment of migraine. Since 2018, the Food and Drug Administration (FDA) has approved four monoclonal antibody (mab) therapies targeting either the CGRP ligand or receptor and 3 oral small molecule CGRP receptor antagonists. These targeted therapies have been shown to be safe and effective for either preventive or acute treatment of migraine in adults. Given their efficacy and tolerability profile, CGRP inhibitors have revolutionized the approach to migraine treatment. Theoretically, combining therapies within this therapeutic class could lead to more CGRP blockade and, subsequently, improved patient outcomes. There are providers currently combining CGRP therapies in clinical practice. However, limited data are available regarding the efficacy and safety of this practice. This mini-review provides a summary of available data and poses important considerations when combining CGRP therapies for migraine treatment.

The discovery of calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology has led to advances in the treatment of migraine. Since 2018, the Food and Drug Administration (FDA) has approved four monoclonal antibody (mab) therapies targeting either the CGRP ligand or receptor and 3 oral small molecule CGRP receptor antagonists. These targeted therapies have been shown to be safe and effective for either preventive or acute treatment of migraine in adults. Given their efficacy and tolerability profile, CGRP inhibitors have revolutionized the approach to migraine treatment. Theoretically, combining therapies within this therapeutic class could lead to more CGRP blockade and, subsequently, improved patient outcomes. There are providers currently combining CGRP therapies in clinical practice. However, limited data are available regarding the efficacy and safety of this practice. This mini-review provides a summary of available data and poses important considerations when combining CGRP therapies for migraine treatment.

Calcitonin gene relating peptide inhibitors in combination for migraine treatment: A mini-review

IntroductionThis study aimed to assess the prevalence and clinical characteristics of headaches, in particular secondary headaches.</sec>Materials and MethodsThis observational study was performed at the ASST Spedali Civili of Brescia, Italy. Visits to the Emergency Department (ED) and subsequent hospitalizations regarding a new or worsening headache in the 16 days following the administration of the COVID-19 vaccine between January 2021 and January 2022 were recorded and compared with those of January 2019–January 2020.</sec>ResultsThe ratio between ED admissions due to headaches and total ED admissions was significantly higher in 2021 compared with 2019 (4.84% vs. 4.27%; p < 0.0001). Two-hundred and eighty-nine ED headache admissions (10.8% of all ED headache admissions) were time-correlated to the COVID-19 vaccination, of which 40 were hospitalized in order to exclude a symptomatic etiology. At discharge, 32 patients had a diagnosis of benign headache not attributed to any cranial/extracranial disorder and eight patients of secondary headache, whose diagnoses were the following: Headache attributed to cranial and/or cervical vascular disorder (n = 4); headache attributed to nonvascular intracranial disorder (n = 2); headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structure (n = 1); and painful lesions of the cranial nerves (n = 1). The headache most frequently reported by patients had migraine-like characteristics: the localization was predominantly frontal or temporal, the pain was described as throbbing and severe in intensity and it was frequently accompanied by nausea/vomit, and photo-phonophobia. Over half—regardless of the final diagnosis—of hospitalized patients had a history of primary headaches.</sec>ConclusionsFollowing the spread of COVID-19 vaccination, the number of ED admissions due to headaches significantly increased. However, less than 14% of all the ED visits due to a headache time-correlated to the COVID-19 vaccination were actually hospitalized, with most patients documenting a benign headache, possibly related to the generic side effects of the vaccination. Only 8/40 hospitalized patients were diagnosed with a secondary headache. These benign headaches would actually fulfill diagnostic criteria for 8.1 Headaches attributed to the use of or exposure to a substance (ICHD-3), although, at the time being, it does not include vaccines as possible substances.The headache migraine-like characteristics’ reported by most patients could suggest activation of the trigeminovascular pathway by all the cytokines and other pro-inflammatory molecules released following the vaccination.</sec>

Introduction: This study aimed to assess the prevalence and clinical characteristics of headaches, in particular secondary headaches.Materials and Methods: This observational study was performed at the ASST Spedali Civili of Brescia, Italy. Visits to the Emergency Department (ED) and subsequent hospitalizations regarding a new or worsening headache in the 16 days following the administration of the COVID-19 vaccine between January 2021 and January 2022 were recorded and compared with those of January 2019–January 2020.Results: The ratio between ED admissions due to headaches and total ED admissions was significantly higher in 2021 compared with 2019 (4.84% vs. 4.27%; p &lt; 0.0001). Two-hundred and eighty-nine ED headache admissions (10.8% of all ED headache admissions) were time-correlated to the COVID-19 vaccination, of which 40 were hospitalized in order to exclude a symptomatic etiology. At discharge, 32 patients had a diagnosis of benign headache not attributed to any cranial/extracranial disorder and eight patients of secondary headache, whose diagnoses were the following: Headache attributed to cranial and/or cervical vascular disorder (n = 4); headache attributed to nonvascular intracranial disorder (n = 2); headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structure (n = 1); and painful lesions of the cranial nerves (n = 1). The headache most frequently reported by patients had migraine-like characteristics: the localization was predominantly frontal or temporal, the pain was described as throbbing and severe in intensity and it was frequently accompanied by nausea/vomit, and photo-phonophobia. Over half—regardless of the final diagnosis—of hospitalized patients had a history of primary headaches.Conclusions: Following the spread of COVID-19 vaccination, the number of ED admissions due to headaches significantly increased. However, less than 14% of all the ED visits due to a headache time-correlated to the COVID-19 vaccination were actually hospitalized, with most patients documenting a benign headache, possibly related to the generic side effects of the vaccination. Only 8/40 hospitalized patients were diagnosed with a secondary headache. These benign headaches would actually fulfill diagnostic criteria for 8.1 Headaches attributed to the use of or exposure to a substance (ICHD-3), although, at the time being, it does not include vaccines as possible substances.The headache migraine-like characteristics&#x2019; reported by most patients could suggest activation of the trigeminovascular pathway by all the cytokines and other pro-inflammatory molecules released following the vaccination.

Post COVID-19 vaccination headache: A clinical and epidemiological evaluation

Migraine is a neurological disorder with a prominent sex difference such that two thirds of sufferers are female. The mechanisms behind the preponderance of migraine in women have yet to be elucidated. With data on 51,872 participants from the Swedish Twin Registry, we report results from two distinct analyses intended to clarify the degree to which genetic and environmental factors contribute to sex differences in migraine. First, we fit a sex-limitation model to determine if quantitative genetic differences (i.e., is migraine equally heritable across men and women) and/or qualitative genetic differences (i.e., are different genes involved in migraine across men and women) were present. Next, we used a multilevel logistic regression model to compare the prevalence of migraine in individuals from opposite-sex and same-sex twin pairs to determine whether differences in the prenatal hormone environment contribute to migraine risk. In the final analytic sample, women were found to have a significantly higher rate of migraine without aura relative to men (17.6% vs. 5.5%). The results from an ADE sex-limitation model indicate that migraine is equally heritable in men and women, with a broad sense heritability of 0.45, (95% CI = 0.40–0.50), while results from a reduced AE sex-limitation model provide subtle evidence for differences in the genes underlying migraine across men and women. The logistic regression analysis revealed a significant increase in migraine risk for females with a male co-twin relative to females with a female co-twin (OR = 1.51, 95% CI = 1.26–1.81). These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females. This effect points to a potential prenatal neuroendocrine factor in the development of migraine.

Migraine is a neurological disorder with a prominent sex difference such that two thirds of sufferers are female. The mechanisms behind the preponderance of migraine in women have yet to be elucidated. With data on 51,872 participants from the Swedish Twin Registry, we report results from two distinct analyses intended to clarify the degree to which genetic and environmental factors contribute to sex differences in migraine. First, we fit a sex-limitation model to determine if quantitative genetic differences (i.e., is migraine equally heritable across men and women) and/or qualitative genetic differences (i.e., are different genes involved in migraine across men and women) were present. Next, we used a multilevel logistic regression model to compare the prevalence of migraine in individuals from opposite-sex and same-sex twin pairs to determine whether differences in the prenatal hormone environment contribute to migraine risk. In the final analytic sample, women were found to have a significantly higher rate of migraine without aura relative to men (17.6% vs. 5.5%). The results from an ADE sex-limitation model indicate that migraine is equally heritable in men and women, with a broad sense heritability of 0.45, (95% CI = 0.40&#x2013;0.50), while results from a reduced AE sex-limitation model provide subtle evidence for differences in the genes underlying migraine across men and women. The logistic regression analysis revealed a significant increase in migraine risk for females with a male co-twin relative to females with a female co-twin (OR = 1.51, 95% CI = 1.26&#x2013;1.81). These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females. This effect points to a potential prenatal neuroendocrine factor in the development of migraine.

Sex Differences in Migraine: A Twin Study

The existence of “sex phenotype” in migraine is a long-standing scientific question. Fluctuations of female sex hormones contribute to migraine attacks, and women also have enhanced brain activity during emotional processing and their functional brain networks seem to be more vulnerable to migraine-induced disruption compared to men. Periaqueductal grey matter (PAG) is a core region of pain processing and modulation networks with possible sex-related implications in migraine. In our study, sex differences of PAG functional resting-state connectivity were investigated in the interictal state in 32 episodic migraines without aura patients (16 women and 16 men). A significant main effect of sex was detected in PAG connectivity with postcentral, precentral, and inferior parietal gyri, and further differences were found between right PAG and visual areas (superior occipital gyrus, calcarine, and cuneus), supplementary motor area, and mid-cingulum connectivity. In all cases, PAG functional connectivity was stronger in female migraineurs compared to males. However, higher average pain intensity of migraine attacks correlated with stronger connectivity of PAG and middle temporal, superior occipital, and parietal gyri in male migraineurs compared to females. Migraine-related disability is also associated with PAG connectivity but without sex differences. Our results indicate that sex differences in PAG connectivity with brain regions involved in sensory and emotional aspects of pain might contribute to the “sex-phenotype” in migraine. The stronger functional connectivity between PAG and pain processing areas may be a sign of increased excitability of pain pathways even in resting-state in females compared to male migraineurs, which could contribute to female vulnerability for migraine. However, pain intensity experienced by male migraineurs correlated with increased connectivity between PAG and regions involved in the subjective experience of pain and pain-related unpleasantness. The demonstrated sex differences of PAG functional connectivity may support the notion that the female and male brain is differently affected by migraine.

The existence of &#x201c;sex phenotype&#x201d; in migraine is a long-standing scientific question. Fluctuations of female sex hormones contribute to migraine attacks, and women also have enhanced brain activity during emotional processing and their functional brain networks seem to be more vulnerable to migraine-induced disruption compared to men. Periaqueductal grey matter (PAG) is a core region of pain processing and modulation networks with possible sex-related implications in migraine. In our study, sex differences of PAG functional resting-state connectivity were investigated in the interictal state in 32 episodic migraines without aura patients (16 women and 16 men). A significant main effect of sex was detected in PAG connectivity with postcentral, precentral, and inferior parietal gyri, and further differences were found between right PAG and visual areas (superior occipital gyrus, calcarine, and cuneus), supplementary motor area, and mid-cingulum connectivity. In all cases, PAG functional connectivity was stronger in female migraineurs compared to males. However, higher average pain intensity of migraine attacks correlated with stronger connectivity of PAG and middle temporal, superior occipital, and parietal gyri in male migraineurs compared to females. Migraine-related disability is also associated with PAG connectivity but without sex differences. Our results indicate that sex differences in PAG connectivity with brain regions involved in sensory and emotional aspects of pain might contribute to the &#x201c;sex-phenotype&#x201d; in migraine. The stronger functional connectivity between PAG and pain processing areas may be a sign of increased excitability of pain pathways even in resting-state in females compared to male migraineurs, which could contribute to female vulnerability for migraine. However, pain intensity experienced by male migraineurs correlated with increased connectivity between PAG and regions involved in the subjective experience of pain and pain-related unpleasantness. The demonstrated sex differences of PAG functional connectivity may support the notion that the female and male brain is differently affected by migraine.