Part 2 explores the transformative potential of artificial intelligence (AI) in addressing the complexities of headache disorders through innovative approaches, including digital twin models, wearable healthcare technologies and biosensors, and AI-driven drug discovery. Digital twins, as dynamic digital representations of patients, offer opportunities for personalized headache management by integrating diverse datasets such as neuroimaging, multiomics, and wearable sensor data to advance headache research, optimize treatment, and enable virtual trials. In addition, AI-driven wearable devices equipped with next-generation biosensors combined with multi-agent chatbots could enable real-time physiological and biochemical monitoring, diagnosing, facilitating early headache attack forecasting and prevention, disease tracking, and personalized interventions. Furthermore, AI-driven advances in drug discovery leverage machine learning and generative AI to accelerate the identification of novel therapeutic targets and optimize treatment strategies for migraine and other headache disorders. Despite these advances, challenges such as data standardization, model explainability, and ethical considerations remain pivotal. Collaborative efforts between clinicians, biomedical and biotechnological engineers, AI scientists, legal representatives and bioethics experts are essential to overcoming these barriers and unlocking AI's full potential in transforming headache research and healthcare. This is a call to action in proposing novel frameworks for integrating AI-based technologies into headache care.

Rimegepant, a novel oral calcitonin gene-related peptide receptor antagonist, has been recently approved for the acute migraine treatment. While its efficacy was confirmed in randomized clinical trials, no data is available regarding real-life effectiveness and tolerability. GAINER, a prospective, multicentric study, aimed to evaluate rimegepant effectiveness and tolerability in the real-world setting.

Migraine is a common primary headache disorder, less frequently affecting men than women, and often regarded as predominantly a "women's disease." Despite this, migraine in men presents with unique characteristics in terms of symptoms, treatment responses, comorbidities, and pain perception. Historically, research has focused more on migraine in women, overlooking critical male-specific aspects.

Diagnosing headache disorders poses significant challenges, particularly in primary and secondary levels of care (PSLC), potentially leading to misdiagnosis and underdiagnosis. This study evaluates diagnostic agreement for migraine, tension-type headache (TTH), and cluster headache (CH) between PSLC and tertiary care (TLC) and assesses adherence to the International Classification of Headache Disorders 3rd edition (ICHD-3) guidelines.

Inter-individual variability in symptoms and the dynamic nature of brain pathophysiology present significant challenges in constructing a robust diagnostic model for migraine. In this study, we aimed to integrate different types of magnetic resonance imaging (MRI), providing structural and functional information, and develop a robust machine learning model that classifies migraine patients from healthy controls by testing multiple combinations of hyperparameters to ensure stability across different migraine phases and longitudinally repeated data. Specifically, we constructed a diagnostic model to classify patients with episodic migraine from healthy controls, and validated its performance across ictal and interictal phases, as well as in a longitudinal setting. We obtained T1-weighted and resting-state functional MRI data from 50 patients with episodic migraine and 50 age- and sex-matched healthy controls, with follow-up data collected after one year. Morphological features, including cortical thickness, curvature, and sulcal depth, and functional connectivity features, such as low-dimensional representation of functional connectivity (gradient), degree centrality, and betweenness centrality, were utilized. We employed a regularization-based feature selection method combined with a random forest classifier to construct a diagnostic model. By testing the models with varying feature combinations, penalty terms, and spatial granularities within a strict cross-validation framework, we found that the combination of curvature, sulcal depth, cortical thickness, and functional gradient achieved a robust classification performance. The model performance was assessed using the test dataset and achieved 87% accuracy and 0.94 area under the curve (AUC) at distinguishing migraine patients from healthy controls, with 85%, 0.97 and 84%, 0.93 during the interictal and ictal/peri-ictal phases, respectively. When validated using follow-up data, which was not included during model training, the model achieved 91%, 94%, 89% accuracies and 0.96, 0.94, 0.98 AUC for the total, interictal, and ictal/peri-ictal phases, respectively, confirming its robustness. Feature importance and clinical association analyses exhibited that the somatomotor, limbic, and default mode regions could be reliable markers of migraine. Our findings, which demonstrate a robust diagnostic performance using multimodal MRI features and a machine-learning framework, may offer a valuable approach for clinical diagnosis across diverse cohorts and help alleviate the decision-making burden for clinicians.

Migraine is the most common complex neurological disorder, affecting over a billion people worldwide. Neurogenic inflammation has long been recognized as a key factor in the pathophysiology of migraine though little research has been directed to investigating whether inflammation is greatest in migraine with aura or without, and whether inflammation is a permanent state in migraine or whether is an event related transitory state. Thus, the primary aim of this single-centre, retrospective study was to explore the potential clinical utility of the Serial Systemic Immune-Inflammatory Indices (SSIIi) as a comparative measure of duration and severity of inflammation derived from routine blood cell counts in migraine patients with aura and no-aura both within an acute inpatient setting and as outpatients. Specifically, we assessed the role of two serial white blood cell counts to calculate the SSIIi using the formula: neutrophil count x platelet count/lymphocyte count) between aura and no-aura migraine patients at time of admission to a tertiary care centre in Melbourne, Australia, and following 24 h post admission versus comparable serial measures in 20 out patients with migraine and ongoing symptoms.

Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly the role of mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in the spinal dorsal horn play a critical role in the initiation and persistence of neuropathic pain. Among the factors involved, TSPO (translocator protein) emerged as a key regulator. Our experimental findings showed that TSPO expression was upregulated during neuropathic pain, accompanied by mitochondrial dysfunction, specifically manifested as impaired mitochondrial biogenesis, disrupted mitochondrial dynamics (including insufficient expression of mitochondrial biogenesis and fusion-related proteins, as well as significantly increased expression of fission-related proteins), and activation of pyroptosis. Pharmacological upregulation of TSPO, but not its downregulation, effectively alleviated SNI-induced pain hypersensitivity, improving mitochondrial function and reducing pyroptosis. Immunofluorescence staining confirmed that TSPO was primarily localized in astrocytes, and its expression mirrored the protective effects on mitochondrial health and pyroptosis prevention. PCR array analysis suggested a strong association between TSPO and the mitochondrial regulation pathway AMPK-PGC-1α. Notably, inhibition of AMPK-PGC-1α abolished TSPO effects on mitochondrial balance and pyroptosis suppression. Furthermore, Mendelian randomization analysis of GWAS data indicated that increased TSPO expression was linked to pain relief. Through drug screening, molecular docking, and behavioral assays, we identified zopiclone as a promising TSPO-targeting drug for pain treatment. In summary, this study enhances our understanding of the molecular interplay between TSPO, mitochondrial health, and neuropathic pain, highlighting TSPO as a potential therapeutic target for pain management.

The term "aura" refers to a well-defined pattern of usually positive, progressive, and reversible neurological symptoms, with spreading depolarization as the underlying mechanism. While commonly associated with migraine, aura can also occur in other neurological disorders (i.e., cerebrovascular disorders). However, current terminology inadequately describes its different underlying clinical etiologies.

Neuroimaging studies have shown that hypothalamic/thalamic nuclei and other distant brain regions belonging to complex cerebral networks are involved in cluster headache (CH). However, the exact relationship between these areas, which may be dependent or independent, remains to be understood. We investigated differences in resting-state functional connectivity (FC) between brain networks and its relationship with the microstructure of the hypothalamus and thalamus in patients with episodic CH outside attacks and healthy controls (HCs).

The neuropeptide calcitonin gene-related peptide (CGRP) has been established to be a key signaling molecule in migraine, but little is known about the differences between the two isoforms: αCGRP and βCGRP. Previous studies have been hampered by their close similarity, making the development of specific antibodies nearly impossible. In this study we sought to test the hypothesis that αCGRP and βCGRP localize differently within the neurons of the mouse trigeminal ganglion (TG), using αCGRP knock out (KO) animals.

Migraine progression, particularly from episodic to chronic migraine (CM), increases disease burden and healthcare costs. Understanding the new concept of "Medication Underuse Headache" should encourage the health care provider to consider early intervention with calcitonin gene-related peptide (CGRP) monoclonal antibodies. Galcanezumab given early in the course of the disease, may prevent migraine chronification and have a robust response, moreso than when initiated in later stages of migraine. We aimed to determine the efficacy of galcanezumab in achieving very low-frequency episodic migraine (VLFEM) among patients with high-frequency episodic migraine (HFEM) and CM in a real world-setting in Thailand.

Migraine is a complex neurological disorder characterized by recurrent episodes of severe headaches. Although genetic factors have been implicated, the precise molecular mechanisms, particularly gene expression patterns in migraine-associated brain regions, remain unclear. This study applies machine learning techniques to explore region-specific gene expression profiles and identify critical gene programs and transcription factors linked to migraine pathogenesis.

Headache is one of the most common post-concussion symptoms following pediatric traumatic brain injury (TBI). To better understand its impact on young individuals, this study aims to investigate the prevalence of headache in a German-speaking post-acute pediatric TBI sample and compare it with the general population. In addition, factors associated with the development of pediatric post-TBI headache are investigated to improve the understanding of this condition.

Migraine is a disabling disorder that impacts 40 million people in the US. Zavegepant is the first calcitonin gene-related peptide (CGRP) receptor antagonist nasal-spray approved for the acute treatment of migraine with or without aura in adults. This study aimed to evaluate the proportion of patients in various pain and functional disability states over 48-h, for patients treated with zavegepant 10 mg nasal-spray versus placebo.

In our previous study, we demonstrated that headaches are highly prevalent among medical students in Vietnam. In the present study, we provide estimates of the associated symptom burden and impaired participation, utilizing these estimates to assess headache-related healthcare needs within this population.

A key unanswered question in migraine neurobiology concerns the mechanisms that make the brain of migraineurs susceptible to cortical spreading depression (CSD, a spreading depolarization that underlies migraine aura and may trigger the migraine pain mechanisms). Important insights into this question can be obtained by studying the mechanisms of facilitation of CSD initiation in genetic mouse models of the disease. These models, all generated from families with hereditary migraine, allow the investigation of the functional consequences of disease-causing mutations at the molecular, cellular, synaptic and neural circuit levels. In this review, after describing the available genetic mouse models of migraine, which all share increased susceptibility to experimentally induced CSD, we will discuss the functional alterations in their cerebral cortex and the mechanisms underlying the facilitation of CSD initiation in their cortex, as well as the insights that these mechanisms may give into the mechanisms of initiation of spontaneous CSDs in migraine.

The aim of this systematic review is to identify pain profiling parameters that are reliably different between patients with migraine and healthy controls, using Quantitative Sensory Testing (QST) including Temporal Summation (TS), Conditioned Pain Modulation (CPM), and Corneal Confocal Microscopy (CCM).

To describe the epidemiology and clinical characteristics of migraine and the status of treatment in Colombia. Additionally, the use of health resources by patients was measured.

People with multiple sclerosis (MS) have an increased risk of migraine. However, little is known about migraine and other headaches during the prodromal phase (before MS symptom onset). Our objective was to study the risk of migraine in women with MS before MS onset.

We have previously shown headache disorders to be prevalent in in the adult general population of Morocco, especially migraine (30.8%) and headache on ≥ 15 days/month (H15+; 10.5%). This study, collecting data from the same population-based sample, is the first to estimate headache-attributed burden not only in Morocco but, more widely, in the Maghreb countries of North Africa.