What predicts citation counts and translational impact in headache research? A machine learning analysis.

BACKGROUND: We aimed to develop the first machine learning models to predict citation counts and the translational impact, defined as inclusion in guidelines or policy documents, of headache research, and assess which factors are most predictive. METHODS: Bibliometric data and the titles, abstracts, and keywords from 8600 publications in three headache-oriented journals from their inception to 31 December 2017 were used. A series of machine learning models were implemented to predict three classes of 5-year citation count intervals (0-5, 6-14 and, >14 citations); and the translational impact of a publication. Models were evaluated out-of-sample with area under the receiver operating characteristics curve (AUC). RESULTS: The top performing gradient boosting model predicted correct citation count class with an out-of-sample AUC of 0.81. Bibliometric data such as page count, number of references, first and last author citation counts and h-index were among the most important predictors. Prediction of translational impact worked optimally when including both bibliometric data and information from the title, abstract and keywords, reaching an out-of-sample AUC of 0.71 for the top performing random forest model. CONCLUSION: Citation counts are best predicted by bibliometric data, while models incorporating both bibliometric data and publication content identifies the translational impact of headache research.

Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

Influence of Role Expectancy on Patient-Reported Outcomes Among Patients With Migraine: A Randomized Clinical Trial.

Importance: It is usually assumed that an individual's classification as a patient or a healthy person is determined by the presence or absence of disease, but little is known about whether the mere awareness of being a patient or a healthy control can play an important role for reporting outcomes. Objective: To investigate whether assignment to the role of a patient or a healthy control has an effect on patient-reported outcomes. Design, Setting, and Participants: This single center, double-blind, 3-group randomized clinical trial included consecutive patients from a tertiary headache clinic based at a single center in Germany who were invited to participate between October 2019 and June 2023. Statistical analysis was performed from January to March 2024. Intervention: Patients with migraine were randomized into 2 groups. The first group was told that this study was centered on migraine symptoms, whereas the second group was told that healthy controls were being sought for a study about patients with vertigo. A third group of age- and sex-matched headache-free participants served as controls. All participants viewed 2 standardized roller coaster videos and provided ratings of their perceived levels of motion sickness and dizziness. Main Outcomes and Measures: The primary outcome was self-reported vestibular symptoms. Secondary outcomes included differences in motion sickness, headache burden, and migraine disability. Outcomes were assessed using standardized questionnaires. Results: The final sample included 366 participants: 122 patients with migraine assigned the role of patient (MP) (migraine as patient): mean [SD] age, 37.56 [12.93] years; 105 [86.1%] female), 122 patients with migraine assigned the role of healthy participant (MH) (migraine as healthy): mean [SD] age, 37.03 [13.10] years; 107 [87.7%] female), and 122 headache-free controls (HC): mean [SD] age, 37.55 [11.56] years; 100 [82.0%] female). The assigned role of the individuals with migraine (MP vs MH) had a significant effect on self-disclosure of (1) estimation that symptoms (dizziness) will occur under specific conditions (self-reported vestibular symptoms: 79 MP [64.8%]; 29 MH [23.8%]; 9 HC [7.4%]; P < .001), (2) the increase of such symptoms (dizziness) after viewing the roller coaster video, and (3) the reported frequency (median [IQR] self-reported monthly headache days for MP: 7 [4-15] days; for MH: 5 [2-10] days; P = .008) and severity (median [IQR] migraine disability assessment score for MP: 35 [20-64] points; for MH: 25 [11-47] points; P = .005) of migraine symptoms. Statistically significant changes were also found for self-reported headache frequency and disability caused by migraine. Conclusions and Relevance: This randomized clinical trial found an effect of expectations regarding the role of a patient with respect to clinical and study outcomes. These findings suggest that role expectations should be taken into account when, for example, invasive treatments are discussed. Trial Registration: ClinicalTrials.gov Identifier: NCT06322550.

New migraine drugs: A critical appraisal of the reason why the majority of migraine patients do not receive an adequate medication.

The last three decades have produced several novel and efficient medications to treat migraine attacks and reduce attack frequency. Additionally, promising approaches for the development of acute therapy and migraine prophylaxis continue to be pursued. At the same time as we witness the development of better and more efficient medications with continuously fewer side effects, we also realise that the high cost of such therapies means that only a minority of migraine patients who could benefit from these medications can afford them. Furthermore, information on cost-effectiveness is still lacking. Here, we compare availiable data, highlight open questions and suggest trials to close knowledge gaps. With good reason, our medicine is evidence-based. However, if this evidence is not collected, our decisions will continue to be based on marketing and assumptions. At the moment, we are not doing justice to our patients.

Functional representation of trigeminal nociceptive input in the human periaqueductal gray.

The periaqueductal gray (PAG) is located in the mesencephalon in the upper brainstem and, as part of the descending pain modulation, is considered a crucial structure for pain control. Its modulatory effect on painful sensation is often seen as a systemic function affecting the whole body similarly. However, recent animal data suggest some kind of somatotopy in the PAG. This would make the PAG capable of dermatome-specific analgesic function. We electrically stimulated the three peripheral dermatomes of the trigemino-cervical complex and the greater occipital nerve in 61 humans during optimized brainstem functional magnetic resonance imaging. We provide evidence for a fine-grained and highly specific somatotopic representation of nociceptive input in the PAG in humans and a functional connectivity between the individual representations of the peripheral nerves in the PAG and the brainstem nuclei of these nerves. Our data suggest that the downstream antinociceptive properties of the PAG may be rather specific down to the level of individual dermatomes.

Double-blind, randomized, placebo-controlled study to evaluate erenumab-specific central effects: an fMRI study.

OBJECTIVE: Given the findings of central effects of erenumab in the literature, we aimed to conduct a rigorous placebo-controlled, double-blind, randomized study to elucidate whether the observed changes are directly attributable to the drug. METHODS: We recruited 44 patients with migraine, randomly assigning them to either the erenumab 70 mg or the placebo group. 40 patients underwent fMRI scanning using a trigeminal nociceptive paradigm both, pre- and four weeks post-treatment. Participants kept a headache diary throughout the whole study period of two months in total. A clinical response was defined as a ≥30% reduction in headache frequency at follow-up. Details of this study have been preregistered in the open science framework: https://osf.io/ygf3t . RESULTS: Seven participants of the verum group (n=33.33%) and 4 of the placebo group (21.05%) experienced improvements in migraine activity, characterized by a minimum of 30% reduction in monthly headache frequency compared to baseline. The imaging data show an interaction between the verum medication and the response. Whilst numbers were too small for individual analyses (Verum vs. Placebo and Responder vs. Non-Responder), the variance-weighted analysis (Verum vs Placebo, scan before vs after weighted for response) revealed specific decrease in thalamic, opercular and putamen activity. INTERPRETATION: The central effects of erenumab could be reproduced in a placebo randomized design, further confirming its central role in migraine modulation. The mechanism, whether direct or secondary to peripheral mode of action, needs further exploration. It is important to note that the response rate to erenumab 70mg in this study was not as substantial as anticipated in 2019, when this study was planned. This resulted in a too small sample size for a subgroup analysis based on the responder status was associated with both the verum drug and the relative reduction in headache days.

Cerebellar somatotopy of the trigemino-cervical complex during nociception.

INTRODUCTION: The somatotopic organization of the human cerebellum processes somato-motoric input. Its role during pain perception for nociceptive input remains ambiguous. A standardized experimental trigeminal nociceptive input in functional imaging might clarify the role of the cerebellum in trigeminal nociception. Also of interest is the greater occipital nerve, which innervates the back of the head, and can influence the trigeminal perception due to functional coupling within the brainstem, forming the so-called trigemino-cervical complex. METHODS: In our preregistered study (clinicaltrials.gov: NTC03999060), we stimulated the greater occipital as well as the three main branches of the trigeminal nerve during functional magnetic resonance imaging in two independent cohorts of young healthy volunteers without psychiatric, neurological or pain-related disorders to disentangle overlapping somatotopic cerebellar organization of the nerves innervating the human head. RESULTS: We found a dominant effect of the first trigeminal branch in the cerebellum, underpinning its particular role for headache diseases, and somatotopic representations in bilateral cerebellar lobules I-IV, V, VIIb, VIIIa and Crus I as well as in the brainstem. SIGNIFICANCE: The study expands the current knowledge on facial and head pain processing by the cerebellum and provides an initial somatotopic map of the trigemino-cervical complex in the human cerebellum with a predominant representation of the first trigeminal branch.

Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

BACKGROUND: Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. CONCLUSION: In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

Aura phenomena do not initiate migraine attacks-Findings from neuroimaging.

OBJECTIVES/BACKGROUND: As cortical spreading depolarization (CSD) has been suggested to be the cause of migraine aura and as CSD can activate trigeminal nociceptive neurons in animals, it has been suggested that CSD may be the cause of migraine attacks. This raises the question of how migraine pain is generated in migraine attacks without aura and has led to the hypothesis that CSD may also occur in subcortical regions in the form of "silent" CSDs, and accordingly "silent auras". METHODS: In this case study, we provide evidence for common neuronal alterations preceding headache attacks with and without aura in a male patient with migraine, who underwent daily event-correlated functional magnetic resonance imaging of trigeminal nociception for a period of 30 days. During these days the man experienced migraine attacks with and without aura. RESULTS: Comparing the preictal phases between both attack types revealed a common hyperactivation of the hypothalamus (p < 0.01), which was already present 2 days before the actual attack. CONCLUSION: The time frame of the central pathophysiological orchestration of migraine attacks, irrelevant of the presence of later aura, strongly suggests that the aura is an epiphenomenon that is unrelated and does not initiate headache attacks.

European Academy of Neurology guidelines on the treatment of cluster headache.

BACKGROUND AND PURPOSE: Cluster headache is a relatively rare, disabling primary headache disorder with a major impact on patients' quality of life. This work presents evidence-based recommendations for the treatment of cluster headache derived from a systematic review of the literature and consensus among a panel of experts. METHODS: The databases PubMed (Medline), Science Citation Index, and Cochrane Library were screened for studies on the efficacy of interventions (last access July 2022). The findings in these studies were evaluated according to the recommendations of the European Academy of Neurology, and the level of evidence was established using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RECOMMENDATIONS: For the acute treatment of cluster headache attacks, there is a strong recommendation for oxygen (100%) with a flow of at least 12 L/min over 15 min and 6 mg subcutaneous sumatriptan. Prophylaxis of cluster headache attacks with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy and tolerability) is recommended. Corticosteroids are efficacious in cluster headache. To reach an effect, the use of at least 100 mg prednisone (or equivalent corticosteroid) given orally or at up to 500 mg iv per day over 5 days is recommended. Lithium, topiramate, and galcanezumab (only for episodic cluster headache) are recommended as alternative treatments. Noninvasive vagus nerve stimulation is efficacious in episodic but not chronic cluster headache. Greater occipital nerve block is recommended, but electrical stimulation of the greater occipital nerve is not recommended due to the side effect profile.

Functional brainstem representations of the human trigeminal cervical complex.

BACKGROUND: The human in-vivo functional somatotopy of the three branches of the trigeminal (V1, V2, V3) and greater occipital nerve in brainstem and also in thalamus and insula is still not well understood. METHODS: After preregistration (clinicaltrials.gov: NCT03999060), we mapped the functional representations of this trigemino-cervical complex non-invasively in 87 humans using high-resolution protocols for functional magnetic resonance imaging during painful electrical stimulation in two separate experiments. The imaging protocol and analysis was optimized for the lower brainstem and upper spinal cord, to identify activation of the spinal trigeminal nuclei. The stimulation protocol involved four electrodes which were positioned on the left side according to the three branches of the trigeminal nerve and the greater occipital nerve. The stimulation site was randomized and each site was repeated 10 times per session. The participants partook in three sessions resulting in 30 trials per stimulation site. RESULTS: We show a large overlap of peripheral dermatomes on brainstem representations and a somatotopic arrangement of the three branches of the trigeminal nerve along the perioral-periauricular axis and for the greater occipital nerve in brainstem below pons, as well as in thalamus, insula and cerebellum. The co-localization of greater occipital nerve with V1 along the lower part of brainstem is of particular interest since some headache patients profit from an anesthetic block of the greater occipital nerve. CONCLUSION: Our data provide anatomical evidence for a functional inter-inhibitory network between the trigeminal branches and greater occipital nerve in healthy humans as postulated in animal work. We further show that functional trigeminal representations intermingle perioral and periauricular facial dermatomes with individual branches of the trigeminal nerve in an onion shaped manner and overlap in a typical within-body-part somatotopic arrangement.Trial registration: clinicaltrials.gov: NCT03999060.

Oxygen inhalation has no effect on provoked cranial autonomic symptoms using kinetic oscillation stimulation in healthy volunteers.

OBJECTIVE: Inhalation of oxygen is highly effective in cluster headache, a subtype of trigeminal autonomic cephalgias. Since oxygen has no effect on nociceptive pain, the mechanism of action is still unknown. The present study investigated whether oxygen inhalation modifies the trigeminal autonomic reflex arc in healthy volunteers. METHODS: 21 healthy volunteers participated in a randomized, placebo controlled, double-blind, cross-over, and within-subject study design. In a randomized order demand valve inhalation of 100% oxygen or medical air were administered. Capillary blood samples were collected to control for blood gas changes. Cranial parasympathetic output (lacrimation) was provoked using kinetic oscillation stimulation of the nasal mucosa. Standardized measurement of lacrimation between baseline and kinetic oscillation stimulation served as a measure of induced cranial autonomic output. RESULTS: There was no significant difference in parasympathetic output after oxygen inhalation when compared to inhalation of medical air. CONCLUSION: The inhalation of 100% oxygen does not affect the parasympathetic reflex arc of the trigeminal autonomic reflex.

Characterization of trigeminal C-fiber reactivity through capsaicin-induced release of calcitonin gene-related peptide.

OBJECTIVE: We hypothesized that the response of trigeminal dermal blood flow (DBF) in the trigeminal system and consecutive expansion of flare response to capsaicin would differ from the somatosensory system (arm). We also investigated whether there are differences between patients with migraine and healthy controls (HC). BACKGROUND: Functional differences between the trigeminal and extracephalic somatosensory systems may partly explain the susceptibility for headaches in patients with migraine. Capsaicin-induced activation of nociceptive C-fibers in the skin is mainly mediated by calcitonin gene-related peptide (CGRP) and induces cutaneous vessel dilatation and flare response. METHODS: Female patients with migraine (n = 38) and age-matched HC (n = 35) underwent DBF measurement at baseline and after topical capsaicin administration using laser speckle imaging. DBF before and after capsaicin stimulation was analyzed over ophthalmic nerve/maxillary nerve/mandibular nerve (V1/V2/V3) dermatomes and the forearm as an extracephalic control. RESULTS: Capsaicin-induced DBF increased more in the trigeminal dermatomes than on the forearm. The V1 dermatome showed a smaller increase of DBF in patients with migraine compared to HC. CONCLUSION: Our results suggest that the trigeminovascular system reacts differently from extracephalic areas, which may explain the trigeminal susceptibility to CGRP-mediated pain attacks. By demonstrating a different reactivity of the V1 dermatome in patients with migraine, our finding suggests that the first trigeminal branch is functionally different from the second and third branches; however, only in patients with migraine.

Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.