Journal of Headache and Pain最新文献

Headache disorders are common, including in the working population. Clinicians caring for patients with headache need to be aware of work-related factors as potential causes or triggers of headache disorders, and consider the impact of headache on fitness-to-work, especially in safety-sensitive and decision-critical roles. Such fitness-to-work determination should include individualized consideration of the nature of the headache disorder itself, the pattern of the headache, the impact of sleep deprivation on the headache as it relates to fitness to do shiftwork, medication and substance side effects, fitness-to-work implications of associated medical or psychiatric conditions, and the potential of symptom feigning or malingering for secondary gain. As clinicians often struggle with fitness-to-work determinations, a structured approach to fitness-to-work assessments in headache conditions and other pain conditions would improve clarity for clinicians and increase the quality of care provided to patients, with potential benefits for workplace safety and policy in this arena as well.

Substance P, previously dismissed as a therapeutic target for migraine due to the failure of neurokinin-1 receptor antagonists, warrants renewed attention. Building on the success of therapies targeting the calcitonin gene-related peptide (CGRP) system and pituitary adenylate cyclase-activating peptide (PACAP) in migraine prevention, which highlight the importance of targeting peptides, this proposal reexamines substance P as a mediator in migraine pathophysiology. Using an established methodological framework, migraine-inducing properties of substance P can be evaluated through randomized, double-blind, placebo-controlled crossover studies involving healthy volunteers and individuals with a history of migraine. This approach aims to establish proof of concept for substance P's role in migraine, laying the groundwork for investigations with animal and cell-based models and advancing the development of innovative treatments for patients refractory to current therapies.

Background: Proton pump inhibitor (PPI) drugs are widely used and are among the most significant achievements of modern pharmacology. Their primary purpose is treating and preventing gastric acid-related disorders. Migraine and PPI intake are prevalent, and many people are affected by both. In the last few years, a potential link between PPI intake and the development of headaches-especially migraine-has come to increased attention. In this review, we critically examine the scientific data concerning the co-occurrence of these two entities.

Findings: There seems to be a possible link between the use of PPIs and the occurrence of headache, especially migraine, suggesting a pathophysiological connection on several levels. Moreover, PPI use is only partially without side effects, even if these may not occur immediately. Whether the relation is causative or merely co-existential is currently not yet clear. The influence of genetics, environment, gut microbiome, medication intake and evolution of headache is multidirectional.

Conclusion: A relation between the prevalence of migraine and the use of PPIs on a population and personal level seems likely. Although PPIs have many advantages, they should be prescribed with caution, especially in patients who suffer from headaches and migraine. In this narrative review, we aim to critically evaluate existing data and offer a potential approach to accurately identify any connections and interactions, leading to a better understanding of how these conditions may influence each other.

Background: 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.

Methods: A post-acute sample (3 months up to 10 years post-injury) comprising N = 463 children and adolescents aged 8 to 17 years from the TBI sample and N = 463 individuals from the general population matched for gender, age, and health status were included in the study. The Postconcussion Symptom Inventory (PCSI) item assessing headache was used as the outcome variable. Logistic regression was used to examine the association between the risk of developing headache and sociodemographic and health-related factors.

Results: Slightly less than half of the participants reported the presence of headache (TBI sample: 46%; matched controls: 44%). Compared with matched controls, the odds of headache in the TBI sample were not significantly different (OR = 1.09, 95% CI 0.85 to 1.4, p = 0.49). The association between PCSI symptoms was generally stronger in adolescents than in children and in the matched controls than in the TBI sample. In the TBI sample, the probability of reporting headache increased with age.

Conclusions: The results of this study suggest that the prevalence of headache in the post-acute phase of pediatric TBI is not significantly different from that in the matched non-TBI population, indicating good recovery from injury. However, due to its high prevalence, follow-up screening for this common TBI symptom, especially in adolescents, may be helpful to prevent further chronification.

Trial registration: The study is retrospectively registered in German Clinical Trials Register and in International Clinical Trials Registry Platform (ID DRKS00032854).

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.

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.

Background: 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.

Methods: We utilized single-nucleus RNA sequencing (snRNA-seq) data from 43 brain regions, along with genome-wide association study (GWAS) data, to investigate susceptibility to migraine. The cell-type-specific expression (CELLEX) algorithm was employed to calculate specific expression profiles for each region, while non-negative matrix factorization (NMF) was applied to decompose gene programs within the single-cell data from these regions. Following the annotation of brain region expression profiles and gene programs to the genome, we employed stratified linkage disequilibrium score regression (S-LDSC) to assess the associations between brain regions, gene programs, and migraine-related SNPs. Key transcription factors regulating critical gene programs were identified using a random forest model based on regulatory networks derived from the GTEx consortium.

Results: Our analysis revealed significant enrichment of migraine-associated single nucleotide polymorphisms (SNPs) in the posterior nuclear complex-medial geniculate nuclei (PoN_MG) of the thalamus, highlighting this region's crucial role in migraine pathogenesis. Gene program 1, identified through NMF, was enriched in the calcium signaling pathway, a known contributor to migraine pathophysiology. Random forest analysis predicted ARID3A as the top transcription factor regulating gene program 1, suggesting its potential role in modulating calcium-related genes involved in migraine.

Conclusion: This study provides new insights into the molecular mechanisms underlying migraine, emphasizing the importance of the PoN_MG thalamic region, calcium signaling pathways, and key transcription factors like ARID3A. These findings offer potential avenues for developing targeted therapeutic strategies for migraine treatment.

Background: 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.

Methods: A single-center, retrospective real-world, cohort study was conducted between 2023 and 2024. Adults aged 18 years or more who were diagnosed with HFEM or CM were included in this trial and categorized into two groups: galcanezumab and oral migraine preventive medication (OMPM). In the galcanezumab group, oral preventive medications were slowly tapered off within 3 months. The primary outcome was the differences in percentage of patients achieving VLFEM at months 3 and 6 between the two groups. Secondary outcomes included the differences in migraine class improvement, sustained response, and headache day reduction.

Results: A total of 62 patients (31 in each group) were included: median age was 36.5 (IQR: 29.0-48.0) and 82% were female. There were no significant differences in the baseline demographic features between the two groups. The cumulative incidence of patients achieving VLFEM was significantly higher among the galcanezumab group compared to OMPM group (45.2% vs. 19.4% at month 3 and 52.9% vs. 32.4% at month 6, p = 0.03). After 6 months of follow-up, patients with HFEM who received galcanezumab were significantly more likely to achieve any improvements in migraine class compared to those who received OMPM (92.9% vs. 46.7%, p = 0.01). Among 15 patients who achieved VLFEM at month 3, 81.8% (9/11) of those who received galcanezumab and 50.0% (2/4) of those who received OMPM were able to sustain VLFEM at month 6.

Conclusions: This study emphasizes the benefit of early anti-CGRP therapy initiation, especially in patients with fewer headache days, and highlights the need for accessible migraine-specific treatments in low- to middle-income countries.

Background: 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).

Methods: We collected 3T MRI data from 26 patients with CH during the in-bout period outside the attacks and compared them with data from 20 HCs. From resting-state data we derived independent component (IC) networks. We calculated the fractional anisotropy (FA) and mean (MD), axial (AD), and radial (RD) diffusivity values of the hypothalamus and bilateral thalami and correlated them with resting-state IC Z-scores and CH clinical features.

Results: Patients with CH had less FC between the salience network (SN) and left executive control network (ECN) than HCs, but more FC between the default mode network and right ECN. Patients with CH showed lower FA and higher MD microstructural hypothalamic metrics than HCs. Patients with CH had a higher bilateral FA metric in the thalamus than HCs. The AD and RD diffusivity metrics of the hypothalamus were positively correlated with the disease history duration. We found no correlations between the hypothalamic and thalamic diffusivity metrics and the FC of the cortical networks.

Conclusion: Our findings presented the possibility of a correlation between the FC of the SN and the inability to switch between internalizing and externalizing brain activity during demanding cognitive tasks, such as recurring headaches. Moreover, we found differences in the thalamic and hypothalamic microstructures that may independently contribute to the pathophysiology of CH. These differences may reflect changes in directional organization, cell size, and density.