Pub Date : 2025-01-27DOI: 10.1186/s10194-025-01951-2
Marina Zeldovich, Leonie Krol, Katrin Cunitz, Christian Auer, Daniel Pinggera, Victoria Schön, Philipp Geiger, Joachim Suss, Inga K Koerte, Emilie Isager Howe, Nada Andelic, Anna Buchheim, Matthias Gondan, Nicole von Steinbüchel
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).
背景:头痛是小儿创伤性脑损伤(TBI)后最常见的脑震荡后症状之一。为了更好地了解头痛对年轻人的影响,本研究旨在调查德语小儿创伤性脑损伤后头痛的发病率,并将其与普通人群进行比较。此外,还调查了与小儿创伤后头痛发病相关的因素,以加深对这一病症的了解:研究对象为急性期后样本(受伤后 3 个月至 10 年),包括来自 TBI 样本的 N = 463 名 8 至 17 岁儿童和青少年,以及来自普通人群的 N = 463 名在性别、年龄和健康状况方面匹配的个体。以脑震荡后症状量表(PCSI)中评估头痛的项目作为结果变量。采用逻辑回归法研究头痛发病风险与社会人口和健康相关因素之间的关系:略低于半数的参与者报告存在头痛(创伤性脑损伤样本:46%;匹配对照组:44%)。与匹配对照组相比,创伤性脑损伤样本出现头痛的几率没有明显差异(OR = 1.09,95% CI 0.85 至 1.4,p = 0.49)。PCSI 症状之间的关联在青少年中普遍强于儿童,在匹配对照组中强于创伤性脑损伤样本。在创伤性脑损伤样本中,报告头痛的概率随着年龄的增长而增加:本研究结果表明,小儿创伤性脑损伤后急性期的头痛发生率与匹配的非创伤性脑损伤人群的头痛发生率无显著差异,表明伤后恢复良好。然而,由于头痛的发病率较高,对这种常见的创伤后症状进行随访筛查(尤其是在青少年中)可能有助于防止进一步慢性化:该研究已在德国临床试验注册中心和国际临床试验注册平台(ID DRKS00032854)进行了回顾性注册。
{"title":"Headache after pediatric traumatic brain injury: a comparison between a post-acute sample of children and adolescents and general population.","authors":"Marina Zeldovich, Leonie Krol, Katrin Cunitz, Christian Auer, Daniel Pinggera, Victoria Schön, Philipp Geiger, Joachim Suss, Inga K Koerte, Emilie Isager Howe, Nada Andelic, Anna Buchheim, Matthias Gondan, Nicole von Steinbüchel","doi":"10.1186/s10194-025-01951-2","DOIUrl":"10.1186/s10194-025-01951-2","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>The study is retrospectively registered in German Clinical Trials Register and in International Clinical Trials Registry Platform (ID DRKS00032854).</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"15"},"PeriodicalIF":7.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1186/s10194-025-01953-0
Baolong Li, Kaiming Yu, Xiongyao Zhou, Jialu Sun, Le Qi, Weiye Li, Tuo Yang, Weizhen Li, Ningning Wang, Xiaosong Gu, Shusen Cui, Rangjuan Cao
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.
{"title":"Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway.","authors":"Baolong Li, Kaiming Yu, Xiongyao Zhou, Jialu Sun, Le Qi, Weiye Li, Tuo Yang, Weizhen Li, Ningning Wang, Xiaosong Gu, Shusen Cui, Rangjuan Cao","doi":"10.1186/s10194-025-01953-0","DOIUrl":"10.1186/s10194-025-01953-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"16"},"PeriodicalIF":7.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1186/s10194-025-01948-x
Daniela Pietrobon, K C Brennan
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.
{"title":"Mechanisms underlying CSD initiation implicated by genetic mouse models of migraine.","authors":"Daniela Pietrobon, K C Brennan","doi":"10.1186/s10194-025-01948-x","DOIUrl":"10.1186/s10194-025-01948-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"17"},"PeriodicalIF":7.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-20DOI: 10.1186/s10194-025-01950-3
Lei Zhang, Yujie Li, Yunhao Xu, Wei Wang, Guangyu Guo
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.
{"title":"Machine learning-driven identification of critical gene programs and key transcription factors in migraine.","authors":"Lei Zhang, Yujie Li, Yunhao Xu, Wei Wang, Guangyu Guo","doi":"10.1186/s10194-025-01950-3","DOIUrl":"10.1186/s10194-025-01950-3","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"14"},"PeriodicalIF":7.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
背景:偏头痛的进展,特别是从发作性偏头痛到慢性偏头痛(CM),增加了疾病负担和医疗保健费用。了解“用药不足头痛”的新概念应鼓励卫生保健提供者考虑使用降钙素基因相关肽(CGRP)单克隆抗体进行早期干预。在病程早期给予Galcanezumab,可以预防偏头痛的慢性化,并有一个强大的反应,比在偏头痛晚期开始。我们的目的是确定galcanezumab在泰国的真实世界环境中治疗高频发作性偏头痛(HFEM)和CM患者的甚低频发作性偏头痛(VLFEM)的疗效。方法:在2023年至2024年间进行了一项单中心、回顾性、真实世界的队列研究。被诊断为HFEM或CM的18岁或以上的成年人被纳入该试验,并分为两组:galcanezumab和口服偏头痛预防药物(OMPM)。在galcanezumab组,口服预防药物在3个月内逐渐减少。主要结果是两组患者在第3个月和第6个月达到VLFEM的百分比的差异。次要结局包括偏头痛分级改善、持续反应和头痛天数减少的差异。结果:共纳入62例患者,每组31例,中位年龄36.5岁(IQR: 29.0 ~ 48.0),女性占82%。两组患者的基线人口统计学特征无显著差异。与OMPM组相比,galcanezumab组患者达到VLFEM的累积发生率显著高于OMPM组(第3个月时为45.2%对19.4%,第6个月时为52.9%对32.4%,p = 0.03)。6个月的随访后,与接受OMPM的患者相比,接受galcanezumab治疗的HFEM患者更有可能在偏头痛类别中获得任何改善(92.9% vs. 46.7%, p = 0.01)。在15例在第3个月达到VLFEM的患者中,接受galcanezumab的患者中有81.8%(9/11)和接受OMPM的患者中有50.0%(2/4)能够在第6个月维持VLFEM。结论:本研究强调了早期开始抗cgrp治疗的益处,特别是对于头痛天数较少的患者,并强调了中低收入国家可获得偏头痛特异性治疗的必要性。
{"title":"Medication underuse in real-life practice: the impact of galcanezumab towards achieving very low frequency episodic migraine in a southeast Asian middle-income nation.","authors":"Wanakorn Rattanawong, Prakit Anukoolwittaya, Akarin Hiransuthikul, Thanakit Pongpitakmetha, Auranee Trisataya, Sekh Thanprasertsuk, Alan Rapoport","doi":"10.1186/s10194-025-01952-1","DOIUrl":"10.1186/s10194-025-01952-1","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"13"},"PeriodicalIF":7.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-15DOI: 10.1186/s10194-024-01920-1
Chiara Abagnale, Antonio Di Renzo, Giada Giuliani, Gabriele Sebastianelli, Francesco Casillo, Lucia Ziccardi, Vincenzo Parisi, Cherubino Di Lorenzo, Mariano Serrao, Francesca Caramia, Vittorio Di Piero, Gianluca Coppola
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.
{"title":"MRI-based analysis of the microstructure of the thalamus and hypothalamus and functional connectivity between cortical networks in episodic cluster headache.","authors":"Chiara Abagnale, Antonio Di Renzo, Giada Giuliani, Gabriele Sebastianelli, Francesco Casillo, Lucia Ziccardi, Vincenzo Parisi, Cherubino Di Lorenzo, Mariano Serrao, Francesca Caramia, Vittorio Di Piero, Gianluca Coppola","doi":"10.1186/s10194-024-01920-1","DOIUrl":"10.1186/s10194-024-01920-1","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"12"},"PeriodicalIF":7.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-14DOI: 10.1186/s10194-025-01949-w
Gurueswar Nagarajan, Yumin Zhang
{"title":"Correction: Distinct expression profile reveals glia involvement in the trigeminal system attributing to post‑traumatic headache.","authors":"Gurueswar Nagarajan, Yumin Zhang","doi":"10.1186/s10194-025-01949-w","DOIUrl":"10.1186/s10194-025-01949-w","url":null,"abstract":"","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"10"},"PeriodicalIF":7.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-14DOI: 10.1186/s10194-024-01945-6
Sofia Lyng Wæver, Kristian Agmund Haanes
Objective: 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.
Methods: We applied immunohistochemistry (IHC) on 15 TGs from three different genotypes of mice; wild type (WT) αCGRP heterozygote (Het) and αCGRP KOs, with a primary antibody targeting the mature neuropeptide sequence of both αCGRP and βCGRP. Subsequently, the localization patterns of the two isoforms were analyzed. Furthermore, similar IHCs were produced in KO animals after being treated with monoclonal CGRP antibodies to study the origin of the observed CGRP. Additional IHCs were conducted in KO and WT mice to locate CGRP sorting peptides within neuronal cell bodies. Lastly, bioinformatical analyses of the primary, secondary, and tertiary structure of the two isoforms were conducted.
Results: The IHC showed that the key isoform localized within the axons of the mouse TG neurons, is αCGRP and not βCGRP. Furthermore, differences in intensities indicate that the model used in this study successfully knocks out αCGRP. We further categorized the localization patterns of CGRP in neuronal cell bodies in the TG and found using bioinformatic analyses that differences in localization might be explained by intracellular peptide sorting. IHC following injections with monoclonal CGRP antibodies in KO mice ruled out the possibility that the βCGRP observed in trigeminal neurons had peripheral origins. This conclusion was enhanced by IHC experiments which showed the presence of CGRP co-localizing sorting peptides in KO mice.
Conclusion: Our data show that mainly αCGRP and not βCGRP locate within the axons of the mouse TG neurons. The βCGRP observed within the TG neuronal cell bodies is synthesized intracellularly and not taken up from the environment. Furthermore, the isoforms appear to be sorted differentially into secretory vesicles in the cell bodies of TG neurons.
{"title":"Differentially localizing isoforms of the migraine component calcitonin gene-related peptide (CGRP), in the mouse trigeminal ganglion: βCGRP is translated but, unlike αCGRP, not sorted into axons.","authors":"Sofia Lyng Wæver, Kristian Agmund Haanes","doi":"10.1186/s10194-024-01945-6","DOIUrl":"10.1186/s10194-024-01945-6","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>We applied immunohistochemistry (IHC) on 15 TGs from three different genotypes of mice; wild type (WT) αCGRP heterozygote (Het) and αCGRP KOs, with a primary antibody targeting the mature neuropeptide sequence of both αCGRP and βCGRP. Subsequently, the localization patterns of the two isoforms were analyzed. Furthermore, similar IHCs were produced in KO animals after being treated with monoclonal CGRP antibodies to study the origin of the observed CGRP. Additional IHCs were conducted in KO and WT mice to locate CGRP sorting peptides within neuronal cell bodies. Lastly, bioinformatical analyses of the primary, secondary, and tertiary structure of the two isoforms were conducted.</p><p><strong>Results: </strong>The IHC showed that the key isoform localized within the axons of the mouse TG neurons, is αCGRP and not βCGRP. Furthermore, differences in intensities indicate that the model used in this study successfully knocks out αCGRP. We further categorized the localization patterns of CGRP in neuronal cell bodies in the TG and found using bioinformatic analyses that differences in localization might be explained by intracellular peptide sorting. IHC following injections with monoclonal CGRP antibodies in KO mice ruled out the possibility that the βCGRP observed in trigeminal neurons had peripheral origins. This conclusion was enhanced by IHC experiments which showed the presence of CGRP co-localizing sorting peptides in KO mice.</p><p><strong>Conclusion: </strong>Our data show that mainly αCGRP and not βCGRP locate within the axons of the mouse TG neurons. The βCGRP observed within the TG neuronal cell bodies is synthesized intracellularly and not taken up from the environment. Furthermore, the isoforms appear to be sorted differentially into secretory vesicles in the cell bodies of TG neurons.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"11"},"PeriodicalIF":7.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1186/s10194-024-01943-8
Umberto Pensato, Andrew M Demchuk, Jens P Dreier, Kevin C Brennan, Simona Sacco, Michele Romoli
Background: 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.
Main body: We propose the following terminology and etiology-based clinical classification for the aura phenomenon: (i) Migrainous Aura (when the etiology is migraine), (ii) Non-migrainous Aura (when there is an alternative etiology), (iii) Aura of uncertain clinical etiology (when etiology is unclear), and (iv) Migrainous Infarction (a typical migrainous aura in a patient with migraine with aura associated with an infarction in a corresponding anatomical brain region).
Conclusion: This nuanced classification aims to aid in the diagnostic evaluation and phenotyping of aura phenomenon, ultimately improving the diagnosis and management of the different associated neurological conditions. Moreover, it could promote effective communication and translational mechanistic research.
{"title":"Aura phenomenon: a proposal for an etiology-based clinical classification.","authors":"Umberto Pensato, Andrew M Demchuk, Jens P Dreier, Kevin C Brennan, Simona Sacco, Michele Romoli","doi":"10.1186/s10194-024-01943-8","DOIUrl":"10.1186/s10194-024-01943-8","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Main body: </strong>We propose the following terminology and etiology-based clinical classification for the aura phenomenon: (i) Migrainous Aura (when the etiology is migraine), (ii) Non-migrainous Aura (when there is an alternative etiology), (iii) Aura of uncertain clinical etiology (when etiology is unclear), and (iv) Migrainous Infarction (a typical migrainous aura in a patient with migraine with aura associated with an infarction in a corresponding anatomical brain region).</p><p><strong>Conclusion: </strong>This nuanced classification aims to aid in the diagnostic evaluation and phenotyping of aura phenomenon, ultimately improving the diagnosis and management of the different associated neurological conditions. Moreover, it could promote effective communication and translational mechanistic research.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"9"},"PeriodicalIF":7.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1186/s10194-024-01929-6
Tissa Wijeratne, Melanie J Murphy, Chanith Wijeratne, Paolo Martelletti, Leila Karimi, Vasso Apostolopoulos, Carmela Sales, Nina Riddell, Sheila G Crewther
Background: 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.
Main body: A retrospective analysis was conducted of medical records using baseline demographics and brain imaging findings from 186 migraine hospitalized in-patients who had at least two sets of white blood cell counts drawn within 24 h following their admission to the emergency department of Western Health a tertiary care center in Melbourne, Australia, over an 18-month period. Patients were categorized as having migraine with aura (MA) (N = 67) or without aura (MO) (N = 119) according to ICHD-3 criteria and compared to 2 serial measures in stable in-community acute migraineur controls (N = 20). A mixed-design ANOVA showed a significant main effect of SSIIi between patients with migraine with aura (MA) and migraine without aura (MO) during acute inpatient presentation, in comparison to a convenience sample of outpatients with migraine (MA and MO).
Conclusion: SSIIi levels were significantly lower in patients with migraine with aura (MA), compared to MO. MA showed a greater, though non-significant, decrease between the two measurements compared to those with migraine without aura (MO) and outpatient controls, whose SSIIi levels remained consistently higher. The control group displayed similar findings to MO inpatients, suggesting persistent systemic inflammation in a subset of migraine patients regardless of in patient or outpatient of presentation and highlighting the need for future studies to more rigorously evaluate the role of systemic inflammation in migraine pathophysiology, chronicity, and progression though the multiple phases of migraine including the interictal phase.
{"title":"Serial systemic immune inflammation indices: markers of acute migraine events or indicators of persistent inflammatory status?","authors":"Tissa Wijeratne, Melanie J Murphy, Chanith Wijeratne, Paolo Martelletti, Leila Karimi, Vasso Apostolopoulos, Carmela Sales, Nina Riddell, Sheila G Crewther","doi":"10.1186/s10194-024-01929-6","DOIUrl":"10.1186/s10194-024-01929-6","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Main body: </strong>A retrospective analysis was conducted of medical records using baseline demographics and brain imaging findings from 186 migraine hospitalized in-patients who had at least two sets of white blood cell counts drawn within 24 h following their admission to the emergency department of Western Health a tertiary care center in Melbourne, Australia, over an 18-month period. Patients were categorized as having migraine with aura (MA) (N = 67) or without aura (MO) (N = 119) according to ICHD-3 criteria and compared to 2 serial measures in stable in-community acute migraineur controls (N = 20). A mixed-design ANOVA showed a significant main effect of SSIIi between patients with migraine with aura (MA) and migraine without aura (MO) during acute inpatient presentation, in comparison to a convenience sample of outpatients with migraine (MA and MO).</p><p><strong>Conclusion: </strong>SSIIi levels were significantly lower in patients with migraine with aura (MA), compared to MO. MA showed a greater, though non-significant, decrease between the two measurements compared to those with migraine without aura (MO) and outpatient controls, whose SSIIi levels remained consistently higher. The control group displayed similar findings to MO inpatients, suggesting persistent systemic inflammation in a subset of migraine patients regardless of in patient or outpatient of presentation and highlighting the need for future studies to more rigorously evaluate the role of systemic inflammation in migraine pathophysiology, chronicity, and progression though the multiple phases of migraine including the interictal phase.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"7"},"PeriodicalIF":7.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}