Chronic neuropathic pain is frequently accompanied by anxiety and depression, yet the cortical circuit mechanisms underlying this comorbidity remain unclear. The medial orbitofrontal cortex (mOFC) is a key cortical region involved in emotional regulation and valuation, and clinical imaging studies have reported altered mOFC activity in patients with chronic pain. However, it remains unclear how mOFC neuronal activity contributes to both the pain hypersensitivity and anxiodepressive-like behaviors associated with neuropathic pain. This study aimed to determine the pathway-specific roles of mOFC glutamatergic neurons in chronic pain and comorbid affective disturbances. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain sensitivity and anxiodepressive-like behaviors were assessed using von Frey, Hargreaves, open field, elevated plus maze, tail suspension, and forced swim tests. Electrophysiological recording and fiber photometry were used to monitor neuronal activity. Neuronal projection tracing identified projection patterns of mOFC glutamatergic neurons to mediodorsal thalamus (MD) and basolateral amygdala (BLA). Chemogenetic and optogenetic manipulations were applied to selectively modulate the mOFCCaMKIIα-MD and mOFCCaMKIIα-BLA pathways. The mOFC glutamatergic neurons are activated in neuropathic pain mice accompanied by anxiodepressive-like phenotypes. Chemogenetic and optogenetic inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. Retrograde labeling result revealed two non-overlapping mOFCCaMKIIα neurons projecting to the MD and BLA, respectively. Selective inhibition of mOFCCaMKIIα-MD pathway leads to amelioration of CCI-induced pain hypersensitivity. While selective inhibition of mOFCCaMKIIα-BLA pathway leads to amelioration of CCI-induced anxiodepressive-like behaviors. The present study has revealed that the critical involvement of mOFC glutamatergic neurons in the comorbidity of chronic pain and affective disturbances. Inhibition of mOFC glutamatergic neurons attenuates both pain hypersensitivity and anxiodepressive-like behaviors after nerve injury. The discrete mOFCCaMKIIα-MD and mOFCCaMKIIα-BLA pathway independently control the sensory and affective components of neuropathic pain.
The insular cortex (IC), a pivotal hub for pain signal integration, projects extensively to the thalamus. However, the functional role of its specific projection to the central medial thalamic nucleus (CM) in pain-affective comorbidities remains elusive. Elucidating the IC-CM pathway is thus critical for revealing endogenous pain regulation and pain-emotion comorbidity mechanisms. A multidisciplinary approach combining neuroanatomical tracing, calcium imaging, electrophysiological recordings, optogenetics, chemogenetics and behavioral observations was used to investigate the role of the IC-CM pathway in pain and emotional modulation with the spared nerve injury (SNI) mouse model. The imaging and 3D visualization methods were also utilized to observe the projection patterns of IC-CM pathway neurons. Neuropathic pain activated neurons, predominantly excitatory neurons, in the deep layers (L5-6) of the IC (dlIC) and rostral CM (rCM) in SNI mice. The vesicular glutamate transporter type 2-immunoreactive (VGluT2+) neurons in the dlIC project to the calcium/calmodulin-dependent protein kinase IIα-immunoreactive (CaMKIIα+) neurons in the rCM, forming a functional pathway for nociceptive information transmission. Fiber photometry and electrophysiological recordings revealed the enhanced excitability in the dlIC-rCM pathway in response to noxious stimuli, confirming its involvement in pain signal transmission. Chemogenetic and optogenetic activation of the dlICVGluT2-rCMCaMKIIα neural pathway significantly reduced mechanical and thermal pain thresholds and evoked anxiety-like behaviors in normal mice. Conversely, inhibition of this pathway alleviated mechanical and thermal hypersensitivity and anxiety-like behaviors in SNI mice. Single-neuron projection pattern analyses revealed 2 distinct axonal arborization phenotypes among dlIC neurons forming synapses with CMCaMKIIα neurons. Collectively, these findings identify the dlICVGluT2-rCMCaMKIIα pathway as a contributor to pain-anxiety comorbidity in mice. The observed distinct axonal arborization phenotypes provide morphological evidence suggesting local integration within the rCM and downstream propagation of nociceptive signals. These results advance our understanding of cortico-thalamic mechanisms in central sensitization and suggest this pathway as a candidate for therapeutic intervention in chronic pain states. Not applicable. The online version contains supplementary material available at 10.1186/s10194-026-02373-4.
Body pain significantly affects the quality of life. However, the relationship between headache and pain across broad body regions remains unclear. This population-based cross-sectional study aimed to investigate the prevalence and impact of body pain in migraine and tension-type headache (TTH). We analyzed baseline data from 2,548 participants in the Korean population-based Circannual Change in Headache and Sleep study. Participants were classified into migraine (n = 145), TTH (n = 805), and no-headache (n = 920) groups. Body pain was assessed across 19 regions using the Widespread Pain Index (WPI). Multivariable analyses adjusted for age, sex, and psychiatric symptoms were performed. Body pain was more widespread in the migraine and TTH than in the no-headache group, showing a gradient of migraine > TTH > no-headache (P < 0.001). Migraine was most strongly associated with neck pain (odds ratio [OR] 2.84, P = 0.008), whereas TTH showed the strongest association with upper back pain (OR 2.74, P = 0.008). Higher WPI and body-pain intensity were associated with higher headache intensity, more monthly headache days, more monthly severe headache days, and higher HIT-6 scores, as well as poorer quality of life and greater depression, anxiety, and insomnia (all P < 0.001). Axial body pain was associated with higher monthly headache days in migraine, whereas upper body pain was associated with higher monthly headache/severe headache days in TTH. Body pain is more prevalent and widespread in patients with migraine and TTH and is associated with a greater disease burden, potentially reflecting central sensitization. Distinct patterns of regional pain, particularly neck pain in migraine and upper back pain in TTH, may provide clinically relevant insights into underlying nociceptive mechanisms.
The pathogenesis of neuropathic pain is complex, and effective treatment methods are lacking in clinical practice. Recent studies have shown that glucose metabolism reprogramming may be involved in the process of neuropathic pain, but its role and molecular regulatory mechanisms in neuropathic pain are still unclear. In this study, a rat model of chronic constriction injury of the sciatic nerve (CCI) was established, and the pain threshold was evaluated through behavioural analysis. Morphological staining, transmission electron microscopy, transcriptome sequencing, Western blotting, immunofluorescence staining, ELISA, and the whole-cell patch clamp technique were used to systematically observe neuropathological changes, identify differentially expressed genes and associated pathways, and measure the expression levels of glycolysis-related indicators and the key regulatory factor fibroblast growth factor 4 (FGF4). The results showed that the pain threshold of rats decreased and that the structure of sciatic nerve tissue was damaged after CCI. Transcriptome sequencing of the sciatic nerve showed a significant increase in the expression levels of glycolysis-related indicators. Subsequent experiments confirmed that FGF4 expression was downregulated in the sciatic nerve and spinal dorsal horn after CCI, whereas the expression of hypoxia-inducible factor-1α (HIF-1α) and its key downstream glycolytic enzymes was upregulated, accompanied by increased levels of lactic acid and proinflammatory cytokines and decreased ATP levels. The spinal dorsal horn exhibited both synaptic structural abnormalities and neuronal hyperexcitability. Inhibiting HIF-1α alleviated pain and suppressed glycolysis, whereas the overexpression of FGF4 specifically reversed the increase in HIF-1α expression, inhibited neuronal glycolysis, and reduced neuroinflammation and central sensitization, ultimately effectively relieving pain. This study reveals the core role of the FGF4/HIF-1α-mediated regulation of neuronal glycolysis in neuropathic pain, providing a new theoretical basis and experimental evidence for a deeper understanding of the metabolic mechanism of neuropathic pain and the development of targeted treatment strategies. [Image: see text] The online version contains supplementary material available at 10.1186/s10194-026-02362-7.
Cluster headache is associated with compensated hypogonadism in males, suggesting impaired testicular steroidogenesis. It is unknown if adrenal steroidogenesis is dysregulated and how this is linked to cluster headache pathophysiology. We therefore aimed to define the adrenal steroid profile in cluster headache and define the differences between the phases of episodic cluster headache. We secondarily aimed to assess whether the steroid profile could distinguish between chronic cluster headache and episodic cluster headache. A prospective case-control study containing adult males with chronic cluster headache (n = 60), paired episodic cluster headache in and out of bout (n = 60) and healthy controls (n = 60). A fasted serum steroid profile for 16 steroid hormones was assessed via liquid chromatography tandem mass-spectrometry, assessing mineralocorticoids, glucocorticoids, and androgens. Explorative machine learning was used to segregate the cluster headache states. The mineralocorticoids 11-deoxycorticosterone (P < 0.05), corticosterone (P < 0.05) and aldosterone (P < 0.05) were lower in those with episodic cluster headache compared to controls. 11-deoxycorticosterone (P < 0.01), corticosterone (P < 0.01), and the glucocorticoids 11-deoxycortisol (P < 0.01) and cortisol (P < 0.05) and cortisol/DHEAS ratio (P < 0.001) are lower in episodic in bout compared to their paired remission state. Those with chronic cluster headache had lower concentrations of 17-OH pregnenolone (P < 0.05) and DHEAS (P < 0.001) and a higher cortisol/DHEAS ratio (P < 0.01). The steroid hormone profile distinguished between chronic and episodic cluster in bout with a specificity of 86% (95%CI: 69%-90%), sensitivity of 81% (95%CI: 73%-93%) and AUC of 0.92 (P < 0.0001). Attack frequency and time from last attack correlated with the degree of steroid dysfunction in episodic cluster headache but not in chronic cluster headache. We identify distinct steroid hormone profiles in episodic and chronic cluster headache. Episodic in bout was associated with reduced adrenal steroid synthesis that resolves in remission. Chronic cluster headache was associated with stress induced androgen suppression. Together, these differences are likely secondary to cluster headache and may reflect distinct neurobiological bases underlying episodic and chronic cluster headache. Not applicable.
The nucleus accumbens (NAc) plays an important role in the chronic pain process and consists of core and shell subregions with distinct connectivity patterns. However, their roles in migraine progression remain unclear. This study explored static and dynamic functional connectivity (FC) patterns of NAc subregions across healthy controls (HCs), patients with episodic migraine (EM) and patients with chronic migraine (CM). 97 participants were enrolled: 70 migraine patients (24 EM, 46 CM) and 27 HCs. All underwent functional magnetic resonance imaging on a GE 3.0T system. Demographic and clinical characteristics were collected. The NAc core and shell were defined as ROIs, and static and dynamic seed-based FC analyses were performed across groups. Partial correlations between FC values and clinical variables were conducted. Significant static FC and dynamic FC were selected through multivariable logistic regression. Receiver operating characteristic curves were used to assess their diagnostic performance for distinguishing CM patients. Compared with HCs, EM showed increased sFC between the right NAc core and right supplementary motor area (SMA), whereas CM exhibited decreased sFC, particularly between the left NAc shell and the left fusiform gyrus and between the right NAc core and the left cerebellum crus II. Relative to EM, CM showed reduced sFC mainly between the left NAc shell and the bilateral precentral gyrus and right superior frontal gyrus (SFG), and between the right NAc core and right SMA, right inferior frontal gyrus, and left inferior temporal gyrus (ITG). The dFC analysis revealed decreased connectivity between the left NAc shell and left precentral gyrus and right SFG, and between the right NAc core and left SMA. Reduced sFC between the right NAc core and left ITG and dFC between the left NAc shell and right SFG effectively distinguished CM from EM. The combined FC calculated from sFC and dFC further improved discrimination (AUC = 0.919). NAc subregions in CM showed reduced connectivity with multiple brain regions, mainly in sensorimotor, executive control, and default mode networks. Significant sFC and dFC of the NAc subregions may serve as potential imaging biomarkers for CM. The online version contains supplementary material available at 10.1186/s10194-026-02351-w.
Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptides (CGRP) are established therapies for migraine. There are currently four CGRP-mAbs available on the market: one targets the CGRP receptor, and the other three target the CGRP ligand. Despite the initial comparability of the two groups regarding efficacy, real-life data demonstrate that up to 30% of non-responders to one class exhibit a positive response to switching classes, indicating different mechanisms. The ligand-mAb, galcanezumab, has previously demonstrated a trigeminal dermatome-specific pain modulatory effect. The present study aims to evaluate the sensory modulatory effect of the receptor-mAb, erenumab. Migraine patients were recruited in two phases. In the first phase of the study, 40 patients were included and randomly assigned to receive either erenumab 70 mg (21 patients) or a placebo (19 patients) in a double-blind manner. In the second phase of the study, 46 patients were included and received erenumab 140 mg in an open-label manner. Quantitative sensory testing (QST) parameters were measured on the right forehead (V1 dermatome) and on the forearm prior to and after treatment. A repeated-measures analysis of variance (ANOVA) was used for the statistical analysis. All three study cohorts (placebo, erenumab 70 mg, and erenumab 140 mg) were comparable in terms of demographics, including age, sex ratio, and baseline headache frequency, and showed no statistically significant differences in QST parameters. Subsequent to the administration of the treatment, no changes or discernible trends were observed in any of the QST parameters in any study cohort. The findings of this study suggest that the receptor-mAb, erenumab, did not modify the sensory thresholds following treatment. This finding is in contrast with the results of galcanezumab in the literature, which demonstrated a trigeminal sensory modulatory effect after treatment. This outcome indicates a different mechanism of action between the anti-CGRP receptor versus ligand mAbs and provides a scientific basis for the rationale of class switching, which aims to achieve additional clinical benefits in patients who are non-responders to anti-CGRP treatment. The study was preregistered at the Open Science Framework (https://osf.io/ygf3t).
Microglial activation is increasingly recognized as a critical contributor to both the initiation and chronification of migraine. Recent advances have highlighted the importance of receptor-mediated signaling pathways in regulating microglial responses; however, their integrated role in central inflammation remains insufficiently characterized. This review aimed to evaluate the mechanistic involvement and therapeutic relevance of microglial receptors in chronic migraine. A comprehensive systematic search was conducted in PubMed, Web of Science, and Scopus to identify studies investigating the mechanisms or effects of microglial receptors in chronic migraine models. Methodological quality and risk of bias were assessed using the CAMARADES checklist and the SYRCLE risk-of-bias tool. Quantitative outcomes, including calcitonin gene-related peptide (CGRP) relative density, Iba-1 immunoreactive cells, paw withdrawal latency, periorbital mechanical threshold, and paw mechanical threshold, were analyzed using Review Manager 5.4. Meta-analyses were performed using fixed-effects or random-effects models based on the degree of heterogeneity. A total of twelve studies met the inclusion criteria. Among these, five studies investigated purinergic P2 receptors, two focused on GLP-1R, and one study each examined TREM1, TREM2, S1PR1, TLR2, and CB2R, encompassing ten distinct microglial receptors. Compared with the nitroglycerin (NTG) control group, receptor-targeted interventions significantly attenuated acute thermal and mechanical hyperalgesia (all p < 0.00001). In addition, these interventions were associated with reduced CGRP expression and a decreased number of Iba-1-positive microglial cells, indicating suppression of neuroinflammatory activation. Notably, substantial heterogeneity was observed in the analysis of Iba-1 immunoreactive cells (I² = 87%), and its source could not be clearly identified despite sensitivity analyses. Overall, the included studies demonstrated moderate-to-high methodological quality; however, the limited number of studies precluded a formal assessment of publication bias. Despite the limited number of available studies, the present findings support the hypothesis that microglial receptors represent promising therapeutic targets in chronic migraine. The data further suggest that modulation of a single receptor pathway may be insufficient, given the complexity and interconnectivity of microglial signaling networks. Future investigations should focus on elucidating receptor-specific mechanisms and the interactions among downstream signaling pathways to inform the development of more effective, multi-target therapeutic strategies. This study was prospectively registered in PROSPERO (CRD420251112473). Not applicable.
Post-traumatic headache (PTH) is a debilitating neurological sequela of mild traumatic brain injury (mTBI) characterized by secondary cephalic pain. The endocannabinoid system (ECS) is a critical modulator of nociception, yet the specific spatiotemporal changes in its metabolic machinery within cephalic pain circuits following mTBI are poorly understood. Using in-situ hybridization (ISH), we first characterized the levels of gene expression of major endocannabinoid (eCB) synthesizing enzymes (Napepld, Gde1, Dagla, Daglb), hydrolyzing enzymes (Faah, Mgll) and cannabinoid receptors (Cnr1 and Cnr2) in the trigeminal complex (trigeminal ganglion - TG, trigeminal root entry zone - TREZ, and trigeminal nucleus caudalis - TNC) and midbrain (periaqueductal gray - PAG, dorsal raphe - DR) regions involved in the modulation of pain. Subsequently, employing a mouse model of repetitive closed head mTBI that induces cephalic pain, we assessed global eCB enzymatic gene expression changes via qPCR and region-specific changes via ISH at one-week post-injury. Baseline characterization revealed complex co-expression patterns, with Gde1 and Daglb transcripts being significantly more abundant than Napepld and Dagla in the TG, TNC, and PAG. Seven days post-mTBI, coinciding with the onset of PTH-like symptoms, we identified a significant upregulation of the hydrolyzing enzymes Faah in the peripheral TREZ but not in the TG sensory neurons. Centrally, although no difference was observed in the TNC, mTBI induced an upregulation of Mgll in the ventrolateral PAG (vlPAG) and the DR, particularly within DR VGlut3+ neurons. These findings demonstrate a novel neuropathological mechanism whereby mTBI triggers a persistent, region-specific upregulation of genes encoding eCB-degrading enzymes. Thus, sub-acute modulation of eCB hydrolyzing enzymes in critical peripheral and central pain-modulating regions may contribute to the maintenance of cephalic pain associated with mTBI. Not applicable. The online version contains supplementary material available at 10.1186/s10194-026-02356-5.
Herpes zoster (HZ) and postherpetic neuralgia (PHN) are severe neuropathic pain disorders. However, the alterations in their macroscopic brain-functional architecture and their potential molecular correlations remain poorly understood. This study was aimed at characterizing the altered functional connectivity patterns in the brains of patients with HZ and PHN using a connectome gradient analysis and further explore the potential associations with gene expression patterns through a spatial transcriptomics correlation analysis. In this study, 95 patients with HZ, 89 patients with PHN, and 84 matched healthy controls were characterized through a connectome gradient analysis. Additionally, transcriptomic neuroimaging association analyses were conducted using gene expression data derived from the Allen Human Brain Atlas and case‒control gradient differences to identify the genes that were associated with gradient variations. Finally, an enrichment analysis was performed on the identified significant genes to explore the biological pathways and cell types in which they may be involved. Compared with the healthy controls, HZ exhibited in the whole-brain gradients shrinkage. HZ showed abnormal subgradient values within the sensorimotor and dorsal attention networks, with exploratory associations to anxiety scores. PHN was characterized by reduced main gradient values in the frontoparietal control network, with exploratory associations to depression scores. The transcriptomic neuroimaging association analysis revealed that the gradient abnormalities in HZ were spatially correlated with gene expression patterns involving synaptic functions and ion channels, whereas the abnormalities in PHN were spatially correlated with the genes involved in postsynaptic signaling and the regulation of endogenous opioids. Cellular analysis indicated that HZ-associated genes were predominantly enriched in inhibitory and excitatory neurons and astrocytes, whereas PHN-associated genes were enriched in both neuron types. This study is the first to identify functional connectome and associated gene expression profiles in HZ and PHN through a cross-scale perspective that encompasses both functional connectome gradients and gene expressions. Our findings provide novel insights into the spatial transcriptomic correlates of functional alterations in the brain under these conditions and provide a foundation for conducting hypothesis-driven research on potential biomarkers and therapeutic strategies. [Image: see text] The online version contains supplementary material available at 10.1186/s10194-026-02331-0.
The interplay between Antiphospholipid syndrome (APS) and migraine is very controversial; migraine is believed to be the most common neurologic symptom in APS, and there are claims that migraineurs have abnormally high Antiphospholipid antibodies (aPL), yet the reports differ widely. Nevertheless, APS could lead to various other types of headaches; both primary and secondary, leaving patients susceptible to exacerbation of symptoms, overlapping of headaches, and atypical presentations. To describe types and characteristics of headache in a cohort of patients with antiphospholipid syndrome (APS) in comparison to healthy controls. And investigate their possible relation with antiphospholipid antibodies (aPL) and MRI brain findings in patients with APS. We recruited 76 patients with APS consecutively, between February 2024 and August 2025. From Ain shams university hospital; neurology, internal medicine, and obstetric and gynecology departments, along with 60 matched controls. Patients and controls underwent neurological examination and were evaluated for headache according to the International Headache Society criteria (IHS), Impact and severity were assessed by Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT). All participants had a brain MRI. A total of 76 patients; 70 females and 6 males, mean age for patients at presentation was 35 ± 8.73 years; mean disease duration was 5 ± 3 years; mean Body mass index (BMI) was 22.38 ± 1.46. Headache was reported by 87% of patients; of which 16 patients suffered secondary type headaches (21%); and 50 patients had primary headaches (65.7%); with migraine being the most common (35%). Anticardiolipin (ACL) antibodies were the most common aPL detected (76.4%) in APS patients. MRI brain was normal in 86% of APS patients with primary headaches, Meanwhile, APS patients with triple positive antibodies showed significantly more abnormal MRI findings (p = 0.04). Headache severity was significantly more in APS patients (p = 0.04) Factors affecting headache severity were APS disease duration, BMI, triple aPL positivity (p = 0.03, 0.00, 0.02 respectively). Primary and secondary types of headaches are frequently reported in Patients with APS, primary headache being more common; migraine in particular. APS patients had significantly more severe headaches. MRI brain was normal in the majority of APS patients with primary headaches and healthy controls. Yet, patients with triple positive antibodies showed more abnormal MRI findings. APS disease duration, BMI, triple aPL were independent factors for headache severity.
Vestibular migraine (VM) is a disabling neurological disorder where neuroinflammation and central sensitization constitute the core pathological mechanisms. Physiological levels of autophagy help maintain cellular homeostasis and regulate neuroinflammation, whereas autophagic dysfunction is closely associated with exacerbated neuroinflammatory responses. Although accumulating evidence has confirmed the presence of robust autophagic dysfunction in VM, the specific role of triggering receptor expressed on myeloid cells 2 (TREM2), a key microglial receptor, in this process remains to be elucidated. A rat model of VM was established via the intraperitoneal injection of nitroglycerin (NTG) combined with variable-speed rotation. To investigate the role of the TREM2/PI3K/Akt/mTOR pathway, we intraperitoneally administered a specific TREM2 inhibitor, a TREM2 agonist, and the mTOR inhibitor rapamycin to SD rats 30 min before each nitroglycerin (NTG) injection. After modeling, pain sensitivity and vestibular function were evaluated. Mechanical pain threshold was measured using the von Frey test, thermal pain sensitivity by the tail-flick test, and vestibular function was assessed with the beam balance test and motion sickness index (MSI). Western blot and immunofluorescence assays were then performed to quantify the expression of TREM2, as well as autophagy-related, neuroinflammation-related, and central sensitization-related proteins in the trigeminocervical complex (TCC) and vestibular nuclei (VN). Meanwhile, microglial number and morphological alterations were analyzed to comprehensively characterize the status of autophagy, neuroinflammation, and central sensitization. In a rat model of VM, immunofluorescence staining confirmed clear co-localization of TREM2 with both neurons and microglia in the TCC and VN, with significantly upregulated TREM2 expression observed in these two nuclei. Notably, this TREM2 upregulation coincided with autophagic dysfunction, Nod-like receptor protein 3 (NLRP3) inflammasome activation, elevated expression of central sensitization markers, as well as microglial activation and proliferation. In vivo functional experiments further confirmed that TREM2 agonist intervention significantly exacerbated autophagic impairment, neuroinflammatory cascades, and central sensitization in the TCC and VN, accompanied by aggravated hyperalgesia and vestibular dysfunction in VM rats. Conversely, targeted inhibition of TREM2 or autophagy activation effectively reversed these molecular and cellular pathological alterations, and significantly alleviated hyperalgesia and vestibular impairment in VM rats. This study demonstrates that TREM2 drives neuroinflammation and central sensitization in VM via PI3K/Akt/mTOR-mediated autophagy inhibition. Targeting TREM2 or restoring autophagy effectively alleviates VM-related phenotypes, offering potential therapeutic strategies for VM and related neuroinflammatory disorders. The online version contains supplementary material available at 10.1186/s10194-026-02337-8.
Medication overuse headache (MOH) is a chronic disorder due to excessive acute headache treatment use. Neuroimaging studies suggest the involvement of the orbitofrontal cortex (OFC) in the pathophysiology of MOH, particularly its connections with the periaqueductal gray (PAG). The OFC-vlPAG circuit has been well-established as a critical neural substrate in pain regulation; while its role in triptan-related MOH pathogenesis remains unclear. This study aims to investigate the role of the OFC-vlPAG circuit and its underlying mechanisms in regulating mechanical hypersensitivity using a triptan-induced MOH mouse model. Male C57BL/6J mice (along with a female exploratory cohort) were used to develop a triptan-induced MOH model through repeated rizatriptan (RIZ) administration. Behavioral assessments of cutaneous allodynia were conducted using von Frey filaments. Immunofluorescence staining was performed to examine neuronal activity and 5-HT1D receptor (5-HT1DR) expression in the OFC. Chemogenetic and optogenetic techniques were employed to modulate vlOFC glutamatergic neurons or the vlOFC-vlPAG pathway, and pharmacological methods were utilized to target the vlOFC's 5-HT1DR. Repeated RIZ administration induced cutaneous allodynia in the MOH mouse model, with significant reductions in hind paw and head withdrawal thresholds. Elevated c-Fos expression in the vlOFC CaMKII-α+ neurons of triptan-induced MOH mice indicated increased glutamatergic neuronal activity. Chemogenetic and optogenetic glutamatergic neuron activation in the vlOFC alleviates allodynia in the triptan-induced MOH model. Furthermore, glutamatergic vlOFC-vlPAG circuit activation significantly improved pain thresholds in these MOH mice. The observed downregulation of 5-HT1DR in the vlOFC of these MOH mice was functionally associated with inhibition relief in this circuit. This adaptation may create a permissive state, allowing for robust analgesic effects upon targeted exogenous activation. Activating the glutamatergic OFC-vlPAG circuit elicits robust analgesia in triptan-induced MOH mice. 5-HT1DR downregulation is hypothesized to unmask the circuit's analgesic potential by elevating vlOFC baseline activity, providing a highly responsive therapeutic target for triptan-related allodynia. Not applicable.
Cognitive impairment and circadian rhythm disturbances are prevalent comorbidities of migraine, yet their underlying neural circuit mechanisms remain poorly understood. The suprachiasmatic nucleus (SCN), as the master circadian pacemaker, and the hippocampus, essential for memory, are key regions involved in these symptoms. The dentate gyrus (DG) in the hippocampus acts as the main entry point for information and is essential for pattern separation, a key memory process. We hypothesized that a direct neural pathway from the SCN to the DG might link circadian dysfunction to cognitive deficits in migraine. Using a nitroglycerin (NTG)-induced chronic migraine mouse model, we combined behavioral assays, immunofluorescence, chemogenetics, monosynaptic retrograde tracing, and projection-specific optogenetics to investigate the role of the SCN and its potential connection to the DG in migraine-related cognitive impairment. NTG-treated mice exhibited not only pain hypersensitivity but also significant circadian rhythm disruption and deficits in recognition and spatial working memory. Our immunofluorescence analysis revealed a marked increase in c-Fos expression within the SCN of NTG-induced migraine mice. Notably, despite increased total c-Fos expression in the SCN, the density and proportion of c-Fos⁺/GAD67⁺ cells were reduced, whereas c-Fos⁺/CaMKII⁺ cells showed no significant change. These findings indicate an altered recruitment of neuronal subpopulations rather than uniform changes in SCN neuronal activity. This interpretation was further supported by chemogenetic manipulation of SCN neurons, in which inhibition exacerbated, whereas activation rescued, cognitive deficits without affecting pain sensitivity. Immunostaining revealed increased c-Fos recruitment of GABAergic interneurons in the DG. Using convergent anterograde and retrograde tracing approaches, we obtained anatomical evidence supporting the presence of a direct SCN→DG projection with preferential association to DG inhibitory interneuron populations. Projection-specific optogenetic activation of SCN terminals in the DG was sufficient to reverse cognitive impairments in migraine mice. Our research reveals a previously underappreciated GABAergic pathway from the SCN to the DG that is functionally implicated in cognitive deficits associated with migraine. The findings suggest that migraine is associated with altered recruitment of neuronal subpopulations and network-level coordination within the SCN and along the SCN-DG pathway. This is accompanied by increased recruitment of GABAergic interneurons in the DG and impaired DG information processing. Together, these results identify the SCN-DG circuit as a potential neuromodulatory target for future investigation of cognitive symptoms associated with migraine.
Occipital nerve stimulation has shown promising results in attack prevention in patients with chronic cluster headache, but evidence from controlled trials is scarce. Conventional (tonic) occipital nerve stimulation elicits paresthesia, hampering blinded comparison to placebo. Using paresthesia-free burst occipital nerve stimulation, we conducted a randomized, placebo-controlled trial. The study is an investigator-initiated, double-blind, randomized, placebo-controlled clinical trial involving participants with chronic cluster headache. It comprised a four-week baseline, a 12-week trial with transcutaneous electrical nerve stimulation, occipital nerve stimulator implantation, a 12-week randomized, double-blind burst occipital nerve stimulation treatment period, and a 12-week open-label tonic occipital nerve stimulation treatment period. The primary outcomes were safety and the proportion of participants reporting a ≥30% reduction in attack frequency in the randomized and open-label trial phases. Participants were enrolled between August 2021 and October 2023. 116 chronic cluster headache patients were assessed for eligibility. Sixty-five were excluded, and 51 entered baseline observation. Before occipital nerve stimulator implantation and randomization, an additional 13 were excluded. Thirty-eight participants underwent occipital nerve stimulator implantation and were randomly assigned to burst occipital nerve stimulation (n = 19) or placebo (n = 19). After the randomized trial phase, the proportion of ≥30% responders was 18.81% (95%CI 0.28%–37.87%) in the burst occipital nerve stimulation group and 50.02% (95%CI 26.87%–73.09%) in the placebo group. The likelihood of reaching the primary endpoint was 31.20% (95%CI 1.29%–61.23%, p = 0.042) higher in the placebo group. After the open-label phase, 42.09% (95%CI 19.91%–64.34%) in the burst occipital nerve stimulation group and 51.11% (95%CI 27.32%–74.88%) in the placebo group had ≥30% frequency reduction. In total, 20 adverse events were registered; eight were treatment-related serious adverse events. The most common adverse event was temporary occipital dysesthesia in eight participants. Occipital nerve stimulation reduced attack frequency but was not superior to placebo. The treatment had an acceptable safety profile and was well-tolerated. The results call for attention to sufficient placebo control when planning further studies. The trial is registered at clinicaltrials.gov (identifier NCT05023460).Study registration date: July 27th 2021.
Medication-overuse headache (MOH) is a prevalent and disabling secondary headache disorder that arises in individuals with a pre-existing primary headache as a consequence of regular overuse of acute medications. Increasing evidence suggests that MOH shares fundamental pathophysiological and behavioural features with nociplastic pain conditions, supporting the view that it cannot be explained solely as a pharmacological complication. Rather, MOH appears to reflect complex interactions between neurobiological vulnerability, maladaptive neuroplasticity, and behavioural factors. In this review, we reappraise MOH through the lens of nociplastic pain to provide a unifying framework for its pathophysiology and management. Evidence from neuroimaging, neurophysiological, genetic, and experimental studies consistently indicates that MOH is associated with central sensitization, impaired descending pain modulation, and dysfunction of reward and cognitive control networks, particularly involving fronto-striatal and brainstem circuits. These alterations closely resemble those observed in other nociplastic pain conditions and appear largely reversible following successful withdrawal and preventive treatment. Behavioural features such as craving, impulsivity, catastrophizing, and cephalalgiophobia play a pivotal role in maintaining medication overuse and predicting poor outcomes, reinforcing the conceptualization of MOH as a biobehavioural syndrome. Management strategies have evolved from detoxification-centered approaches toward integrated, patient-centered care. While withdrawal remains a cornerstone of treatment, growing evidence supports flexible strategies in which preventive therapies, especially CGRP-targeting monoclonal antibodies and gepants, can be initiated before or alongside withdrawal, reducing headache burden and facilitating disengagement from acute medication overuse. Behavioural and psychological interventions, including cognitive behavioural therapy and mindfulness-based approaches, are essential to address emotional drivers, enhance adherence, and modulate nociplastic mechanisms. Current guidelines increasingly endorse multimodal and multidisciplinary management, although evidence quality remains heterogeneous. Reframing MOH within a nociplastic pain framework supports a shift from rigid detoxification models toward personalized, mechanism-based, and multidisciplinary care. Future research integrating clinical, imaging, neurobiological, and behavioural markers, potentially supported by artificial intelligence–based predictive models, may further refine patient stratification and optimize long-term outcomes in MOH.
Visual discomfort and sensory overload are common complaints in migraine patients without aura (MwoA), even between attacks, yet their neural basis remains poorly understood. We aimed to explore brain activation patterns in response to complex visuospatial tasks with higher ecological validity by using functional magnetic resonance imaging in migraine patients without aura. Fifty-nine right-handed female participants (30 interictal MwoA and 29 non-headache controls, aged 18–46 years) were included in the study. Subjects completed visually demanding fMRI tasks, which were designed based on aversive visuals that are frequently encountered in daily routine. Participants were asked to locate a target presented within either a high-frequency grating or a crowded geometric array in two runs while undergoing an fMRI scan. Both behavioral, clinical, and neuroimaging data were analyzed to examine repetition-related neural dynamics. A complex visual task induced higher BOLD activations in salience, executive control, and dorsal attention networks, particularly in visual areas, in migraine without aura patients compared to non-headache sufferers. Unlike controls, migraine patients exhibited repetition enhancement in the orbitofrontal cortex and the periaqueductal gray. Repetition suppression is impaired in higher-order visual areas of LOC, Pulvinar, and IPS compared to the control group. Reaction time and initial learning ability were comparable in the two groups; however, the accuracy rate decreased towards the end of the second run. Changes in the accuracy rate were positively correlated with changes in the OFC BOLD signal. Increased photophobia correlated with BOLD activation changes in the periaqueductal gray, the lateral occipital cortex, and the insula in migraine. Lack of repetition suppression in higher-order cortical and thalamic visual areas, and repetition enhancement in the OFC and PAG, are novel findings in migraine. Orbitofrontal activation correlated with task performance, indicating increased effortful top-down control to sustain accuracy, despite substantial metabolic demands, in migraine patients without aura. The enhanced BOLD activation in higher-order visual processing, along with reduced accuracy performance during repetition, may also reflect a prolonged reliance on aerobic glycolysis to meet neuronal energy demands. Abnormal engagement of pain-modulatory regions during visual processing suggests that sensory input is processed as aversive rather than neutral. These results provide a network-level explanation in which disrupted sensory gating and altered cortico-midbrain interactions impair predictive suppression, contributing to cognitive fatigue, sustained sensory gain, and visual hypersensitivity in migraine without aura. The online version contains supplementary material available at 10.1186/s10194-026-02327-w. [Image: see text]
Migraine is a very common chronic neurological disorder associated with severe disability and significant social burden worldwide. Beyond recurrent headache attacks, increasing evidence indicates that migraine often coexists with a broad range of systemic disorders, forming complex and often bidirectional relationships. These overlapping conditions complicate clinical management and suggest the presence of shared pathophysiological mechanisms extending beyond the central nervous system. Epidemiological studies have consistently shown strong associations between migraine and multiple comorbidities, including epilepsy, psychiatric disorders, sleep disturbances, cardio-cerebrovascular diseases, multiple sclerosis, asthma, other chronic pain syndromes, gastrointestinal disorders, and metabolic‒endocrine abnormalities. The presence of these conditions is generally associated with increased disease severity, higher rates of migraine chronification, poorer treatment responses, and increased healthcare utilization. Emerging mechanistic evidence indicates that migraine and its comorbidities share common biological pathways, including dysregulation of neurovascular signaling, neuroinflammation, central sensitization, alteration in autonomic nervous system and brain function, and disturbances in immune and metabolic homeostasis. Importantly, the presence of comorbid conditions may affect the efficacy, tolerance and safety of treatment, highlighting the limitations of symptom-oriented treatment strategies that fail to address these shared mechanisms. This review synthesizes current evidence on the epidemiological associations, shared pathophysiological mechanisms, and clinical implications of migraine and its common comorbidities. By elucidating these interrelated pathways, we aim to inform the development of comprehensive, personalized management strategies that transcend symptom-oriented treatment towards mechanism-based, comorbidity-informed approaches. Future research should prioritize the identification of biomarkers and the refinement of patient stratification tools to facilitate precision medicine in migraine and its associated conditions.
Spontaneous intracranial hypotension (SIH) is an underrecognized condition with rapidly evolving diagnostic and therapeutic strategies. This study investigated temporal and regional trends in diagnostic and therapeutic modalities for SIH in the published literature. We systematically reviewed SIH-related clinical studies in PubMed from inception through December 2024. Data on study site (continent/country/institute) and diagnostic and treatment modalities used in clinical settings were extracted. To assess temporal and regional trends, the reported use of each modality was analyzed over 5-year intervals and across regions, separately for case reports and original articles, which respectively reflect real-world and research settings. A total of 789 articles (529 case reports and 260 original articles) were included. In case reports, brain MRI (84.4%), lumbar puncture (84.4%), and RI cisternography (50%) were the most frequently used diagnostics in 1990–1999, while brain MRI (91.1%) and spine MRI (74.8%) became predominant in 2020–2024. The use of lumbar puncture and RI cisternography declined to 24.4% and 5.9%, respectively, while dynamic CT myelography (18.5%) and digital subtraction myelography (23.7%) became more common in 2020–2024. Conservative management (81.3%) was the most common treatment in 1990–1999, while surgical repair increased to 39.8% in 2020–2024. Similar trends were observed in original articles. These temporal trends were similar across regions; however, in 2020–2024, dynamic CT myelography, DSM, and surgical repair were reported more frequently in publications from North America and Europe than in those from Asia (dynamic CT myelography: 35.4% and 22.0% vs. 4.7%; DSM: 40.8% and 33.0% vs. 6.7%; surgical repair: 59.3% and 42.5% vs. 13.6%). Diagnostic and therapeutic modalities for SIH have markedly shifted over time, reflecting the actual changes both in real-world practice and academic settings. Standardized diagnostic and treatment guidelines and broader global awareness of evolving practice are warranted. [Image: see text] The online version contains supplementary material available at 10.1186/s10194-026-02326-x.
Machine learning provides a powerful framework to model the complex patterns underlying migraine attack onset from real-world high dimensional datasets. In this study, we used machine learning to forecast headache days using mobile health (mHealth) data from a migraine biofeedback treatment app. This was a machine learning analysis of data from the BioCer clinical trial (NCT05616741) evaluating app-based biofeedback for preventive treatment of episodic migraine. Participants completed three months of daily biofeedback sessions with wearables measuring trapezius muscle tension, heart rate variability, and peripheral skin temperature. Input data for the models included summary metrics from the biofeedback sessions and daily headache diary entries. The outcome of interest was the presence of a moderate-to-severe headache (defined as an intensity of 4 or higher on an 11-point scale of 0-10) on the next calendar day and the next three calendar days. The dataset was randomly split into training, validation, and test sets. Multiple standard machine learning architectures, foundation models, and time-series models were trained and optimized using the area under the receiver operating characteristics curve (AUC) as the primary scoring metric. Among these three classes of machine learning models, the best optimized model in each class identified during training was applied on the unseen test set. Permutation feature importance (PFI) was created for model explainability. 146 individuals, with a total of 21,550 headache days, were included in the forecasting models. For the next calendar day predictions, the top performing standard machine learning approach (decision tree) and foundation model achieved a test set AUC of 0.59 (95% CI 0.56 to 0.61) and 0.55 (95% CI 0.55 to 0.56), respectively. The best time-series model achieved a test set AUC of 0.84 (95% CI 0.82 to 0.85). For the three-calendar day forecasting window, the test set performances were 0.55 (95% CI 0.53 to 0.56), 0.55 (95% CI 0.54 to 0.57), and 0.76 (95% CI 0.74 to 0.77), respectively. The most important features were headache intensity, duration of the headache, and heart rate scores. Time-series machine learning models using a relatively large dataset could forecast moderate-to-severe headaches with good accuracy in patients with episodic migraine.