The research, published in Frontiers in Neurology, was led by a team at the First Affiliated Hospital of Zhengzhou University in Henan, China. Between April 2020 and December 2023, the investigators consecutively enrolled patients with drug-resistant focal epilepsy (DRFE) who underwent resection surgery of the epileptogenic focus, then followed them for at least one year after the operation. To qualify as drug-resistant under the criteria proposed by the International League Against Epilepsy in 2010, patients must have failed to achieve sustained seizure freedom after adequate trials of at least two appropriately selected and correctly used anti-seizure medications. Of 132 patients initially screened, 103 made it into the final analysis after exclusions for unclear epileptogenic foci, missing data, inability to describe headache reliably, or loss to follow-up. The cohort skewed young, with a median age of 24 years and a median epilepsy duration of nine years, and most patients — 76 of the 103 — had temporal lobe epilepsy.

The headline finding is deceptively simple: headache is extraordinarily common in this population, yet its mere presence does not tip the surgical scales. Among the 103 patients, 46 — 44.7 percent — had comorbid headache. That figure aligns with meta-analyses suggesting that roughly 49 percent of epilepsy patients experience headache, and that the lifetime prevalence of migraine is 52 percent higher in people with epilepsy than in those without. Within the headache group, 22 patients had migraine (21.4 percent of the full cohort), 13 had tension-type headache (12.6 percent), 9 had unclassified headache (8.7 percent), and 2 had both migraine and tension-type headache. When the researchers compared the seizure-free rate within one year after surgery between the headache and non-headache groups, the difference was not statistically significant: 78.3 percent versus 73.7 percent, with a p-value of 0.590. Headache subtypes fared no better as predictors — migraine, tension-type, and unclassified headache groups all showed seizure-free rates in the 78 to 92 percent range, none reaching statistical significance.

But the story deepens when the researchers dissected the temporal relationship between headache and seizures. Using the International Classification of Headache Disorders-3 (ICHD-3) framework, they sorted headaches into peri-ictal and interictal categories, with peri-ictal headaches further divided into preictal, ictal, and postictal phases. Preictal headache was defined as pain starting within 24 hours before a seizure and continuing into it; ictal headache occurs simultaneously with the seizure and eases markedly when it stops; postictal headache begins within 3 hours after a seizure and resolves spontaneously within 72 hours. The distribution was striking: 41 patients (39.8 percent) had peri-ictal headache, dominated overwhelmingly by the postictal type (38 patients, 36.9 percent), while only 4 had preictal headache and just 1 had ictal headache — an extreme rarity consistent with prior EEG-confirmed studies that identified ictal headache in fewer than 1 percent of epilepsy patients. Another 14 patients (13.6 percent) had interictal headache occurring independently of seizures. Notably, 10 patients — 21.7 percent of the headache group — experienced headaches in two or more temporal phases, with the coexistence of postictal and interictal headache accounting for 80 percent of these multi-phase cases. Patients with a family history of headache were significantly more likely to fall into the multi-phase category, hinting at a stronger familial predisposition.

The most eye-catching spatial finding emerged among patients with unilateral headache. Of the 46 patients with comorbid headache, 23 had pain confined to one side of the head — and in 22 of those 23 patients, a remarkable 95.7 percent, the headache side matched the side of the epileptogenic focus. This is not the first time such lateralizing value has been reported. Previous work found that among temporal lobe epilepsy patients with unilateral peri-ictal headache, 90 percent had headache ipsilateral to the focus, and comparable figures of 93.75 percent for temporal and 70 percent for extratemporal epilepsy have been documented. The consistency across studies suggests that unilateral headache is not a random symptom but a spatially anchored signal, one that points directly at the abnormal brain tissue generating the seizures.

Why would the brain produce such a geographically faithful pain signal? The answer lies in two intertwined pathophysiological mechanisms: cortical spreading depression (CSD) and activation of the trigeminovascular system (TVS). CSD is a wave of brief cortical excitation followed by prolonged suppression of neuronal activity. When the abnormal discharges generated by a localized epileptogenic focus trigger CSD, the wave can activate the trigeminovascular system, unleashing a cascade of inflammatory molecules and neurotransmitters that produce the throbbing pain of a migraine attack. Because the threshold for inducing CSD is lower than the threshold required for an outright epileptic seizure, seizures directly triggered by migraine are vanishingly rare, whereas comorbid migraine in epilepsy patients is common — and recurrent seizures in DRFE may themselves facilitate CSD, further raising migraine prevalence. Local vasodilation and reactive hyperemia at the site of the focus may also activate trigeminal sensory fibers, and electrical stimulation of cortical regions such as the anterior cingulate cortex, the entorhinal cortex, and the insula has been shown to evoke headache directly. When CSD spreads from one hemisphere to the other, bilateral headache results — which is precisely why unilateral headache may be the more diagnostically valuable pattern.

That mechanistic logic dovetails with the study’s subgroup analysis, which is where the clinical payoff emerges. Among the 46 patients with comorbid headache, the researchers compared those who were seizure-free within one year after surgery against those who still had seizures. Univariate analysis revealed that unilateral headache was significantly more frequent in the seizure-free group — 58.3 percent versus 20.0 percent, p = 0.032 — and that the mean preoperative visual analogue scale (VAS) score, a 0-to-10 measure of headache intensity, was significantly lower in the seizure-free group: 5.50 ± 2.171 versus 7.60 ± 1.578, p = 0.007. When these variables were entered into a multivariate binary logistic regression, unilateral headache remained independently associated with higher odds of seizure freedom (OR = 1.854, 95% CI 1.112–3.092, p = 0.018), while a higher preoperative VAS score was independently associated with lower odds (OR = 0.136, 95% CI 0.020–0.923, p = 0.041). The interpretation offered by the authors is that unilateral headache may reflect a more localized epileptogenic network — one that surgery can more cleanly excise — whereas intense headache, as indexed by a high VAS score, may signal stronger trigeminovascular activation by CSD, with CSD-induced cerebral ischemia, hypoxia, and energy metabolism disorders contributing to broader brain cell damage and poorer surgical outcomes.

The study also painted a demographic portrait of who develops comorbid headache in DRFE. Compared with the non-headache group, the headache group had a significantly higher proportion of female patients (56.5 percent versus 35.1 percent, p = 0.030), a significantly higher rate of family history of headache (15.2 percent versus 0.0 percent, p = 0.003), and a significantly higher preoperative seizure frequency, with half of the headache group experiencing seizures at least once per week versus 24.6 percent of the non-headache group (p = 0.027). The female predominance is consistent with the generally higher susceptibility to headache in women, possibly linked to hormonal fluctuations during the postpartum period and late luteal phase that affect serotonergic and GABAergic activity. The familial clustering points to shared genetic susceptibility — genes such as CACNA1A, ATP1A2, and SCN1A have been implicated in both conditions — though the study did not find a significant association between family history of epilepsy and comorbid headache. The link with frequent seizures echoes prior findings that patients with recurrent seizures are more likely to develop headache, likely because each seizure can trigger postictal pain through the same CSD-trigeminovascular pathway.

During follow-up, the researchers also tracked what happened to the headaches themselves after surgery. Among the 41 patients with peri-ictal headache who were seizure-free within one year, the peri-ictal headache resolved — a satisfying consequence of removing the seizure generator. Among patients with interictal headache, the picture depended on temporal sequence: when epilepsy onset preceded headache onset, the headache resolved after surgery in most cases, but when headache onset preceded epilepsy onset, the headache showed no significant improvement. This pattern reinforces the idea that seizure-driven headache is surgically curable, while headache with an independent origin may follow its own course regardless of the operation.

The authors are careful to frame these findings within their limits. This was a single-center study with a modest sample size, so selection bias cannot be ruled out and multi-center replication is needed. The one-year follow-up captures only short-term outcomes, and long-term data consistently show that the proportion of patients remaining seizure-free declines over time — among patients seizure-free at the end of the first postoperative year, the annual probability of recurrence is 5.6 percent between years 1 and 5, dropping to 4.2 percent beyond year 5. In pediatric epilepsy surgery, seizure freedom within the first year raises the chance of long-term remission to 87 percent, underscoring why even short-term success matters. The study also did not systematically control for the types and durations of anti-seizure medications patients took preoperatively, and headache classification inevitably depended on patient recall, introducing potential recall bias. Still, the practical message stands: headache itself should not discourage DRFE patients from surgery, but a detailed preoperative inquiry into headache characteristics — laterality and intensity in particular — has genuine guiding value for individualized treatment decisions. In a field where roughly 70 million people worldwide live with epilepsy and comorbid headache is sometimes more disabling than the seizures themselves, teaching clinicians to read the headache as a clinical signal may be one of the quiet advances to emerge from this work.

Subject of Research: The relationship between comorbid headache characteristics and short-term surgical outcomes in drug-resistant focal epilepsy

Article Title: The impact of comorbid headache on surgical outcomes in drug-resistant focal epilepsy

Article References: Cheng, W., Shi, A., Du, M., Ma, Y., Wang, Y., Jiao, H., Geng, J., Lian, Y., Tian, Y., & Lian, X. (2026). The impact of comorbid headache on surgical outcomes in drug-resistant focal epilepsy. Frontiers in Neurology, 17, Article 1964217. https://doi.org/10.3389/fneur.2026.1964217

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1964217

Keywords: epilepsy, headache, migraine, epilepsy surgery, drug-resistant focal epilepsy, cortical spreading depression, trigeminovascular system, neurology, impact, comorbid, surgical, outcomes

Central sensitization describes structural, functional, and neurochemical changes in the central nervous system that heighten sensitivity to pain and other sensory inputs. It is considered a key mechanism in migraine chronification, and the review’s authors, based at Henan University of Traditional Chinese Medicine and affiliated clinical centers, contend that it may similarly drive both the headache and vertigo of vestibular migraine. Microglia serve as the resident immune cells of the brain, while astrocytes, the most abundant glial cells, regulate neurotransmission, inflammation, neurogenesis, and synaptic plasticity. When these two cell types exchange inflammatory signals, the review suggests, they can amplify neuroinflammation and neuronal excitability in ways that promote and maintain sensitization.

The authors are careful to distinguish between loose functional relationships and what they call true crosstalk. In their framework, crosstalk requires experimental evidence that a signal produced or regulated by one cell type influences the molecular or functional response of the other, with both cell types clearly identified. Such evidence may include a temporal or functional association, a ligand–receptor pairing, changes in downstream signaling, or support from pharmacological or genetic manipulation. Bidirectional communication is not required; where evidence supports signaling in only one direction, the direction is stated explicitly. They also caution that simple binary classifications of microglia into M1 and M2 states and astrocytes into A1 and A2 phenotypes are inadequate, since glial responses are shaped by stimulus type and disease stage into dynamic, heterogeneous states.

One of the better-supported signaling routes runs from microglia to astrocytes. In experimental studies, activated microglia release the cytokines IL-1α, TNF-α, and C1q, which induce reactive changes in astrocytes. Microglia-derived TNF-α promotes inflammatory signaling in astrocytes through nuclear translocation of the transcription factor NF-κB. Timing experiments with lipopolysaccharide stimulation show a sequential pattern: pro-inflammatory cytokine expression in microglia peaks two to four hours after stimulation, while cytokine and chemokine induction in astrocytes peaks later, at twelve hours, consistent with microglia detecting stimuli early and shaping the subsequent astrocyte response. In a migraine model induced by dural infusion of inflammatory soup, interleukin-18 was localized mainly in microglia while its receptor was found mainly on astrocytes, and blocking this IL-18 signaling reduced astrocyte reactivity and migraine-like pain hypersensitivity, providing relatively direct cell-specific evidence of microglia-to-astrocyte transmission.

Signaling in the reverse direction is also documented. TNF-α-stimulated astrocytes can express and release the chemokine CCL2, which modulates microglial inflammatory responses through the CCR2 receptor; inhibiting CCR2 attenuates the effect. In a rat model of chronic migraine, increased CCL2 in the trigeminal nucleus caudalis was mainly colocalized with astrocytes, while CCR2 was associated with microglia, and recombinant CCL2 enhanced NLRP3-related inflammatory responses in microglia alongside elevations of the sensitization markers c-Fos and phosphorylated ERK. In a neuropathic pain study, astrocyte-derived CSF1 acted on CSF1R receptors on microglia, promoting microglial responses and brain-derived neurotrophic factor production that increased spinal neuron excitability; blocking this pathway attenuated central sensitization and allodynia. The CXCL12–CXCR4 axis offers a further candidate route from astrocytes to microglia.

Within vestibular migraine models specifically, evidence is emerging but still limited. Animal studies have found significantly increased IL-1β levels in both the vestibular nucleus and the trigeminal nucleus caudalis, along with reactive glial changes in the vestibular nucleus–trigeminal nucleus region. One recent study reported increased expression of the ion channel TRPV2 in microglia of the trigeminal nucleus caudalis in a vestibular migraine mouse model, accompanied by enhanced NLRP3 inflammasome activity and elevated pro-inflammatory mediators; in vitro experiments confirmed functional TRPV2 activity, and its inhibition reduced inflammasome activation, implicating a TRPV2–calcium–NLRP3 signaling axis. Another study in vestibular migraine models found that the CXCL10/CXCR3 pathway, acting through PI3K/AKT signaling, was associated with increased IL-1β, IL-6, and TNF-α in trigeminal-related regions.

The downstream consequences of these glial signals converge on the trigeminovascular system, the network whose activation releases vasoactive neuropeptides such as calcitonin gene-related peptide, promoting vasodilation, sterile inflammation, and pain signal transmission into the central nervous system. In migraine models, reactive microglia and astrocytes appear within the trigeminal nucleus caudalis, and the duration of their reactivity correlates with trigeminovascular sensitization. Microglial P2X4 receptor signaling promotes BDNF release, raising neuronal excitability in the trigeminal nucleus, while inhibition of the microglial NLRP3–IL-1β pathway reduces markers of central sensitization including p-ERK, c-Fos, and CGRP and alleviates hyperalgesia. On the astrocyte side, reduced expression of the glutamate transporter EAAT2 in chronic migraine rats impaired glutamate homeostasis, and upregulating EAAT2 reduced NMDA receptor-related signaling and abnormal synaptic plasticity, suggesting astrocytes tune trigeminal neuron excitability through glutamate clearance.

Glutamate dysregulation emerges as a central theme linking glial crosstalk to symptoms. Reactive microglia can release glutamate directly and can stimulate astrocyte glutamate release via ATP-driven P2Y1 receptor signaling, while microglial reactivity disrupts the astrocyte-dependent glutamate–glutamine cycle that normally clears synaptic glutamate and prevents excitotoxic damage. Microglia can even prune astrocytic processes, reducing their coverage of neurons and promoting activation of extrasynaptic NMDA receptors. Excess glutamate relieves the magnesium block of NMDA receptor channels, allowing calcium influx and intracellular cascades that sustain sensitization. Notably, magnetic resonance measurements in patients during vestibular migraine attacks have found elevated levels of the glutamate–glutamine complex in the bilateral thalamus, hinting that this cycle is disturbed in the human condition, although the review stresses that most mechanistic detail comes from animal work.

The review also sketches an upstream pathway from the body’s periphery. Peripheral inflammation can induce widespread glial and cytokine responses in the central nervous system, with the microglial response preceding the astrocytic one, and inflammatory factors such as TNF-α and IL-1β can disrupt blood–brain barrier tight junctions. In one chronic migraine model, the cytokine IL-17A penetrated the blood–brain barrier into the medulla and activated the trigeminal nucleus caudalis through microglia-mediated neuroinflammation. Separately, migraine-related neuropeptides including CGRP may enter the inner ear through a disrupted blood–labyrinth barrier; animal studies show CGRP injection alters auditory and vestibular evoked potentials and induces behaviors resembling the phonophobia and postural instability of patients, and repeated nitroglycerin treatment raised CGRP and its receptors in cochlear outer hair cells, causing mitochondrial stress, DNA leakage, and cell death that CGRP receptor antagonists reduced. Trigeminal fibers innervate the labyrinthine vasculature, and glutamatergic projections run from the trigeminal nucleus caudalis to the vestibular nucleus, silencing which markedly improves nitroglycerin-induced vestibular dysfunction in rats.

Synthesizing this evidence, the authors propose a pathological sequence for vestibular migraine running from peripheral trigger, through abnormal sensory input or neuroimmune transmission, to glial response, to central sensitization, with glial crosstalk then amplifying neuroinflammation in a bidirectional feedback loop. They acknowledge substantial limitations: most mechanistic insights derive from animal models of migraine, chronic migraine, or pain rather than vestibular migraine itself, direct evidence for microglia–astrocyte crosstalk within the trigeminovascular system remains sparse, and no therapies that explicitly target glial crosstalk have yet been validated. The authors call for human-centered approaches, including neuroimaging, cerebrospinal fluid analysis, single-cell sequencing, and spatial transcriptomics, along with better animal models that reproduce both headache-like behaviors and vestibular dysfunction, before these mechanisms can be translated into biomarkers or treatments for patients.

Subject of Research: Microglia–astrocyte signaling crosstalk in central sensitization of vestibular migraine

Article Title: Research progress on the mechanism of microglia–astrocyte signal crosstalk in central sensitization of vestibular migraine

Article References: Jin, T., Wang, W., Qin, J., Liu, Y., Fan, X., Zhang, D., & Zhang, H. (2026). Research progress on the mechanism of microglia–astrocyte signal crosstalk in central sensitization of vestibular migraine. Frontiers in Neuroscience, 20, Article 1844932. https://doi.org/10.3389/fnins.2026.1844932

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1844932

Keywords: vestibular migraine, microglia, astrocytes, central sensitization, neuroinflammation, trigeminovascular system, glutamate, CGRP, NLRP3 inflammasome, blood-brain barrier, glial crosstalk, trigeminal nucleus caudalis

Calcitonin gene-related peptide, commonly abbreviated CGRP, is a key neurotransmitter in the trigeminovascular system and plays a central role in migraine pathophysiology. Plasma levels of CGRP are elevated during migraine attacks, and the development of CGRP-targeting therapies, including monoclonal antibodies and gepants, has further underscored the peptide’s importance. Despite its established therapeutic relevance, the clinical significance of circulating peripheral CGRP concentrations as a biomarker of migraine activity or treatment response remains uncertain. A recent large-scale registry using a validated high-affinity radioimmunoassay found no significant adjusted differences in plasma CGRP concentrations among individuals with episodic migraine, chronic migraine, and healthy controls. Whether circulating CGRP changes longitudinally following therapeutic interventions, particularly non-pharmacological ones, has remained unclear.

To address this gap, a team of Italian researchers conducted a single-center, prospective, longitudinal pilot study, the first to investigate changes in plasma CGRP levels following acupuncture in patients with episodic migraine. The study, published in Frontiers in Neurology, enrolled 52 patients diagnosed with episodic migraine according to the International Classification of Headache Disorders, third edition, who were referred to the tertiary Headache Center of IRCCS Institute of Neurological Sciences of Bologna. Recruitment took place between March 2021 and May 2024. Participants received a total of 10 sessions of standardized manual acupuncture, administered once weekly over 10 weeks by trained medical acupuncturists, each with at least 10 years of clinical experience, in collaboration with the Bologna Association of Medical Acupuncturists.

The acupuncture intervention followed the STRICTA guidelines for reporting interventions in clinical trials of acupuncture. The core prescription consisted of bilateral LR3, GB34, SP6, LI4, and TE5, together with GV20, with additional points selected individually according to Traditional Chinese Medicine principles based on each patient’s diagnosis and headache localization. Sterile, single-use, disposable stainless-steel needles of varying diameters and lengths were inserted to depths generally ranging from approximately 5 to 35 mm, with superficial or oblique insertion used for cranial and facial points and deeper insertion for limb and muscular points. Manual stimulation combining rotation and lifting-and-thrusting techniques was performed to elicit the characteristic de qi sensation, assessed by the patient’s subjective report of soreness, heaviness, and distension. Needles were retained for approximately 30 minutes per session.

The primary endpoint was the change in plasma CGRP levels before and after the 10-session acupuncture cycle. Venous blood samples were collected at baseline and again one week after treatment completion, always during the interictal period, at the same time of day between 8:00 and 10:00 am, with no participant having taken acute triptans within the 48 hours preceding either sampling. EDTA plasma samples were collected from the antecubital vein, aliquoted, and stored at −80 °C. CGRP plasma concentrations were measured using enzyme-linked immunosorbent assay kits according to the manufacturer’s specifications. Secondary outcomes included changes in migraine frequency, pain intensity, acute medication intake, and migraine-related disability assessed with the Headache Impact Test, a validated six-item questionnaire known as HIT-6.

The results revealed a striking dissociation between the biological marker and the clinical picture. Median plasma CGRP levels were 60.9 pg/ml at baseline and 62.4 pg/ml after treatment, with a Wilcoxon signed-rank test showing no statistically significant difference between the two time points (p = 0.841). The median individual percentage change in CGRP levels from baseline was just 0.28 percent. Moreover, no significant association was identified between CGRP concentrations and the time elapsed since the most recent migraine attack at either baseline or follow-up. In other words, the peptide widely regarded as central to migraine biology remained essentially flat throughout the study period, even as patients reported meaningful improvements across every clinical outcome measured.

Those clinical improvements were substantial and statistically robust. Median migraine frequency decreased by 1.5 days per month, from 8 days at baseline to 7 days after treatment (p < 0.001). Median headache intensity on a 10-point numerical rating scale fell by one point, from 7 to 6.2 (p < 0.001). Median monthly acute medication use dropped by 2 units, from 10 to 7 (p < 0.001), representing a 16.7 percent reduction. HIT-6 scores, which quantify headache-related disability, decreased by a median of 6 points, from 65 to 60 (p < 0.001), a relative reduction of 8.7 percent. Only mild, transient side effects, namely needle stick pain, were reported by five individuals, and no serious adverse events occurred.

The dissociation between unchanged CGRP levels and significant clinical gains raises important questions about how acupuncture might exert its effects in migraine. The authors suggest that acupuncture may act through alternative mechanisms, such as modulation of pain processing pathways, autonomic nervous system regulation, and neuroimmune interactions. Changes in serotonin levels following acupuncture have been reported both in migraine and in other pain conditions, pointing to serotonergic pathway modulation as a potential mechanism. It is also possible that peripheral plasma CGRP concentrations simply do not reliably reflect the central neurochemical changes where acupuncture is more likely to act. Methodological factors may have contributed as well, including the substantial heterogeneity among commercially available CGRP assay kits, the absence of standardized measurement guidelines, and the biological variability of CGRP, which fluctuates with migraine phase, medication use, and time since the last attack. Blood samples in this study were collected a mean of 2.5 days after the last attack at baseline and 3.5 days at follow-up, intervals that may have introduced variability.

The study has notable strengths, including stringent inclusion criteria that yielded a relatively homogeneous patient sample, the combination of clinical assessments with a biological marker within the same cohort, and the standardized, STRICTA-compliant acupuncture protocol delivered by experienced practitioners. However, the single-arm design represents a major limitation. Without a control group, the observed improvements cannot be specifically attributed to acupuncture, as placebo and nonspecific effects, regression to the mean, and natural fluctuations in migraine symptoms cannot be excluded. The relatively small sample size of 52 patients may also have limited the statistical power to detect subtle changes in CGRP levels. The authors emphasize that the findings should be considered exploratory and hypothesis-generating rather than evidence of clinical effectiveness, and they call for controlled trials, ideally including a sham-acupuncture comparator and standardized methods for blood sampling and CGRP measurement.

Despite these caveats, the study delivers a provocative message for the migraine field: peripheral plasma CGRP may not be a straightforward biomarker of the clinical changes observed following acupuncture. As the role of CGRP as a therapeutic target continues to expand with monoclonal antibodies and gepants, understanding which patients respond to which treatments, and why, remains a central challenge. This pilot investigation, the first of its kind to track plasma CGRP longitudinally after acupuncture in episodic migraine, suggests that the peptide’s story in migraine biology is more nuanced than a simple blood test can capture. Future studies could assess CGRP in plasma alongside other biological fluids such as saliva or tears, explore the potential role of electroacupuncture, and investigate whether specific subgroups of patients respond differently. For now, the clinical improvements observed in this cohort, whatever their precise mechanism, offer a reminder that meaningful patient benefit and measurable biomarker change do not always travel together.

Subject of Research: Changes in plasma CGRP levels and clinical outcomes following acupuncture in episodic migraine

Article Title: Changes in plasma CGRP levels and clinical outcomes following acupuncture in episodic migraine: a prospective pilot study (the AcuCGRP study)

Article References: Favoni, V., Giusti, L., Bartiromo, F., Poini, A., Calabrò, C., Merli, E., Polischi, B., Baccari, F., Zenesini, C., Mascarella, D., Pierangeli, G., Giovanardi, C. M., & Cevoli, S. (2026). Changes in plasma CGRP levels and clinical outcomes following acupuncture in episodic migraine: a prospective pilot study (the AcuCGRP study). Frontiers in Neurology, 17, Article 1946490. https://doi.org/10.3389/fneur.2026.1946490

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1946490

Keywords: acupuncture, CGRP, episodic migraine, biomarker, migraine prophylaxis, HIT-6, pilot study, trigeminovascular system, non-pharmacological treatment, Frontiers in Neurology, Changes, plasma

The research team, based at Ludwig-Maximilians-University Munich, took their laboratory into the field, following healthy volunteers on a five-day expedition through the Italian Alps in August 2022. Rather than simulating altitude in a hypoxic chamber, the investigators measured participants under genuine expedition conditions, ascending from the valley town of Varallo at 450 meters to the Capanna Regina Margherita at 4554 meters, one of the highest permanently staffed buildings in Europe. At each stage of the climb, participants completed structured headache questionnaires, rated their pain on a numerical scale from zero to ten, filled in the 2018 Lake Louise Acute Mountain Sickness Score, and provided samples of tear fluid for neuropeptide analysis. Certified mountain guides from the International Federation of Mountain Guides Association accompanied every group, and the protocol was approved by the university ethics committee.

The choice of tear fluid as the sampling medium is one of the study’s most intriguing technical features. Collecting blood at 4554 meters is cumbersome, and obtaining cerebrospinal fluid is out of the question in a field setting. Tear fluid, by contrast, can be aspirated from the lateral corner of each eye with a thin plastic capillary in under a minute, provided the investigator avoids irritating the ocular surface and triggering reflex tearing, which would dilute the sample. The researchers collected fluid from both eyes, pooled it after confirming no significant left-right differences at baseline, stabilized it in protein extraction reagent, kept it on dry ice, and later quantified CGRP concentrations with a commercial enzyme-linked immunosorbent assay read in duplicate on a spectrometer. The approach offers a noninvasive window into a neuropeptide that is otherwise difficult to track outside a hospital laboratory.

CGRP itself is a potent vasodilatory neuropeptide released from the endings of the trigeminovascular system, the network of sensory nerves that innervates the blood vessels of the brain’s protective membranes. Decades of work have established it as a central player in migraine: levels rise during spontaneous attacks, injecting CGRP can provoke migraine-like headaches in susceptible patients, and drugs that block the molecule or its receptor have transformed migraine prevention in recent years. Because high-altitude headache shares clinical features with migraine, including aggravation by physical activity, and because a history of migraine is a known risk factor for altitude headache, the Munich team hypothesized that hypobaric hypoxia might activate the same trigeminovascular pathway and drive CGRP release at altitude.

The expedition data gave that hypothesis substantial support. Of the 24 originally recruited participants, 13 completed the full protocol with usable tear samples, a reduction the authors attribute to early terminations and insufficient fluid volumes. Among these 13, headache burden climbed steadily with altitude. No one reported headache at baseline in the valley, but 46 percent did so after reaching 3498 meters on day two, 62 percent at 3647 meters on day three, and a striking 85 percent at 4554 meters on day four, when the mean pain score reached 3.2 on the ten-point scale. Eight participants, or 62 percent, fulfilled the formal ICHD-3 criteria for high-altitude headache at the highest hut, a figure consistent with the 36 to 73 percent incidence reported in earlier studies at comparable elevations.

The CGRP measurements revealed a pattern that was invisible in the group average. Across all participants, tear fluid CGRP levels at 4554 meters were not significantly different from baseline values, a result that on its own might have suggested the neuropeptide was irrelevant. But when the researchers split the cohort by symptom severity, a clear signal emerged. The six participants who developed moderate-to-severe headaches, with mean pain scores of 5.0, showed a substantial rise in tear fluid CGRP, averaging an increase of 1.86 nanograms per milliliter from baseline, while the seven participants with only mild headaches actually showed a slight decrease of 0.19 nanograms per milliliter. The difference between the groups was statistically significant, and baseline CGRP levels had been virtually identical, indicating that the elevation was triggered by the altitude exposure itself rather than reflecting a pre-existing trait.

The same dissociation appeared when participants were classified by diagnosis. Those meeting ICHD-3 criteria for high-altitude headache showed a mean CGRP increase of 1.49 nanograms per milliliter, compared with a decrease of 0.42 in those without the diagnosis. Even more striking, six participants, nearly half the cohort, developed a headache that met criteria for migraine without aura, complete with moderate-to-severe pulsating pain, nausea or vomiting in half of cases, and photophobia in some. These migraine-like sufferers reported higher pain intensity and a significantly larger CGRP rise of 1.75 nanograms per milliliter than their symptom-free counterparts. Notably, oxygen saturation, which hovered around 78 percent at the highest altitude for everyone, did not differ between headache and non-headache groups, suggesting that the degree of hypoxia alone did not determine who suffered.

The cerebral circulation told a quieter story. Using transcranial color-coded duplex sonography at baseline and at 4554 meters, the team measured blood flow velocity in the middle cerebral arteries on both sides, calculating mean flow velocities and the Lindegaard index to screen for vasospasm. Neither the presence of high-altitude headache nor of migraine-like symptoms was associated with differences in flow velocity or in the change from baseline, and there was no evidence of vasospasm in any group. This absence of a vascular signature is itself informative: it shifts attention away from simple blood-vessel constriction or dilation as the cause of altitude pain and toward neurogenic inflammation, the process by which activated trigeminal nerves release CGRP and other mediators directly around meningeal vessels.

Disentangling the two candidate triggers of that activation, hypoxia and reduced barometric pressure, remains difficult in a field design, and the authors are careful on this point. Animal experiments have shown that lowering atmospheric pressure by as little as 40 hectopascals increases firing in neurons of the spinal trigeminal nucleus, particularly those with corneal afferents, and human volunteers exposed to modest pressure drops in a climate chamber have reported head compression and mild-to-moderate headache. Meanwhile, chamber studies of pure normobaric hypoxia have induced headache in roughly 80 percent of healthy volunteers and elevated plasma CGRP in migraine patients. Because tear fluid CGRP did not rise uniformly across the expedition and did not track oxygen saturation, the new data hint that hypoxia by itself may be insufficient, and that the interplay of low pressure and low oxygen, possibly amplified in susceptible individuals, is what ignites the trigeminovascular system.

The study’s limitations are real and acknowledged by its authors. Thirteen completers is a small sample, nearly half the original cohort was excluded, tear fluid CGRP has not been formally validated against plasma or cerebrospinal fluid concentrations, and an observational design cannot establish whether the neuropeptide rise precedes the pain or merely accompanies it. Even so, the implications are tantalizing. If CGRP release genuinely drives altitude headache, then the CGRP-targeted monoclonal antibodies and small-molecule antagonists that have revolutionized migraine care might, in principle, be repurposed as prophylaxis for mountaineers, an idea the authors say deserves interventional study. And if tear fluid proves to be a reliable surrogate medium, field researchers could gain a practical, needle-free biomarker for headache severity in some of the most remote environments on Earth, from Himalayan base camps to aerospace settings, where the biology of low pressure and low oxygen has long outpaced our ability to measure it.

Subject of Research: The role of the neuropeptide CGRP in high-altitude headache and migraine-like headache during hypobaric hypoxia

Article Title: The Role of Calcitonin Gene‐Related Peptide in High‐Altitude Headache: A Prospective Field Study

Article References: Schniepp, R., Karrasch, L., Breitenstein, H., Straube, A., & Kamm, K. (2026). The Role of Calcitonin Gene‐Related Peptide in High‐Altitude Headache: A Prospective Field Study. Annals of Clinical and Translational Neurology, 13(10), 2046-2056. https://doi.org/10.1002/acn3.70374

Image Credits: AI Generated

DOI: 10.1002/acn3.70374

Keywords: high-altitude headache, CGRP, migraine, hypobaric hypoxia, trigeminovascular system, tear fluid biomarker, acute mountain sickness, transcranial duplex sonography, neuropeptides, Alps expedition, headache disorders, neurology