Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure and disabling headaches, yet its underlying mechanisms remain poorly defined. Calcitonin gene-related peptide (CGRP) is a key neuropeptide implicated in migraine and headache attributed to IIH. CGRP-driven neuroinflammation is implicated in migraine generation but whether CGRP-provoked headache in IIH is accompanied by dynamic neuroimmune activation during the ictal phase remains unknown. We aimed to characterise cytokine alterations during experimentally-induced IIH headache attacks provoked by CGRP. In a randomised, double-blind, placebo-controlled, two-way crossover study (IIH Provoke: ISRCTN13251508), 16 women with IIH underwent two inpatient visits receiving intravenous CGRP (1.5 µg/min for 20 min) or placebo (isotonic saline). Blood samples were collected at baseline and either at peak headache or at the end of the visit, if no headache occurred. Plasma cytokines were measured using the Olink® Target 48 Cytokine Panel. CGRP induced a typical IIH headache attack within the sampling period in 7/16 participants. Compared with baseline, eight cytokines were significantly elevated during CGRP-provoked headache attacks: C-C motif chemokine 4 (CCL4), CCL8, interleukin-6 (IL-6), IL-17C, IL-27, oncostatin M (OSM), hepatocyte growth factor (HGF), and transforming growth factor-α (TGF-α) (P < 0.05). These changes were not observed after placebo or in participants who received CGRP without developing headache. CGRP-provoked IIH headache attacks were associated with elevations in pro-nociceptive mediators (IL-6, CCL4, OSM) and immune-related cytokines (IL-17C, IL-27, HGF, TGF-α). These findings suggest that CGRP-provoked headache in IIH is associated with changes in circulating cytokines consistent with a neuroimmune response during the ictal phase. Larger cohorts are required to validate these observations and explore neuroinflammation as a therapeutic target in IIH headache.

BACKGROUND AND OBJECTIVES:Idiopathic intracranial hypertension (IIH) is characterized by raised intracranial pressure (ICP). It predominantly affects women with obesity and can cause disabling headaches and permanent visual loss. IIH is misdiagnosed in up to 40% of cases. Diagnosis and monitoring often rely on frequent invasive lumbar puncture. This pilot study aimed to identify serum microRNA (miRNA) markers associated with a diagnosis of IIH and disease activity and to assess their relevance in the CNS through identification in CSF. METHODS:Serum and CSF samples from participants in the IIH-Weight Trial (a randomized controlled trial comparing the effectiveness of bariatric surgery with that of a community weight management intervention in lowering ICP, recruited 2014-2017) were analyzed at baseline (active disease) and 12 months (participants in remission with no papilledema). Eligible participants were adult women with active IIH (those without papilledema were excluded). Disease activity was assessed by quantifying the degree of papilledema using Spectralis spectral-domain optical coherence tomography. A panel of 40 candidate miRNAs was assessed. Comparator groups included participants with obesity or migraine. Analyses used Student t tests and one-way ANOVA followed by Tukey multiple comparisons test. Differentially expressed miRNAs were evaluated in relation to clinical disease activity and metabolic profiles, using linear regression analysis. RESULTS:Five of 40 serum miRNAs showed significantly lower expression in active IIH (n = 9; 100% female, mean 30.25 ± 4.75 years) compared with IIH in remission. Serum hsa-miR-16-5p had the highest diagnostic performance for active IIH (area under the curve 0.951). Serum hsa-miR-16-5p (p < 0.0001; CI -7.286 to -2.503) and hsa-miR-7-5p (p = 0.0032; CI -7.240 to -1.372) were significantly lower in active IIH compared with obesity controls (n = 9; 100% female, mean 38.22 ± 7.99 years). Serum hsa-miR-7a-5p were significantly higher in active IIH compared with migraine (n = 12; 100% female, mean 44.67 ± 8.88 years). Only hsa-miR-16-5p differentiated active IIH from both participants with migraine and obesity. hsa-miR-16-5p also differentiated active IIH from IIH remission in CSF (p = 0.0354; CI -3.062 to -0.1282). Serum and CSF hsa-miR-16-5p correlated significantly with ICP (serum p < 0.0001; CI -0.1660 to -0.0732; CSF p = 0.046; CI 0.0018-0.1841), papilledema (serum p = 0.0236; CI -0.01548 to -0.0001; CSF p = 0.0241; CI 0.002-0.033). hsa-miR-16-5p was associated with metabolites involved in fatty acid metabolism and lipid biosynthesis. DISCUSSION:Serum hsa-miR-16-5p emerged as a candidate biomarker associated with active IIH. It differentiated active disease from remission, migraine, and obesity. It correlated with clinical and metabolic markers of disease activity. These findings warrant validation in larger studies to assess its potential as a minimally invasive biomarker for IIH diagnosis and monitoring. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that serum microRNA markers may potentially distinguish active idiopathic intracranial hypertension from remission and controls in adult women.

Spaceflight-associated neuro-ocular syndrome (SANS) is a disorder primarily characterised by changes in the eye and optic nerve, but changes in brain features are also noted after spaceflight. SANS is caused by exposure to prolonged microgravity and at least one feature of SANS has been reported in 81% of National Aeronautics and Space Administration (NASA) astronauts. Early clinical features of SANS are observed in almost all individuals undergoing spaceflight, with the condition exacerbated by the duration of spaceflight. Knowledge of the features of SANS and the aetiology has rapidly grown since its first description in 2011. As international space agencies plan exploration beyond low Earth orbit and with the expansion of the commercial space sector, a publicly available consensus guide on diagnosis and potential management would be instructive to flight surgeons who manage SANS. Harmonising case identification will not only enhance clinical management but is also vital to set a framework for research into SANS. Here we collate and interpret the up-to-date phenotyping and clinical insight in SANS, with expertise from the leading SANS experts at NASA. A consensus on diagnosis and management with countermeasures is detailed. Space exploration is a rapidly evolving field and consequently, insights into SANS will undoubtedly grow and allow us to further refine our understanding of this condition.

Large multi-site, multi-vendor MRI studies offer opportunities to advance clinical practice and neuroscience research by increasing sample sizes, especially in clinical populations. However, variability between scanners or sites can affect the reproducibility of quantitative MRI metrics, which is vital for using MRI beyond visual inspection of structural images. This study aimed to assess the reproducibility of MRI metrics for the mild traumatic brain injury-Predict (mTBI-Predict) consortium, spanning Philips and Siemens scanners across three sites. We conducted a travelling head study (n=1), acquiring repeated measurements from a healthy participant across three sites. Evaluated metrics included cortical thickness and subcortical volume from T1-weighted images, fractional anisotropy (FA) and mean diffusivity (MD) from diffusion-weighted imaging (DWI), temporal signal-to-noise ratio (tSNR) from echo planar imaging, and cerebral blood flow (CBF) from arterial spin labelling (ASL). Image quality metrics (point spread function and motion) were also assessed across all DWI, functional magnetic resonance imaging (fMRI), and pseudo-continuous arterial spin labelling (pCASL) data. Standardised pipelines were used for preprocessing and analysis. Within-subject coefficients of variation (wCV%) and linear regressions assessed repeatability and consistency. Structural measures, including cortical thickness, subcortical volume, FA, and MD, demonstrated excellent reproducibility (wCV ≤5%, R² ≥0.85) within and between-sites. Minimal differences in participant motion were observed across sessions. However, as expected, tSNR and CBF showed greater variability than structural measures, due to their functional nature. Despite this, wCV% remained below 10% for all metrics, a threshold indicating very good agreement for biological measures. These findings align with previous work, demonstrating the feasibility of obtaining comparable MRI measurements across sites for studying brain structure and function. This study lays the groundwork for further evaluation of clinically relevant MRI biomarkers for mTBI.

This opinion piece discusses the challenges of managing a person with sight-threatening papilloedema due to idiopathic intracranial hypertension (IIH). With no available randomised controlled trials, clinicians often choose locally available surgical intervention. An increasing number of studies have advocated using dural venous sinus stenting in IIH. Big data studies show that shunts have been the mainstay of surgical treatment for IIH, and recent evidence shows improved outcomes and fewer revision surgeries. There remains genuine equipoise in the choice of intervention between shunting and dural venous stenting in IIH. The IIH Intervention Trial funded by the National Institute of Health Research is underway in the UK, the first randomised control trial to evaluate both of these surgical interventions in people with sight-threatening IIH.

This is a consensus guidance document developed by the British Association for the Study of Headache (BASH), of practical recommendations in the use of advanced migraine treatments based on the current literature, guidelines, real-world experience and opinion from an expert consensus group. The target audience for this statement includes all clinical and allied healthcare professionals interested in headache. The introduction of calcitonin gene-related peptide-targeted migraine treatments in addition to botulinum toxin has widened the choice of migraine treatment options. However, there is a lack of consistency in the use and treatment of accessibility across the UK. We have developed a multidisciplinary consensus clinical guidance that makes recommendations on how to use advanced preventative treatments for migraine. The BASH consensus group was composed of consultants, nurses and general practitioners with specialist's experience in headache. Key clinical questions were agreed by consensus. Each recommendation was based on a selective search of evidence, including meta-analyses, systematic reviews and considered relevant national standards of care. A modified Delphi process was used to obtain consensus on the recommendations via an anonymous voting process by the Consensus Group and BASH Council members. Those not reaching the minimum required consensus level (≥75%) were amended until agreement was reached or were designated as lacking consensus. Expert practical recommendations on advanced migraine treatments covering common dilemmas are presented. These recommendations aim to optimise patient access and experience of advanced migraine treatments. This document will need to be revised periodically as new evidence emerges.

Calcitonin gene-related peptide (CGRP) is a key mediator in migraine pathophysiology. Idiopathic intracranial hypertension (IIH) headache phenotype is now understood to be typically migraine-like, but it is unclear whether CGRP directly provokes IIH headaches or alters intracranial pressure (ICP) dynamics. We conducted a randomized, double-blind, placebo-controlled, two-way crossover trial to address this. Twenty women with IIH and no prior migraine were randomly assigned to receive a 20-min continuous intravenous infusion of CGRP (1.5 μg/min) or placebo (isotonic saline). The primary outcome was the difference in the proportion of participants who developed a provoked headache attack between CGRP and placebo during the 12 h observation after infusion. Secondary outcomes included the area under the curve (AUC) for headache intensity from -10 min to 12 h, the timing and duration of headache features, and baseline-adjusted changes for vital signs, cerebrovascular haemodynamics and ICP. Seventeen participants with mean age (standard deviation) 26.7 (6.4) years completed both visits. Twelve (71%) participants developed a typical IIH headache attack with migraine-like features after CGRP compared with three (18%) after placebo (risk difference 53%; 95% confidence interval, 26-79; P = 0.004). The AUC-10min-12h for headache intensity was higher after CGRP than after placebo (P = 0.016). The mean ICP remained unchanged, whereas ICP amplitude increased significantly after CGRP (P = 0.005). Vital signs and cerebrovascular haemodynamics AUC-10min-90min were significantly altered after CGRP [increased: heart rate (P < 0.001), tissue oxygenation index (P = 0.041), and oxygenated haemoglobin (P < 0.001); decreased: mean arterial pressure (P = 0.010) and middle cerebral artery blood velocity (P = 0.006)]. CGRP reliably provoked typical IIH headache attacks (which have migraine-like features) and increased ICP pulse amplitude, as a measure of intracranial compliance, without altering mean pressure. These findings provide mechanistic support for CGRP involvement in headache attributed to IIH and justify prospective evaluation of CGRP pathway blockade in this population.

Spreading depolarization is a wave of neuronal and glial depolarization that propagates through brain tissue, triggering neuropeptide release and altered blood flow. It has been observed in ischemic stroke, traumatic brain injury, subarachnoid haemorrhage, epilepsy, and migraine aura. Spreading depolarization imposes a high energetic demand, and recovery impaired under metabolic substrate deficiency. Despite its clinical relevance, metabolic responses remain poorly understood, limiting therapeutic progress. We investigated metabolic effects of spreading depolarisation using an ex vivo brain slice model, aiming to characterise changes in intracellular calcium signalling, mitochondrial function, and central carbon metabolism, and to assess the impact of glucose deprivation. We further tested whether coenzyme Q10 could improve recovery under metabolically compromised conditions. Spreading depolarization increased mitochondrial activity and shifted metabolism toward anaerobic respiration and glycolysis. Glucose deprivation impaired recovery, inducing mitochondrial dysfunction and accumulation intermediates indicative of tricarboxylic acid cycle stalling and disrupted central carbon metabolism. Supplementing glucose-deprived brain slices with coenzyme Q10 shortened spreading depolarization repolarization duration, indicating enhanced metabolic recovery. These findings demonstrate that spreading depolarization imposes a significant metabolic burden, particularly under glucose limitation, and that mitochondrial-targeted interventions such as coenzyme Q10 may enhance tissue resilience in neurological disorders.

Spreading depolarization (SD) is a wave of neuronal and glial depolarization observed in various neurological conditions, including stroke, traumatic brain injury, subarachnoid haemorrhage, and migraine aura. This depolarization disrupts ion homeostasis, creating high energy demand for recovery. While healthy tissue can compensate, pathological tissue may develop ischemia, worsening brain injury and outcomes. Identifying inflammatory mediators that exacerbate neuroinflammation after SD could guide targeted therapies. This review aimed to explore both the neuroinflammatory effects of SD and the impact of experimentally induced inflammatory states on SD characteristics. PubMed and Scopus were systematically searched for preclinical studies that examined the effects of SD on inflammation, and the effects of an inflammatory state on SD responses. Data extracted included authors, publication details, study type, animal characteristics, group sizes, exclusions, relevant findings, and limitations. Additional details were collected for studies on SD and neuroinflammation, including induction methods, inflammatory markers and SD characteristics in altered inflammatory states. Several studies indicated that SD triggered a robust neuroinflammatory response, marked by upregulation of cytokines—interleukin-1β, tumour necrosis factor-α, and interleukin-6—alongside transcription factors such as nuclear factor kappa B, and activation of astrocytes and microglia. Key mediators including toll-like receptors, cyclooxygenase-2 and high mobility group box 1 were also implicated, with evidence of neurogenic involvement via the release of calcitonin gene-related peptide. Differences in inflammatory responses were identified between single and multiple SD induction. Studies measuring the effect of altered inflammatory states on SD propagation were limited. Models of peripheral inflammation and non-demyelinating autoimmune encephalomyelitis did not lead to significant alterations in SD characteristics. However, administration of tumour necrosis factor was able to reduce SD amplitude, suggesting a possible neuroprotective effect. This review suggests potential mechanisms underlying the role of SD in neurological disorders. While SD is associated with inflammatory markers, evidence for the impact of heightened inflammatory states on cortical susceptibility to SD remains limited. Significant methodological variability and inflammatory disease models underscores the need for standardization to validate these findings. Further research into these mechanisms could identify novel therapeutic targets to mitigate SD-related neuroinflammation in neurological disorders.

This opinion paper on the acute treatment of migraine addresses the definition and recognition of acute migraine attacks, highlighting the variety of symptoms and manifestations. It describes the available treatments and guidelines, noting significant country-specific variations. The paper also discusses the prescribers’ knowledge and updates, recognizing the segment-specific differences. Despite nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans being universally recommended as first-line treatments, their visibility in the field has diminished due to the promotion of newer medicines. The authors, a panel of 15 experts from six European countries, emphasize the underutilization of triptans and advocate for their prescription, and also their use in combination with NSAIDs, when NSAIDs alone are not sufficiently effective. The panel specifically considered the sumatriptan succinate–naproxen sodium combination, which was recently introduced in Europe and may be beneficial in patients not responding to NSAIDs, particularly for special patient groups, such as those with menstrual-related acute migraine or migraine attacks with prolonged pain or postdrome. Finally, the consensus highlights the need for individualized treatment plans and the importance of considering patient preferences and specific symptoms, integrating evidence-based recommendations with patient-centered care to optimize migraine management.

OBJECTIVE:To gain initial insight into the efficacy to lower intracranial pressure (ICP), side effects, and effects on cognition of five drugs commonly used to treat idiopathic intracranial hypertension (IIH). BACKGROUND:Limited clinical data exist for the treatment for IIH. Impaired cognition is recognized in IIH and can be exacerbated by medications. METHODS:This human experimental medicine study was a secondary analysis that focused on an unblinded randomized, sequential, cross-over extension of a previously completed randomized controlled trial. This study evaluated females with active IIH, recruited from University Hospital Birmingham, UK. Participants were treated, in randomized order, for 2 weeks with acetazolamide, amiloride, furosemide, spironolactone, and topiramate; assessment was at baseline and 2 weeks with a minimum 1-week drug washout between drugs. The primary outcome was change in ICP at 2 weeks post-drug administration. The cognitive evaluation was an exploratory study of the trial. ICP was recorded with telemetric, intraparenchymal ICP monitors (Raumedic, Hembrechts, Germany). Adverse events were recorded, and cognition was assessed utilizing the National Institutes of Health Toolbox Cognitive Battery. RESULTS:Fourteen participants were recruited and evaluated by intention-to-treat analysis. Mean (standard deviation) body mass index was 37.3 (7.0) kg/m2 and ICP was 33.2 (7.1) cm cerebrospinal fluid (CSF) at baseline. ICP fell with four drugs (mean [standard error (SE)]), acetazolamide -3.3 (1.0) mmHg, p = 0.001, furosemide -3.0 (0.9) mmHg, p = 0.001, spironolactone -2.7 (0.9) mmHg, p = 0.003, and topiramate -2.3 (0.9) mmHg, p = 0.010. There was no significant difference between drugs. Side effects were common with acetazolamide (100%, 11/11) and topiramate (93%, 13/14). Baseline cognitive performance was impaired, T-score (mean [SE]) 37.2 (2.6). After treatment, there was a further significant reduction in the fluid cognition domain (ability to process and integrate) with acetazolamide (mean T-score [SE]), -5.0 (2.6), p = 0.057 and topiramate -4.1 (2.0), p = 0.061. CONCLUSIONS:Acetazolamide, furosemide, spironolactone, and topiramate marginally reduced ICP. While their effects were not significant, this study was not powered to detect a difference between drugs. Participants reported significant side effects with acetazolamide and topiramate including cognitive decline. Cognitive measures were impaired by acetazolamide and topiramate. Therapeutics with greater efficacy and a favorable side effect profile are an unmet need in the treatment of IIH.

Spaceflight-Associated Neuro-Ocular Syndrome (SANS) affects astronaut vision, causing refraction and acuity changes during and after long-duration missions. As space agencies plan for extended exploration, real-time SANS detection is crucial. A systematic review of PubMed and EMBASE yielded 72 relevant studies out of 196 screened. Current measurement techniques, including invasive and noninvasive intracranial pressure (ICP) assessments and novel technologies, have limitations in quantifying SANS changes and lack remote monitoring capability. Emerging tools such as telemetric ICP monitoring, optical coherence tomography (OCT), and ultrasound show promise but require further validation. Given the constraints of invasive techniques in space, non-invasive technologies should be tested in terrestrial analogs before spaceflight implementation. The precise SANS etiology will determine optimal monitoring approaches, whether ICP-focused, ocular-based, or a combination of both. No single technology can independently track SANS progression, emphasizing the need for multiparametric integration and post hoc analysis to enhance in-flight monitoring and mitigation strategies.

BACKGROUND:There is substantial evidence linking migraines to gastrointestinal (GI) issues. Conditions such as irritable bowel syndrome and colitis often co-occur with migraines and GI symptoms are common among migraine patients. However, the evidence supporting the efficacy of gut microbiome-targeted therapies for managing migraines is limited. This systematic review aimed to describe the existing evidence of the gut microbiome in patients with migraine compared to healthy individuals. Additionally, it sought to examine how therapies targeting the gut microbiome including prebiotics, probiotics and synbiotics, might influence clinical outcomes. METHODS:We performed searches on Embase, PubMed, and the Cochrane Library to identify studies in migraines and the gut microbiome, focusing on those which investigated the gut microbiome composition and gut microbiome-targeted therapies. Key data was extracted and analysed including study details, patient demographics, migraine type, comorbidities, and clinical outcomes. For gut microbiome composition studies, bacterial diversity and abundance was noted. For gut microbiome-targeted therapies studies, treatment types, dosages, and patient outcomes was recorded. RESULTS:A significant difference between various genera of microbes was reported between migraine patients and controls in several studies. Bacteroidetes (also named Bacteroidota), proteobacteria, and firmicutes (also named Bacillota) phyla groups were found significantly abundant in migraine, while studies were conflicted in the abundance of Actinobacteria and Clostridia with regards to increased migraine risk in migraine patients. Patients with migraine had a gut microbiome with reduced species number and relative abundance, as well as a distinct bacterial composition compared to controls. Synbiotic and synbiotic/probiotic combination treatments have been shown in five randomised controlled trials and one open label pilot study to significantly decrease migraine severity, frequency, duration and painkiller consumption. CONCLUSIONS:The significant alterations in microbial phyla observed in migraine patients suggest a potential microbial signature that may be associated with migraine risk or chronic progression. However, the mechanistic underpinnings of these associations remain unclear. This systemic review found that probiotic and synbiotic/probiotic combination therapies may be promising interventions for migraine management, offering significant reductions in migraine frequency and painkiller use. Future randomised controlled studies are needed to evaluate the optimal length of treatment and impact on patient related quality of life.

Introduction Mild traumatic brain injury (TBI) affects a significant number of military personnel, primarily because of physical impact, vehicle incidents, and blast exposure. Post-traumatic headache (PTH) is the most common symptom reported following mild TBI and can persist for several years. However, the current International Classification of Headache Disorders lacks phenotypic characterization for this specific headache disorder. It is important to appropriately classify the headache sub-phenotypes as it may enable more targeted management approaches. This systematic review seeks to identify the most common sub-phenotype of headaches in military personnel with PTH attributed to mild TBI.Methods We conducted a systematic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines, focusing on the military population. PubMed, Web of Science, Cochrane, and Clinicaltrials.gov databases were searched. Abstracts and full texts were independently reviewed by two authors using predefined inclusion and exclusion criteria. Data extraction was performed using a standardized form. The risk of bias was assessed using the Newcastle-Ottawa Scale.Results Eight papers related to the military population were included in this review. Migraine was the most commonly reported headache sub-phenotype, with a prevalence ranging from 33 to 92%. Additionally, one military study identified tension-type headaches as the most prevalent headache phenotype. Although not the primary phenotype, one military cohort reported that approximately one-third of their cohort experienced trigeminal autonomic cephalalgias, which were associated with exposure to blast injuries and prior concussions.Conclusion This systematic review demonstrated that PTH in the military population frequently exhibit migraine-like features. Tension-type headache and trigeminal autonomic cephalalgias also occur, although less commonly reported. Sub-phenotyping PTH may be important for initiating effective treatment since different phenotypes may respond differently to medications. The study populations analyzed in this systematic review display heterogeneity, underscoring the necessity for additional research features, more stringent criteria and comprehensive recording of baseline characteristics. Characterizing headaches following injury is crucial for an accurate diagnosis to enable effective management and rehabilitation planning for our armed forces.

Raised intracranial pressure (ICP) is associated with altered cerebral haemodynamics and cephalic pain. The relationship between the algetic response and cortical neurovascular changes in raised ICP is unclear. This study aimed to evaluate this relationship and determine whether lowering ICP (using a glucagon-like peptide-1 receptor agonist) could ameliorate the algetic response. We also sought to explore the role of calcitonin gene-related peptide in cephalic pain driven by raised ICP by inhibiting calcitonin gene-related peptide signalling and quantifying changes in the algetic response. In a rat model of raised ICP, created by intracisternal kaolin injection, mechanical thresholds were measured alongside steady-state potential and cerebral blood flow responses to spreading depolarization. Nuclear magnetic resonance spectroscopy evaluated energetic substrates in animals with raised ICP ex vivo. The glucagon-like peptide-1 receptor (GLP-1R) agonist exenatide and the calcitonin gene-related peptide receptor (CGRP-R) antagonist olcegepant were injected daily, and measurements were repeated. Kaolin increased ICP [median (range) 15.96 (8.97) mmHg, n = 8] versus controls [6.02 (1.79) mmHg, n = 6, P = 0.0007]. Animals with raised ICP exhibited reduced mechanical thresholds [mean (standard deviation) hind paw baseline: 5.78 (2.81) g, Day 7: 3.34 (2.22) g, P < 0.001; periorbital baseline: 6.13 (2.07) g, Day 7: 2.35 (1.91) g, n = 12, P < 0.001]. Depolarization and repolarization durations were increased [depolarization, raised ICP: 108.81 (222.12) s, n = 11, controls: 37.54 (108.38) s, n = 9, P = 0.038; repolarization, raised ICP: 1824.26 (3499.54) s, n = 12, controls: 86.96 (140.05) s, n = 9, P < 0.0001]. Cerebral blood flow change was also reduced [85.55 (30.84)%, n = 9] compared with controls [217.64 (37.70)%, n = 8, P < 0.0001]. Substrates for cellular energetics (ADP, ATP and NAD+) were depleted in rodent brains with raised ICP (P = 0.009, P = 0.018 and P = 0.011, respectively). Exenatide significantly lowered ICP [exenatide: 9.74 (6.09) mmHg, n = 19, vehicle: 18.27 (6.67) mmHg, n = 16, P = 0.004] and rescued changes in mechanical withdrawal. Exenatide recovered characteristic spreading depolarization responses [depolarization duration, exenatide: 56.46 (25.10) s, n = 7, vehicle: 115.98 (58.80) s, n = 6, P = 0.033; repolarization duration, exenatide: 177.55 (562.88) s, n = 7, vehicle: 800.85 (1988.67) s, n = 6, P = 0.002]. In the setting of raised ICP, olcegepant prevented changes in periorbital mechanical thresholds. We conclude that raised ICP disrupted the cortical neurovascular responses, reduced algetic thresholds and depleted crucial energetic substrates. Exenatide reduced ICP, improving algetic thresholds and cortical neurovascular changes. Importantly, olcegepant alleviated the cerebral algesia, suggesting a role for calcitonin gene-related peptide in driving pain responses in elevated ICP. These studies support the rationale that reducing ICP improves cephalic pain in conditions of raised ICP. Furthermore, the data suggest that headache pain in diseases associated with raised ICP could be ameliorated therapeutically though blockade of the calcitonin gene-related peptide pathway.