The Journal of Headache and Pain

Background: Light hypersensitivity, or photophobia, affects nearly 80% of people with migraine and is the most prevalent symptom after headache. Despite its high prevalence, the neural pathways underlying migraine-associated light hypersensitivity remain poorly understood, in part due to the lack of behavioral assays that directly assess light sensitivity in mice. Consequently, whether nociceptors contribute to the development of photophobia remains unclear. Methods: We established a novel light sensitivity assay (LSA) to quantify the response to light in mice by measuring facial grimacing. The assay was applied to evaluate light hypersensitivity elicited by three established migraine triggers: calcitonin gene-related peptide (CGRP), nitric oxide donor (sodium nitroprusside), and repeated stress. To determine the contribution of TRPV1 nociceptors, mice were treated with resiniferatoxin (RTX) to ablate these neurons. Results: The LSA detected light hypersensitivity following administration of CGRP, sodium nitroprusside, and repeated stress in wild-type (WT) mice. Sex differences were not observed in CGRP- or stress-induced light hypersensitivity. Furthermore, ablation of TRPV1 nociceptors did not reduce light hypersensitivity induced by migraine triggers. Conclusions: These findings present the LSA as a robust, reproducible, and easy to implement behavioral assay for measuring light sensitivity in preclinical migraine models. Our results further demonstrate that TRPV1 nociceptors are dispensable for the development of migraine-associated light hypersensitivity. This assay provides a useful method for investigating the mechanisms underlying light sensitivity and for evaluating potential therapeutic strategies.

Background: Attention-deficit/hyperactivity disorder (ADHD) and migraine frequently co-occur, but the mechanisms underlying this association remain unclear. Examining migraine with aura and without aura separately may help clarify whether ADHD-related pathways are shared across migraine subtypes or differ by aura status. Methods: Two-sample Mendelian randomization (MR) was used to examine the effect of genetic liability to ADHD on overall migraine and on migraine subtypes defined by aura status. MR-based mediation was then used to assess whether behavioural, psychiatric, sleep-related, education, and cardiometabolic traits contribute to these effects. Results: MR provided evidence for an effect of ADHD genetic liability on overall migraine risk (OR = 1.48, 95% CI =1.2, 1.82), with similar effect sizes for migraine with aura (MA) (OR=1.52, 95% CI = 1.18, 1.96) and migraine without aura (MO) (OR = 1.65, 95% CI = 1.19, 2.31). Depression, alcohol intake frequency, lifetime smoking index, ever smoke, risk taking behaviours, insomnia, and college education showed evidence for partial mediation, explaining approximately 34.17% (95% CI = 6.17%, 61.63%), 14.44% (95% CI = 0%, 28.87%), 37.25% (95% CI = 11.86%, 63.64%), and 29.24% (95% CI = 6.12%, 52.37%) of the total effect, individually. Subtype analyses suggested broadly similar patterns across MA and MO, with no clear subtype-specific differences. Conclusion: Our findings provide evidence that ADHD common variant genetic liability increases migraine risk, including both MA and MO. The association appears unlikely to be explained by a single pathway and may involve the contribution of depression-related, lifestyle-related, and education-related processes.

Objective: To describe the self-reported effects of incobotulinumtoxinA treatments on migraine-like headache in participants who experienced traumatic brain injury versus Anomalous Health Incidents. Background: Persistent headache attributed to traumatic injury to the head has been widely recognized as among the most common sequelae of concussion/mild traumatic brain injury. Such persistent headaches often have migraine-like characteristics and are typically treated similarly to idiopathic migraine. Patients who have experienced Anomalous Health Incidents have also commonly reported migraine-like headaches, but to our knowledge, no reports describing treatment for persistent headaches attributed to Anomalous Health Incidents have been published. Methods: We describe the self-reported effects of incobotulinumtoxinA treatments on headache with migraine-like characteristics in 19 participants with traumatic brain injury and 11 who had experienced Anomalous Health Incidents from a single center. Results: Self-reported benefits from incobotulinumtoxinA treatments were generally similar and statistically indistinguishable between groups. The Headache Impact Test-6 score decreased by a mean of 12 points in the traumatic brain injury group and 9.5 points in the Anomalous Health Incidents group from baseline to peak efficacy (p = 0.43), with concomitant reductions in work/school hours lost (62% vs. 50%) and family/leisure hours lost (75% vs. 33%). Furthermore, reductions in headache frequency (67% for the traumatic brain injury group vs. 57% for the Anomalous Health Incidents group), headache severity (36% vs. 23%), headache duration (37% vs. 50%), nausea/vomiting (50% vs. 25%), photophobia (34% vs. 29%), phonophobia (30% vs. 37%), visual aura (50% vs. 29%), vestibular aura (50% vs. 33%), and other aura (21% vs. 25%) from baseline to peak efficacy were similar in both groups. Likewise, time from treatment to response (6.5 vs. 7 days), duration of response (10.2 vs. 9.1 weeks), adverse effects (3/19 for the traumatic brain injury group, 3/11 for the Anomalous Health Incidents group), and improved efficacy of concomitant abortive treatments (30% vs. 50% for pain, 50% vs. 55% for aura) did not differ between groups. Osmophobia and cogniphobia, when present, did not improve on average in either group. Notably, the mean duration of response was less than 12 weeks in both groups, with only 3 participants with traumatic brain injury and 1 participant who had experienced Anomalous Health Incidents reporting benefit beyond the typical 12-week incobotulinumtoxinA treatment interval. Conclusion: Overall, these findings provisionally indicate that at least some patients who have experienced Anomalous Health Incidents may subjectively benefit from incobotulinumtoxinA treatment for persistent migraine-like headaches similarly to patients with traumatic brain injury. Limitations include the open-label, single-center, primarily retrospective design; small sample size; and limited representativeness. Further prospective controlled studies are needed to determine whether these groups truly respond similarly to incobotulinumtoxinA and other standard treatments.

Objective: To identify demographic and daily cognitive, affective, and contextual predictors of headache-related interference with activity and concentration in a smartphone-based migraine cohort, using statistical models appropriate to the ordinal structure of patient-reported interference. Background: Migraine burden extends beyond headache to encompass cognitive and affective disturbance, yet most disability instruments summarize functioning retrospectively and cannot capture day-to-day variability in interference. Ecological momentary assessment addresses this limitation, yet few studies have examined cognitive and affective correlates of interference independent of pain intensity or have modeled interference using methods that respect its ordinal, non-equal-interval structure. Methods: From May 2025 to April 2026, adult participants were enrolled in this prospective, decentralized observational study via specialty clinics and social media campaigns. Eligibility required fulfilling ICHD-3 diagnostic criteria for migraine using a validated electronic survey and experiencing between 3 and 20 monthly headache days. Enrolled individuals recorded daily smartphone diary entries and performed three brief cognitive tests over a 30-day monitoring period. Daily interference with activities and concentration were captured on 5-point ordinal scales and analyzed via cumulative link mixed-effects models incorporating participant-specific random intercepts. Predictor selection across nested specifications relied on likelihood ratio testing and Akaike Information Criterion (AIC) metrics, prioritizing the more parsimonious model when goodness-of-fit was comparable. Results: The analytic sample comprised 1,267 headache-day observations from 143 participants. In the final models, brain fog (OR = 2.49 for activity, 3.19 for concentration), forgetfulness (OR = 1.48, 1.65), and mood disturbance (OR = 1.19, 1.31) were each independently associated with both outcomes (all p < 0.01), while age, sex, and employment status showed no significant association with either. Sleep quality (OR = 0.86) and anticipated next-day enjoyment (OR = 0.81) provided additional explanatory value for activity interference (p < 0.05) but not for concentration interference, for which the three-predictor model of brain fog, forgetfulness, and mood alone was retained as the most parsimonious final model. Conclusions: Cognitive and affective symptoms, rather than demographic or socioeconomic characteristics, are the primary correlates of headache-related functional interference in this cohort. Activity and concentration interference are explained by partially distinct sets of daily influences, supporting the clinical value of assessing cognitive and affective symptoms alongside conventional pain-focused evaluation.

Aim: To develop and evaluate a contactless, camera-only method for measuring pre-attack physiology in migraine at home, and to assess its feasibility over four weeks. Methods: In this longitudinal observational feasibility study, adults with a neurologist diagnosis of migraine used a browser-based, camera-only application on their own device three times daily for four weeks. The application derived heart rate and heart-rate variability from facial video, together with proxies for eyelid and mouth movement and blink rate, each referenced to a person-specific baseline. Measurements within twelve hours before a self-reported attack were compared with attack-free measurements using linear mixed models, and individual prediction was tested with leave-one-subject-out cross-validation. The complete analysis was independently re-implemented and reproduced. Results: Nine of thirteen recruited participants completed the study and contributed 549 measurements (547 reliable). Heart rate was higher in the twelve hours before an attack than in attack-free periods (66.0 versus 60.4 beats per minute), confirmed by a mixed model (plus 5.54 beats per minute) and unchanged after adjustment for stress; no other signal differed after correction. Individual-level prediction remained weak (best cross-validated area under the curve 0.58). Conclusion: Contactless, camera-only measurement of pre-attack physiology at home is feasible and reproducible. A group-level rise in heart rate was demonstrable but did not translate into usable individual prediction, motivating a larger study with electrocardiographic validation.

Background: Temporary 60-day percutaneous peripheral nerve stimulation (PNS) can relieve pain in refractory occipital neuralgia (ON), but whether it alters acute healthcare utilization relative to the natural trajectory of the disease is unknown, because prior studies have lacked a concurrent comparator. Methods: We performed a secondary analysis of prospectively collected data from a tertiary interventional pain center. Adults with medically refractory ON (primary diagnosis occipital neuralgia, ICD-10-CM M54.81) who underwent 60-day occipital PNS (n = 42) were compared with concurrent patients who were clinically eligible for PNS but were denied insurance authorization and continued optimized non-PNS management (usual care; n = 63). Headache-related emergency department (ED) encounters - index (occipital neuralgia) and non-index (other headache/facial-pain diagnoses) - were ascertained over the 12 months before and after the treatment window via the electronic record and the statewide health information exchange. Patients were 1:1 propensity-matched on a priori confounders (age, sex, baseline total headache-related ED utilization, HIT-6, and baseline headache-medication use). The primary analysis was a difference-in-differences (DiD) comparison of the change in headache-related ED utilization, reported as the additive difference (Hodges-Lehmann estimate, distribution-free 95% CI) and, alongside, as a multiplicative rate ratio (RR). Results: Thirty-six matched pairs were well balanced. Baseline headache-related ED utilization was nearly identical between matched groups (6.3 vs. 6.2 visits/year). Over the following year, PNS patients' utilization fell to 2.5 while usual-care patients' rose to 6.9. The DiD was 5.0 fewer headache-related ED visits per patient (95% CI 3.0-6.0; p < 0.001), corresponding to a rate ratio of 0.36 (95% CI 0.27-0.48; p < 0.001). Results were consistent in the full sample, in covariate-adjusted models, and after excluding controls denied for incomplete conservative-therapy trials. The effect was driven by non-index headache visits. Conclusions: Relative to a concurrent, matched usual-care cohort whose headache related ED utilization rose over time, 60-day occipital PNS was associated with a substantial reduction in acute-care use, strengthening the case for a role of PNS on healthcare utilization in refractory ON.

Background Fibromyalgia (FM) is a disorder characterized by chronic pain and somatic symptoms that are not fully understood. Central sensitization, a process by which the central nervous system amplifies pain signals, is a key aspect of the pathophysiology of fibromyalgia. Despite its prevalence, effective treatment options are limited and the underlying pathophysiological mechanisms are not fully understood. Network pharmacology, which analyzes the interactions between diseases, targets, and biological pathways, can be used to identify potential molecular targets and pathways associated with fibromyalgia. In this study, we aimed to identify potential hub genes and the underlying biological pathways involved in fibromyalgia. Methods Four online databases, GeneCards, DisGeNET, OMIM, and PharmGKB, were initially screened for genes associated with fibromyalgia. GeneCards and DisGeNET were subsequently used to identify common genes, which were used to generate a protein association network using the STRING database. Cytoscape software was used to analyze the network, and the CytoHubba plugin was used to identify hub genes based on degree and betweenness centrality. Functional enrichment analysis was performed using ShinyGO to identify significantly enriched KEGG pathways. Results TNF and IL6 were identified as the top two hub genes with the highest degree of centrality. Functional enrichment analysis identified the Toll-like receptor (TLR) signaling pathway as a significantly enriched pathway among the prioritized hub genes, with a fold enrichment of 6.78 and FDR of 0.0346. Conclusion This study identified TNF, IL6 and other highly connected genes, along with TLR signaling as an enriched pathway in the fibromyalgia-associated gene network. These findings provide potential molecular targets and pathways for further investigation into the pathophysiology of fibromyalgia. Further experimental and clinical studies are required to independently validate these findings and determine their therapeutic relevance.

Trigeminal pain produces persistent facial hypersensitivity that is difficult to treat. Ion channels contribute to the pathology of trigeminal pain, but the consequences of their modulation remain poorly understood. We previously demonstrated that voltage-gated sodium channel Nav1.7 is a therapeutic target that can be indirectly modulated via interaction with collapsin mediated response protein 2 (CRMP2) to reduce membrane expression of Nav1.7 and trigeminal ganglion neuronal excitability. We used the Foramen Rotundum Inflammatory Constriction of the Trigeminal InfraOrbital Nerve (FRICT-ION) model of trigeminal neuropathic pain to characterize behavioral and supraspinal effects of indirectly modulating the peripheral CRMP2-Nav1.7 interaction via our novel Compound 194 (C194). FRICT-ION produced mechanical and cold allodynia, which were reduced by C194, but had no effect on non-evoked affective behaviors. Despite behavioral improvement, C194 did not normalize heightened glutamatergic activity in the parabrachial nucleus (PBN), revealing a dissociation between behavioral analgesia and activity of a central pain circuit. These findings extend mechanistic studies of C194 in the trigeminal system and demonstrate efficacy of CRMP2-Nav1.7 disruption in modulating facial pain-like behavior. These results support the CRMP2-Nav1.7 axis as a promising therapeutic target while highlighting the need to define how peripheral and central adaptations interact to shape persistent facial pain.

Background: Chronic musculoskeletal pain (CMP) is a common and debilitating symptom of Long COVID (LC), which shares several clinical features with Fibromyalgia Syndrome (FMS). Aims: This longitudinal study investigated whether the symptom overlap between LC-CMP and FMS persists over time, whether patterns differ according to pre-COVID CMP history, and the extent to which neuropathic pain features are present. Methods: Individuals with LC completed questionnaires assessing the symptom-based component of the 2010 American College of Rheumatology criteria for FMS and the presence of neuropathic pain features (PainDetect Questionnaire, PDQ) at baseline, 6- and 12-month follow-ups. Participants were grouped according to pre-COVID CMP history. Group differences were analysed using mixed-effects logistic regression. Results: 240 individuals completed the baseline assessment at a mean of 2.61 years after LC onset, including 131 (100 females) with new-onset CMP and 94 (87 females) with pre-existing CMP. The prevalence of participants meeting the symptom-based criteria for FMS remained high across follow-up (67.5-78.6%), with 50.0-61.0% of those with complete follow-up data fulfilling criteria at all timepoints. No significant subgroup differences were observed (OR = 0.43, 95% CI [0.14 1.39], p = 0.160). Across follow-up, 22.2-36.1% of participants reported likely neuropathic pain features, with significantly higher odds in the pre-existing CMP group (OR = 3.17, 95% CI [1.22 8.18], p = 0.017). Conclusions: FMS-like symptoms remain highly prevalent several years after acute COVID-19 and persist over a further 12 months, suggesting that LC-CMP frequently represents a persistent long-term condition with substantial overlap with FMS. These findings support closer integration of LC and chronic pain rehabilitation services and add to the wider literature linking post-infectious processes with FMS-like symptoms.

Background: Chronic pain affects approximately 20% of children and youth worldwide and is associated with mental and physical health impacts. Canada-specific data on the prevalence of chronic pain in children and youth are limited, highlighting the need for current high-quality population-based estimates Aims: The aim of this study is to provide national estimates of self-reported chronic pain among Canadian children and youth by pain type (headache stomach ache, backache), sex (female, male), age group (5-11, 12-17 years) and province or territory. Methods: Publicly available data were used from the 2019 Canadian Health Survey on Children and Youth (CHSCY), a population-based survey conducted by Statistics Canada using a nationally representative sample of Canadian children and youth Results: Overall, headaches were the most commonly reported pain type (15.4%), followed by stomach aches (12.5%), and backaches (11.1%). Prevalence was consistently higher among females than males and among youth than children, with youth girls reporting the highest prevalence across all pain types. Prevalence also varied geographically, with some of the highest estimates observed in the Atlantic Provinces. Conclusions: Chronic pain affects substantial proportions of Canadian children and youth with disparities observed by pain type, sex, age, and geography. These findings under score pediatric chronic pain as an important public health issue and highlight the need for equity-oriented approaches that address the needs of populations experiencing the greatest burden.

Background: Fluctuations in pain intensity are intrinsic to non-specific chronic low back pain (nsCLBP). Nevertheless, pain fluctuations have rarely been considered when investigating pathophysiological mechanisms. Therefore, a novel study protocol was developed and implemented to systematically assess the impact of fluctuating pain states on pain-related measures. Methods: The final study cohort consisted of 45 nsCLBP patients and 47 age- and sex-matched healthy controls (HCs). Patients participated in three visits, conducted during different pain states (i.e. clinically relevant pain, low-intensity clinical pain / pain-free, clinically irrelevant pain induced using a Qutenza 8% capsaicin patch). Pain fluctuations were monitored through online assessments every four days and guided the pseudorandomized visit scheduling. HCs participated in a single visit. Each study visit comprised a multimodal battery of pain-related measures. Results: 93.33% of patients completed all three visit types in a pseudorandomized order (chi-squared=1.50, p=0.826). Visit scheduling was possible due to the high self-report adherence (median=93.48%), unrelated to self-report burden (rho=-0.097, p=0.53). Study visits were conducted during different pain states, as indicated by: i) the significantly higher low back pain intensity in the clinically relevant pain visit (mean[SD]: 3.98[0.90]), compared to the low-intensity clinical pain (1.03[0.86]) and clinically irrelevant pain (1.13[0.82]) visits (p-values<0.001), as well as by ii) the successful induction of a moderate-to-high clinically irrelevant pain across assessments. Conclusion: Despite scheduling complexity and pain state transition uncertainty, a pain state-dependent pseudorandomized study design is feasible and could improve the understanding of nsCLBP mechanisms.

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, fatigue and cognitive difficulties, but its underlying mechanisms remain incompletely understood. The uncertainty of the origins of FMS has hampered the development of treatments and diagnostic methods, and the available therapeutic options offer limited relief to patients, an estimated 2-4% of the population. The severe burden of FMS thus represents an urgent unmet clinical need. MicroRNAs (miRNAs), non-coding short RNAs that have vital inhibitory roles in gene expression, have been explored in FMS pathophysiology. MicroRNA signatures associated with FMS may facilitate diagnosis and reveal new insights into the cellular and molecular mechanisms of FMS. We compiled and analyzed publicly available data of dysregulated miRNAs in FMS. MiRNAs were categorized according to the direction of dysregulation (levels up or down in FMS vs health) and compared across studies. Only miRNAs identified as dysregulated in the same direction in at least two studies were included. RNA targets of at least two microRNAs were inferred using TargetScan and subjected to pathway enrichment analysis using Reactome , ShinyGo v.8, miRNA Tissue Atlas 2025 and EnrichR. This analysis revealed enrichment in pathways central to cell signaling and immune function, such as regulation of PTEN, circadian rhythm and RNA metabolic processes. Additionally, the dysregulated miRNAs in FMS were over-represented in immune-related tissues such as lymph node and spleen. Collectively, these findings support a role for immune dysregulation in FMS. By using an integrative approach, we identified candidate pathways and molecular targets that warrant further experimental validation.

Neuropathic pain involves spinal microglial activation and metabolic changes.Forsythoside B (FB) has anti-inflammatory effects, but its role in neuropathic pain and microglial glycolysis remains unclear. We investigated the effects and mechanisms of FB in mice with chronic constriction injury (CCI) and in LPS-stimulated BV2 microglia.FB reduced mechanical allodynia and thermal hyperalgesia in CCI mice. FB also reduced the spinal levels of HIF-1, HK2, PKM2, LDHA, and CD86. It decreased the proportion of IBA1+/CD86+ cells and the levels of IL-1{beta}, IL-6, and TNF-. In LPS20 stimulated BV2 microglia, FB reduced glycolysis-related proteins, proinflammatory markers, and cytokine release. FB also reduced glycolytic activity and partly restored basal mitochondrial respiration. FB did not change Hif1a mRNA levels. However, it Manuscript Click here to access/download;Manuscript;Manuscript.docx increased HIF-1 ubiquitination and promoted its proteasome-dependent degradation. HIF-1 overexpression partly reversed the effects of FB on glycolytic enzymes, CD86 expression, and proinflammatory cytokine production. Immunoprecipitation followed by mass spectrometry and UbiBrowser analysis identified USP7 as a candidate HIF27 1-associated deubiquitinase. Molecular docking and cellular thermal shift assays supported a possible interaction between FB and USP7. FB reduced the association between USP7 and HIF-1. USP7 knockdown produced effects similar to those of FB on HIF-1 ubiquitination and downstream glycolytic and inflammatory responses.Overall, FB alleviated neuropathic pain and reduced proinflammatory microglial responses. These effects may involve the promotion of HIF-1 degradation through modulation of the USP7-HIF-1 regulatory axis.

Despite advances in understanding the mechanistic underpinnings of chronic pain (CP) conditions, knowledge on the brain anatomy microstructure associated to CP trajectories is still scarce. We sought to fill this knowledge gap by combining longitudinal self-reported CP assessments with brain imaging in a community dwelling adult population (n = 976). Aiming to provide anatomical insights beyond morphometry (based on T1 brain images), we analyzed the derived relaxometry measures MTsat, R1 and R2* and we could investigate myelin and iron content. Participants were divided in three groups according to persistent, resolved or new CP and were compared to those without CP at timepoint. Participants with persistent CP exhibited lower grey matter (GM) in fronto-temporal cortical regions and reduced myelin-related signal in subcortical and thalamic areas, alongside higher iron-sensitive metrics in the entorhinal cortex. Those who recovered from CP showed reduced cortical GM and myelin encompassing subcortical nuclei, thalamus, frontal, parietal, and temporal regions. New-onset CP participants displayed reduced GM in cortical areas. Overall, we observed reduced GM volume in a widespread network of fronto-temporal cortical areas in participants with current, resolved and new-onset CP. Myelin-related metrics were lower in the subcortical nuclei and thalamus in participants with persistent and -to a greater extent- with resolved CP, whilst persistent CP was associated with higher iron-sensitive metrics in the entorhinal cortex. Hence, CP trajectories appear to leave differential imprints on brain morphometry and tissue microstructure, with each trajectory associated with distinct non-overlapping spatial and temporal patterns in GM, myelin, and iron content.

Background: Neuropathic pain (NP) remains a therapeutic challenge, with conventional repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) yielding a response rate of approximately 40%. Personalised targeting based on dysfunctional neurocircuitry offers a promising strategy to enhance efficacy, yet its application in NP is unexplored. This open-label trial investigated a novel targeting approach guided by the recently described cingulo-opercular and somato-cognitive action (CON-SCAN) network, a circuit integrating cognitive and affective dimensions of pain. Methods: Twenty patients with NP received 10 sessions of M1-rTMS over two weeks, with the stimulation site individually localised based on maximal functional connectivity to a CON template. Results: Increased CON-SCAN connectivity from baseline to post-treatment was associated with reduction in pain interference, anxiety and depression scores. The response rate was 50% post-treatment, which was maintained at the 1-month follow-up. Improvements were also observed in neuropathic pain symptoms, negative affect, and overall health. Conclusions: As the first connectivity-guided rTMS trial for NP, this study provides preliminary evidence that personalised targeting of the CON-SCAN network is feasible and associated with the analgesic effects of M1-rTMS, supporting further investigation in randomised controlled trials. Trial registration: Chinese Clinical Trial Registry, ChiCTR2500104679. Registered 20 June 2025, http://www.chictr.org.cn. Chinese Clinical Trial Registry, ChiCTR2400094568. Registered 24 December 2024, http://www.chictr.org.cn. Keywords: Personalised TMS; Pain; M1; CON; SCAN

Background and Objectives Transient ischemic attack (TIA) diagnosis is challenging because it relies mainly on clinical assessment and exclusion of common differential. Functional MRI (fMRI) may provide a diagnostic biomarker by detecting transient brain dysfunction not visible on conventional imaging. This pilot study aimed to characterize acute motor-task BOLD activation in patients with suspected DWI-negative TIA and compare functional patterns between confirmed TIA and alternative diagnoses. Secondary objectives were to assess longitudinal changes in activation and connectivity at 3 months. Methods In this prospective single-center study, adults presenting within 24 h of transient anterior-circulation neurological symptoms underwent conventional MRI and additional motor-task fMRI. Patients with acute DWI lesions were excluded. Final diagnosis was established after 3-month follow-up. Whole-brain analyses, individualized motor cortex region-of-interest (ROI) analyses, and generalized psychophysiological interaction (gPPI) connectivity analyses were performed during the acute phase and at 3 months. Results Eight patients were enrolled; six had complete longitudinal imaging data and were included in the final analyses. Final diagnoses were TIA (n=2), migraine aura (n=2), functional neurological disorder (n=1), and hypoglycemia (n=1). Whole-brain and ROI analyses showed reduced bilateral motor-related BOLD responses during the acute phase in both TIA patients and in the patient with hypoglycemia. In contrast, patients with migraine and functional neurological disorder exhibited less marked longitudinal changes. In TIA patients, motor cortex activation increased at 3 months, tending to normalize toward values observed in non-TIA participants. Connectivity analyses revealed heterogeneous patterns, but the 2 TIA patients demonstrated increased longitudinal connectivity between the motor cortex contralateral to symptoms and other sensorimotor regions, including supplementary motor, premotor, parietal, and postcentral cortices. Discussion These preliminary findings suggest that TIA may be associated with transient bilateral reductions in motor-network activity. Functional abnormalities appeared to improve over time, supporting the hypothesis of reversible network dysfunction. Although limited by the very small sample size, this study provides the first longitudinal assessment of emergency task-based fMRI in rigorously defined TIA and supports further investigation of acute functional MRI as a potential biomarker of transient cerebral dysfunction.

Chiari I malformation (CM-I) is conventionally defined by cerebellar tonsil position, yet tonsil position is an indirect surrogate for the anatomic obstruction that impairs cerebrospinal fluid (CSF) flow across the craniocervical junction (CCJ). We hypothesized that CCJ crowding, quantified as subarachnoid space narrowing at the foramen magnum and C1, would explain CSF flow impairment more directly than tonsil position. Using non-invasive low b-value diffusion-weighted MRI (low-b dMRI), we quantified effective CSF motility, indexed by mean pseudo diffusivity (M{psi}), across the upper cervical spine, CCJ, and posterior fossa. Voxel-wise CCJ CSF pseudo-diffusion spatial statistics were integrated with CSF Waterways atlas-based regional analyses. We applied this approach in 81 pediatric and adult participants with CM I to determine how CCJ structural features shape regional CSF dynamics and clinical outcomes. Voxel wise analyses revealed that crowding at the foramen magnum was the dominant structural determinant of reduced intracranial CSF effective motility across the CCJ, basilar cisterns, and fourth ventricular outflow pathways (family-wise error corrected p < 0.05). While lower tonsil position and C1 level crowding were also associated with reduced CSF effective motility across the CCJ and fourth ventricular outflow pathways, but their associations within the basilar cisterns were spatially restricted to regions adjacent to the Liliequist membrane. Atlas-based region-of-interest analyses confirmed that greater foramen magnum crowding was associated with lower M{psi} across multiple basilar cisterns, but with higher M{psi} in the ventral spinal CSF compartment. Mediation analyses indicated that CCJ crowding at the foramen magnum and C1 accounted for the majority of the relationship between tonsil position and reduced CSF motility in the basilar cisterns. Multivariate M{psi} profiles across the CSF regions identified data-driven foramen magnum crowding thresholds of 69.5% and 77.5%, stratifying patients into mild, moderate, and severe physiological crowding groups. Exploratory analyses linked lower pre-operative CSF M{psi} to greater pain-related functional impairment, reduced cognitive function, and a higher likelihood of subsequent decompression surgery. Together, these findings demonstrate that CCJ crowding, particularly at the foramen magnum, exerts a quantifiable, region specific impact on CSF effective motility in CM I, and that low b dMRI provides a sensitive, complementary marker of CSF flow impairment. This integrative CCJ structural and CSF flow imaging framework establishes a mechanistic link between CCJ anatomy, CSF dynamics, and symptom burden, offering a scalable tool for phenotyping CM I and informing clinical decision making.

Chronic pain is highly heterogeneous, with individuals varying substantially in symptoms. pain severity, disability, affective distress, cognitive functioning, and trauma-related symptoms. This study examined whether working memory, post-traumatic stress symptoms (PTSS), trauma exposure, and pain modulation explain distinct or shared dimensions of chronic pain variability. Individuals with chronic pain completed clinical, cognitive, trauma-related, and behavioural pain modulation measures, as well as resting-state functional magnetic resonance imaging. Multivariate regressions were used to determine whether working memory, PTSS, trauma exposure, and pain modulation independently predicted chronic pain outcomes. Principal component analysis was used to identify latent dimensions of chronic pain, and mediation analyses tested whether behavioural pain modulation explained relationships between dlPFC to vlPAG resting-state functional connectivity and clinical pain outcomes. PTSS independently predicted affective outcomes, including depression, state anxiety, and trait anxiety, whereas working memory independently predicted pain severity and pain interference. Trauma exposure was associated with greater PTSS and poorer working memory, but did not independently predict core pain outcomes after accounting for these more proximal factors. Principal component analysis identified partially distinct affective and sensory-disability dimensions, while trauma exposure loaded primarily on a separate component characterized by greater PTSS and poorer working memory. Behavioural pain modulation showed broader relationships across symptom dimensions and was associated with dlPFC to vlPAG connectivity. Exploratory mediation analyses demonstrated that pain modulation mediated relationships between dlPFC to vlPAG connectivity and both pain severity and affective distress. These findings support an integrated model where PTSS and working memory are more proximal predictors of affect and severity respectively, and trauma exposure represents a more distal vulnerability factor that predicts both. Thus, pain modulation represents a shared mechanism linking cortico-brainstem connectivity to chronic pain intensity and affect. These variables need further testing for phenotyping people with chronic pain based on their specific clinical needs.

Background: Stroke remains a leading cause of death and disability worldwide. Matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-12, contribute to early blood-brain barrier (BBB) disruption, neuroinflammation, haemorrhagic transformation, and intracerebral haemorrhage (ICH). Intravenous thrombolysis is the only widely used pharmacological therapy for acute ischaemic stroke, but its utility is limited by narrow eligibility criteria and haemorrhagic risk. Inhibition of MMPs in the acute phase may offer a complementary neurovascular protective strategy. Methods: AZD1236, a selective dual MMP-9/-12 inhibitor, was evaluated in transient and permanent middle cerebral artery occlusion models and in a collagenase-induced ICH model in young, aged, obese, and female mice. Drug or vehicle was administered 2-6 hours after stroke onset. Outcomes included infarct or haematoma volume, BBB integrity, neurological function, and pain-related behaviours. Results: AZD1236 given within 2-4 hours after ischaemic or haemorrhagic insult significantly reduced infarct and haematoma volumes, improved short- and long-term neurological scores, and preserved BBB integrity, whereas treatment at 6 hours was largely ineffective. AZD1236 also attenuated the development of post-stroke mechanical allodynia and thermal hyperalgesia. Mechanistically, treatment reduced MMP-9 and MMP-12 activity, increased tight junction protein expression, and dampened inflammatory responses. Conclusions: Dual inhibition of MMP-9/-12 with AZD1236 confers robust neurovascular protection and mitigates post-stroke pain across clinically relevant models of ischaemic and haemorrhagic stroke. These findings provide a strong preclinical rationale for clinical evaluation of dual MMP-9/12 inhibition as an adjunctive neuroprotective strategy for acute stroke.

Cervical spondylotic myelopathy (CSM) is the most common cause of nontraumatic spinal cord dysfunction in adults and is an increasingly important source of disability as populations age. Gabapentin is widely prescribed for neuropathic pain and may therefore be used for symptoms related to known or undiagnosed CSM. However, there is sparse evidence related specifically to gabapentin's use for CSM-related pain. We investigate gabapentin use and trends over time in patients with CSM compared to matched controls. We observed that gabapentin prescriptions were higher in CSM patients compared to controls across two multi-hospital datasets. These results highlight the need for further research into pharmacologic treatment for chronic pain in CSM.