The Journal of Headache and Pain

ObjectiveThe most common forms of migraine are complex disorders characterized by significant clinical diversity. The genetic basis of migraine has been the subject of many studies but remains largely unknown. We present the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility risk loci through a case-control study, in order to unravel population-specific variants. MethodsGenotyping was conducted on 380 individuals using the Applied Biosystems Axiom PMDA array. A vast dataset of 8,031,293 single-nucleotide polymorphisms (SNPs) was available, providing a comprehensive scope for GWAS analysis. PRS models were created and tested on subsets of the genotyping data, and the optimal statistical significance threshold was assessed. ResultsWe detected nine risk loci corresponding to nine lead SNPs (ZNF385D, YTHDF3, NPS, RAP1A/INKA2, CTA-481E9.4/CTA-481E9.3, AC092079.1, PPHLN1, SMYD3 and AL355597.1 (near ADARB2)). Additionally, eleven variants, without any previous association to pathogenicity in migraine, were highlighted by the chosen PRS model. Among our results, a new locus within the NPS gene, representing a novel association with migraine, is a potential new target directly related to recent and effective migraine treatments. ConclusionsThese findings reinforce the importance of neurotransmitter release and synaptic transmission, as well as the involvement of vascular components, in migraine pathophysiology. This work underscores that GWAS can provide novel, clinically valuable insights into populational and disease-associated genetic landscapes, enabling therapeutic developments and bolstering personalized medicine strategies.

Migraine is a common and disabling neurological disorder linked to alterations in neuronal activity and waste clearance in the brain. MRI-visible perivascular spaces (PVS) are key components of the glymphatic system which may serve as imaging biomarker of such disorder. We hypothesised that higher frequency of migraine episodes would be associated with increased PVS burden, reflecting greater levels of impaired glymphatic clearance. In this retrospective case-control study of 90 participants (20 episodic migraineurs, 18 chronic migraineurs, and 52 age- and sex-matched healthy controls; 58 females, median [Q1, Q3] age=28.6 [25.1, 39.4] years) we investigated PVS alterations in episodic migraineurs (n=20) and 18 chronic migraineurs (n=18). PVS volumes and cluster counts were quantified in the white matter (WM), basal ganglia (BG), midbrain, and hippocampus. We stratified PVS metrics by white matter lobes and arterial vascular territories. After adjusting for age, sex, and total brain volume, episodic migraineurs exhibited significantly lower BG-PVS volumes (exp({beta})=0.76, 95%CI [0.61, 0.94], p=0.01) compared to controls. Chronic migraineurs exhibited significantly lower PVS cluster counts in the parietal (exp({beta})=0.8, 95%CI [0.68, 0.94], p=0.01) and temporal lobes (exp({beta})=0.72, 95%CI [0.53, 0.96], p=0.03) and middle cerebral artery territory (exp({beta})=0.82, 95%CI [0.68, 0.97], p=0.03) compared to healthy controls. Within migraineurs, those with aura (n=20) exhibited significantly lower PVS burden in all brain regions, vascular territories, and across the frontal, parietal, and temporal lobes (all pFDR<0.05). Our findings suggest that the aura symptom, rather than the migraine disorder itself, may primarily drive changes in perivascular spaces, with effects varying across brain regions.

ObjectiveTo identify patient characteristics and medication factors associated with perceived comfort with migraine treatments and control of migraine symptoms. BackgroundPatient perceptions of migraine treatment influence adherence and outcomes, yet little is known about their underlying drivers. Our study objective was to identify clinical features of migraine associated with comfort and perceived control of symptoms, and medication classes associated with higher patient comfort and efficacy. MethodsParticipants in the Headache Assessment via Digital Platform in United States (HeAD-US) study completed a cross-sectional survey on demographics, migraine burden, mood, disability, and medication use. Comfort and control were defined using corresponding items from the Migraine Treatment Optimization Questionnaire (mTOQ-6) and categorized as "high" or "low". We compared patient characteristics, clinical features, and medication classes by reported comfort and control. ResultsAmong 5717 participants (mean age 41.5 {+/-} 13.1 years, 91.2% female), 58.5% reported high comfort with migraine treatments, while only 27.5% reported high control of migraine symptoms. High comfort was associated with fewer monthly headache days (mean 9.9 vs. 14.2, p<0.001), lower migraine symptom severity (median MSSS 18 vs. 19, p<0.001), and lower disability (MIDAS severe: 72.7% vs 91.2%, p<0.001) and mood symptom scores (PHQ-4 severe: 9.5% vs. 21.0%, p<0.001). High perceived control showed similar associations with employment (OR=1.25, CI 1.15-1.48, p = 0.013), monthly headache days (mean 9.0 vs 12.7,p<0.001), migraine severity (median MSSS 18 vs 19, p<0.0001), disability (severe: 66.0 vs 85.8, p<0.001), and mood symptoms (severe: 7.6 vs 16.9, p<0.001) but was not associated with income or education. Among those on monotherapy, gepants and triptans were associated with higher comfort and efficacy than OTC medications or opioids/barbiturates. For preventive therapy, beta blockers and botulinum toxin were associated with the lowest perceived comfort and efficacy. ConclusionPerceived comfort and control were linked to headache frequency, severity and disability and mood symptoms. Medication class use influenced perceptions, with gepants and triptans rated most favorably. These findings underscore the importance of incorporating patient perspectives into treatment planning, with particular attention to mood, disability, and choice of medication.

IntroductionVestibular migraine is a major cause of recurrent vertigo, yet its mechanisms and diagnostic markers remain limited. Abnormal vestibular-cervical integration and convergence insufficiency, reflected by impaired near point convergence (NPC),suggest multisensory dysfunction. This study tested whether cervical proprioceptive perturbation provokes vertigo and nystagmus in vestibular migraine and evaluated NPC as a predictor of these responses. MethodsFifty-one vestibular migraine patients and 12 controls underwent interictal vestibular testing. Peripheral function was assessed with vHIT. Participants received randomized 100-Hz cervical (proprioceptive) and mastoid (vestibular) vibration without visual fixation, with eye movements recorded via video Frenzel goggles and NPC measured using standard methods. Analyses included McNemars, Wilcoxon signed-rank, Mann-Whitney U, correlations, and multivariable logistic regression. ResultsNeck vibration provoked vertigo in all vestibular migraine patients and none of the controls, producing nystagmus in 76.5%. Horizontal, ipsiversive nystagmus predominated, while less frequent vertical responses showed higher velocities. Mastoid vibration elicited no nystagmus. NPC was the only independent predictor of nystagmus and correlated with slow-phase velocity and bilateral responses. Age correlated with drift velocity, whereas vestibulo-ocular reflex gain showed no association. DiscussionNeck vibration elicits vertigo and nystagmus in vestibular migraine, providing the first objective physiological marker. NPC predicts and correlates with nystagmus severity, highlighting its value as a surrogate of multisensory dysfunction. Together, these findings implicate abnormal cervical-vestibular integration and position NPC and neck-vibration testing as practical tools for diagnosis and phenotyping. Key pointsO_LIVestibular migraine affects [~]3% of population yet remains highly controversial. C_LIO_LIObjective measures reveal reproducible vertigo and nystagmus in vestibular migraine. C_LIO_LIImpaired convergence strongly predicts vibration-induced nystagmus in VM patients. C_LIO_LIFindings support sensory mismatch model linking cervical proprioception to vertigo. C_LI

Structured AbstractO_ST_ABSObjectiveC_ST_ABSWe represent primary headaches of the ICHD3 in matrix form and show that this representation allows for automated diagnosis as well as additional insights into headache classification. MethodsEach diagnosis in the ICHD3 is defined by a list of characteristics; combinations of characteristics form phenotypes. Multiple phenotypes may fit a given diagnosis. We first translated all characteristics for primary headache diagnoses in the ICHD3 into true/false statements. We generated a matrix of valid ICHD3 diagnosis as follows: O_LIEach row of the matrix represents a phenotype. C_LIO_LIEach column of the matrix represents a characteristic. C_LIO_LIIf any phenotype contains a characteristic, then that element is encoded as 1. Otherwise, it is encoded as 0. C_LI From this matrix, we calculated its bipartite projection and Markov cluster. We also row reduced to derive the basis vectors that span the space of all headache phenotypes. ResultsChronic migraine diagnoses as well as the characteristics "greater than 15 days per month" and "more than 3 months" have the strongest associations based on bipartite projection. Markov clustering yields 64 clusters. These clusters can be organized by ICHD3 diagnoses and demonstrates the level of fragmentation of individual diagnosis in the classification: Migraine is composed of 1 cluster, for example, whereas paroxysmal hemicrania can be broken down into 9 clusters. Finally, row reduction of our matrix yields 63 basis vectors, implying that all headache diagnoses in the ICHD3 can be represented as linear combinations of 63 characteristics. These 63 characteristics corresponds to the following: duration, frequency, aura characteristics, size/location, laterality, clearly remembered onset, TAC features, total number of episodes, severity, nausea/vomiting, photophobia, pulsating, alleviation by triptans, and association with awakening, sexual activity, physical activity, temperature, compression or traction, coughing. ConclusionOur result demonstrates that ICHD3 is a mathematical entity and that headache diagnoses exist in a 63-dimensional vector space. This mathematical embodiment of classification allows us to conduct 1) large scale systematic investigations of relationships between headache and phenotypes, 2) generate a graphical representation of characteristics and phenotypes and 3) improves diagnostic accuracy and efficiency.

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are two highly comorbid, nociplastic pain conditions that belong to a broader group of commonly co-occurring chronic pain conditions. Most of these chronic overlapping pain conditions (COPCs), including TMD and IBS, disproportionately affect females and are highly stress sensitive. Our previous study illustrated sex differences in brain activity during colorectal distension specific to our model of comorbid pain hypersensitivity (CPH), in which masseter muscle inflammation followed by restraint stress elicits IBS-like visceral hypersensitivity. Since insular cortex (Ins) activity increased in female CPH rats only and abnormal Ins activity has been identified in TMD and IBS patients, we sought to characterize patterns of Ins-based functional connectivity (FC) by performing functional MRI (fMRI) scans at baseline, 1 week, and 7 weeks post-injury/stress in groups of male and female Sprague-Dawley rats randomized to the following conditions: CPH, stress-induced hypersensitivity (SIH), Complete Freunds Adjuvant (CFA)-induced masseter muscle inflammation, and naive. CPH females displayed extensive Ins FC with brain regions in the cortex and limbic system, including the thalamus. Compared to CPH males, CPH females showed robust insular-thalamo connectivity at week seven, a time point where visceral hypersensitivity and referred pain-like behavior persists in CPH females but not males. This trend is also apparent in CPH females week seven versus week one Ins FC, whereas CPH males tend to decrease Ins FC broadly. These findings potentially suggest sensitization within the insular-thalamo and -cortical networks in CPH females, warranting future investigation of Ins circuit involvement in comorbid pain.

Sensory transmission in the monosynaptic stretch reflex (MSR) from proprioceptive Ia afferents to motoneurons is markedly inhibited by serotonin, providing a mechanism by which the brain gates spinal cord function. However, the main serotonin receptor subtype that modulates the MSR is the 5-HT1D receptor that is expressed almost exclusively on nociceptive C-fibres, suggesting an unexpected gating of proprioceptive transmission by regulation of nociceptive pathways. We demonstrate here that activation of C-fibres (electrically or pharmacologically by TRPM8 agonists) increases action potential propagation in proprioceptive Ia afferents by producing a very long-lasting tonic depolarization in Ia afferents (tonic primary afferent depolarization, tonic PAD). This tonic PAD is produced indirectly by C-fibres augmenting axoaxonic GABAergic input onto Ia afferents (bicuculline sensitive), which activates nodal GABAA receptors that aid sodium spike initiation. In contrast, activation of 5-HT1D receptors with the anti-migraine drug zolmitriptan inhibits C-fibre activity, which in turn reduces the GABAA receptor-mediated tonic PAD on Ia afferents, and reduces spike propagation to motoneurons. Overall, these findings demonstrate a mechanism by which brainstem derived serotonin not only inhibits ongoing nociceptive C-fibres activity, but also indirectly inhibits GABAergic neurons and sensory transmission in large proprioceptive sensory afferents, leading to reduced motoneuron activity. Furthermore, these findings suggest that spontaneous nociceptive C-fibres activity may provide a general increase in proprioception, opposite to the classical gating of nociceptive pathways by low threshold afferents, and impacting the clinical use of zolmitriptan.

Objective: Migraine attacks are frequently accompanied by patient-reported subjective cognitive symptoms, but objective findings have been inconsistent. We used high-frequency, smartphone-based cognitive testing to assess within-person changes in subjective and objective cognition across migraine phases using daily diaries. Methods: Adults with migraine were recruited through social media. Eligible participants met ICHD-3 migraine criteria and had 3 to 22 monthly headache days. For 30 days, they completed daily smartphone-based reports on headache features, cognitive symptoms, and three smartphone-based objective cognitive tasks. Objective tests included Symbol Search (processing speed/visual search), Color Dots (visual working memory/attention), and Grid Memory (visuospatial working memory). Primary analyses contrasted assessments on current headache days (ictal) versus days with no headache (nonictal). When possible, non-ictal days were subclassified using information from adjacent days as pre-ictal, post-ictal, and interictal days. Outcomes included subjective cognition, reaction time (mean across correctly scored trials), accuracy, and a speed-accuracy composite (Reaction Time/Accuracy). Mixed-effects models adjusted for age, sex, and practice effects. Results: The 139 eligible participants (84.9% female; mean age 38.2 years) contributed 3,014 person-days for ictal versus nonictal comparisons (2,097 nonictal; 917 ictal); for 1,828 person-days precise phase classification was possible. Subjective cognitive symptoms were worse on ictal days, with higher odds of more severe brain fog (OR=3.39, 95% CI 2.70-4.27) and task forgetting (OR=2.82, 95% CI 2.29-3.49). In adjusted models, reaction times were slower on ictal days for Symbol Search (reaction time ratio =1.043, 95% CI 1.028-1.059) and Color Dots (ratio=1.015, 95% CI 1.003-1.026) but not Grid Memory (reaction time ratio =1.006, 95% CI 0.985-1.028). Grid Memory accuracy was lower on ictal days (OR=0.867, 95% CI 0.823-0.914). In analyses based on phase, most nonictal phases showed faster reaction time and lower subjective symptom burden relative to ictal days, with limited differentiation among preictal, postictal, and interictal periods. Conclusions: In persons with migraine, daily smartphone assessments revealed subjective cognitive impairment on ictal vs nonictal days in brain fog and forgetfulness. Objective testing revealed slowing in processing speed and attention and modest differences in the accuracy of working-memory. High-frequency digital cognition appears feasible and may provide scalable functional endpoints for real-world monitoring and treatment evaluation.

Traumatic Brain Injury (TBI) patients may suffer from a number of long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here we investigate the effect of exercise on pain outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with PGE2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies employed the administration of noradrenergic (NA) and serotoninergic receptor blockers. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of the acute phase of pain from [~]5 weeks to 2-3 weeks in female and male TBI rats respectively, gains that could be reversed using the 1-adrenoceptor (1AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT7 receptor antagonist, SB-267790, the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Therefore, the transition from a noradrenergic to a serotonergic inhibitory pain pathway that we typically see in male TBI rats, was blocked by exercise. Assessment of neuropathology, acutely after TBI, reveals that both the astrocyte and microglial response to injury is significantly greater in male TBI compared to female TBI, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. In contrast, exercise significantly decreased the amount of axonal loss in the corpus callosum in both male and female TBI rats compared to sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups respectively. These results demonstrate that exercise is a promising treatment for chronic pain after TBI in both male and females. It also highlights that dysfunction of the endogenous pain modulatory pathways observed in male rats after TBI can be prevented by exercise, possibly by reducing axonal loss.

Chronic pain and post-traumatic stress symptoms (PTSS) frequently co-occur. However, how they interact in the brain to influence cognition and emotion is not well understood. Here, we examined how PTSS affects working memory-related networks during an N-back task. In addition, we examined how these networks interact with subcortical threat regions and influence working memory and pain symptoms. Fifty-three chronic low back pain participants completed the N-back task during fMRI. Brain activation was analyzed in relation to PTSS as both a continuous measure and as high-versus-low groups, using whole-brain parcellation across task loads (FDR corrected). We also examined whether abnormally activated regions were functionally connected to periaqueductal gray subregions, the amygdala, or hippocampus, and how these connections related to PTSS. Although higher PTSS did not affect task performance, it was associated with reduced activation in dorsal and inferior lateral frontal regions during the 3-back condition. PTSS was also associated with increased functional connectivity between the dorsolateral prefrontal cortex and periaqueductal gray, but not with the amygdala or hippocampus. Reduced prefrontal activations and high connectivity with periaqueductal gray predicted higher depression and catastrophizing symptoms. Thus, in chronic pain, PTSS selectively disrupts prefrontal circuits, suggesting that greater trauma symptoms interact with prefrontal circuits when cognitive demand is high. PTSS strengthens coupling between prefrontal regions and brainstem threat/pain circuits, suggesting cognitive-affective coupling. These neural alterations occur even when working memory performance is intact and are linked to higher depression and pain catastrophizing. Larger studies are needed to confirm and clarify these mechanisms.

New-onset chronic pain is a common and debilitating symptom of Long COVID (LC) that remains not fully understood in terms of pathophysiology and therapeutic targets. A growing body of evidence in chronic pain syndromes similar to LC demonstrates an association between EEG alpha oscillatory activity and the experience of pain, with clinical studies showing maladaptive changes in oscillatory activity, particularly a slowing of alpha activity. This study aims to investigate the association between EEG alpha oscillatory activity and pain perception in new-onset LC-chronic pain. We recruited 31 individuals (20 females) with a clinical diagnosis of LC reporting new-onset chronic pain and 31 healthy pain-free age-and sex-matched controls. Participants completed questionnaires regarding symptoms and psychological functioning prior to recording eyes-open resting-state EEG. Peak alpha frequency (PAF) and spectral power within the alpha band (8-13 Hz) were extracted from EEG signals. Lower PAF over the posterior scalp region was significantly associated with higher LC-chronic pain severity when controlling for age and depression. This observation was consistent across PAF estimation methods. PAF was significantly increased, particularly in the posterior region, in the moderate pain LC subgroup compared to both severe pain subgroup and controls, while alpha power did not differ between the three groups and was not associated with pain severity. Our findings highlight associations between PAF and pain symptoms in a new post-infection chronic pain syndrome. PAF can thus be explored as a potential biomarker and therapeutic target for EEG-based neuromodulation interventions in LC-chronic pain. These results may have implications for other similar chronic pain syndromes. SummaryLower resting-state EEG peak alpha frequency in posterior scalp region is associated with higher severity of new-onset Long COVID chronic pain.

AimWe investigated the heterogeneity of treatment effects in transcranial direct current stimulation (tDCS) with mindfulness-based meditation (MBM) and within each individual study group (tDCS alone, MBM alone, and sham) among individuals with symptomatic knee osteoarthritis. We also explored participant characteristics underlying this heterogeneity. MethodsThis secondary analysis drew on a double-blind, randomized, sham-controlled, phase II, parallel-group trial in which 200 participants were assigned to one of four groups: (1) active tDCS + active MBM, (2) active tDCS + sham MBM, (3) sham tDCS + active MBM, or (4) sham tDCS + sham MBM. Participants received ten 20-minute tDCS sessions (active or sham) administered concurrently with MBM (active or sham). Latent class growth analysis was used to identify subgroups with distinct treatment response trajectories (responders vs. non-responders) based on changes in clinical pain (Numeric Rating Scale) from baseline to post-intervention. Generalized linear models were then applied to determine baseline factors associated with participants response classification, including demographic, clinical, and psychological characteristics; quantitative sensory testing battery; and pain-related cortical hemodynamic activity measured using functional near-infrared spectroscopy (fNIRS) in response to punctate and thermal stimuli. ResultsResponders in the active tDCS + active MBM and active tDCS + sham MBM groups demonstrated greater improvements in clinical pain from baseline to post-intervention than non-responders (p < 0.001). In the active tDCS + active MBM group, greater cortical activation in the fNIRS channel S06-D06 of the left somatosensory cortex in response to punctate stimuli, identifying as white, and lower conditioned pain modulation (reflecting less efficient endogenous pain modulation), were significantly associated with being responders (p < 0.05). In the active tDCS + sham MBM group, younger age and lower heat pain tolerance at the knee were significantly associated with being responders (p < 0.05). No clear response patterns were observed in the remaining groups. ConclusionFactors underlying heterogeneity of treatment effects, including somatosensory cortical activation and pain modulatory profiles, may provide preliminary insights to inform the development of personalized neuromodulation (stimulation) protocols.

ObjectiveMany deep brain stimulation (DBS) systems sense local field potentials (LFPs) for patient monitoring or closed-loop therapy (CL-DBS). LFPs can be impacted by artifacts, including a recently discovered cardiac non-electrocardiographic pulse signal that can be visually masked by commercial device filters. We aimed to establish its prevalence across patient groups and brain areas, and to investigate its spectral impact. MethodsWe performed a cross-sectional analysis of LFPs recorded from the cranially mounted Picostim from the pedunculopontine nucleus in multiple systems atrophy patients, periacqueductal gray and sensory thalamus in chronic pain patients, and the centromedian thalamic nucleus (CMT) in paediatric epilepsy patients. For comparison, we analyse externalised recordings from the subthalamic nucleus in Parkinsons disease patients. The PulsAr algorithm was developed to detect and extract pulsatile signals, and we characterised contamination level and spectral content. ResultsThough not visually obvious in CMT, the pulsatile signal was algorithmically detected in all targets, with 33% of LFPs across targets classed as contaminated. Pulse signal power was similar across targets and may have been masked by higher endogenous activity in CMT. While its dominant frequencies were in the heartbeat range, the signal had spectral content extending up to >10Hz. ConclusionsA heart pulse signal affects LFP recordings from DBS leads across brain regions and patient groups. While masked by some device filters, spectral content can extend into higher (clinically relevant) frequencies. Researchers and clinicians should exercise caution when sensing lower LFP frequencies, especially for automated control of therapy in CL-DBS. HighlightsO_LIHistorically, electrocardiographic artifacts have been a major source of artifact affecting deep brain stimulation recordings, however pulsatile artifact is less well described. C_LIO_LIA cardiac pulse signal affects local field potentials recorded from deep brain stimulation electrodes across clinical targets. C_LIO_LIWe introduce an ECG-independent algorithm that detects and extracts this pulsatile signal. C_LIO_LIThe heart pulse signal looks like the intracranial pressure waveform and affects spectral frequencies above the heart rate range up to >10Hz. C_LIO_LIClinicians should incorporate screening and procedures to ensure accurate biomarker detection for clinical decision making. C_LI

Senescence of peripheral sensory neurons has recently been associated with increased nociceptive signalling and pain chronification. Whether this association is found across pain conditions and independent study settings remains to be investigated. In this study, we made use of publicly available whole-genome transcriptome data sets on rodent dorsal root ganglion (DRG) tissue to investigate pain-related peripheral sensory neuron senescence across pain models and independent study settings. We focused on Cdkn1a (p21) and Cdkn2a (p16) expression levels as two widely-used senescence markers, and to explore their potential role in peripheral sensory neuron senescence. We found that Cdkn1a but not Cdkn2a RNA is significantly increased across different axotomy- and lesion-based neuropathic pain models, but less consistent in other pain models including inflammatory pain. We observed a sex-dependent effect of Cdkn1a upregulation following nerve injury, with significantly increased Cdkn1a RNA levels in DRG cells from female but not male rats. Lastly, Cdkn1a RNA levels are increased among all DRG neuronal subtypes, seem to reach their maximum three to seven days following nerve injury, and afterwards go back to baseline. These data suggest that Cdkn1a upregulation in DRG neurons is a widespread response to nerve injury that is found across independent study settings. SummaryAnalysis of publicly available whole-genome transcriptome data sets shows that senescence-associated Cdkn1a but not Cdkn2a expression is upregulated in DRG neurons across neuropathic pain models.

BackgroundStress and pain are two adaptive mechanisms, driving human behavior and cognition. They are bidirectionally related, and modulating factors such as sleep or physical activity were identified. However, how stable individual differences in pain-related distress, including individual dispositions for pain catastrophizing, and person-specific pain sensitivities relate to the strength of stress responses remains unclear. This preregistered study closes this gap by investigating how trait pain-related distress and pain sensitivity changes relate to individuals stress response. MethodsTrait pain-related distress was assessed in 148 healthy males with the Pain Catastrophizing Scale, the Tampa Scale of Kinesiophobia, and the Fear of Pain Questionnaire. Baseline blood pressure, pulse rate, alpha-amylase, and cortisol were obtained as well as initial heat pain thresholds and tolerances. One participant group underwent the Maastricht Acute Stress Task, while a control group performed the placebo version of this task, and consecutively all stress- and experimental pain indicators were examined again. ResultsIndividuals with lower kinesiophobia demonstrated higher stress-induced increases in alpha-amylase. Furthermore, stress-induced changes in pain sensitivity showed high individual variability, but were not associated with the stress response. Finally, in individuals with a higher tendency to catastrophize and to fear pain, stronger alpha-amylase increases were associated with larger post-stressor increases in pain threshold, indicating reduced pain sensitivity. ConclusionOur study suggests that stable individual differences influence the stress-pain link beyond physiology. This underscores the importance of considering trait differences in future research on stress-pain interactions with the goal of better tailoring preventions and treatments for patients with chronic pain.

ImportancePain is inherently aversive but provides emotional relief for individuals engaging in non-suicidal self-injury (NSSI). Despite the high prevalence and severity of NSSI, the neural mechanisms underlying pain processing in individuals with NSSI remain poorly understood. ObjectiveTo compare brain structure and functional connectivity between individuals with NSSI and controls and to relate brain function to pain inhibition. DesignCross-sectional, experimental. SettingMR Center at the Karolinska University Hospital in Stockholm, Sweden. ParticipantsWomen aged 18-35 years with NSSI (n=41) or matched healthy controls (n=40). ExposuresEngagment in self-injury [&ge;] 5 days during the last year. Main outcomes and measuresMagnetic Resonance Imaging (MRI) was used to examine brain structure and function related to pain regulation in individuals with NSSI (n=41) and healthy controls (n=40). The experimental pain test Conditioned Pain Modulation (CPM) was used to determine descending pain inhibition. ResultsWe found higher connectivity between the brains somatomotor networks and subcortical areas during resting-state functional MRI in NSSI compared to controls (P=.009; Bonferroni corrected), particularly involving the thalamus and caudate nucleus. The connectivity was linked to the level of descending pain inhibition during CPM. There was no difference between NSSI and controls regarding brain morphometry. Conclusions and relevanceOur findings suggest that individuals with NSSI may rely more on sensory-motor activations to regulate emotions. This study provides the first evidence linking specific brain circuits to pain regulation and self-injury behavior, highlighting potential pathways for more effective treatments for NSSI and related mental health conditions.

Intervertebral disc degeneration (IVDD) compromises disc structures and mechanics, yet systematic evaluations of the mechanical responses and their relationship to morphological changes in preclinical models remain limited. This systematic review and meta-analysis synthesized mechanical and morphological alterations following experimental disc injury in in vivo animal models. Searches of MEDLINE, EMBASE and Web of Science databases were conducted in accordance with PRISMA guidelines. Study quality and risk of bias were assessed using modified CAMARADES and SYRCLE tools. Twenty-eight studies were included. Pooled analyses showed significant reductions in stiffness, Youngs modulus, and disc height, and significant increases in range of motion and degeneration grade, indicating both mechanical and structural deterioration. Youngs modulus appeared to be the most sensitive marker of functional degeneration. By contrast, creep and other viscoelastic responses showed non-significant changes. High heterogeneity was evident across studies, reflecting variability in injury models, species, timepoints, and testing methods. Evidence of publication bias was detected in several domains, and moderate methodological quality was noted with overall insufficient blinding and lack of sample size calculations. In vivo animal models of IVDD demonstrate robust and consistent mechanical and morphological degeneration after injury. Youngs modulus is a sensitive mechanical indicator, supporting its use in future preclinical research. Standardization of outcome definitions, methodology, and reporting is essential to improve comparability and enhance translation of preclinical findings to clinical research.

Background and AimFibromyalgia is an idiopathic chronic widespread pain syndrome affecting 2-4% of the general population globally. Besides widespread fibromyalgia pain, morning stiffness, associated neurologic as well as sleep problems are also reported. Disease is more prevalent in females of middle-age group with low socioeconomic status, thus deteriorating overall productivity and psychosocial health. There is no permanent cure of the disease. This study aimed to explore, validate and assess the effect of four weeks of supervised yogic intervention on pain status, quality of life, sleep, cortical excitability, flexibility and range of motion in fibromyalgia patients, as compared to standard therapy. MethodCase-control study, interventional study and assessor-blined randomized controlled trial, conducted in 120 fibromyalgia patients (60 yoga group: 60 waitlisted controls) and 60 age-matched healthy controls. Pain was assessed subjectively, using questionnaires and objectively, using quantitative sensory testing and ELISA. Sleep and quality of life were assessed using common and disease specific decsiptors. Flexibility and range of motion was assessed using sit and reach box, lateral goniometry and modified Schobers test. Transcranial magnetic stimulation on M1 was used to assess corticomotor excitability of participants. Study parameters were assessed at baseline and after four weeks of the intervention. ResultsA significantly poor sleep, flexibility and quality of life was reported in the fibromyalgia patients due to excruciating pain (VAS = 6.92{+/-}0.12); corticomotor function was also abnormal in the patients, which were restored after four weeks of yogic intervention. On subjective and objective assessment of pain, we found significant relief and improvement in pain status in the yoga group as compared to the waitlisted controls. Fibromyalgia impact, sleep, quality of life and flexibility were also found solely better in fibromyalgia patients undergoing yogic interventions. Cortical parameters, specifically RMT, MEPs and MEP recruitment curves showed a significant improvement in yoga group as compared to waitlisted controls. ConclusionFour weeks of regular and supervised yogic intervention may ameliorate pain, improve flexibility and range of motion and changes cortical plasticity in the Indian cohort of fibromyalgia patients, as compared to standard therapy. Yoga-based interventions can also improve overall quality of life and sleep impairmentsby reducing catastrophization and fibromyalgia impact.

BackgroundProteases and histamine, co-secreted by mast cells and bacteria, sensitize colonic nociceptors and contribute to irritable bowel syndrome (IBS) pain. ObjectiveTo determine whether irreversible proteolytic cleavage of protease-activated receptor-2 (PAR2) and its continued activity in endosomes amplify and sustain otherwise transient pronociceptive actions of histamine receptors (HRs) to cause recurrent pain, the defining symptom of IBS. DesignWe investigated the coexpression of PAR2 and H1R in nociceptors using RNAscope in situ hybridization and assessed the consequences of coactivation using electrophysiological assays of nociceptor sensitization and biophysical measurements of receptor and effector activity. ResultsPAR2 and H1R were coexpressed by human and mouse dorsal root ganglion nociceptors. Intracolonic infusion of fecal supernatants from IBS patients enhanced mechanosensitivity of colonic nociceptors in mice. Antagonists of PAR2 or H1-4R abolished this response. Combined administration of subthreshold concentrations of trypsin and histamine replicated the effects of fecal supernatant and caused hyperexcitability of isolated nociceptors. Pre-activation of PAR2 sensitized histamine-induced hyperexcitability. Endocytosis inhibitors prevented this hypersensitivity, consistent with sustained endosomal signaling of PAR2 and persistent nociceptor hyperexcitability. Trypsin amplified histamine-induced activation of H1R and {beta}-arrestin2 and Gq effectors at the plasmalemma and in endosomes. Conversely, histamine did not sensitize trypsin-induced hyperexcitability of neurons, in line with the inability of histamine to induce sustained nociceptor hypersensitivity. ConclusionsBy amplifying and maintaining the otherwise transient actions of H1R and possibly other pain receptors, persistent PAR2 endosomal signaling makes a dominant contribution to IBS-related colonic pain. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSProteases and histamine are increased in IBS patients and cause visceral pain. What this study addsProlonged intracellular PAR2 signaling sensitizes and maintains H1R activity to amplify and maintain pain. How this might affect research, practice or policyAlthough neuroactive factors can act synergistically to amplify and maintain IBS pain, antagonists of dominant receptors (e.g., PAR2) can provide effective treatment.

Objective: Myofascial pain (MP) is a leading cause of disability globally. Pain quality and severity vary widely for people with MP, making it difficult to accurately assess the spectrum of symptoms and develop appropriate treatments. We assessed potential contributors to variability in the clinical spectrum of unexplained neck/shoulder pain and associated myofascial component(s). Design: Prospective cross-sectional study of adults reporting neck/shoulder pain and pain-free individuals. Outcomes Measures: Pain intensity and interference (PEG); Symptom burden measured using patient-reported outcomes and objective measures: pain catastrophizing (PCS); PROMIS physical function (PF); sleep disturbance; anxiety (GAD-2); depression (PHQ-2); hypermobility (Beighton/Brighton); Objective measures in the medial upper trapezius: pressure pain threshold (PPT) and quantitative sensory testing (QST). Results: Of the 96 adults recruited for the study, 82 had complete records (age 32.2 +/-13.1 years, 57% women). On physical exam, 23 were assessed to be in an active group (those with spontaneous MP without provocation), 38 in a latent group (those with MP upon provocation), and 21 in a normal group (no MP in neck and shoulder). The symptom burden explained 75% of the variance in PEG in the overall sample, 85% in the active group and 92% in the normal group. PF and PCS are key predictors of PEG. Network analysis identified unique symptom clusters in the active and latent groups. Conclusions: The symptom burden explains the variability in the clinical spectrum of pain intensity and interference in unexplained neck/shoulder MP. Network analysis can further improve clinical risk stratification. These findings represent a step towards an eventual goal of developing multidisciplinary clinical guidance for managing the whole patient, rather than the current emphasis on regional pain contributors in MP.