Post-traumatic Headache Research Articles

Chronic headaches after traumatic brain injury: Diagnostic complexity associated with increased cost.

Chronic headache after traumatic brain injury (TBI) is a common, yet disabling, disorder whose diverse clinical characteristics and treatment needs remain poorly defined. To examine diagnostic coding patterns and cost among military Veterans with comorbid chronic headache and TBI. We identified 141,125 post-9/11 era Veterans who served between 2001 and 2019 with a headache disorder diagnosed after TBI. We first identified patterns of Complex Headache Combinations (CHC) and then compared the patterns of healthcare costs in 2022-dollar values in the three years following the TBI diagnosis. Veterans had diverse individual headache and CHC diagnoses with uniformly high cost of care. Post-whiplash and post-TBI CHCs were common and consistently associated with higher costs after TBI than those with other types of headache and CHCs. Post-TBI migraine had the highest unadjusted mean inpatient ($27,698), outpatient ($61,417), and pharmacy ($4,231) costs, which persisted even after adjustment for confounders including demographic, military, and clinical characteristics. Headache diagnoses after TBI, particularly those diagnosed with post-traumatic headache, are complex, and associated with dual high cost and care burdens. More research is needed to examine whether this higher expenditure reflects more intensive treatment and better outcomes or refractory headache with worse outcomes.

Acupuncture Treatment for Chronic Post-Traumatic Headache in Individuals with Mild Traumatic Brain Injury: A Pilot Study.

Chronic post-traumatic headache (CPTH) after a mild traumatic brain injury (mTBI) has been reported in up to 60% of patients and can be extremely debilitating. While pharmacological treatments are typically used for CPTH, they frequently cause side effects and have limited effectiveness, leading individuals with CPTH to be unsatisfied with current treatment options and to seek nonpharmacological options. Acupuncture has been identified as a potential treatment option; however, the evidence in this population remains limited. The overall goal of this study was to examine the effect of a once weekly (e.g., low dose) versus twice weekly (e.g., high dose) of acupuncture treatment on CPTH in individuals with mTBI. Thirty-eight individuals were randomized to receive either 5 or 10 acupuncture treatments using a standard protocol over 5 weeks. The protocol consisted of 14 points using traditional acupuncture and 4 points using electroacupuncture. Headache outcomes, safety, treatment adherence, sleep quality, and quality of life (QOL) were assessed. The results showed that while there were no differences between dose groups for any of the outcomes assessed, acupuncture significantly reduced the number of headache days and headache pain intensity in individuals with CPTH. There were no significant changes in acute medication use or sleep quality. While there were some QOL improvements identified, these results should be interpreted with caution. Overall, acupuncture was shown to be safe and well-tolerated in people with CPTH after mTBI, and five acupuncture treatments using a standardized protocol shows promise in providing headache relief for this population.

Advancements in pediatric headache.

To provide an update on advancements in pediatric headache. The symptomatology associated with primary headache disorders has been compared with ICHD-3 criteria. Primary stabbing headache pain lasts longer than 3 seconds in over half of patients. Persistent posttraumatic headache or new daily persistent headache have significant overlap in pain character and nonpain-related symptoms with migraine. In a large cohort with continuous headache at first follow-up, 47% reported resolution of their continuous headache and 19.4% had a 50% or greater reduction in frequency with improvements in fluid intake, sleep, not skipping meals, and exercise. There was no correlation with improved lifestyle habits and clinical outcomes despite the overall improvement. Studies noted significant improvement in headache scores with onabotulinum toxin A and incobotulinum toxin A injections with limited side effects. Intranasal sumatriptan without concurrent intravenous therapies found a clinically meaningful decrease in pain score prior to discharge with shorter lengths of stay and lower emergency department costs compared with the those who received intravenous therapies. Newer studies have suggested changes to symptomatology and duration of pediatric headache syndromes. Onabotulinum toxin A and incobotulinum toxin A injections, and emergency department intranasal sumatriptan are well tolerated therapies in pediatric headache.

Onabotulinumtoxin A for the Treatment of Post-Traumatic Headache: Is It Better than Anti-CGRP Antibodies?

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A's ability to target multiple pain pathways may make it a more promising candidate.

Biological markers of brain network connectivity and pain sensitivity distinguish low coping from high coping Veterans with persistent post-traumatic headache.

Headache is the most common type of pain following mild traumatic brain injury. Roughly half of those with persistent post-traumatic headache (PPTH) also report neck pain which is associated with greater severity and functional impact of headache. This observational cohort study aimed to identify biological phenotypes to help inform mechanism-based approaches in the management of PPTH with and without concomitant neck pain. Thirty-three military Veterans (mean (SD) = 37±16 years, 29 males) with PPTH completed a clinical assessment, quantitative sensory testing, and magnetic resonance imaging of the brain and cervical spine. Multidimensional phenotyping was performed using a Random Forest analysis and Partitioning Around Medoids (PAM) clustering of input features from three biologic domains: 1) resting state functional connectivity (rsFC) of the periaqueductal gray (PAG), 2) quality and size of cervical muscles, and 3) mechanical pain sensitivity and central modulation of pain. Two subgroups were distinguished by biological features that included forehead pressure pain threshold and rsFC between the PAG and selected nodes within the default mode, salience, and sensorimotor networks. Compared to the High Pain Coping group, the Low Pain Coping group exhibited higher pain-related anxiety (p=0.009), higher pain catastrophizing (p=0.004), lower pain self-efficacy (p=0.010), and greater headache-related disability (p=0.012). Findings suggest that greater functional connectivity of pain modulation networks involving the PAG combined with impairments in craniofacial pain sensitivity, but not cervical muscle health, distinguish a clinically important subgroup of individuals with PPTH who are less able to cope with pain and more severely impacted by headache.

Effectiveness and Tolerability of Anti-Calcitonin Gene-Related Peptide Therapy for Migraine and Other Chronic Headaches in Adolescents and Young Adults: A Retrospective Study in the USA.

This retrospective study assesses the efficacy and tolerability of anti-calcitonin gene-related peptide (anti-CGRP) therapy in adolescents and young adults (ages 12-21) with migraine and chronic daily headaches unresponsive to standard treatments. Migraines in this demographic significantly impair school performance, self-esteem, psychological well-being, and cognitive health. These young patients are also particularly sensitive to the side effects of conventional medications, which are often prescribed off-label and come with high insurance denial rates. Medication overuse, including analgesics, triptans, and NSAIDs, is prevalent due to treatment failures. Elevated plasma CGRP levels observed during migraines suggest that anti-CGRP therapies, successful in adult populations, may also benefit this younger age group. Over a three-year period, patients at a specialized pediatric headache center were evaluated for the impact of anti-CGRP treatments, including monoclonal antibodies (erenumab, fremanezumab, and galcanezumab) and small-molecule CGRP receptor antagonists (ubrogepant, rimegepant, and atogepant), administered either alone or in combination with OnabotulinumtoxinA. Data were extracted from the hospital's electronic medical records, and patient progress was consistently documented using a structured template for each clinic visit. Additional patient satisfaction data were collected via telephone follow-ups and patient message reviews. The study included 23 patients, primarily treated for chronic migraine (CM) (78.3%), with a smaller subset addressing episodic migraine (EM), new daily persistent headaches (NDPHs), and post-traumatic headaches (PTHs). Comprehensive demographic and clinical data, including age, treatment duration, history of preventive treatment failures, and comorbidities like psychiatric conditions and sleep disorders, were collected. Anti-CGRP therapies, particularly when combined with traditional treatments or OnabotulinumtoxinA, resulted in significant improvements: 91.3% of patients experienced reduced migraine duration and intensity, 82.6% reported improvements in other bothersome symptoms, and 73.9% saw an improved response to rescue medications. Additionally, 78.3% of patients reported a reduction in their use of rescue medications per week by more than 50%, and emergency room visits were reduced for 56.5% of patients. Significant reductions in headache days were observed in 82.6% of patients after one month and 87% after three months, with nearly 40% experiencing more than a 50% reduction in both periods. The greatest benefits were observed in patients treated for more than six months. Adverse effects were minimal, with 95.7% of patients reporting no side effects, and patient satisfaction was high, with 69.6% opting to continue treatment. Overall, this study highlights the substantial potential of anti-CGRP therapy in improving outcomes for adolescents and young adults with CM and EM, offering a promising approach for a demographic that faces considerable challenges with conventional treatment options. However, further research is needed to confirm these findings and expand clinical applications in this age group.

The impact of headache intensity on speech in participants with migraine and acute post-traumatic headache.

Slower speaking rates and higher pause rates are found in individuals with migraine or post-traumatic headache during headache compared to when headache-free. We aimed to determine whether headache intensity influences the speaking rate and pause rate of participants with migraine or acute post-traumatic headache (aPTH) following mild traumatic brain injury (mTBI). Using a speech elicitation tool, participants with migraine, aPTH, and healthy controls (HC) submitted speech samples over a period of 3 months. Speaking and pause rates were calculated when participants were headache-free and when they had mild or moderate headache. In this observational study, speaking and pause rates in participants with migraine and aPTH were compared to HC, controlling for age, sex, and days since mTBI (participants with aPTH only). A total of 2902 longitudinal speech samples from 13 individuals with migraine (mean age = 33.5, SD = 6.6; 12 females/1 male), 43 individuals with aPTH (mean age = 44.4, SD = 13.5; 28 females/15 males), and 56 HC (mean age = 40.8, SD = 13.0; 36 females/20 males) were collected. There was no difference in speaking rate between HC and the combined headache cohort of participants (migraine and aPTH) when they had headache freedom or a mild headache. When participants had moderate intensity headache, their speaking rate was significantly slower compared to that of HC and compared to their speaking rate during mild headache intensity or headache freedom. For the combined headache cohort of participants, pause rates were significantly higher when they had headache freedom or had a headache of mild or moderate intensity relative to HC. Compared to participants' pause rate during headache freedom, their pause rate was significantly higher during mild and moderate headache intensity. Participants with aPTH had significantly slower speaking rates compared to participants with migraine during headache freedom, mild headache intensity, and moderate headache intensity. Participants with aPTH had significantly higher pause rates compared to participants with migraine when experiencing moderate headache intensity. For both aPTH and migraine, more severe headache pain was associated with higher pause rates and slower speaking rates, suggesting that speaking rate and pause rate could serve as objective biomarkers for headache-related pain. Slower speaking rate in participants with aPTH could reflect additional consequences of TBI-related effects on motor control and speech production.

Pilot study evaluating treatment with sumatriptan for moderate to severe post-traumatic headache: A phase 2 open-label study.

Our primary outcome was to determine the feasibility of patients with post-traumatic headache (PTH) keeping a daily headache diary and using sumatriptan as directed. Secondary outcomes include determining if sumatriptan is effective in aborting PTH and whether headache resolution is dependent on PTH phenotype. PTH is prevalent and persistent after traumatic brain injury, yet there have been few studies evaluating the effects of pharmacological treatments in individuals with PTH. This is a single-arm, prospective, non-randomized phase 2 clinical trial registered at Clinicaltrials.gov (NCT01854385) and conducted from 2013 to 2017. Data analysis was completed in 2022. Of the 299 participants screened, 40 were enrolled in the study. Participants kept a headache diary documenting headache characteristics and severity. Headache characteristics were used to determine PTH phenotypes of migraine-like, probable migraine-like, or non-migraine-like. Participants reported whether sumatriptan was used for their headache, their response to the medication, if a second dose was taken, and their response to the second dose. A total of 15 participants out of the 40 enrolled (mean [SD] age, 41.9 [14.2] years, and 53% [21/40] male), met the criteria for the use of sumatriptan, and completed all assessments. Average headache diary compliance rate for the final month of the study was 80% (372/465). While sumatriptan was used for only 19% (122/654) of all reported headaches, 72% (88/122) of those headaches resolved within 2 h of taking the medication. Resolution of headaches with sumatriptan was not significantly different among headache phenotypes (migraine-like: 22/38 [58%], probable migraine-like: 24/29 [83%], non-migraine-like: 6/15 [40%]; p = 0.154). A daily headache diary is feasible for tracking headache symptoms. Preliminary results also suggest that sumatriptan, a migraine-specific medication, may be beneficial for the treatment of PTH of different clinical phenotypes. Future studies, such as a phase 3 clinical trial with a larger sample size, are needed to better understand the efficacy of sumatriptan in the treatment of PTH.

Biomarkers and Endophenotypes of Post-traumatic Headaches.

To review existing literature on biomarkers for post-traumatic headache (PTH). Preclinical models and clinical findings have started to elucidate the biology that underlies PTH. Traumatic brain injury results in ionic flux, glutamatergic surge, and activation of the trigeminal cervical complex resulting in the release of pain neuropeptides. These neuropeptides, including calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP), play a key role in the pathophysiology of migraine and other primary headache disorders. Only two studies were identified that evaluated CGRP levels in PTH. Neither study found a consistent relationship between CGRP levels and PTH. One study did discover that nerve growth factor (NGF) was elevated in subjects with PTH. There is no conclusive evidence for reliable blood-based biomarkers for PTH. Limitations in assays, collection technique, and time since injury must be taken into account. There are multiple ideal candidates that have yet to be explored.

Relationship Between Posttraumatic Headache and Depression After Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) can lead to psychiatric and somatic symptoms for some patients, including posttraumatic headache (PTH) and depression. This study attempted to further establish the relationship between PTH and depression following mTBI and investigate whether the presence of PTH immediately following injury can identify patients at risk for developing depressive symptoms up to 6 months later. This study was a secondary analysis of data from Head Injury Serum Markers for Assessing Response to Trauma (HeadSMART), a prospective study of adult patients in the emergency department with head injury. Participants included 265 patients who met criteria for mTBI and completed the Rivermead Post-Concussion Symptoms Questionnaire, to identify PTH within 24 hours after injury, and the Patient Health Questionnaire-9, to assess depressive symptoms during follow-up. Measures were completed at the initial visit immediately after the injury in the emergency department and at 1-, 3-, and 6-month follow-up visits. Patients with acute PTH (aPTH) at time of injury were more likely to report PTH at 1, 3, and 6 months. They also had more severe depressive symptoms and a greater likelihood of clinically significant depression at all time points. Patients with aPTH within 24 hours after injury were more likely to report continued symptoms of PTH and clinically significant depression at 1, 3, and 6 months. These findings provide support for using the presence of aPTH in the emergency department following mTBI as an indicator for monitoring persistent PTH and depressive symptoms in the postacute recovery period.

White matter microstructural changes in post-traumatic headache: A diffusion tensor imaging (DTI) study.

Post-traumatic headache (PTH) is a common consequence of mild traumatic brain injury (mTBI) that can severely impact an individual's quality of life and rehabilitation. However, the underlying neuropathogenesis mechanisms contributing to PTH are still poorly understood. This study utilized diffusion tensor imaging (DTI) to detect microstructural alterations in the brains of mTBI participants with or at risk of developing PTH. This study investigated associations between DTI metrics 1-month postinjury and pain sensitivity, as well as psychological assessments 6-months postinjury to identify differences between mTBI (n = 12) and healthy controls (HC; n = 10). MRI scans, including T1-weighted anatomical imaging and DTI were acquired at 1-month postinjury. Pain sensitivity assays included quantitative sensory testing and psychological assessment questionnaires at 1-month and 6-months postinjury. Significant aberrations of mean axial diffusivity in the forceps major were observed in mTBI relative to HCs at 1-month postinjury (p =0.02). Within the mTBI group, DTI metrics at 1-month postinjury were significantly associated (p's < 0.05) with pain-related measures and psychological outcomes at 6-month postinjury in several white matter tracts (right sagittal stratum, left anterior thalamic radiation, left corticospinal tract, left insula, left superior longitudinal fasciculus). Notably, the associations between DTI metrics at 1-month postinjury and pain-related measures at 6-month postinjury showed significant group differences in the right sagittal stratum (p's < 0.01), white matter tract in left insula (p < 0.04), and left superior longitudinal fasciculus (p's < 0.05). This study suggests that "Post-Traumatic Stress Disorder for DSM-5" and "Center for Epidemiological Studies-Depression Scale" are the most sensitive psychological measures to early microstructural changes after mTBI, and that the DTI metrics are predictive of pain and psychological measures in mTBI. Together, these results suggest that white matter microstructure plays an important role in the PTH following mTBI.

American Headache Society white paper on treatment of post-traumatic headache from concussion in youth.

To provide healthcare professionals guidance on youth at risk for prolonged recovery and post-traumatic headache (PTH), and on pharmacologic and non-pharmacologic management of PTH due to concussion and mild traumatic brain injury. Headache is the most common persistent post-concussive symptom affecting 8% of youth for >3 months after concussion. Over the past decade, many studies have explored the treatment of PTH in youth, but there are no established guidelines. This white paper is based on a synthesis of an updated systematic review of the literature on treatment of PTH and a narrative review of the literature on risk factors for prolonged recovery and health disparities. Results were interpreted by a group of expert providers in PTH in children and adolescents through collaboration of the PTH and pediatric special interest groups of the American Headache Society. Factors that consistently were associated with prolonged recovery from concussion and persistent PTH included female sex, a high number of acute symptoms, and adolescent age. Social determinants of health also likely play an important role in PTH and deserve consideration in the clinical and research settings. A total of 33 studies met the criteria for inclusion in the systematic review of PTH treatment in youth, although most were retrospective and of fair-to-poor quality. Treatment strategies included acute and preventive pharmacologic management, procedures, neuro-modulatory devices, physical therapy, physical activity, and behavioral health support. A collaborative care approach that includes a thoughtful combination of these management strategies is likely most effective. This white paper provides a roadmap for tailoring the treatment of PTH based on factors influencing prolonged headache, the timing of therapies, and therapies with the most evidence for treating PTH in youth. We also highlight research needed for developing more definitive guidelines on PTH management in youth.

Low-Dose Interleukin-2 Reverses Traumatic Brain Injury-Induced Cognitive Deficit and Pain in a Murine Model.

Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits. mTBI was induced by a noninvasive closed-head weight drop method. LD-IL-2 was administered 4-6 weeks post-mTBI to assess its effects on chronic PTH-related facial mechanical hypersensitivity as well as mTBI-induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD-IL-2. Delayed LD-IL-2 treatment abolished chronic PTH-related behaviors. It also completely reversed mTBI-induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH-related behaviors but also abolished the effects of LD-IL-2. Interestingly, LD-IL-2 treatment significantly increased the number of Treg cells in dura but not in brain tissues. These results suggest that the beneficial effects of LD-IL-2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD-IL-2 as a promising therapy for both chronic PTH and mTBI-induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508-525.

Evaluating the Phenotypic Patterns of Post-Traumatic Headache: A Systematic Review of Military Personnel.

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. 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. 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. 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.

Inhibition of 2-AG hydrolysis alleviates posttraumatic headache attributed to mild traumatic brain injury

BackgroundPosttraumatic headache (PTH) is a common and debilitating symptom following repetitive mild traumatic brain injury (rmTBI), and it mainly resembles a migraine-like phenotype. While modulation of the endocannabinoid system (ECS) is effective in treating TBI and various types of pain including migraine, the role of augmentation of endocannabinoids in treating PTH has not been investigated.MethodsRepetitive mild TBI was induced in male C57BL/6J mice using the non-invasive close-head impact model of engineered rotational acceleration (CHIMERA). Periorbital allodynia was assessed using von Frey filaments and determined by the “Up-Down” method. Immunofluorescence staining was employed to investigate glial cell activation and calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) of the rmTBI mice. Levels of 2-arachidonoyl glycerol (2-AG), anandamide (AEA), and arachidonic acid (AA) in the TG, medulla (including TNC), and periaqueductal gray (PAG) were measured by mass spectrometry. The therapeutic effect of endocannabinoid modulation on PTH was also assessed.ResultsThe rmTBI mice exhibited significantly increased cephalic pain hypersensitivity compared to the sham controls. MJN110, a potent and selective inhibitor of the 2-AG hydrolytic enzyme monoacylglycerol lipase (MAGL), dose-dependently attenuated periorbital allodynia in the rmTBI animals. Administration of CGRP at 0.01 mg/kg reinstated periorbital allodynia in the rmTBI animals on days 33 and 45 post-injury but had no effect in the sham and MJN110 treatment groups. Activation of glial cells along with increased production of CGRP in the TG and TNC at 7 and 14 days post-rmTBI were attenuated by MJN110 treatment. The anti-inflammatory and anti-nociceptive effects of MJN110 were partially mediated by cannabinoid receptor activation, and the pain-suppressive effect of MJN110 was completely blocked by co-administration of DO34, an inhibitor of 2-AG synthase. The levels of 2-AG in TG, TNC and PAG were decreased in TBI animals, significantly elevated and further reduced by the selective inhibitors of 2-AG hydrolytic and synthetic enzymes, respectively.ConclusionEnhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation.

Posttraumatic headache: pain related evoked potentials (PREP) and conditioned pain modulation (CPM) to assess the pain modulatory function

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

White matter fiber morphology in persisting postconcussive symptoms and posttraumatic headache after pediatric concussion: a fixel-based analysis.

Posttraumatic headache (PTH) represents the most common acute and persistent postconcussive symptom (PCS) in children after concussion, yet there remains a lack of valid and objective biomarkers to facilitate risk stratification and early intervention in this patient population. Fixel-based analysis of diffusion-weighted imaging, which overcomes constraints of traditional diffusion tensor imaging analyses, can improve the sensitivity and specificity of detecting white matter changes postconcussion. The aim of this study was to investigate whole-brain and tract-based differences in white matter morphology, including fiber density (FD) and fiber bundle cross-section (FC) area in children with PCSs and PTH at 2 weeks after concussion. This prospective longitudinal study recruited children aged 5-18 years who presented to the emergency department of a tertiary pediatric hospital with a concussion sustained within the previous 48 hours. Participants underwent diffusion-weighted MRI at 2 weeks postinjury. Whole-brain white matter statistical analysis was performed at the level of each individual fiber population within an image voxel (fixel) to compute FD, FC, and a combined metric (FD and bundle cross-section [FDC]) using connectivity-based fixel enhancement. Tract-based Bayesian analysis was performed to examine FD in 23 major white matter tracts. Comparisons of 1) recovered (n = 27) and symptomatic (n = 16) children, and those with 2) PTH (n = 13) and non-PTH (n = 30; overall mean age 12.99 ± 2.70 years, 74% male) found no fiber-specific white matter microstructural differences in FD, FC, or FDC at 2 weeks postconcussion, when adjusting for age and sex (family-wise error rate corrected p value > 0.05). Tract-based Bayesian analysis showed evidence of no effect of PTH on FD in 10 major white matter tracts, and evidence of no effect of recovery group on FD in 3 white matter tracts (Bayes factor < 1/3). Using whole-brain fixel-wise and tract-based analyses, these findings indicate that fiber-specific properties of white matter microstructure are not different between children with persisting PCSs compared with recovered children 2 weeks after concussion. These data extend the limited research on white matter fiber-specific morphology while overcoming limitations inherent to traditional diffusion models. Further validation of our findings with a large-scale cohort is warranted.

Connectivity of the insular subdivisions differentiates posttraumatic headache-associated from nonheadache-associated mild traumatic brain injury: an arterial spin labelling study

ObjectiveThe insula is an important part of the posttraumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) neuropathological activity pattern. It is composed of functionally different subdivisions and each of which plays different role in PTH neuropathology.MethodsNinety-four mTBI patients were included in this study. Based on perfusion imaging data obtained from arterial spin labelling (ASL) perfusion magnetic resonance imaging (MRI), this study evaluated the insular subregion perfusion-based functional connectivity (FC) and its correlation with clinical characteristic parameters in patients with PTH after mTBI and non-headache mTBI patients.ResultsThe insular subregions of mTBI + PTH (mTBI patients with PTH) and mTBI-PTH (mTBI patients without PTH) group had positive perfusion-based functional connections with other insular nuclei and adjacent discrete cortical regions. Compared with mTBI-PTH group, significantly increased resting-state perfusion-based FC between the anterior insula (AI) and middle cingulate cortex (MCC)/Rolandic operculum (ROL), between posterior insula (PI) and supplementary motor area (SMA), and decreased perfusion-based FC between PI and thalamus were found in mTBI + PTH group. Changes in the perfusion-based FC of the left posterior insula/dorsal anterior insula with the thalamus/MCC were significant correlated with headache characteristics.ConclusionsOur findings provide new ASL-based evidence for changes in the perfusion-based FC of the insular subregion in PTH patients attributed to mTBI and the association with headache features, revealing the possibility of potential neuroplasticity after PTH. These findings may contribute to early diagnosis of the disease and follow-up of disease progression.

Hypersensitivity to BKCa channel opening in persistent post-traumatic headache

BackgroundLarge conductance calcium-activated potassium (BKCa) channels have been implicated in the neurobiological underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to examine whether MaxiPost (a BKCa channel opener) could induce migraine-like headache in persons with PPTH.MethodsThis is a randomized double-blind, placebo-controlled, two-way crossover study from September 2023 to December 2023. Eligible participants were adults with PPTH after mild traumatic brain injury who reported having no personal history of migraine. The randomized participants received a single dose of either MaxiPost (0.05 mg/min) or placebo (isotonic saline) that was infused intravenously over 20 minutes. The two experiment sessions were scheduled at least one week apart to avoid potential carryover effects. The primary endpoint was the induction of migraine-like headache after MaxiPost as compared to placebo within 12 hours of drug administration. The secondary endpoint was the area under the curve (AUC) values for headache intensity scores between MaxiPost and placebo over the same 12-hour observation period.ResultsTwenty-one adult participants (comprising 14 females and 7 males) with PPTH were enrolled and completed both experiment sessions. The proportion of participants who developed migraine-like headache was 11 (52%) of 21 participants after MaxiPost infusion, in contrast to four (19%) participants following placebo (P = .02). Furthermore, the median headache intensity scores, represented by AUC values, were higher following MaxiPost than after placebo (P < .001).ConclusionsOur results indicate that BKCa channel opening can elicit migraine-like headache in persons with PPTH. Thus, pharmacologic blockade of BKCa channels might present a novel avenue for drug discovery. Additional investigations are nonetheless needed to confirm these insights and explore the therapeutic prospects of BKCa channel blockers in managing PPTH.ClinicalTrials.gov IdentifierNCT05378074.

COVID-19 та його наслідки для емоційно-вольової сфериосіб похилого і старечого віку

The presence of a variety of symptoms that last longer than the acute phase of COVID-19 is called post-COVID syndrome (PCS). Musculoskeletal, digestive (i.e., diarrhea), and neurological symptoms, including depression (according to the Zung scale), were most commonly observed in patients with PCS. Fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression, and impaired concentration were observed in more than 20% of patients. PCS is mainly characterized by musculoskeletal, lung, digestive and neurological disorders, including depression. PCS is independent of the severity of the acute illness and the humoral response. During and after infection with COVID-19, patients are at increased risk of developing depression and anxiety. Many people with COVID-19 are at risk of long-term impairment and disability, especially in critical cases. Symptoms after acute COVID-19 are highly variable and varied. Not only the stressors associated with the consequences of the infection of COVID-19, but also the measures taken against the pandemic can lead to the development of new mental illnesses or the worsening of existing mental health disorders. Depressive disorders affect physical, mental, and social functioning and increase the risk of premature death. People who survived COVID-19 had a high prevalence of acute psychiatric complications. Common neuropsychiatric sequelae following SARS-CoV-2 infection included fatigue, sleep problems, anxiety, depression, post-traumatic stress disorder, headache, raving, and cognitive impairment. Additional diverse manifestations of COVID-19 have been noted, such as delirium, peripheral neuropathy, dizziness, and mood disorders.