The Effects of cervical mobilization and clinical pilates exercises in cervicogenic headache: randomized controlled trial.

OBJECTIVES: To investigate the effects of Cervical Mobilization (CM) and Clinical Pilates Exercises (CPE) in Cervigogenic Headache (CHA). METHODS: The 37 patients were randomized into the 3 groups. The CM for 1st group, CPE for 2nd group and CM+CPE for 3rd group were applied 3 days/a week for 6 weeks. Pain frequency, pain intensity, number of analgesic, were recorded. The posture was measured by Posture Screen application, the cervical range of motion by the CROM device, deep neck flexor muscle endurance by the pressurized biofeedback device. Evaluations were applied 2 times as pre-post treatment. RESULTS: In within-group comparison a decrease in pain parameters, neck-shoulder postural deviation and an increase DNFE and CROM were observed in all groups (p<0.05). In between-group comparison pain frequency, intensity and number of analgesics were significant changes in the CM and CM+CPE groups according to CPE (respectively p<0,001, p=0,001, p=0,018). Head and shoulder angulation were significant in the CPE and CM+CPE groups according to CM (respectively p=0.009, p=0,011). It was determined that the cervical right lateral flexion range of motion and right rotation were significant changes in the CM and CM+CPE groups according to CPE (respectively p=0,026, p=0,040). DNFE were significantly increased in CM+CPE according to CM and CPE (p=0.001). CONCLUSION: This study suggests that it would be beneficial to add CM and CPE to the treatment plans of patients with CHA.

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

OBJECTIVE: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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

OBJECTIVE: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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

BACKGROUND: Posttraumatic 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. METHODS: Repetitive 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. RESULTS: The 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. CONCLUSION: Enhancing 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.

Headache management in traumatic brain injury.

Traumatic brain injury (TBI) is estimated to rank as the third most important disease burden worldwide. About 60% of the survivors develop chronic headaches and visual symptoms, and the long-term management of headaches in these patients is controversial. Importantly, the care pathway of most patients is fragmented, complicating conclusive headache management. Here we review the epidemiology and aetiology of post traumatic headaches (PTH), discuss the diagnostic work up and summarise the acute and long-term management.

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.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Mulligan manual therapy added to exercise improves headache frequency, intensity and disability more than exercise alone in people with cervicogenic headache: a randomised trial.

QUESTION: What is the effect of a 4-week regimen of Mulligan manual therapy (MMT) plus exercise compared with exercise alone for managing cervicogenic headache? Is MMT plus exercise more effective than sham MMT plus exercise? Are any benefits maintained at 26 weeks of follow-up? DESIGN: A three-armed, parallel-group, randomised clinical trial with concealed allocation, blinded assessment of some outcomes and intention-to-treat analysis. PARTICIPANTS: Ninety-nine people with cervicogenic headache as per International Classification of Headache Disorders (ICHD-3). INTERVENTIONS: Participants were randomly allocated to 4 weeks of: MMT with exercise, sham MMT with exercise or exercise alone. OUTCOME MEASURES: The primary outcome was headache frequency. Secondary outcomes were headache intensity, headache duration, medication intake, headache-related disability, upper cervical rotation range of motion, pressure pain thresholds and patient satisfaction. Outcome measures were collected at baseline and at 4, 13 and 26 weeks. RESULTS: MMT plus exercise reduced headache frequency more than exercise alone immediately after the intervention (MD between groups in change from baseline: 2 days/month, 95% CI 2 to 3) and this effect was still evident at 26 weeks (MD 4 days, 95% CI 3 to 4). There were also benefits across all time points in several secondary outcomes: headache intensity, headache duration, headache-related disability, upper cervical rotation and patient satisfaction. Pressure pain thresholds showed benefits at all time points at the zygapophyseal joint and suboccipital areas but not at the upper trapezius. The outcomes in the sham MMT with exercise group were very similar to those of the exercise alone group. CONCLUSIONS: In people with cervicogenic headache, adding MMT to exercise improved: headache frequency, intensity and duration; headache-related disability; upper cervical rotation; and patient satisfaction. These benefits were not due to placebo effects. TRIAL REGISTRATION: CTRI/2019/06/019506.

Cross-sectional experimental assessment of pain modulation as part of multidimensional profiling of people with cervicogenic headache: protocol for a feasibility study.

BACKGROUND: An endogenous pain modulation profile, reflecting antinociceptive and pronociceptive mechanisms, may help to direct management by targeting the involved pain mechanism. For individuals with cervicogenic headache (CeH), the characteristics of such profiles were never investigated. However, the individual nature of experiencing pain demands profiling within a multidimensional framework including psychosocial lifestyle characteristics. The objective of the current protocol is to assess the pain modulation profile, which includes psychosocial lifestyle characteristics among people with CeH. METHODS AND ANALYSIS: A protocol is described to map pain modulation profiles in people with CeH. A cross-sectional non-randomised experimental design will be used to assess feasibility of mapping these profiles. The pain modulation profile is composed based on results on the Depression, Anxiety, Stress Scale, Pittsburgh Sleep Quality Index, Headache Impact Test and on responses to temporal summation of pain (pinprick), conditioned pain modulation and widespread hyperalgesia (mechanical pressure pain threshold and cuff algometry). Primary analyses will report results relating to outcomes on feasibility. Secondary analyses will involve an analysis of proportions (%) of the different psychosocial lifestyle profiles and pain profiles. ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee Research UZ/KU Leuven (Registration number B3222024001434) on 30 May 2024. Results will be published in peer-reviewed journals, at scientific conferences and, through press releases. Protocol V.3. protocol date: 3 June 2024.

Hypersensitivity to BKCa channel opening in persistent post-traumatic headache.

BACKGROUND: Large 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. METHODS: This 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. RESULTS: Twenty-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). CONCLUSIONS: Our 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. GOV IDENTIFIER: NCT05378074.

Cervical ganglioneuroma as a rare cause of cervicogenic headache: A case report and literature review.

BACKGROUND: Cervicogenic headache is characterized by chronic posterior neck pain radiating to one side of the head, resulting from cervical spine bone or soft tissue diseases. Cervical ganglioneuroma (GN), a rare benign neuroblastic tumor, especially in the cervical spine, may cause cervicogenic headache-like symptoms. OBJECTIVE: We report a case of GN which was surgically removed successfully to relieve the symptom. CASE REPORT: A 68-year-old male presented with right posterior neck pain with referred pain to the ipsilateral occipital area in May 2020. Despite administration of medications, physical therapy, and spine interventions, the symptoms intermittently recurred over one year. In July 2021, the patient complained of painful limitation of neck motion, especially on right-sided bending; no motor or sensory deficits, except for subjective numbness of the finger tips, were detected. Plain radiography of the cervical spine showed moderate degenerative changes in the mid-cervical spine. Cervical MRI revealed a cystic mass (1.5 cm × 0.5 cm × 1 cm-in size) around the right C2 dorsal root ganglion adjacent to the C1-C2 facet joint. His symptoms significantly improved after complete tumor excision. CONCLUSION: GN of the upper cervical spine should be considered when persistent cervicogenic headache is refractory to conservative management. In such a case, advanced imaging studies such as MRI should be performed for early diagnosis and appropriate treatment.

The Effects of Cervical Mobilization with Clinical Pilates Exercises on Pain, Muscle Stiffness and Head and Neck Blood Flow in Cervicogenic Headache: Randomized Controlled Trial.

Background and Objectives: Physiotherapy approaches are used to eliminate the problems caused by cervicogenic headache (CHA), known as secondary headache associated with the structures of the upper cervical region. This study aimed to investigate the effects of cervical mobilization (CM) with clinical Pilates exercises (CPE) on pain, muscle stiffness and head-neck blood flow in CGH. Materials and Methods: A total of 25 patients participated in this randomized controlled study and were randomized into either the CM group or the CM+CPE group. All treatment methods were applied 3 days a week for 6 weeks. The outcome measure was headache intensity and frequency, the number of analgesics, muscle stiffness and vertebral artery (VA) and internal carotid artery (ICA) blood flow. Headache intensity was measured by a visual analogue scale, muscle stiffness by a myotonometer and blood flow by Doppler US. Evaluations were repeated after 6 weeks of treatment. Within-group comparisons were made by the Wilcoxon signed rank test, and between-group comparisons were made by the Mann-Whitney U test. Results: After treatments in the two groups, headache intensity and frequency and the number of analgesics decreased, the muscle stiffness of the suboccipital, upper trapezius and sternocleidomastoid (SCM) muscles decreased, and the blood flow of the ICA and VA increased (p < 0.05). There was a significant difference between the groups in terms of headache intensity (p = 0.025) and muscle stiffness in SKM (p = 0.044) in favor of the CM+CPE group. Conclusions: Non-pharmacological treatment approaches have an important role in CHA related to the upper cervical region. This study suggests that it would be beneficial to add CM in combination with CPE to the non-pharmacological treatment of patients with CHA.

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

OBJECTIVE: The 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. METHODS: Ninety-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. RESULTS: The 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. CONCLUSIONS: Our 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.

Meta-Analysis of Acupuncture Treatment for Cervicogenic Headache.

OBJECTIVE: To analyze and evaluate the clinical effect of acupuncture on cervicogenic headache (CEH), and provide evidence-based basis for clinical selection of acupuncture for CEH. METHODS: Databases including China Knowledge Network, Wanfang, VIP Chinese sci-tech journals, Chinese Biomedical, and PubMed were searched to collect clinical randomized controlled trials on the effectiveness of acupuncture in the treatment of CEH until November 2023. Statistical analysis was performed using the RevMan 5.4.1 software, and heterogeneity was assessed using the Q test (P value), allowing for the calculation of the combined effect odds ratio through either the fixed or random-effect model. Sensitivity analysis will be conducted by excluding articles with the highest weight, while the validity of the literature will be evaluated through the creation of a funnel plot to identify any potential biases. RESULTS: A total of 400 articles were retrieved, and eventually, 20 clinical randomized controlled trials were included in the analysis. Comparing with control, acupuncture exhibited a higher total effective rate in treating CEH. The cure rate was also higher in the experimental group, and improvements in short-term and long-term visual analogue scale scores outcomes were significantly greater than those in the control group. The quality-of-life scores were higher in CEH patients treated with acupuncture. Sensitivity analysis confirmed the stability and reliability of the pooled effect size results. The results of the funnel plot indicated the presence of publication bias. CONCLUSIONS: Acupuncture treatment is effective for CEH relief and worthy of clinical application.

Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury.

Mild traumatic brain injury (mTBI)-induced post-traumatic headache (PTH) is a pressing public health concern and leading cause of disability worldwide. Although PTH is often accompanied by neurological disorders, the exact underlying mechanism remains largely unknown. Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH. In this study, a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery. Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage. Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum, temporal lobe/cortex, and hippocampal regions during the early stages of PTH. Additionally, variations in brain functional activities and connectivity were further detected in the early stage of PTH, particularly in the cerebellum and temporal cortex, suggesting that these regions play central roles in the mechanism underlying PTH. Moreover, our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH. Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex, with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

Can Long-Term Outcomes of Posttraumatic Headache be Predicted?

PURPOSE OF REVIEW: Headache is one of the most common symptoms of traumatic brain injury, and it is more common in patients with mild, rather than moderate or severe, traumatic brain injury. Posttraumatic headache can be the most persistent symptom of traumatic brain injury. In this article, we review the current understanding of posttraumatic headache, summarize the current knowledge of its pathophysiology and treatment, and review the research regarding predictors of long-term outcomes. RECENT FINDINGS: To date, posttraumatic headache has been treated based on the semiology of the primary headache disorder that it most resembles, but the pathophysiology is likely to be different, and the long-term prognosis differs as well. No models exist to predict long-term outcomes, and few studies have highlighted risk factors for the development of acute and persistent posttraumatic headaches. Further research is needed to elucidate the pathophysiology and identify specific treatments for posttraumatic headache to be able to predict long-term outcomes. In addition, the effect of managing comorbid traumatic brain injury symptoms on posttraumatic headache management should be further studied. Posttraumatic headache can be a persistent symptom of traumatic brain injury, especially mild traumatic brain injury. It has traditionally been treated based on the semiology of the primary headache disorder it most closely resembles, but further research is needed to elucidate the pathophysiology of posttraumatic headache and determine risk factors to better predict long-term outcomes.

Brain structural and functional abnormalities associated with acute post-traumatic headache: iron deposition and functional connectivity.

BACKGROUND: The purpose of this study was to interrogate brain iron accumulation in participants with acute post-traumatic headache (PTH) due to mild traumatic brain injury (mTBI), and to determine if functional connectivity is affected in areas with iron accumulation. We aimed to examine the correlations between iron accumulation and headache frequency, post-concussion symptom severity, number of mTBIs, and time since most recent TBI. METHODS: Sixty participants with acute PTH and 60 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging including quantitative T2* maps and resting-state functional connectivity imaging. Between group T2* differences were determined using T-tests (p < 0.005, cluster size threshold of 90 voxels). For regions with T2* differences, two analyses were conducted. First, the correlations with clinical variables including headache frequency, number of lifetime mTBIs, time since most recent mTBI, and Sport Concussion Assessment Tool (SCAT) symptom severity scale scores were investigated using linear regression. Second, the functional connectivity of these regions with the rest of the brain was examined (significance of p < 0.05 with family wise error correction for multiple comparisons). RESULTS: The acute PTH group consisted of 60 participants (22 male, 38 female) with average age of 42 ± 14 years. The HC group consisted of 60 age-matched controls (17 male, 43 female, average age of 42 ± 13). PTH participants had lower T2* values compared to HC in the left posterior cingulate and the bilateral cuneus. Stronger functional connectivity was observed between bilateral cuneus and right cerebellar areas in PTH compared to HC. Within the PTH group, linear regression showed negative associations of T2* in the left posterior cingulate with SCAT symptom severity score (p = 0.05) and T2* in the left cuneus with headache frequency (p = 0.04). CONCLUSIONS: Iron accumulation in posterior cingulate and cuneus was observed in those with acute PTH relative to HC; stronger functional connectivity was detected between the bilateral cuneus and the right cerebellum. The correlations of decreased T2* (suggesting higher iron content) with headache frequency and post mTBI symptom severity suggest that the iron accumulation that results from mTBI might reflect the severity of underlying mTBI pathophysiology and associate with post-mTBI symptom severity including PTH.