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.

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.

Posttraumatic headache is a distinct headache type from migraine.

PURPOSE OF REVIEW: Posttraumatic headache (PTH), a headache that develops within 7 days of a causative injury, is one of the most common secondary headaches, mostly attributed to mild traumatic brain injury (mTBI). Because presence of preinjury headache is a risk factor for developing PTH and PTH symptoms often resemble migraine or tension-type headache, the association between PTH and primary headaches has attracted attention from clinicians and scientists. RECENT FINDINGS: Recent studies on epidemiological aspects, headache features, risk factors, imaging characteristics, and response to treatment, suggest overlapping features and distinct objective findings in PTH compared to migraine. SUMMARY: We argue that PTH is distinct from migraine. Therefore, PTH epidemiology, pathophysiology, diagnosis, treatment, and prognosis should continue to be investigated separately from migraine.

Persistent posttraumatic headaches and functioning in veterans: Injury type can matter.

OBJECTIVE: To characterize the relationship between head trauma types (blast injury, blunt injury, combined blast+blunt injury) with subsequent headache presentations and functioning. BACKGROUND: Posttraumatic headaches (PTHs), the most common sequelae of traumatic brain injury (TBI), are painful and disabling. More than 400,000 veterans report having experienced a TBI, and understanding the predictors of PTHs may guide treatment developments. METHODS: This study used a nested-cohort design analyzing baseline data from a randomized clinical trial of cognitive behavioral therapy for PTH (N = 190). Participants had PTH (from blast and/or blunt head trauma) and symptoms of posttraumatic stress disorder (PTSD). The Structured Diagnostic Interview for Headache-Revised and Ohio State University Traumatic Brain Injury Identification Method were used to phenotype headaches and head injury histories, respectively. RESULTS: Individuals with persistent PTHs after a combined blast and blunt head trauma were more likely (OR =3.45; 95% CI [1.41, 8.4]) to experience chronic (vs. episodic) PTHs compared with the blunt trauma only group (23/33, 70% vs. 26/65, 40%, respectively); and they were more likely (OR =2.51; 95% CI [1.07, 5.9]) to experience chronic PTH compared with the blast trauma only group (44/92, 48%). There were no differences between head injury type on headache-related disability, depression symptoms, or severity of PTSD symptoms. CONCLUSION: The combination of blast and blunt injuries was associated with headache chronicity, but not headache disability. Considering the refractory nature of chronic headaches, the potential added and synergistic effects of distinct head injuries warrant further study.

Spinal postural variability relates to biopsychosocial variables in patients with cervicogenic headache.

Patients with cervicogenic headache (CeH) showed lower spinal postural variability (SPV). In a next step, the complex character of such SPV needs to be analysed. Therefore, variables influencing SPV need to be explored. A non-randomized repeated-measure design was applied to analyse relations between biopsychosocial variables and SPV within a CeH-group (n = 18), 29-51 years, and matched control-group (n = 18), 26-52 years. Spinal postural variability, expressed by standard deviations, was deducted from 3D-Vicon motion analysis of habitual spinal postures (degrees). Interactions between SPV and pain processing, lifestyle, psychosocial characteristics were analysed. Pain processing characteristics included symptoms of central sensitization (Central Sensitization Inventory), (extra)-cephalic pressure pain thresholds (kPa/cm2/s). Lifestyle characteristics included sleep quality (Pittsburgh Sleep Quality Index), physical activity, screen-time, sedentary-time (hours a week), position (cm) and inclination (degrees) of the laptop (= desk-setup). Psychosocial characteristics included degree of depression, anxiety and stress (Depression Anxiety Stress Scale-21), impact of headache on quality of life (Headache Impact Test-6). Spinal postural variability related significantly to intrinsic (stress, anxiety, extra-cephalic pressure pain thresholds, sleep-duration) and extrinsic (desk-setup, screen-time) variables in the CeH-group. In the control-group, SPV related significantly to extra-cephalic pressure pain thresholds. Spinal postural variability related to diverse variables in the CeH-group compared to the control-group. More research is needed into a possible causal relationship and its clinical implication.

Models for Treating Post-traumatic Headache.

PURPOSE OF REVIEW: To discuss the treatment of post-traumatic headache (PTH) and how to choose pharmacotherapy based upon known pathophysiology. RECENT FINDINGS: Preclinical models of traumatic brain injury are finally revealing some of the mechanisms of PTH, including the significant role that inflammatory neuropeptides like calcitonin gene-related peptide (CGRP) play in the initiation and persistence of symptoms. To effectively treat post-traumatic headache (PTH), one needs to understand the pathophysiology behind the initiation and persistence of symptoms. Recent animal models are starting to elucidate these mechanisms, but effective treatment will also likely rely on the identification of patients who are most at risk for persistent PTH. Trials of early, targeted therapy for at-risk patients will be needed to validate these hypotheses. Additionally, high powered clinical trials are lacking in the field of persistent PTH for medications that are known to be effective in primary headache disorders. Effective treatment for persistent PTH also requires understanding how headache interacts with the complex nature of persistent post-concussion symptoms, as this disease often necessitates a multi-disciplinary approach. Regardless, with the knowledge gained by new PTH models cited in this paper, and an increasing availability of novel headache medications, more effective treatment models are on the horizon.

Post-traumatic Headache in Children and Adolescents.

PURPOSE OF REVIEW: Post-traumatic headache is a common disorder in the pediatric age group, seen both by child neurologists and by non-neurologists. The current review of post-traumatic headache in children and adolescents aims to review the pathophysiology, risk factors, clinical features, neuroimaging, and both acute and preventive treatment options. RECENT FINDINGS: Recent literature provides insight into specific risk factors in the pediatric age group for developing post-traumatic headache as well as unique pathophysiologic changes seen in neuroimaging and neurometabolic pathways. It also elucidates common treatment options and novel treatments being currently explored, such as with monoclonal antibodies to CGRP. Finally, current evidence and guidelines recommend the benefit of a gradual return to normal activity based on symptom stability rather than a specific time period. Review of literature on pediatric post-traumatic headache reveals a growing understanding of the factors involved in developing headache after head trauma and the diagnosis/treatment of headache though future research will help further elucidate these areas.

Assessment of the efficacy of tuina on treating cervicogenic headache: A protocol for systematic review and meta-analysis.

BACKGROUND: Cervicogenic headache is a secondary headache characterized by unilateral headache, symptoms, and signs of neck involvement. It is often worsened by neck movement, sustained awkward head position, or external pressure over the upper cervical or occipital region on the symptomatic side. In this systematic review, we aimed to evaluate the efficacy and safety of massage therapy for the treatment of cervicogenic headache. METHODS: We searched the China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, China Doctoral Dissertations Full-Text Database, China Master's Theses Full-Text Database, Cochrane Central Register of Controlled Trials, PubMed, and Embase. We will select all eligible studies published on or before April 1, 2021. We will use Review Manager 5.4, provided by the Cochrane Collaborative Network for statistical analysis. We then assessed the quality and risk of the included studies and observed the outcome measures. RESULTS: This meta-analysis further confirmed the benefits of tuina in the treatment of cervicogenic headache. CONCLUSION: The purpose of this meta-analysis was to explore the effect of tuina on patients with cervicogenic headache and to provide more options for clinicians and patients to treat cervicogenic headache. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of tuina in the treatment of cervicogenic headache. Since all the data included were published, the systematic review did not require ethical approval. REGISTRATION NUMBER: INPLASY202150053.

Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment.

Post-traumatic headache is a common sequela of traumatic brain injury and is classified as a secondary headache disorder. In the past 10 years, considerable progress has been made to better understand the clinical features of this disorder, generating momentum to identify effective therapies. Post-traumatic headache is increasingly being recognised as a heterogeneous headache disorder, with patients often classified into subphenotypes that might be more responsive to specific therapies. Such considerations are not accounted for in three iterations of diagnostic criteria published by the International Headache Society. The scarcity of evidence-based approaches has left clinicians to choose therapies on the basis of the primary headache phenotype (eg, migraine and tension-type headache) and that are most compatible with the clinical picture. A concerted effort is needed to address these shortcomings and should include large prospective cohort studies as well as randomised controlled trials. This approach, in turn, will result in better disease characterisation and availability of evidence-based treatment options.

Lower spinal postural variability during laptop-work in subjects with cervicogenic headache compared to healthy controls.

Spinal postural variability (SPV) is a prerequisite to prevent musculoskeletal complaints during functional tasks. Our objective was to evaluate SPV in cervicogenic headache (CeH) since CeH is characterized by such complaints. A non-randomized repeated-measure design was applied to compare SPV between 18 participants with reporting CeH aged 29-51 years, and 18 matched controls aged 26-52 years during a 30-min-laptop-task. Habitual spinal postures (degrees) of the cervical, thoracic and lumbar spine were analysed using 3D-Vicon motion analysis. SPV, to express variation in mean habitual spinal posture, was deducted from the postural analysis. Mean SPV of each spinal segment was lower in the CeH-group compared to the control-group. Within the CeH-group, SPV of all except one spinal segment (lower-lumbar) was higher compared to the group's mean SPV. Within the control-group, SPV was more comparable to the group's mean SPV. SPV differed between groups. Averaging data resulted in decreased SPV in the CeH-group compared to the control-group during the laptop-task. However, the higher within-group-SPV in the CeH-group compared to the group's mean SPV accentuated more postural heterogeneity. It should be further determined if addressing individual SPV is a relevant intervention.

Feasibility of Smartphone-Delivered Progressive Muscle Relaxation in Persistent Post-Traumatic Headache Patients.

Persistent post-traumatic headache (PPTH) is often the most common injury after mild traumatic brain injury (mTBI), reported by 47-95% of patients. Progressive muscle relaxation (PMR) has level A evidence in preventing migraine and tension headaches. However, research on this behavioral therapy for PPTH, let alone smartphone delivered, is limited. We performed a single-arm study of prospective patients calling our Concussion Center between June 2017 and July 2018. Inclusion criteria were that subjects had to meet International Classification of Headache Disorders, 3rd Edition criteria for PPTH secondary to mTBI, have four or more headache days a month, be age 18-85 years and 3-12 months post-injury, own a smartphone, and not tried headache behavioral therapy within the year. We recorded baseline headache and neuropsychiatric data. Using the RELAXaHEAD smartphone application, which has a headache diary and PMR audio files, participants were instructed to record headache symptoms and practice 20 min of PMR daily. There were three monthly follow-up assessments. There were 49 subjects enrolled. Basic demographics were: 33 (67%) female with mean age 40.1 ± 14.6 [20, 75] years. Of the 49 subjects, 15 (31%) had pre-existing headaches. In 11 (22%) subjects, mTBI was sports related. Subjects reported 17.7 ± 9.3 [4, 31] headache days in the month before enrollment, and 49 (100%) experienced over three concussion symptoms. Participants inputted data in the RELAXaHEAD app on average 18.3 ± 12.0 days [0, 31] the first month. Number of participants who did PMR over four times per week was 12 (24.5%) the first month, 9 (22.5%) the second month, and 6 (15%) the third month. After 3 months, 17 (42.5 %) participants continued doing PMR. Participants cited time constraints, forgetfulness, application glitches, and repetitiveness as obstacles to practicing PMR. It is feasible to get PPTH subjects to practice behavioral therapy through low-cost smartphone-based PMR two times weekly. Future work will assess efficacy and examine how to optimize barriers to PMR.

Examining the association between traumatic brain injury and headache.

Traumatic brain injury is a common and major cause of disability and death that might require emergency neurological and neurosurgical interventions. Traumatic brain injury can result in temporary or permanent physical, cognitive and psychological impairments. One of the most common complications associated with traumatic brain injury is post-traumatic headache, associated with significant disability and reduced quality of life. Post-traumatic headache is a public health concern that can affect the long-term outcome of traumatic brain injury patients. Clinical symptoms of post-traumatic headache significantly overlap with common primary headaches such as migraine and tension-type headaches. Beyond neurobiological factors, psychological factors can play crucial roles in the initiation and sustainment of post-traumatic headache. While neurological mechanisms underlying post-traumatic headache remains unknown, different studies suggest various mechanisms such as physical damages to the cranial nerves and neck structure, hyper-sensitization of the pain modulatory pathway, and inflammation as underlying causes for the neurobiology of headache. I explore the hypothesis that traumatic brain injury is associated with headaches. In particular, I provide an overview of the neurobiology of post-traumatic headache, its diagnosis, presenting recent findings on the etiology, explaining similarities and differences between with primary headaches such as migraine and tension-type headache, discuss pharmacological and non-pharmacological interventions for the treatments, as well as emphasising on the psychological importance of post-traumatic headache.

Post-traumatic cephalalgia.

After traumatic brain injury (TBI), a host of symptoms of varying severity and associated functional impairment may occur. One of the most commonly encountered and challenging to treat are the post-traumatic cephalalgias. Post-traumatic cephalalgia (PTC) or headache is often conceptualized as a single entity as currently classified using the ICHD-3. Yet, the terminology applicable to the major primary, non-traumatic, headache disorders such as migraine, tension headache, and cervicogenic headache are often used to specify the specific type of headache the patients experiences seemingly disparate from the unitary definition of post-traumatic headache adopted by ICHD-3. More complex post-traumatic presentations attributable to brain injury as well as other headache conditions are important to consider as well as other causes such as medication overuse headache and medication induced headache. Treatment of any post-traumatic cephalalgia must be optimized by understanding that there may be more than one headache pain generator, that comorbid traumatic problems may contribute to the pain presentation and that pre-existing conditions could impact both symptom complaint, clinical presentation and recovery. Any treatment for PTC must harmonize with ongoing medical and psychosocial aspects of recovery.

Altered hypothalamic functional connectivity in post-traumatic headache after mild traumatic brain injury.

BACKGROUND: Post-traumatic headache (PTH) is one of the most frequent symptoms following mild traumatic brain injury (mTBI). Neuroimaging studies implicate hypothalamic function connectivity (FC) disruption as an important factor in pain disorders. However, it is unknown whether there are alterations in the hypothalamus-based resting state FC within PTH following mTBI at the acute stage and its relationship with headache symptom measurement. METHODS: Forty-four mTBI patients with PTH, 27 mTBI patients without PTH and 43 healthy controls who were well matched for age, gender, and years of education were enrolled in this study. All participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning as well as headache symptom measurement and cognitive assessment. Hypothalamic resting state networks were characterized by using a standard seed-based whole-brain correlation method. The bilateral hypothalamic FC was compared among the three groups. Furthermore, the correlations between hypothalamic resting state networks and headache frequency, headache intensity and MoCA scores was investigated in mTBI patients with PTH using Pearson rank correlation. RESULTS: Compared with mTBI patients without PTH, mTBI patients with PTH at the acute stage presented significantly decreased left hypothalamus-based FC with the right middle frontal gyrus (MFG) and right medial superior frontal gyrus (mSFG), and significantly decreased right hypothalamus-based FC with the right MFG. Decreased FC of the right MFG was significantly positively associated with headache frequency and headache intensity (r = 0.339, p = 0.024; r = 0.408, p = 0.006, respectively). Decreased FC of the right mSFG was significantly positively associated with headache frequency and headache intensity (r = 0.740, p < 0.0001; r = 0.655, p < 0.0001, respectively). CONCLUSION: Our data provided evidence of disrupted hypothalamic FC in patients with acute mTBI with PTH, while abnormal FC significantly correlated with headache symptom measurement. Taken together, these changes may play an essential role in the neuropathological mechanism of mTBI patients with PTH.

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence.

BACKGROUND: According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months. MAIN BODY: Currently, due to the high prevalence of this disorder, several preclinical studies have been conducted using different animal models of mild TBI to reproduce conditions that engender PTH. Despite representing a simplification of a complex disorder and displaying different limitations concerning the human condition, animal models are still a mainstay to study in vivo the mechanisms of PTH and have provided valuable insight into the pathophysiology and possible treatment strategies. Different models reproduce different types of trauma and have been ideated in order to ensure maximal proximity to the human condition and optimal experimental reproducibility. CONCLUSION: At present, despite its high prevalence, PTH is not entirely understood, and the differential contribution of pathophysiological mechanisms, also observed in other conditions like migraine, has to be clarified. Although facing limitations, animal models are needed to improve understanding of PTH. The knowledge of currently available models is necessary to all researchers who want to investigate PTH and contribute to unravel its mechanisms.

Habitual Cervical Posture in Women With Episodic Cervicogenic Headache Versus Asymptomatic Controls.

OBJECTIVE: The purpose of this study was to compare the habitual cervical posture between a headache group and control group by using a (1) relative approach (ratio habitual cervical posture to maximal active cervical flexion) and a (2) longitudinal approach compared with a conventional approach. METHODS: Case-controlled longitudinal (pre-post) comparison of the habitual cervical posture referred to the maximal active cervical flexion between 17 women with secondary episodic cervicogenic headache (23.2 ± 1.8 years) and 17 matched controls (23.6 ± 2.2 years) before and after a desk task. Habitual cervical posture and maximal active cervical flexion were measured with a cervical range of motion device (degrees) before and after a desk task (manually completing the Headache Impact Test-6, 36-Item Short Form Health Survey, and general informative questionnaire during 20 minutes). RESULTS: During the pretest, the headache group differed significantly (P < .05) from the control group by showing a (1) smaller maximal active cervical flexion, and (2) positive correlation (ρ 0.56) between maximal active cervical flexion and the habitual cervical posture. After the desk task, the headache group vs the control group showed a significant (P < .05) (1) habitual cervical posture toward flexion, (2) negative correlation (ρ -0.64) between more cervical flexion at the pretest and a more cervical extension during the post-test, and (3) positive association (P < .001) between a larger habitual cervical posture referred to the maximal active cervical flexion and a higher headache intensity. CONCLUSION: Longitudinal measurements of the ratio habitual cervical posture to the maximal active cervical flexion seem to be more sensitive to capture small cervical postural differences between patients with secondary cervicogenic headache and a control group compared with absolute, cross-sectional measurements.

Utilizing the Biopsychosocial Model in Concussion Treatment: Post-Traumatic Headache and beyond.

PURPOSE OF REVIEW: To discuss recent literature concerning the application of the biopsychosocial model in the management of concussion and post-concussion headache. RECENT FINDINGS: Current research suggests that the biopsychosocial model is applicable to the concussion management process, particularly management of post-concussion headache. Such application is best illustrated by current active treatment strategies such as exercise, multifaceted rehabilitation, and psychosocial interventions targeting improved patient outcomes. Overall, the biopsychosocial model has significant applications to the management of concussion, particularly post-concussion headache. Presentation and recovery following concussion and post-traumatic headache is multifaceted and includes the continuum of biological, psychological, and social considerations. In order to fully understand the widespread clinical utility and application of such models, there is a continued need for researcher, practitioner, and patient integration and collaboration to determine the most effective assessment and treatment strategies.

Validation of a clinical examination to differentiate a cervicogenic source of headache: a diagnostic prediction model using controlled diagnostic blocks.

OBJECTIVES: Neck pain commonly accompanies recurrent headaches such as migraine, tension-type and cervicogenic headache. Neck pain may be part of the headache symptom complex or a local source. Patients commonly seek neck treatment to alleviate headache, but this is only indicated when cervical musculoskeletal dysfunction is the source of pain. Clinical presentation of reduced cervical extension, painful cervical joint dysfunction and impaired muscle function collectively has been shown to identify cervicogenic headache among patients with recurrent headaches. The pattern's validity has not been tested against the 'gold standard' of controlled diagnostic blocks. This study assessed the validity of this pattern of cervical musculoskeletal signs to identify a cervical source of headache and neck pain, against controlled diagnostic blocks, in patients with headache and neck pain. DESIGN: Prospective concurrent validity study that employed a diagnostic model building approach to analysis. SETTING: Hospital-based multidisciplinary outpatient clinic in Joliet, Illinois. PARTICIPANTS: A convenience sample of participants who presented to a headache clinic with recurrent headaches associated with neck pain. Sixty participants were enrolled and thirty were included in the analysis. OUTCOME MEASURES: Participants underwent a clinical examination consisting of relevant tests of cervical musculoskeletal dysfunction. Controlled diagnostic blocks of C2/C3-C3/C4 established a cervical source of neck pain. Penalised logistic regression identified clinical signs to be included in a diagnostic model that best predicted participants' responses to diagnostic blocks. RESULTS: Ten of thirty participants responded to diagnostic blocks. The full pattern of cervical musculoskeletal signs best predicted participants' responses (expected prediction error = 0.57) and accounted for 65% of the variance in responses. CONCLUSIONS: This study confirmed the validity of the musculoskeletal pattern to identify a cervical source of headache and neck pain. Adopting this criterion pattern may strengthen cervicogenic headache diagnosis and inform differential diagnosis of neck pain accompanying migraine and tension-type headache.